Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](I)=[N:7][NH:8]2)=[C:4]([F:12])[CH:3]=1.[H-].[Na+].C([Mg]Cl)(C)C.[CH2:20]([Sn:24](Cl)([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH3:23].[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([Sn:24]([CH2:25][CH2:26][CH2:27][CH3:28])([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:20][CH2:21][CH2:22][CH3:23])=[N:7][NH:8]2)=[C:4]([F:12])[CH:3]=1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Fc1cc(Cl)cc2[nH]nc(I)c12
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCC[Sn](CCCC)(CCCC)c1n[nH]c2cc(Cl)cc(F)c12
Temperature: -15 °C
Reaction time: 0.67 h

Procedure:
6-Chloro-4-fluoro-3-iodo-1H-indazole (10.1 g, 34.1 mmol) was dissolved in THF (170 ml). The reaction flask was stirred in a water bath and sodium hydride (60% dispersion, 1.64 g, 40.9 mmol) was added. The mixture was stirred for 15 min then cooled in an ice/salt bath to −15° C. Isopropylmagnesium chloride (2.0 M in THF, 20.6 ml, 41.2 mmol) was added dropwise. After 40 min, tributyltin chloride (11.6 ml, 42.6 mmol) was slowly added and the reaction was allowed to warm to room temperature. After an additional 2 h stirring, ammonium chloride solution and ethyl acetate were added. The layers were separated and the aqueous layer was extracted once more with ethyl acetate. The combined organic layers were washed with sodium chloride solution and dried over sodium sulfate. Evaporation of the solvent provided 6-chloro-4-fluoro-3-tributylstannanyl-1H-indazole as an oil which was used directly in the next step.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][OH:5].[CH2:6]([NH:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([O-:29])=[O:28])=[CH:25][CH:24]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].[Na+]>>[CH2:6]([NH:22][C:23]1[CH:24]=[CH:25][C:26]([C:27]([O:29][CH2:2][CH2:3][CH2:4][OH:5])=[O:28])=[CH:30][CH:31]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: OCCCBr
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)[O-])cc1
Agent: [Na+]
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OCCCO)cc1

Procedure:
In the manner described in Example 19, treatment of 3-bromopropanol with sodium 4-(n-hexadecylamino)benzoate affords 3-hydroxypropyl 4-(n-hexadecylamino)benzoate, mp 67°-69° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[C:7](N1C=CN=C1)([N:9]1[CH:13]=[CH:12][N:11]=[CH:10]1)=[S:8]>C(#N)C>[S:3]1[CH:4]=[CH:5][N:6]=[C:2]1[NH:1][C:7]([N:9]1[CH:13]=[CH:12][N:11]=[CH:10]1)=[S:8]
Reactant: Nc1nccs1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: S=C(Nc1nccs1)n1ccnc1
Yield: 89.1 %

Procedure:
35 g (349.5 mmol) of 2-aminothiazole and 62.3 g (349.5 mmol) thiocarbonyldiimidazole were stirred in 1300 ml acetonitrile for a total of four days at room temperature. Filtration of the precipitate formed and drying yielded 65.5 g of light yellow solid.
Reaction SMILES: [OH:1]O.[CH3:3][S:4][CH2:5][CH2:6][NH:7][C:8]([NH2:10])=[O:9]>C(O)C.C(O)=O>[CH3:3][S:4]([CH2:5][CH2:6][NH:7][C:8]([NH2:10])=[O:9])=[O:1]
Reactant: CSCCNC(N)=O
Reactant: OO
Solvent: CCO
Solvent: O=CO
Product: CS(=O)CCNC(N)=O
Reaction time: 2 h
Yield: 85 %

Procedure:
There are slowly added 3 ml of H2O2 (110 volumes) to a well agitated solution of 20 moles of 2-methylthio ethylurea in a mixture of ethanol and formic acid. The solution obtained is agitated for 2 hours after which it is concentrated under reduced pressure. The resulting residue is then crystallized in ethylacetate thus providing white crystals melting at 88° C. in a yield of 85%.
Reaction SMILES: [CH3:1][C:2]1[C:7]([OH:8])=[C:6]([CH2:9]O)[C:5]([CH:11]=[CH:12][C:13]([OH:15])=[O:14])=[CH:4][N:3]=1.[Na].C(=S)=[S:18].[ClH:20]>C(O)C>[ClH:20].[CH3:1][C:2]1[C:7]([OH:8])=[C:6]([CH2:9][SH:18])[C:5]([CH:11]=[CH:12][C:13]([OH:15])=[O:14])=[CH:4][N:3]=1
Reactant: S=C=S
Reactant: Cc1ncc(C=CC(=O)O)c(CO)c1O
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: Cc1ncc(C=CC(=O)O)c(CS)c1O

Procedure:
A mixture of 1.23 g. of 2-methyl-3-hydroxy-4-hydroxymethylpyridine-5-acrylic acid, 1 g. of sodium metal, 5 ml. of carbon disulfide, and 75 ml. of absolute ethanol was refluxed for 26 hours. Concentrated hydrochloric acid (3 ml.) was added and the mixture was evaporated to dryness. The residue was extracted with 125 ml. of boiling ethanol and filtered hot. Evaporation of the extract gave a syrup which was crystallized from chloroform-ether to give 2-methyl-3-hydroxy-4-mercaptomethylpyridine-5-acrylic acid hydrochloride, m.p. 227°-228° C.
Reaction SMILES: [NH2:1][C@H:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][OH:4].[C:11]([N:15]=[C:16]=[S:17])([CH3:14])([CH3:13])[CH3:12]>C(O)C.C(OCC)(=O)C>[C:11]([NH:15][C:16]([NH:1][C@H:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][OH:4])=[S:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: N[C@@H](CO)c1ccccc1
Reactant: CC(C)(C)N=C=S
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)NC(=S)N[C@@H](CO)c1ccccc1

Procedure:
N-(tert-Butyl)-N′-[(1R)-2-hydroxy-1-phenylethyllthiourea: The process is performed under the conditions of Example 1, starting with 2.74 g of (R)-(−)-2-amino-2-phenylethanol and 2.8 cm3 of tert-butyl isothiocyanate in 15 cm3 of ethanol for 20 hours at a temperature in the region of 20° C. The reaction medium is concentrated under reduced pressure (5 kPa) at a temperature in the region of 50° C. A yellow oil is obtained, which is dissolved in 100 cm3 of ethyl acetate and the organic solution is then washed with twice 50 cm3 of aqueous sodium hydrogen carbonate solution and twice with aqueous sodium chloride solution. After drying over sodium sulfate, the organic solution is filtered and then concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. 4.9 g of N-(tert-butyl)-N′-[(1R)-2-hydroxy-1-phenylethyl]thiourea are obtained in the form of a yellow solid melting at 98° C.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([NH2:12])=[O:11].B(Br)(Br)Br.O>C(Cl)Cl>[OH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([NH2:12])=[O:11]
Reactant: COc1ccccc1CC(N)=O
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: NC(=O)Cc1ccccc1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Methoxyphenyl acetamide (13.0 g, 78.6 mmol) was dissolved in methylene chloride (10.0 mL). Subsequently, 1.0M boron tribromide in methylene chloride solution (157 mL, 157 mmol) was slowly added dropwise under ice-cooling, and the mixture was stirred for one hour at room temperature. Subsequently, water was slowly added thereto under ice-cooling, and the mixture was stirred for 30 minutes. The mixture was extracted with chloroform, followed by washing the organic layer with brine, drying over anhydrous sodium sulfate. The reaction mixture was subjected to concentration under reduced pressure and purification by column chromatography (n-hexane/ethyl acetate=20/1), whereby a white solid was obtained (1.8 g, 11.9 mmol, 15%).
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:11]=1[Cl:17])=[O:9].[N:18](OCCCCC)=[O:19]>C(O)(C)(C)C>[Cl:17][C:11]1[C:12]([Cl:16])=[CH:13][CH:14]=[CH:15][C:10]=1[C:8](=[O:9])[CH:7]=[N:18][OH:19]
Reactant: CC(=O)c1cccc(Cl)c1Cl
Reactant: CCCCCON=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: O=C(C=NO)c1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.8 %

Procedure:
Potassium t-butoxide (239.7 g, 2.136 mol) was dissolved in t-butanol (1.5 liters) and allowed to stir at room temperature for 30 minutes. 2,3-Dichloroacetophenone (67.26 g, 0.356 mol) was added in one portion and the resulting mixture stirred overnight at room temperature. Amyl nitrite (83.41 g, 0.712 mol) was added slowly dropwise, with stirring. When the addition was complete the reaction mixture was stirred at room temperature for 2 hours and then heated at 50° C. for 2 hours. The solution was allowed to cool and stirred at room temperature overnight. The reaction mixture was poured into ice/water (1.5 liters), and the aqueous solution extracted with diethyl ether (3×500 ml). The aqueous phase was acidified with concentrated hydrochloric acid and allowed to stand at room temperature overnight. The solid which precipitated was filtered at the pump and dried under vacuum over anhydrous phosphorus pentoxide to give 2,3-dichlorophenylglyoxal aldoxime (57.3 g, 73.8%) as a brown solid. T.l.c. (SiO2 ; CHCl3) showed little impurity, but subsequent dehydration of the oxime showed that recrystallisation would be advisable. The oxime may be recrystallised from toluene, m.p. 109° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:25]=[CH:24][C:16]([O:17][CH:18]([CH3:23])[C:19]([O:21]C)=[O:20])=[CH:15][CH:14]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[OH-].[K+]>CO.O>[Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:25]=[CH:24][C:16]([O:17][CH:18]([CH3:23])[C:19]([OH:21])=[O:20])=[CH:15][CH:14]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: COC(=O)C(C)Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1)C(=O)O
Temperature: 25 °C

Procedure:
To a solution of methyl 2-[4-(3-chloro-5-trifluoromethyl-2-pyridyloxy)phenoxy]propionate (1.75 g) in methanol (15 ml) is added potassium hydroxide (1.0 g) in water (10 ml). The resulting mixture is stirred at RT until a clear solution is obtained (~20 min). Most of the methanol is removed, and the aqueous solution is acidified with dilute HCl and extracted with ether. The combined ether extracts are dried and concentrated to dryness to give 2-[4-(3-chloro-5-trifluoromethyl-2-pyridyloxy)-phenoxy]propionic acid.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[NH:12]1[C:20]2[C:15](=[CH:16][C:17]([CH2:21][N:22]3[CH2:27][CH2:26][CH:25]([C:28]4[CH:29]=[C:30]([NH:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH:31]=[CH:32][CH:33]=4)[CH2:24][CH2:23]3)=[CH:18][CH:19]=2)[CH:14]=[CH:13]1>>[CH3:37][CH:36]([CH3:38])[C:35]([NH:34][C:30]1[CH:31]=[CH:32][CH:33]=[C:28]([CH:25]2[CH2:24][CH2:23][N:22]([CH2:21][C:17]3[CH:16]=[C:15]4[C:20](=[CH:19][CH:18]=3)[N:12]([C:2]3[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=3)[CH:13]=[CH:14]4)[CH2:27][CH2:26]2)[CH:29]=1)=[O:39]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc4[nH]ccc4c3)CC2)c1
Reactant: FC(F)(F)c1ccc(I)cc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc4c(ccn4-c4ccc(C(F)(F)F)cc4)c3)CC2)c1

Procedure:
Prepared by Procedure C and Scheme Q1, with CuBr in place of Cu, using 1-iodo-4-(trifluoromethyl)benzene and N-{3-[1-(1H-indol-5-ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 520.2 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[CH2:12]O)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].P(Br)(Br)[Br:15].O>C(OC(C)C)(C)C>[Br:15][CH2:12]/[CH:11]=[CH:10]/[C:7]1[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=1
Reactant: BrP(Br)Br
Reactant: CC(C)c1ccc(/C=C/CO)cc1
Solvent: O
Solvent: CC(C)OC(C)C
Product: CC(C)c1ccc(/C=C/CBr)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 107.4 %

Procedure:
To a solution of (E)-3-(4-isopropylphenyl)-2-propen-1-ol (10.5 g, 59.6 mmol) in isopropyl ether (100 ml) was added under ice cooling phosphorus tribromide (10.7 g, 39.7 mmol) and the resulting mixture was stirred at room temperature for 30 minutes. Water was added into the reaction solution and the product was extracted with isopropyl ether. The organic layer was washed with water and an aqueous saturated solution of sodium hydrogen carbonate, dried on magnesium sulfate, filtered, and then concentrated under reduced pressure to obtain 10.2 g (72% yield) of the oily title compound.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:4]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:25])=[CH:20][N:19]=2)[C:3]1=[O:32].[C:33]([C:37]1[CH:38]=[C:39]2[C:44](=[C:45]([F:47])[CH:46]=1)[C:43](=[O:48])[N:42]([C:49]1[CH:54]=[CH:53][CH:52]=[C:51](Cl)[C:50]=1[CH2:56][OH:57])[N:41]=[CH:40]2)([CH3:36])([CH3:35])[CH3:34].C(=O)([O-])[O-].[K+].[K+]>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].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>[C:33]([C:37]1[CH:38]=[C:39]2[C:44](=[C:45]([F:47])[CH:46]=1)[C:43](=[O:48])[N:42]([C:49]1[CH:54]=[CH:53][CH:52]=[C:51]([C:6]3[CH:5]=[C:4]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([C:24]([N:26]5[CH2:27][CH2:28][O:29][CH2:30][CH2:31]5)=[O:25])=[CH:20][N:19]=4)[C:3](=[O:32])[N:2]([CH3:1])[CH:7]=3)[C:50]=1[CH2:56][OH:57])[N:41]=[CH:40]2)([CH3:36])([CH3:34])[CH3:35]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Reactant: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(Cl)c3CO)ncc2c1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cn1cc(-c2cccc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2CO)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Temperature: 96 °C
Reaction time: 5 h
Yield: 67.1 %

Procedure:
To a 2 mL vial were added 1-methyl-3-(5-(morpholine-4-carbonyl)pyridin-2-ylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (171 mg, 0.39 mmol), 6-tert-Butyl-2-(3-chloro-2-hydroxymethyl-phenyl)-8-fluoro-2H-phthalazin-1-one (100 mg, 0.28 mmol), Potassium carbonate (76.6 mg, 0.55 mmol), tricyclohexylphosphine (4.7 mg, 16.6 μmol) and Pd(dba)2 (4.78 mg, 8.31 μmol). The vial was evacuated and backfilled with Nitrogen. This sequence was repeated three times. Then, 20% aqueous 1,4-dioxane, (1.5 ml) was added to the reaction mixture by syringe. The resulting mixture was heated to 96° C. for gentle reflux and stirred for 5 hr. After cooling down to room temperature, DCM (1 mL) and trithiocyanuric acid trisodium salt, 15% aqueous solution (1 ml) were added to the reaction mixture, then the resulting solution was stirred at 40° C. for 4 hr and additional for 4 hr after addition of 20 mg of activated carbon, then filtered through Celite pad and washed with DCM. DCM layer was collected by phase separation, and the aqueous layer was extracted with additional DCM. The combined organics were diluted with IPA, and DCM was distilled out completely. The desired product was crystallized out from IPA, collected by filtration and washed with IPA. The filter cake was dried under vacuum oven at 50° C. to afford 120 mg of the title compound (68% isolated yield) as a yellow solid. MS (ESI) 640 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:15]=1[C:9]1([CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)[CH2:8][CH:7]2[CH2:16][C:17]([O:19]C)=[O:18].[F:21][C:22]1[CH:32]=[CH:31][C:25]([CH:26]=[CH:27][C:28](O)=[O:29])=[C:24]([C:33]([F:36])([F:35])[F:34])[CH:23]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:15]=1[C:9]1([CH2:14][CH2:13][N:12]([C:28](=[O:29])/[CH:27]=[CH:26]/[C:25]3[CH:31]=[CH:32][C:22]([F:21])=[CH:23][C:24]=3[C:33]([F:34])([F:35])[F:36])[CH2:11][CH2:10]1)[CH2:8][CH:7]2[CH2:16][C:17]([OH:19])=[O:18]
Reactant: O=C(O)C=Cc1ccc(F)cc1C(F)(F)F
Reactant: COC(=O)CC1CC2(CCNCC2)c2c(Cl)cccc21
Product: O=C(O)CC1CC2(CCN(C(=O)/C=C/c3ccc(F)cc3C(F)(F)F)CC2)c2c(Cl)cccc21

Procedure:
The title compound was prepared employing a procedure analogous to that described in Example 1 using methyl 2-(7-chloro-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate and 4-fluoro-2-(trifluoromethyl)cinnamic acid followed by a procedure analogous to that described in Example 2. LC-MS Method 1 tR=1.95, min, m/z=496, 498; 1H NMR (CDCl3) 1.20-1.40 (3H), 1.70 (m, 1H), 2.40 (m, 1H), 2.53 (m, 1H), 2.65-3.05 (4H), 3.30 (m, 1H), 3.62 (m, 1H), 4.06 (d, 1H), 4.79 (d, 1H), 6.80 (d, 1H), 7.1-7.5 (5H), 7.68 (m, 1H), 7.85 (d, 1H).
Reaction SMILES: Br[C:2]1[CH:26]=[CH:25][C:5]([CH2:6][C@@:7]2([CH3:24])[N:11]3[CH:12]=[CH:13][N:14]=[C:10]3[N:9]([C:15]3[CH:20]=[C:19]([Cl:21])[CH:18]=[C:17]([Cl:22])[CH:16]=3)[C:8]2=[O:23])=[CH:4][CH:3]=1.[C:27]([Cu])#[N:28]>CN(C=O)C>[C:27]([C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C@@:7]2([CH3:24])[N:11]3[CH:12]=[CH:13][N:14]=[C:10]3[N:9]([C:15]3[CH:20]=[C:19]([Cl:21])[CH:18]=[C:17]([Cl:22])[CH:16]=3)[C:8]2=[O:23])=[CH:25][CH:26]=1)#[N:28]
Reactant: N#C[Cu]
Reactant: C[C@@]1(Cc2ccc(Br)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2nccn21
Solvent: CN(C)C=O
Product: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2nccn21
Temperature: 140 °C
Yield: 77.4 %

Procedure:
(R)-3-(4-Bromobenzyl)-1-(3,5-dichlorophenyl)-3-methyl-imidazo[1,2-a]-imidazol-2-one (13.5 g, 29.9 mmol) was dissolved in anhydrous DMF (70 mL) and CuCN (3.22 g, 35.9 mmol) was added. The reaction mixture was heated to 140° C. under argon for 40 h. When the reaction was complete, the solvent was removed under reduced pressure and the residue was diluted with CH2Cl2. The organic solution was washed four times alternately with 5% aqueous pyridine then water. The organic layer was dried over Na2SO4 and filtered through a diatomaceous earth pad. The filtrate was concentrated and purified by silica gel column chromatography using a mixture of CH2Cl2-hexane (10:1) as an eluent to afford 9.19 g of (R)-3-(4-cyanobenzyl)-1-(3,5-dichlorophenyl)-3-methyl-imidazo[1,2-a]-imidazol-2-one.
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([CH:12](O)[CH3:13])=[CH:8][CH:7]=1)[CH:2]=[C:3]([CH3:5])[CH3:4].N1C=CC=CC=1.S(Cl)([Cl:23])=O>C1C=CC=CC=1>[Cl:23][CH:12]([C:9]1[CH:10]=[CH:11][C:6]([CH2:1][CH:2]=[C:3]([CH3:5])[CH3:4])=[CH:7][CH:8]=1)[CH3:13]
Reactant: O=S(Cl)Cl
Reactant: CC(C)=CCc1ccc(C(C)O)cc1
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CC(C)=CCc1ccc(C(C)Cl)cc1
Yield: 97.6 %

Procedure:
To a solution of 9.5 g of 1-(p-prenylphenyl)-ethanol, 4.0 ml of pyridine and 60 ml of benzene, a solution of 5.9 g of thionyl chloride in 10 ml of benzene was added dropwise at 0°-5° C. with stirring. After stirring at room temperature for an hour, the reaction mixture was washed with water, aqueous sodium hydrogen carbonate and water successively and dried. Removal of the benzene gave 10.1 g of 1-chloro-1-(p-prenylphenyl)ethane.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:5]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:7][C:8]=1[CH3:9].[N-:16]=[N+:17]=[N-:18].[Na+]>CN(C=O)C>[N:16]([CH2:3][C:4]1[N:5]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:7][C:8]=1[CH3:9])=[N+:17]=[N-:18]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1[nH]c(-c2ccccc2)nc1CCl
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1[nH]c(-c2ccccc2)nc1CN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.8 %

Procedure:
To a solution of 4-chloromethyl-5-methyl-2-phenyl-1H-imidazole hydrochloride (4.86 g) [CAS 58731-95-6] in DMF (50 ml) was added sodium azide (7.79 g). The reaction mixture was stirred at room temperature for 18 h under argon and concentrated without heating under high vacuum. To the residue was added ice/1 molar K2CO3 solution, and the mixture was extracted with ethyl acetate. The organic phase washed with brine, dried over magnesium sulphate and concentrated. The residue was purified by chromatography on silica gel using methylene chloride/methanol 2% as eluent to obtain 4-azidomethyl-5-methyl-2-phenyl-1H-imidazole (3.70 g) as a light yellow amorphous powder.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[N:7][C:8](Cl)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4].[NH:12]1[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19][O:20][C:21]2[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][CH:22]=2)[CH2:14][CH2:13]1.C(=O)([O-])[O-].[Na+].[Na+]>O.ClCCl>[CH2:1]([C:5]1[N:6]=[N:7][C:8]([N:12]2[CH2:13][CH2:14][CH:15]([CH2:18][CH2:19][O:20][C:21]3[CH:22]=[CH:23][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:30][CH:31]=3)[CH2:16][CH2:17]2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(Cl)nn1
Reactant: CCOC(=O)c1ccc(OCCC2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCCCc1ccc(N2CCC(CCOc3ccc(C(=O)OCC)cc3)CC2)nn1
Temperature: 140 °C
Reaction time: 4 h
Yield: 20.8 %

Procedure:
A mixture of 2.4 parts of 3-butyl-6-chloropyridazine, 4.2 parts of ethyl 4-[2-(4-piperidinyl)ethoxy]benzoate and 2.1 parts of sodium carbonate was stirred for 4 hours at 140° C. After cooling, the reaction mixture was taken up in water and dichloromethane. The separated organic layer was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2,2'-oxybispropane. The product was filtered off, washed with 2,2'-oxybispropane and dried at 50° C., yielding 1.2 parts (20.8%) of ethyl 4-[2-[1-(6-butyl-3-pyridazinyl)-4-piperidinyl]ethoxy]benzoate; mp. 91.4° C. (comp. 84).
Reaction SMILES: C(N(CC)CC)C.Cl.Cl.Cl.[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[C:22]([C:24]3[CH:33]=[C:32]4[C:27]([CH2:28][CH2:29][NH:30][CH2:31]4)=[CH:26][CH:25]=3)[N:21]=[C:20]([NH2:34])[N:19]=2)[CH2:14][CH2:13]1.[Br:35][C:36]1[CH:37]=[C:38]([CH2:42][C:43](O)=[O:44])[CH:39]=[N:40][CH:41]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>O>[Br:35][C:36]1[CH:37]=[C:38]([CH2:42][C:43]([N:30]2[CH2:29][CH2:28][C:27]3[C:32](=[CH:33][C:24]([C:22]4[CH:23]=[C:18]([N:15]5[CH2:14][CH2:13][N:12]([CH3:11])[CH2:17][CH2:16]5)[N:19]=[C:20]([NH2:34])[N:21]=4)=[CH:25][CH:26]=3)[CH2:31]2)=[O:44])[CH:39]=[N:40][CH:41]=1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Reactant: O=C(O)Cc1cncc(Br)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)Cc3cncc(Br)c3)CC4)nc(N)n2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triethylamine (16 uL, 0.12 mmol) was added to a mixture of 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine trihydrochloride (50 mg, 0.1 mmol), (5-bromopyridin-3-yl)acetic acid (30.0 mg, 0.14 mmol) (Lancaster, Cat. #L13579), and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (56 mg, 0.13 mmol) in N,N-dimethylformate (1.5 mL). The reaction mixture was stirred at r.t. overnight. The mixture was diluted with water, and extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with MeOH in dichloromethane (0-10%) to afford the desired product. Analytic LCMS (M+H)+: m/z=521.95/523.95.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH3:23])=[C:6]([NH:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[N:10][NH2:11])[CH:7]=1.[C:24](N1C=CN=C1)(N1C=CN=C1)=[S:25].[K+].[Br-].CC#N>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH3:23])=[C:6]([N:8]2[C:9]([C:12]3[CH:13]=[CH:14][C:15]([C:18]([F:20])([F:21])[F:19])=[CH:16][CH:17]=3)=[N:10][NH:11][C:24]2=[S:25])[CH:7]=1
Reactant: COc1ccc(Cl)cc1NC(=NN)c1ccc(C(F)(F)F)cc1
Reactant: S=C(n1ccnc1)n1ccnc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC#N
Product: COc1ccc(Cl)cc1-n1c(-c2ccc(C(F)(F)F)cc2)n[nH]c1=S

Procedure:
N-(5-Chloro-2-methoxyphenyl)-4-(trifluoromethyl)benzene carbohydrazonamide (2.5 g, 7.27 mmol) was dissolved in THF (450 ml) under N2 and 1,1′-thiocarbonyldiimidazole (1.95 g, 11.0 mmol) added. The solution was stirred at reflux for 18 h and solvent removed by rotary evaporation. The residue was taken up in ethyl acetate (400 ml) and washed with 0.1N HCl solution (100 ml), water (100 ml) and brine prior to drying over MgSO4. Recrystallization from acetonitrile gave 1.91 g (68%) mp 275-280° C.; IR(KBr, υ=cm−1) 3080, 3058, 3020, 2916, 1506, 1488, 1322, 1288, 1174, 1130, 1110; 1H NMR (300 MHz, DMSO-d6) δ 3.51 (3H, s), 7.17 (1H, d, J=9.0 Hz), 7.53-7.57 (3H, m), 7.69 (1H, d, J=2.6 Hz), 7.77 (2H, d, J=8.4 Hz.s), 14.29 (1H, s); MS(DCl)m/z: 386(MH+). Anal. calcd. for C16H11ClF3N3OS.0.06 CH3CN: C, 49.87; H, 2.90; N, 11.04. Found: C, 50.03; H, 2.94; N, 11.07.