Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][CH:6]=[CH:5][C:4]=2[C:3]=1[C:12]([OH:14])=[O:13].B(F)(F)F.[C:19](=O)(O)[O-].[Na+]>>[CH3:19][O:13][C:12]([C:3]1[C:4]2[CH:5]=[CH:6][CH:7]=[N:8][C:9]=2[CH:10]=[CH:11][C:2]=1[OH:1])=[O:14]
Reactant: O=C(O)c1c(O)ccc2ncccc12
Reactant: O=C([O-])O
Agent: FB(F)F
Agent: [Na+]
Product: COC(=O)c1c(O)ccc2ncccc12

Procedure:
6-Hydroxy-5-quinolinecarboxylic acid [as reported by Da Re, P. et al. in Ann. Chem. (Rome) 1970, 60(3), 215-24 (C.A. 73, 25338m)] is reacted with methanolic boron trifluoride solution for several hours. The resulting mixture is added to an aqueous solution of sodium bicarbonate to give finally a basic solution. The solution is extracted with chloroform. The chloroform extract is dried over anhydrous sodium sulfate and concentrated and the residue is crystallized from a suitable solvent.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH2:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[F:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][CH:13]=1>C(OCC)(=O)C.C(=O)([O-])O.[Na+]>[F:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([NH:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[O:17])=[CH:14][CH:13]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Nc1cccc([N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C(Nc1cccc([N+](=O)[O-])c1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
3-Nitro-phenylamine (5 g, 36.2 mmol) was dissolved in a biphasic mixture of ethyl acetate (100 ml) and aqueous sodium hydrogen carbonate (1N) (100 ml). 4-Fluoro-benzoyl-chloride (8.7 ml, 41.6 mmol) was added under vigorous stirring. The mixture was stirred for 2 hours at ambient temperature. The phases were separated, the organic phase was dried over sodium sulfate and concentrated. The residue was used without further purification (9.4 g, 100% yield). 1H-NMR (CDCl3, 400 MHz) as disclosed in Magnetic Resonance in Chemistry (1997), 35(8), 543-548.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].[Cl:16][C:17]1[C:26]([I:27])=[CH:25][C:20]2[NH:21][C:22](=[S:24])[NH:23][C:19]=2[CH:18]=1>C1COCC1>[Cl:16][C:17]1[C:26]([I:27])=[CH:25][C:20]2[N:21]=[C:22]([S:24][CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[NH:23][C:19]=2[CH:18]=1
Reactant: S=c1[nH]c2cc(Cl)c(I)cc2[nH]1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CSc1nc2cc(I)c(Cl)cc2[nH]1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Cs2CO3 (2.3 g, 7.08 mmol), followed by tert-butyl bromoacetate (0.52 mL, 3.54 mmol), was added to a solution of 5-chloro-6-iodo-1,3-dihydro-2H-benzimidazole-2-thione (Intermediate 7, 1.1 g, 3.54 mmol) in THF (20 mL) at 0° C. The reaction was stirred at rt for 0.5 h. Volatiles were removed and the residue was partitioned between EtOAc and water. Concentration afforded the desired product as a white power. LC-MS: calculated for C13H14ClIN2O2S 423.95, observed m/e 424.8 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH2:7]2)([OH:3])=O.C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH2:29]([N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C=O)C>[CH2:29]([N:36]1[CH2:41][CH2:40][N:39]([C:1]([C:4]2[CH:5]=[C:6]3[C:10](=[CH:11][CH:12]=2)[NH:9][C:8](=[O:13])[CH2:7]3)=[O:3])[CH2:38][CH2:37]1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C1Cc2cc(C(=O)O)ccc2N1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: CC(C)COC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1Cc2cc(C(=O)N3CCN(Cc4ccccc4)CC3)ccc2N1
Reaction time: 1 h
Yield: 42 %

Procedure:
To a solution of 0.88 g of 5-carboxyoxindol in 10 ml of DMF was added under ice-cooling 0.82 ml of triethylamine, and 0.77 ml of isobutyl chloroformate was added thereto subsequently. The mixture was stirred at the same temperature for 1 hour. Then, 1.1 g of 1-benzylpiperazine was added thereto, and the mixture was stirred at room temperature overnight. After the reaction was completed, DMF was removed under reduced pressure, and to the residue was added an aqueous sodium hydrogencarbonate solution and extracted with chloroform. After washing with water and drying over magnesium sulfate, chloroform was distilled off under reduced pressure. The resultant residue was purified by silica-gel column chromatography (eluent: methylene chloride:methanol=50:1) and recrystallized from isopropyl alcohol to give 0.7 g of 5-(4-benzyl-1-piperazinylcarbonyl)oxindol.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[CH:12]1([N:18]=[C:19]=[O:20])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>>[CH:12]1([NH:18][C:19]([NH:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][CH:6]=[CH:5]3)=[O:20])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=C=NC1CCCCC1
Reactant: Nc1ccc2ncccc2c1
Product: O=C(Nc1ccc2ncccc2c1)NC1CCCCC1

Procedure:
Prepared from 6-aminoquinoline and cyclohexyl isocyanate. m/z (ES+) 270 (M+H)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]1[C:23](=[O:28])N(OC)C)=[O:16])([CH3:13])([CH3:12])[CH3:11]>>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]1[C:23]([C:5]1[S:1][C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=1)=[O:28])=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: c1ccc2sccc2c1
Reactant: CON(C)C(=O)C1CCCCN1C(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)N1CCCCC1C(=O)c1cc2ccccc2s1

Procedure:
The title compound (1.60 g) was prepared from benzo[b]thiophene (0.80 g) and (RS)-1-(tert-butyloxycarbonyl)-2-(N-methoxy-N-methylcarbamoyl)-piperidine, D1 (1.62 g) according to a procedure similar to that for Description 2.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:9][NH2:10])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:11]1(=O)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C([O-])(=O)C.[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1([CH2:9][NH:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: O=C1CCCCC1
Reactant: CCOC(=O)C1(CN)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)C1(CNC2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 63.9 %

Procedure:
To a solution of ethyl1-(aminomethyl)cyclopropane-1-carboxylate (Intermediate 114; 20.65 g, 50 mmol) in DCM (200 mL) was added cyclohexanone (Aldrich; 5.28 mL, 51 mmol). After stirring at room temperature for 15 minutes, sodium acetate (4.185 g, 75 mmol) was added, followed by sodium triacetoxyborohydride (15.905 g, 75 mmol). The suspension was stirred at room temperature for 2 days then partitioned between DCM and saturated aqueous sodium hydrogen carbonate solution. The organic solution was dried over sodium sulphate and evaporated to yield the title compound as a colourless oil (7.2 g, 64%).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7](=[O:20])[N:8]([CH2:18][CH3:19])[C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([CH3:17])[N:10]=2)=O)C.[NH2:21][NH2:22]>C(O)C>[CH2:18]([N:8]1[C:9]2[C:14](=[CH:13][CH:12]=[C:11]([CH3:17])[N:10]=2)[C:15]([OH:16])=[C:6]([C:4]([NH:21][NH2:22])=[O:3])[C:7]1=[O:20])[CH3:19]
Reactant: CCOC(=O)c1c(O)c2ccc(C)nc2n(CC)c1=O
Reactant: NN
Solvent: CCO
Product: CCn1c(=O)c(C(=O)NN)c(O)c2ccc(C)nc21

Procedure:
A stirred mixture of 1.38 g. (0.005 mole) of 1-ethyl-1,2-dihydro-4-hydroxy-7-methyl-2-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester (prepared as in Example 1) and 0.32 g. (0.01 mole) of hydrazine in 30 ml. of ethanol was heated under reflux for 1 hour. The mixture was filtered and the filter cake was triturated with 100 ml. of 20% aqueous acetic acid. The insoluble material was collected, air dried and was recrystallized from ethanol to give 0.7 g. of the title compound, m.p. 211°-13° C.
Reaction SMILES: C(N(C(C)C)C(C)C)C.[CH:10]1([CH2:13][CH:14]([OH:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:11]1.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>ClCCl>[CH:10]1([CH2:13][CH:14]([O:20][S:22]([CH3:21])(=[O:24])=[O:23])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:11]1
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)C(O)CC1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)C(CC1CC1)OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
At RT, 2 ml (11.5 mmol, 2.4 eq.) of N-ethyl-N-(propan-2-yl)propan-2-amine were added to a solution of 1.9 g (purity 40%, 4.8 mmol) of ethyl 3-cyclopropyl-2-hydroxypropanoate (racemate) in 100 ml of dichloromethane, followed by the quick addition, at 0° C., of 0.45 ml (5.8 mmol, 1.2 eq.) of methanesulphonyl chloride. The reaction mixture was stirred at RT for 2 h and then quenched with ice. After phase separation, the organic phase was washed with three times with water and once with saturated sodium chloride solution. The combined organic phases were dried (sodium sulphate), filtered and concentrated under reduced pressure. The crude product was used for the next step without further purification.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([CH3:23])[CH:14]=2)=[O:10])[CH2:5][CH2:4]1.CCN(C(C)C)C(C)C.[NH:33]1[CH:37]=[C:36]([CH2:38][CH2:39][CH2:40][C:41](Cl)=[O:42])[N:35]=[N:34]1>C(Cl)Cl>[NH:33]1[CH:37]=[C:36]([CH2:38][CH2:39][CH2:40][C:41]([NH:2][CH:3]2[CH2:4][CH2:5][N:6]([C:9]([O:11][CH2:12][C:13]3[CH:18]=[C:17]([C:19]([F:22])([F:20])[F:21])[CH:16]=[C:15]([CH3:23])[CH:14]=3)=[O:10])[CH2:7][CH2:8]2)=[O:42])[N:35]=[N:34]1
Reactant: O=C(Cl)CCCc1c[nH]nn1
Reactant: Cc1cc(COC(=O)N2CCC(N)CC2)cc(C(F)(F)F)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(COC(=O)N2CCC(NC(=O)CCCc3c[nH]nn3)CC2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred suspension of 3-methyl-5-(trifluoromethyl)benzyl 4-aminopiperidine-1-carboxylate hydrochloride salt (201 mg, 0.570 mmol) in DCM (5 mL) at RT under nitrogen was added Huenig's Base (0.199 mL, 1.140 mmol). 4-(1H-1,2,3,-triazol-4-yl)butanoyl chloride (99 mg, 0.570 mmol) in DCM (2 mL) was added and the reaction mixture stirred at RT for 2 hours. The reaction mixture was diluted with DCM and washed with a 10% solution of citric acid, and saturated brine solution, before the organic portion was dried over MgSO4, filtered and concentrated under reduced pressure. Purification was carried out by chromatography on silica using 0-10% MeOH in DCM as eluent to afford the title product;
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([OH:13])=O)=[CH:2]1.C(N(CC)CC)C.[I-].ClC1C=CC=C[N+]=1C.[NH2:30][CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][CH:36]([NH:39][C:40]2[N:44]([CH2:45][C:46]3[CH:51]=[CH:50][C:49]([F:52])=[CH:48][CH:47]=3)[C:43]3[CH:53]=[CH:54][CH:55]=[CH:56][C:42]=3[N:41]=2)[CH2:35][CH2:34]1>ClCCl>[F:52][C:49]1[CH:50]=[CH:51][C:46]([CH2:45][N:44]2[C:43]3[CH:53]=[CH:54][CH:55]=[CH:56][C:42]=3[N:41]=[C:40]2[NH:39][CH:36]2[CH2:37][CH2:38][N:33]([CH2:32][CH2:31][NH:30][C:11](=[O:13])[CH2:10][C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][CH:2]=3)[CH2:34][CH2:35]2)=[CH:47][CH:48]=1
Reactant: NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Reactant: O=C(O)Cc1c[nH]c2ccccc12
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Cc1c[nH]c2ccccc12)NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Reaction time: 0.25 h
Yield: 43 %

Procedure:
To a stirred mixture of 3.5 parts of 1H-indol-3-acetic acid, 4.05 parts of N,N-diethylethanamine and 260 parts of dichloromethane were added 5.1 parts of 2-chloro-1-methylpyridinium iodide and stirring was continued for 15 minutes at room temperature. Then there were added 7.2 parts of N-[1-(2-aminoethyl)-4-piperidinyl]-1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-amine and the whole was stirred for 1 hour at room temperature. The reaction mixture was poured onto water and the layers were separated. The organic phase was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (96:4 by volume) saturated with ammonia, as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile, yielding 4.5 parts (43%) of N-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]-1H-indol-3-acetamide; mp. 193.6° C. (compound 77).
Reaction SMILES: [SH:1][CH2:2][CH2:3][CH2:4][CH2:5][OH:6].[H-].[Na+].Br[CH2:10][CH2:11][CH:12]1[O:16][CH2:15][CH2:14][O:13]1>C(#N)C>[O:13]1[CH2:14][CH2:15][O:16][CH:12]1[CH2:11][CH2:10][S:1][CH2:2][CH2:3][CH2:4][CH2:5][OH:6]
Reactant: OCCCCS
Reactant: BrCCC1OCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: OCCCCSCCC1OCCO1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 4-mercaptobutanol (4.936 g) in dry acetonitrile under argon was cooled to 0° C. and sodium hydride (60% in mineral oil, 2.044 g) was added portionwise. The mixture was stirred for 1 hour at 0° C. then 2-(2-bromoethyl)-1,3-dioxolane (9.26 g) was added and the resultant grey suspension was warmed to room temperature and stirred overnight. The reaction was quenched by addition of saturated aqueous sodium bicarbonate solution (150 mL) and then extracted with ethyl acetate (3×150 mL). The organics were combined and washed with brine (150 mL), dried over sodium sulfate, filtered and dried to afford the crude product. Purification was by silica gel chromatography eluting with 0-50% ethyl acetate in cyclohexane to afford the subtitled compound as a yellow oil. Yield 7.3 g.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].[CH2:13]([C@@H:15]1[O:17][CH2:16]1)Cl>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1.C(O)(C)C>[CH2:13]([C:10]1[CH:9]=[CH:8][CH:7]=[C:3]2[C:4]([NH:5][C:1](=[O:11])[C:2]=12)=[O:6])[C@H:15]1[O:17][CH2:16]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: ClC[C@H]1CO1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Agent: [K]
Solvent: CC(C)O
Product: O=C1NC(=O)c2c(C[C@@H]3CO3)cccc21
Reaction time: 46 h
Yield: 83.1 %

Procedure:
Into a reaction vessel were put potassium phthalimide (50.0 g, 0.27 mol), benzyltrimethylammonium chloride 5.00 g, 0.027 mol) and isopropanol (500 ml), and the mixture was cooled to 10° C. Thereto was added (R)-epichlorohydrin (74.9 g, 0.81 mol) and the mixture was stirred for 46 hours while being cooled. The solvent was removed and to the residue was added ethyl acetate (250 ml). The mixture was washed with water (250 ml), and then ethyl acetate was removed to give crude (R)-glycidylphthalimide (optical purity: 97% e.e.). The crude product was crystallized from ethyl acetate-hexane to give the object (R)-glycidylphthalimide (45.6 g, yield: 83%, optical purity: 98% e.e.) as white crystals. mp 100-102° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH:10]=O)=[C:5](Cl)[C:6]=1[C:7]#[N:8].C(=O)([O-])[O-].[K+].[K+].[CH2:18]([SH:22])[C:19]([CH3:21])=[O:20]>CN(C)C=O>[C:19]([C:18]1[S:22][C:5]2[C:6]([C:7]#[N:8])=[C:2]([NH2:1])[S:3][C:4]=2[CH:10]=1)(=[O:20])[CH3:21]
Reactant: N#Cc1c(N)sc(C=O)c1Cl
Reactant: CC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1cc2sc(N)c(C#N)c2s1
Temperature: 60 °C
Yield: 81 %

Procedure:
A mixture of 18.7 parts of 2-amino-4-chloro-3-cyano-5-formylthiophene, 13.8 parts of potassium carbonate and 80 parts of N,N-dimethylformamide was introduced first, and 9 parts of acetonylmercaptan were then added. After the exothermic reaction had died down, the mixture was heated at 60° C. for 1 hour and then discharged onto water. The precipitate was filtered off with suction, washed with water and dried. This gave 17.9 parts (81% of theory) of 5-acetyl-2-amino-3-cyanothieno[3,2-b]thiophene.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:22])[N:13]([C:15]3[N:20]=[CH:19][NH:18][C:17](=[O:21])[CH:16]=3)[CH:14]=2)[CH:5]=[CH:4][N:3]=1.CI.[C:25](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:22])[N:13]([C:15]3[N:20]=[CH:19][N:18]([CH3:25])[C:17](=[O:21])[CH:16]=3)[CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)cn1-c1cc(=O)[nH]cn1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: Cc1nc(C#Cc2ccnc(Cl)c2)cn1-c1cc(=O)n(C)cn1
Temperature: 25 °C
Yield: 11.2 %

Procedure:
To a solution of 50.0 mg (0.160 mmol) of 6-[4-(2-chloro-pyridin-4-ylethynyl)-2-methyl-imidazol-1-yl]-3H-pyrimidin-4-one and 0.020 ml (45.5 mg, 0.321 mmol) of methyl iodide in 10 ml of acetone were added 44 mg (0.321 mmol) of potassium carbonate. The suspension was stirred for 48 at room temperature. The suspension was filtered and the salts were washed with acetone. The filtrate was concentrated in vaccuo. The residue was dissolved in ethyl acetate/methanol, 1 g of silicagel was added and the suspension was concentrated in vaccuo. The silicagel containing adsorbed product was loaded onto a flash chromatography column and eluted with a 90:10 mixture of ethyl acetate and methanol. One obtains 6 mg (0.018 mmol, 11.5%) of the title compound as a crystalline light yellow solid, MS: 326.2, 328.2 (M+H+) separated from the undesired O-alkylation product.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]1(B(O)O)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.C(=O)=O>CCOCC>[C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: Ic1ccccc1
Agent: O=C=O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: c1ccc(-c2ccccc2)cc1
Reaction time: 64 h
Yield: 52 %

Procedure:
Bis{di(1H,1H,2H,2H-perfluorooctyl)phenylphosphino}palladium dichloride (89 mg, 0.05 mmol), iodobenzene (0.11 ml, 1 mmol), phenylboronic acid (122 mg, 1 mmol) and triethylamine (0.15 ml, 1.1 mmol) were placed in a 10 ml stainless steel cell. The cell was sealed and pressurised to approximately 5520 kPa (800 psi) (i.e. full of carbon dioxide). The cell was then heated to 100 C. for 64 hrs and then allowed to cool. When the pressure had dropped below 13800 kPa (2000 psi) the cell was vented into ether (100 ml), the cell was opened once atmospheric pressure was reached and washed out with dichloromethane (20 ml). The organic fractions were combined and concentrated in vacuo to give the crude product. The product was purified by flash column chromatography on silica gel, eluting with hexane to give a white crystalline solid (80 mg, 0.52 mmol, 52%); δH (250 MHz; CDCl3) 7.34-7.65 (10H, m, aryl).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:9]=[C:10]([NH:14][C:15]([NH:17]C(=O)C3C=CC=CC=3)=[S:16])[CH:11]=[CH:12][CH:13]=2)[CH:3]=1.[OH-].[Na+].Cl>CO.O>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:9]=[C:10]([NH:14][C:15]([NH2:17])=[S:16])[CH:11]=[CH:12][CH:13]=2)[CH:3]=1
Reactant: Cc1ccnc(-c2cccc(NC(=S)NC(=O)c3ccccc3)c2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ccnc(-c2cccc(NC(N)=S)c2)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 94.1 %

Procedure:
To a suspension of N-(3-(4-methylpyridin-2-yl)phenyl)-N′-benzoylthiourea (540 mg) in methanol (5 ml) was added an aqueous sodium hydroxide solution (1N, 1.55 ml) dropwise. The mixture was stirred at 60° C. for 1 hour, cooled to ambient temperature, and the pH was adjusted to 8.0 with 1N hydrochloric acid. The mixture was diluted with water (50 ml) and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was triturated with diisopropyl ether, collected by filtration, washed with diisopropyl ether and dried under reduced pressure to give N-(3-(4-methylpyridin-2-yl)phenyl)thiourea (356 mg).
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:24]=[C:23]([C:25]3[CH:34]=[C:33]4[C:28]([CH2:29][CH2:30][NH:31][CH2:32]4)=[CH:27][CH:26]=3)[N:22]=[C:21]([NH2:35])[N:20]=2)[CH2:15][CH2:14]1>>[CH3:12][N:13]1[CH2:14][CH2:15][N:16]([C:19]2[CH:24]=[C:23]([C:25]3[CH:34]=[C:33]4[C:28]([CH2:29][CH2:30][N:31]([S:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)(=[O:9])=[O:8])[CH2:32]4)=[CH:27][CH:26]=3)[N:22]=[C:21]([NH2:35])[N:20]=2)[CH2:17][CH2:18]1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(S(=O)(=O)c3ccccc3)CC4)nc(N)n2)CC1

Procedure:
This compound was prepared from benzenesulfonyl chloride and 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt using procedures analogous to those for Example 2. Analytic LCMS (M+H)+: m/z=465.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]23[CH2:18][CH2:17][CH2:16][CH:15]=[C:14]2[C:13](=[O:19])[NH:12][C:11](=[O:20])[CH2:10]3)[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].S(O[CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=1)(=O)(=O)C.O>CN(C)C=O>[CH3:36][C:33]1[CH:34]=[CH:35][C:30]([CH2:29][CH2:28][N:12]2[C:11](=[O:20])[CH2:10][C:9]3([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=4)[C:14](=[CH:15][CH2:16][CH2:17][CH2:18]3)[C:13]2=[O:19])=[CH:31][CH:32]=1
Reactant: Cc1ccc(CCOS(C)(=O)=O)cc1
Reactant: COc1cccc(C23CCCC=C2C(=O)NC(=O)C3)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc(C23CCCC=C2C(=O)N(CCc2ccc(C)cc2)C(=O)C3)c1

Procedure:
4a-(m-Methoxyphenyl)-1,3-diketo-1,2,3,4,4a,5,6,7-octahydroisoquinoline (6 g) in 75 ml of anhydrous dimethylformamide was added to a 55% suspension of sodium hydride in mineral oil (1.2 g) in 50 ml of dimethylformamide at 70°. The reaction mixture was heated for one hour at 80° and then cooled to 25°. p-Methylphenethyl mesylate (7.0 g) was added and the reaction heated at 70° for 18 hours. It was poured into water and extracted with ether. The residue after evaporation of the ether was chromatographed on 800 g. of Florisil. This yielded 4.4 g, mp 134°-140°; recrystallized from ethanol, mp 149°-151°.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[C:4]([F:11])[CH:3]=1.[CH:12]1([CH2:15][CH:16]=O)[CH2:14][CH2:13]1.[OH-].[Na+]>CC(O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:10]=[CH:9][C:5](/[C:6](=[CH:16]/[CH2:15][CH:12]2[CH2:14][CH2:13]2)/[C:7]#[N:8])=[C:4]([F:11])[CH:3]=1
Reactant: N#CCc1ccc(Cl)cc1F
Reactant: O=CCC1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: N#C/C(=C\CC1CC1)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.1 %

Procedure:
To a solution of 4-chloro-2-fluoro-benzyl cyanide (Oakwood) (3.39 g, 20.0 mmol) and cyclopropyl-acetaldehyde (Aldrich) (1.68.0 g, 20.0 mmol) in iPrOH (25 mL) was added 2 N NaOH (2.0 mL) dropwise at rt and the reaction mixture was stirred at rt overnight. The reaction mixture was diluted with EtOAc and the organic layer was separated, washed with water, brine, dried over Na2SO4 and concentrated. The residue was dried overnight under reduced pressure to afford (Z)-2-(4-chloro-2-fluoro-phenyl)-4-cyclopropyl-but-2-enenitrile (2.36 g, 50.0%) as a colorless oil which was used in the next step without further purification.
Reaction SMILES: [Cl:1]C1C=C(C=CC=1)C([O-])=O.O[N+:12]1[CH:17]=[CH:16][CH:15]=[C:14]2[CH:18]=[CH:19][NH:20][C:13]=12>O=P(Cl)(Cl)Cl>[Cl:1][C:15]1[CH:16]=[CH:17][N:12]=[C:13]2[NH:20][CH:19]=[CH:18][C:14]=12
Reactant: O[n+]1cccc2cc[nH]c21
Reactant: O=C([O-])c1cccc(Cl)c1
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1ccnc2[nH]ccc12
Temperature: 90 °C
Yield: 57.8 %

Procedure:
POCl3 (10 mL) was added to 7-hydroxy-1H-pyrrolo[2,3-b]pyridin-7-ium 3-chlorobenzoate (1.0 g, 3.4 mmol). The resulting mixture was heated to 90° C. for 18 hours. The mixture was then cooled to room temperature and concentrated. The resulting residue was diluted with acetonitrile (“ACN”; 3 mL) and water (3 mL). The pH was adjusted with 50% NaOH to a pH of 9. The resulting solid was filtered and washed with water. The solid was then washed with DCM to give 4-chloro-1H-pyrrolo[2,3-b]pyridine (0.30 g, 57% yield).