Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:19][C:20]([OH:22])=O)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:11].[CH2:23]([O:25][C:26]([C:28]1[CH:33]=[CH:32][C:31]([C:34]#[C:35][CH:36]2[CH2:40][CH2:39][CH2:38][NH:37]2)=[CH:30][CH:29]=1)=[O:27])[CH3:24].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.Cl>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:19][C:20]([N:37]2[CH2:38][CH2:39][CH2:40][CH:36]2[C:35]#[C:34][C:31]2[CH:32]=[CH:33][C:28]([C:26]([O:25][CH2:23][CH3:24])=[O:27])=[CH:29][CH:30]=2)=[O:22])[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:11]
Reactant: CCOC(=O)c1ccc(C#CC2CCCN2)cc1
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCOC(=O)c1ccc(C#CC2CCCN2C(=O)Cc2ccc(NC(=O)Nc3ccccc3)c(OC)c2)cc1
Yield: 60.9 %

Procedure:
A mixture of 3-methoxy-4-(N′-phenylureido)phenylacetic acid (180 mg, 0.6 mmol), 2-(2-(4-ethoxycarbonylphenyl)ethynyl)pyrrolidine (146 mg, 0.6 mmol), EDC (173 mg, 0.9 mmol), DMAP (73 mg, 0.6 mmol), and cat. HOBt in DMF (10 mL) was stirred overnight. The mixture was poured into 1 N HCl and the solid was collected with suction. The residue was dissolved in CHCl3 and dried over MgSO4. After removal of the solvent, the residue was chromatographed on silica-gel with CHCl3-MeOH (10:1, v/v) as eluent to give 192 mg (61%) ethyl 4-[2-[1-[3-methoxy-4-(N′-phenylureido)phenylacetyl]-2-pyrrolidinyl]ethynyl]benzoate as a light yellow amorphous solid. 1H-NMR (CDCl3) δ 1.38 (3 H, t, J=6.8 Hz), 1.98–2.24 (4 H, m), 3.48–3.89 (2 H, m), 3.53 (2 H, s), 3.62 (3 H, s), 4.33–4.40 (2 H, m), 4.78–5.04 (1 H, m), 6.77–8.00 (14 H, m).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([OH:15])[CH:11]=[CH:12][C:13]=2[CH3:14])[CH:5]=[C:4]([Cl:16])[N:3]=1.N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])(=O)=O>ClCCl>[Si:31]([O:15][C:10]1[CH:11]=[CH:12][C:13]([CH3:14])=[C:8]([C:6]2[CH:5]=[C:4]([Cl:16])[N:3]=[C:2]([NH2:1])[N:7]=2)[CH:9]=1)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]
Reactant: Cc1ccc(O)cc1-c1cc(Cl)nc(N)n1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: Cc1ccc(O[Si](C)(C)C(C)(C)C)cc1-c1cc(Cl)nc(N)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 76.5 %

Procedure:
3-(2-amino-6-chloropyrimidin-4-yl)-4-methylphenol (2.12 g, 9.00 mmol) obtained in Step 4 above was placed in a reaction vessel, and then dichloromethane (60 ml) was added thereto. The mixture was cooled to 0° C. 2,6-Lutidine (1.25 ml, 10.7 mmol) and tert-butyldimethylsilyl trifluoromethanesulfonate (2.27 ml, 9.88 mmol) were sequentially added to the solution. The mixture was stirred at 0° C. for 1 hour and then at room temperature for 30 minutes. The resulting reaction solution was diluted with dichloromethane (150 ml), and sequentially washed with a saturated aqueous sodium bicarbonate solution (150 ml), water (150 ml), and a saturated aqueous sodium chloride solution (150 ml). The dichloromethane solution was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (developing solvent: n-hexane:ethyl acetate=9:1 to 6:1) to yield 4-[5-(tert-butyldimethylsilanyloxy)-2-methylphenyl]-6-chloropyrimidin-2-ylamine (Compound 1-5) (2.41 g, 77%).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5](/[CH:6]=[CH:7]/[S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18]>>[Cl:1][C:2]1[CH:13]=[CH:12][C:5](/[CH:6]=[CH:7]/[S:8]([NH:18][C:17]2[CH:19]=[CH:20][CH:21]=[C:15]([Cl:14])[CH:16]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)/C=C/c1ccc(Cl)cc1
Reactant: Nc1cccc(Cl)c1
Product: O=S(=O)(/C=C/c1ccc(Cl)cc1)Nc1cccc(Cl)c1
Yield: 31.8 %

Procedure:
A solution of (E)-4-chlorostyrylsulfonyl chloride (10 mmol) and 3-chloroaniline (10 mmol) was subjected to General Procedure 1, part B. The title compound, melting point 118-120° C., was obtained in 31.8% yield.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:13])=[N:4][C:5]([C:9]([Cl:12])([Cl:11])[Cl:10])=[N:6][C:7]=1[CH3:8].[F:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](Cl)=O.C(N(CC)CC)C>C(OCC)C>[Cl:1][C:2]1[C:3]([O:13][CH2:17][C:16]2[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=2[F:14])=[N:4][C:5]([C:9]([Cl:10])([Cl:11])[Cl:12])=[N:6][C:7]=1[CH3:8]
Reactant: O=C(Cl)c1ccccc1F
Reactant: Cc1nc(C(Cl)(Cl)Cl)nc(O)c1Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: Cc1nc(C(Cl)(Cl)Cl)nc(OCc2ccccc2F)c1Cl
Yield: 113.5 %

Procedure:
A solution of 5.8 g (0.02 mole) 5-chloro-4-hydroxy-6-methyl-2-trichloromethylpyrimidine, 3.2 g (0.02 mole) 2-fluorobenzoyl chloride, and 2.0 g (0.02 mole) triethylamine in 100 ml diethyl ether was refluxed for 17 hours. After removal of triethylamine hydrochloride by filtration, the filtrate was concentrated in-vacuo to leave 8.4 g of residue, which, after recrystallization from ligroin, gave 4.6 g (59% yield) of pure product; m.p. 101° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]#[C:15][C:16]3[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=3)[CH:5]=[CH:4][C:3]1=2.C(N(CC)CC)C.Cl[Si:35]([CH3:38])([CH3:37])[CH3:36]>C(Cl)Cl>[CH3:13][C:9]1([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]#[C:15][C:16]3[CH:17]=[CH:18][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:25][CH:26]=3)[CH:5]=[CH:4][C:3]=2[CH:2]([O:1][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH2:11][CH2:10]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3O)cc1
Reactant: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3O[Si](C)(C)C)cc1
Temperature: 25 °C

Procedure:
To a solution of 0.23 g (0.54 mmol) of ethyl 4-[(5,6,7,8-tetrahydro-5-hydroxy-8,8-dimethylnaphth-2-yl)ethynyl]benzoate (Compound 9) in 4 ml of dry CH2Cl2 was added 0.06 ml of triethylamine (0.81 mmol). The solution was flushed with nitrogen and then 0.12 g (0.81 mmol) of chlorotrimethylsilane was slowly added by syringe. The mixture was stirred at room temperature (flushed with nitrogen) for 30 minutes, concentrated in vacuo to an oil and purified by flash chromatography (silica, 10% EtOAc-hexane) to yield the title compound as a clear oil.
Reaction SMILES: O.O.O.O.O.O.O.O.O.[S-2:10].[Na+].[Na+].[S].Cl[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=1[NH:24][C:25](=O)[C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1.Cl>C(O)C.O>[N+:21]([C:18]1[CH:19]=[CH:20][C:15]2[S:10][C:25]([C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)=[N:24][C:16]=2[CH:17]=1)([O-:23])=[O:22]
Reactant: Cc1ccc(C(=O)Nc2cc([N+](=O)[O-])ccc2Cl)cc1
Reactant: [S-2]
Agent: Cl
Agent: [Na+]
Agent: [S]
Solvent: CCO
Solvent: O
Product: Cc1ccc(-c2nc3cc([N+](=O)[O-])ccc3s2)cc1
Temperature: 85 °C
Reaction time: 3 h
Yield: 43 %

Procedure:
Sodium sulfide nonahydrate (875 mg, 3.78 mmol) and sulfur (120 mg, 3.78 mmol) were heated until molten. The water was driven off with nitrogen to give a solid. The obtained solid was added in portions to N-(2-chloro-5-nitrophenyl)-4-methylbenzamide (1 g, 3.44 mmol) in ethanol (20 mL) at 85° C. The solution was stirred at 85° C. for 3 h. After cooling, 2M aqueous HCl was added, and the solution was extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous MgSO4 and evaporated. The resulting solid was purified by column chromatography eluting with ethyl acetate/hexanes 10:90 v/v to afford 400 mg (43%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[NH:9][CH:10]=[CH:11][N:12]=2)[N:3]=1.Br[CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:18]([O:17][C:15](=[O:16])[CH2:14][N:9]1[CH:10]=[CH:11][N:12]=[C:8]1[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[N:3]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Fc1cccc(-c2ncc[nH]2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Cn1ccnc1-c1cccc(F)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.5 %

Procedure:
A mixture of 2-Fluoro-6-(1H-imidazol-2-yl)pyridine (410 mg; 2.51 mmol), tert-butyl bromoacetate (539 mg; 2.76 mmol), potassium carbonate (520 mg; 3.77 mmol), and N,N-dimethylformamide (20 mL) is stirred at room temperature for 16 h. Water (60 mL) is added and the mixture extracted with ethyl acetate (3×70 mL). The organic extracts are washed with water (3×40 mL) and brine (1×40 mL), dried (MgSO4), and concentrated to give [2-(6-Fluoropyridin-2-yl)-imidazol-1-yl]acetic acid tert-butyl ester as an orange oil (630 mg). 1H NMR (CDCl3) δ 8.12 (dd, 1H), 7.82 (q, 1H), 7.16 (s, 1H), 6.98 (s, 1H), 6.81 (dd, 1H), 5.14 (s, 2H), 1.44s, (9H), LCMS: 276.1 (M−).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH2:22][S:23][C:24]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:14](Br)[CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])(C)(C)C.CN(C)[CH:51]=[O:52]>C1(C)C=CC=CC=1.CCCCC>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH2:22][S:23][C:24]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:14]([CH:51]=[O:52])[CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3cc(Br)c(CSC(c4ccccc4)(c4ccccc4)c4ccccc4)nc3N21
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: Cc1ccccc1
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3cc(C=O)c(CSC(c4ccccc4)(c4ccccc4)c4ccccc4)nc3N21
Reaction time: 0.25 h

Procedure:
To a solution of 0.39 g product of step 2 in 10 ml toluene was dropwise added 1.0 ml of a 1.7 M solution of tert-butyllithium in pentane at −78 C. The resulting orange solution was stirred at −78 C. for 15 min. to the resulting orange solution was added 1.00 ml dimethylformamide at −78 C. The initially read but soon bright yellow solution was stirred at −78 C. for 15 min and was then allowed to thaw to room temperature over 30 min. The reaction mixture was quenched with 10% aqueous ammonium chloride, the phases were separated and the organic phase was purified by chromatography on silica gel with dichloromethane:ethyl acetate=19:1. to yield 0.21 g of the title compound as colorless foam (MS: 606.4(M+H+)).
Reaction SMILES: [I-].[K+].[CH3:3][N:4]([CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)[C:5]1[N:10]=[C:9]([N:11]([CH3:13])[CH3:12])[CH:8]=[CH:7][N:6]=1.Cl[CH2:21][CH2:22][CH2:23][CH:24]([C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=1)[C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1>>[F:31][C:28]1[CH:27]=[CH:26][C:25]([CH:24]([C:32]2[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=2)[CH2:23][CH2:22][CH2:21][N:17]2[CH2:18][CH2:19][CH:14]([N:4]([CH3:3])[C:5]3[N:10]=[C:9]([N:11]([CH3:12])[CH3:13])[CH:8]=[CH:7][N:6]=3)[CH2:15][CH2:16]2)=[CH:30][CH:29]=1
Reactant: CN(C)c1ccnc(N(C)C2CCNCC2)n1
Reactant: Fc1ccc(C(CCCCl)c2ccc(F)cc2)cc1
Agent: [I-]
Agent: [K+]
Product: CN(C)c1ccnc(N(C)C2CCN(CCCC(c3ccc(F)cc3)c3ccc(F)cc3)CC2)n1

Procedure:
Using the same procedure as describe in example B.1 and adding a small amount of potassium iodide to the reaction mixture, intermediate 2 was reacted with 1,1′-(4-chlorobutylidene)bis[4-fluorobenzene] to form N2-[1-[4,4-bis(4-fluorophenyl)butyl]-4-piperidinyl]-N2,N4,N4-trimethyl-2,4-pyrimidinediamine (comp. 44, mp. 106.3° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:11][C@@H:12]([CH3:17])[CH2:13][C:14]([NH2:16])=[O:15])[CH2:9][CH3:10])=[C:4]([F:18])[C:3]=1[C:19]([C:21]1[CH:26]=[CH:25]C(C#N)=[CH:23][CH:22]=1)=[O:20].Cl.CC[O:32][C:33]([CH3:35])=[O:34]>>[C:14]([CH2:13][C@@H:12]([NH:11][C@@H:8]([C:5]1[C:4]([F:18])=[C:3]([C:19]([C:21]2[CH:26]=[CH:25][C:35]([C:33]([OH:32])=[O:34])=[CH:23][CH:22]=2)=[O:20])[C:2]([Cl:1])=[CH:7][CH:6]=1)[CH2:9][CH3:10])[CH3:17])(=[O:15])[NH2:16]
Reactant: CCOC(C)=O
Reactant: CC[C@@H](N[C@@H](C)CC(N)=O)c1ccc(Cl)c(C(=O)c2ccc(C#N)cc2)c1F
Agent: Cl
Product: CC[C@@H](N[C@@H](C)CC(N)=O)c1ccc(Cl)c(C(=O)c2ccc(C(=O)O)cc2)c1F
Reaction time: 48 h

Procedure:
To (3S)-3-{[(1R)-1-{4-chloro-3-[(4-cyanophenyl)carbonyl]-2-fluorophenyl}propyl]amino}-butanamide (compound of Example 91) (0.024 g, 0.06 mmol) added EtOAc (0.1 ml) and 6M HCl (0.1 ml)stirred at ambient 48 hours, evaporated down, residue dissolved in DMSO (0.1 ml) treated with K2CO3 (spatula end) stirred ambient for 16 hours, some primary amide product visible, further DMSO (0.1 ml) and 2M NaOH (0.2 ml) added stirred ambient 16 hours to give predominantly the acid. Reaction products purified by Prep HPLC to give 4-({3-[(1R)-1-{[(2S)-1-carbamoylpropan-2-yl]amino}propyl]-6-chloro-2-fluorophenyl}carbonyl)-benzoic acid (0.09 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([CH3:16])[CH3:15])=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[C:17]([C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1)([O:19][CH2:20][CH3:21])=[O:18].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O.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>[CH:14]([C:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:26]3[CH:27]=[C:22]([CH:23]=[CH:24][CH:25]=3)[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:7]=2)=[CH:9][CH:10]=1)([CH3:16])[CH3:15]
Reactant: CC(C)c1ccc(-c2ccnc(Cl)c2)cc1
Reactant: CCOC(=O)c1cccc(B(O)O)c1
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: O
Solvent: CC#N
Product: CCOC(=O)c1cccc(-c2cc(-c3ccc(C(C)C)cc3)ccn2)c1
Yield: 70 %

Procedure:
Part D. A solution of 2-chloro-4-(4-isopropyl-phenyl)-pyridine (110 mg, 0.48 mmol) in acetonitrile-water (1 mL/0.5 mL) is treated with 3-carboethoxybenzeneboronic acid (186 mg, 0.96 mmol), sodium carbonate (153 mg, 1.44 mmol) and tetrakis(triphenylphosphine)palladium (cat. amount). The mixture is heated to reflux for 12 h., then cooled and partitioned between water and ethyl acetate. The organic phase is washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue is separated by column chromatography to afford ethyl 3-[4-(4-isopropyl-phenyl)-pyridin-2-yl]-benzoate (116 mg, 70%).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].O=[C:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[N:14]1[C:19](=[O:20])[CH:18]=[CH:17][C:16]([C:21]2[C:22]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[N:23][N:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=23)=[N:15]1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH2:1]=[C:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[N:14]1[C:19](=[O:20])[CH:18]=[CH:17][C:16]([C:21]2[C:22]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[N:23][N:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=23)=[N:15]1
Reactant: O=C1CCCCC1n1nc(-c2c(-c3ccccc3)nn3ccccc23)ccc1=O
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=C1CCCCC1n1nc(-c2c(-c3ccccc3)nn3ccccc23)ccc1=O
Reaction time: 1.5 h
Yield: 37.4 %

Procedure:
To a stirred suspension of methyltriphenylphosphonium bromide (1.39 g) in tetrahydrofuran (30 ml) was added potassium tert-butoxide (437 mg) under nitrogen atmosphere at 0° C. After the mixture was stirred at 0°-5° C. for 1.5 hours, to this was added a solution of 3-[2-(2-oxocyclohexyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (500 mg) in tetrahydrofuran (10 ml). The mixture was stirred at room temperature for 4 hours and stood at room temperature overnight. Insoluble materials were filtered off and the filtrate was evaporated in vacuo. The residue was dissolved in dichloromethane (30 ml). The dichloromethane solution was washed with brine (20 ml), dried over anhydrous sodium sulfate, and evaporated in vacuo. The crude material was purified by column chromatography on silica gel using dichloromethane as an eluant to give colorless crystals of 3-[2-(2-methylenecyclohexyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (186 mg).
Reaction SMILES: CC1N=C(N2CCN(C3C=CC=CC=3)C2=O)SC=1C(OCC)=O.[F:24][CH:25]([F:49])[C:26]1[O:30][C:29]([CH2:31][N:32]2[CH2:36][CH2:35][N:34]([C:37]3[S:38][C:39]([C:43]([O:45]CC)=[O:44])=[C:40]([CH3:42])[N:41]=3)[C:33]2=[O:48])=[CH:28][CH:27]=1>>[F:49][CH:25]([F:24])[C:26]1[O:30][C:29]([CH2:31][N:32]2[CH2:36][CH2:35][N:34]([C:37]3[S:38][C:39]([C:43]([OH:45])=[O:44])=[C:40]([CH3:42])[N:41]=3)[C:33]2=[O:48])=[CH:28][CH:27]=1
Reactant: CCOC(=O)c1sc(N2CCN(Cc3ccc(C(F)F)o3)C2=O)nc1C
Agent: CCOC(=O)c1sc(N2CCN(c3ccccc3)C2=O)nc1C
Product: Cc1nc(N2CCN(Cc3ccc(C(F)F)o3)C2=O)sc1C(=O)O
Yield: 58 %

Procedure:
Following the procedure as described in Example 6, making variations as required to replace ethyl 4-methyl-2-(2-oxo-3-phenylimidazolidin-1-yl)thiazole-5-carboxylate with ethyl 2-(3-((5-(difluoromethyl)furan-2-yl)methyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylate, the title compound was obtained as a white solid in 58% yield: MS (ES+) m/z 358.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([S:13][C:14]([F:17])([F:16])[F:15])=[CH:11][CH:12]=2)=[CH:4][CH:3]=1.[Br:18]Br>C(Cl)(Cl)Cl>[Br:18][C:12]1[CH:11]=[C:10]([S:13][C:14]([F:15])([F:17])[F:16])[NH:9][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1
Reactant: BrBr
Reactant: FC(F)(F)Sc1ccc(-c2ccc(Cl)cc2)[nH]1
Solvent: ClC(Cl)Cl
Product: FC(F)(F)Sc1cc(Br)c(-c2ccc(Cl)cc2)[nH]1
Reaction time: 2 h
Yield: 80.2 %

Procedure:
A solution of 2-(p-chlorophenyl)-5-[(trifluoromethyl)thio]pyrrole (1.94 g, 0.00699 mol) in chloroform is cooled, treated with a solution of bromine (1.16 g, 0.00699 mol) in chloroform, stirred for two hours, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain a dark syrup. Flash chromatography of the syrup using silica gel and a 1:10 ethyl acetate/hexanes solution gives the title product as a pink syrup (2.0 g) which is identified by 1HNMR and 13CNMR spectral analyses.
Reaction SMILES: [C:1]([CH:5]1[NH:10][NH:9][C:8](=[S:11])[N:7]([CH3:12])[C:6]1=[O:13])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[CH3:16]I.CBr>O>[C:1]([C:5]1[C:6](=[O:13])[N:7]([CH3:12])[C:8]([S:11][CH3:16])=[N:9][N:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CN1C(=O)C(C(C)(C)C)NNC1=S
Agent: CBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CSc1nnc(C(C)(C)C)c(=O)n1C

Procedure:
30 ml of 3-benzyl-4-hydroxy-biphenyl polyglycol ether, as an emulsifier, and 5,690 g (28.6 mol) of 6-tert.-butyl-4-methyl-5-oxo-3-thioxo-tetrahydro-1,2,4-(2H,4H)-triazine were added to a solution of 1,145 g of NaOH in 57 liters of water. 4,302 g (30.3 mol) of methyl iodide were added dropwise (or 2,900 g of methyl bromide were passed in) and the mixture was subsequently stirred until the slightly exothermic reaction had ended and the pH value had reached 7-8. After filtering off the product, washing it with water and drying it at 50° C., 5,810 g (95% of theory) of the compound (IIa) of melting point 90°-100° C. were obtained. The crude product was sufficiently pure for further reaction. A sample recrystallised from methanol or petroleum ether melted at 104°-105° C.
Reaction SMILES: [C:1]1([OH:11])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CC(C)=O.CCOCC>[CH2:18]([O:11][C:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Oc1cccc2c1CCCC2
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC(C)=O
Product: c1ccc(COc2cccc3c2CCCC3)cc1
Yield: 99.1 %

Procedure:
5,6,7,8-tetrahydro-1-naphthol (5.9 g, 39mM) was added to a suspension of potassium carbonate (8.3 g, 60mM) in acetone (100 ml) and heated under reflux for 0.5 hour. Benzyl bromide (7.5 g, 43.8mM) was then added and the mixture was heated under reflux for a further 3 days with stirring. The resulting suspension was filtered and the filtrate was evaporated under reduced pressure to give an oil. This oil was dissolved in ether, washed with water, dried (sodium sulphate) and evaporated to giving an oil which was distilled under high vacuum to give the benzyl ether (3) (9.4 g, b.p. 170°-176° C. at 0.8 mm Hg).
Reaction SMILES: CS(O[CH2:6][C@@H:7]1[CH2:9][C@@H:8]1[C:10]1[C:15]2[CH2:16][CH2:17][O:18][C:14]=2[CH:13]=[CH:12][CH:11]=1)(=O)=O.[N-:19]=[N+:20]=[N-:21].[Na+]>CN(C)C=O.C(Cl)Cl>[O:18]1[C:14]2[CH:13]=[CH:12][CH:11]=[C:10]([C@H:8]3[CH2:9][C@H:7]3[CH2:6][N:19]=[N+:20]=[N-:21])[C:15]=2[CH2:16][CH2:17]1
Reactant: CS(=O)(=O)OC[C@@H]1C[C@@H]1c1cccc2c1CCO2
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: [N-]=[N+]=NC[C@@H]1C[C@@H]1c1cccc2c1CCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.2 %

Procedure:
A solution of (cis)-[2-(2,3-dihydrobenzofuran-4-yl)cycloprop-1-yl]methyl methane sulfonate (5.0 mmol) and sodium azide (10.0 mmol) in 100 mL of dimethylformamide was heated at 70° C. for 1 h. The reaction mixture was allowed to cool to room temperature and stirred overnight. The crude reaction mixture was then diluted with CH2Cl2 (100×mL) and washed sequentially with water (3×100 mL) and then brine (1×100 mL). The organic phase was separated, dried over magnesium sulfate, filtered and concentrated in vacuo to provide 1.1 g of the desired product as an oil (quantitative yield).
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH2:12]([Mg]Cl)[C:13]([CH3:16])([CH3:15])[CH3:14].C(OCC)C>C(OCC)C.C1COCC1>[OH:3][C:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1)([CH3:2])[CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)C[Mg]Cl
Reactant: CC(=O)c1ccc(C#N)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)CC(C)(O)c1ccc(C#N)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 24 %

Procedure:
Dissolve 4-acetylbenzonitrile (1 g, 6.88 mmol) in diethyl ether/THF (1:1, 60 mL) and cool the solution to 0° C. Add 1 M neopentylmagnesium chloride in diethyl ether (8.3 mL, 8.3 mmol) under nitrogen and stir the mixture at room temperature overnight. Add saturated aqueous NH4Cl and extract the mixture twice with EtOAc. Dry the combined organic extracts over MgSO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane and hexane/EtOAc (19:1, 9:1) to give the desired intermediate (364 mg, 24%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([C:8](=O)[CH3:9])[CH:7]=1.[O:14]1[CH2:19][CH2:18][N:17]([S:20]([C:23]2[CH:24]=[C:25]([CH:30]=[CH:31][CH:32]=2)[C:26]([NH:28][NH2:29])=[O:27])(=[O:22])=[O:21])[CH2:16][CH2:15]1>CO.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6](/[C:8](=[N:29]/[NH:28][C:26](=[O:27])[C:25]2[CH:30]=[CH:31][CH:32]=[C:23]([S:20]([N:17]3[CH2:18][CH2:19][O:14][CH2:15][CH2:16]3)(=[O:21])=[O:22])[CH:24]=2)/[CH3:9])[CH:7]=1
Reactant: NNC(=O)c1cccc(S(=O)(=O)N2CCOCC2)c1
Reactant: CC(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Solvent: CO
Solvent: CC(=O)O
Product: C/C(=N\NC(=O)c1cccc(S(=O)(=O)N2CCOCC2)c1)c1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 120 °C
Yield: 20 %

Procedure:
1-(5-chloro-2-nitrophenyl)ethanone (30 mg, 0.150 mmol) and 3-(morpholinosulfonyl)benzohydrazide (42.9 mg, 0.150 mmol) was dissolved in Methanol (Volume: 4 ml) in the presence of acetic acid as a catalyst and then the reaction mixture was heated via microwave irradiation to 120° C. for 30 min. Reaction was monitored by TLC. After completion of the reaction, following cooling, the solvent was removed by vacuum and the resulting crude material was purified by flash column chromatography (2% CH3OH/CH2Cl2), afforded the product (E)-N′-(1-(5-chloro-2-nitrophenyl)ethylidene)-3-(morpholinosulfonyl)benzohydrazide (15 mg, 0.030 mmol, 20.09% yield) as a solid. 1H NMR (CDCl3, 400 MHz): δ 8.20 (m, 1H), 8.07 (m, 1H), 7.88 (m, 1H), 7.66 (m, 1H), 7.51 (m, 2H), 7.39 (m, 1H), 3.69 (m, 4H), 2.99 (m, 4H), 2.29 (s, 3H). Mass [M+H]+:468.0