Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[N:14]=3)=[CH:11][NH:10][N:9]=2)=[CH:4][CH:3]=1.C1C=NC(NS(C2C=CC(N)=CC=2)(=O)=O)=NC=1.Cl[C:38]([O:40][CH2:41][CH3:42])=[O:39].O>N1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:38](=[O:39])[O:40][CH2:41][CH3:42])[N:14]=3)=[CH:11][NH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: Nc1nccc(-c2c[nH]nc2-c2ccc(F)cc2)n1
Reactant: CCOC(=O)Cl
Agent: Nc1ccc(S(=O)(=O)Nc2ncccn2)cc1
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)Nc1nccc(-c2c[nH]nc2-c2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a suspension of 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyrimidinamine prepared in accordance with Example A-306 (0.26 g, 0.001 mol) in 5 mL of pyridine was added ethyl chloroformate dropwise. After the addition, the clear solution was stirred at room temperature for 6 hours. Water was added and the aqueous phase was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and the crude was trituated with ether to give 0.15 g of product, ethyl [4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyrimidinyl]carbamate, as a white solid (46% yield), mp: 163–165° C.; Anal. Calc'd for C16H14FN5O2: C, 58.71; H, 4.31; N, 21.04. Found: C, 59.22; H, 4.51; N, 21.66.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]2[N:10]([C:15]3[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=3[F:22])[C:11](=[O:14])[NH:12][CH2:13][C:3]=12.[CH3:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][C:25]=1B1OC(C)(C)C(C)(C)O1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>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.O>[F:22][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]([F:21])[C:15]=1[N:10]1[C:4]2[N:5]=[C:6]([S:8][CH3:9])[N:7]=[C:2]([C:25]3[CH:26]=[C:27]([CH:31]=[CH:32][C:24]=3[CH3:23])[C:28]([OH:30])=[O:29])[C:3]=2[CH2:13][NH:12][C:11]1=[O:14]
Reactant: Cc1ccc(C(=O)O)cc1B1OC(C)(C)C(C)(C)O1
Reactant: CSc1nc(Cl)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CSc1nc(-c2cc(C(=O)O)ccc2C)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Temperature: 150 °C
Yield: 62.4 %

Procedure:
To a stirring solution of 3-iodo-4-methylbenzoic acid (60 g, 0.22 mol, 1 eq) in degassed DMF (1400 mL, 23.3 vol.) was charged 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (81.4 g, 0.32 mol, 1.4 eq) followed by potassium acetate (112 g, 1.14 mole, 5 eq) and [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (18.7 g, 0.02 mole, 01.eq). The resulting mixture was placed under a nitrogen atmosphere and was heated to 80° C. with the exclusion of light overnight. The mixture was then concentrated under high vacuum and the residue partitioned between EtOAc and 2M HCl. The mixture was then filtered and the layers separated. The aqueous phase was re-extracted with EtOAc. The combined organics were then washed with brine, dried and evaporated to yield a brown solid that was applied to a silica plug then eluted with 2:1 cyclohexane:ethyl acetate. Fractions were then combined and evaporated to yield a brown foam that was triturated with cyclohexane, collected by filtration then dried in vacuo to yield 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid. (CDCl3) 8.50-8.49 (1H, d), 8.04-8.02 (1H, dd), 7.27-7.25 (1H, d), 2.61 (3H, s), 1.36 (12H, s) 5-Chloro-1-(2,6-difluorophenyl)-7-(methylthio)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (200 mg, 0.58 mmol) was mixed with 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (0.23 g), K2CO3 (0.485 g), dioxane (18 mL) and H2O (6 mL). The resultant mixture was passed through by a stream of argon for 10 min, mixed with Pd(PPh3)4 (34 mg) and heated at 150° C. for 1 h. It was filtered through celite, mixed with 1 mL acetic acid and washed with brine. The organic layers were collected, dried over MgSO4, filtered and concentrated and the residue was purified by flash column chromatography to provide the title compound (160 mg). LC-MS m/z 443.2 (M+H)+, 1.98 min (ret. time).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].[C:9](OC(=O)C)(=[O:11])[CH3:10].C(OC(C)C)(C)C>CN(C1C=CN=CC=1)C.C1COCC1>[C:9]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Br:1])(=[O:11])[CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: OCCCCCCBr
Agent: CN(C)c1ccncc1
Solvent: CC(C)OC(C)C
Solvent: C1CCOC1
Product: CC(=O)OCCCCCCBr
Reaction time: 0.5 h
Yield: 96.3 %

Procedure:
20.1 g (0.16 mol) of DMAP were added to 297.4 g (1.64 mol) of 6-bromo-1-hexanol in 1500 ml of THF. A solution of 184.4 g (1.81 mol) of acetic anhydride in 300 ml of THF was added dropwise in such a way that the reaction temperature did not exceed 30° C. After completion of the addition, the mixture was stirred for a further 30 minutes. The reaction mixture was mixed with 500 ml of diisopropyl ether and extracted successively with 700 ml each of water, 2× saturated NaHCO3 solution and water. After drying over sodium sulfate, the solvent was removed in vacuo. 352.8 g (1.58 mol, 96%) of 6-bromohexyl acetate were obtained.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][C@H:5]1[C:18](=[O:19])[CH2:17][C@H:16]2[N:7]([CH2:8][CH2:9][C:10]3[C:15]2=[CH:14][C:13]([O:20][CH3:21])=[C:12]([O:22][CH3:23])[CH:11]=3)[CH2:6]1)[CH3:3].CC(C[C@@H]1C(=O)C[C@@H]2N(CCC3C2=CC(OC)=C(OC)C=3)C1)C>>[CH3:3][CH:2]([CH2:4][CH:5]1[C:18](=[O:19])[CH2:17][CH:16]2[N:7]([CH2:8][CH2:9][C:10]3[C:15]2=[CH:14][C:13]([O:20][CH3:21])=[C:12]([O:22][CH3:23])[CH:11]=3)[CH2:6]1)[CH3:1]
Reactant: COc1cc2c(cc1OC)[C@H]1CC(=O)[C@H](CC(C)C)CN1CC2
Agent: COc1cc2c(cc1OC)[C@@H]1CC(=O)[C@@H](CC(C)C)CN1CC2
Product: COc1cc2c(cc1OC)C1CC(=O)C(CC(C)C)CN1CC2

Procedure:
To a round bottom flask was added 6,7-dimethoxy-3,4-dihydroisoquinoline (13 g, 67.8 mmol), 3-dimethylaminomethyl-5-methyl-hexan-2-one methiodide 1b (26 g, 81.4 mmol) and EtOH (130 mL). The suspension was heated to 80° C. overnight. The reaction mixture was allowed to cool to room temperature and H2O (200 mL) was added forming a precipitate. The EtOH was removed in vacuo and CH2Cl2 (400 mL) was added. A 10% NaOH solution was added to the mixture until basic. The aqueous layer was then extracted 3× with CH2Cl2 (250 mL). The organic layers were combined, dried over MgSO4 and concentrated. The crude reaction mixture was purified via flash column chromatography (0.5:9.5 Acetone:CH2Cl2) and further recrystallized from EtOAc and Hexanes to give 16.1 g (51 mmol) of a racemic mix of (3S,11bS) and (3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-pyrido[2,1-a]isoquinolin-2-one 1c (tetrabenazine, TBZ) in a 75% yield. The enantiomers of tetrabenazine were separated by SFC utilizing a Chiralpak AD-H column with 15% CAN/MeOH plus 0.5% DMEA at 2.5 mL/min at 100 bar and 35° C. to yield 4.3 g of (3R,11bR)-tetrabenazine 1c.1 and 4.3 g of (3S,11bS)-tetrabenazine 1c.2. (3R,11bR)-tetrabenazine 1c.1: MS calcd: (317); Found 318.7 (M+H). (3S,11bS)-tetrabenazine 1c.2: MS calcd: (317); Found 318.7 (M+H).
Reaction SMILES: C[Si](C=[N+]=[N-])(C)C.[C:8]([C:11]1[CH:29]=[CH:28][C:14]2[CH:15]=[C:16]([C:18]3[O:23][C:22](=[O:24])[C:21]([CH3:25])=[C:20]([OH:26])[C:19]=3[CH3:27])[O:17][C:13]=2[CH:12]=1)([OH:10])=[O:9].[C:30](O)(=O)C>CO.C1(C)C=CC=CC=1>[CH3:25][C:21]1[C:22](=[O:24])[O:23][C:18]([C:16]2[O:17][C:13]3[CH:12]=[C:11]([C:8]([O:10][CH3:30])=[O:9])[CH:29]=[CH:28][C:14]=3[CH:15]=2)=[C:19]([CH3:27])[C:20]=1[OH:26]
Reactant: CC(=O)O
Reactant: Cc1c(-c2cc3ccc(C(=O)O)cc3o2)oc(=O)c(C)c1O
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)c1ccc2cc(-c3oc(=O)c(C)c(O)c3C)oc2c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Trimethylsilyldiazomethane (2 M hexane solution, 85 μl) was added to a mixed solution of 6-(6-carboxybenzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one (50 mg) in MeOH (5 ml) and toluene (1 ml), and the mixture was stirred at room temperature for 10 minutes. After adding acetic acid to the reaction solution for quenching of the excess trimethylsilyldiazomethane, it was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH2Cl2/MeOH =9/1) to obtain 3,5-dimethyl-4-hydroxy-6-(6-(methoxycarbonyl) benzofuran-2-yl)-2H-pyran-2-one.
Reaction SMILES: [C:1]([NH:4][C:5]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(SC)[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2].[C:17]1(S)C=CC=CC=1.C(N(CC)CC)C>CO>[C:1]([NH:4][CH:5]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:6]([O:8][CH3:17])=[O:7])(=[O:3])[CH3:2]
Reactant: CSC(NC(C)=O)(C(=O)O)c1ccccc1
Reactant: Sc1ccccc1
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)C(NC(C)=O)c1ccccc1

Procedure:
173 Milligrams of a methanethiol ester of α-acetylamino-α-methylthiophenylacetic acid and 50 mg of thiophenol were dissolved in 10 ml of methanol. To the solution 1 ml of triethylamine was added, and the system was refluxed for 1.5 hours. Concentrating the reaction mixture under reduced pressure, the residue was parted by a column chromatography (silica gel and methylene chloride). Thus 127 mg of methyl α-acetylaminophenylacetate was obtained.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH2:12])=[N:8][CH:9]=[CH:10][CH:11]=1.S(=O)(=O)(O)O.[Br:23]Br>C(O)(=O)C.C(OCC)(=O)C>[Br:23][C:10]1[CH:11]=[C:6]([O:5][CH2:4][C:3]2[C:13]([F:17])=[CH:14][CH:15]=[CH:16][C:2]=2[F:1])[C:7]([NH2:12])=[N:8][CH:9]=1
Reactant: Nc1ncccc1OCc1c(F)cccc1F
Reactant: BrBr
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Nc1ncc(Br)cc1OCc1c(F)cccc1F
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
32.6 g of 3-[(2,6-difluorobenzyl)oxy]pyridine-2-amine (Example 1A; 138 mmol, 1 equivalent) were suspended in 552 ml of 10% strength sulphuric acid, and the mixture was cooled to 0° C. 8.5 ml of bromine (165 mmol, 1.2 equivalents) were dissolved in 85 ml of acetic acid and then, over a period of 90 min, added dropwise to the ice-cooled reaction solution. After the dropwise addition had ended, the mixture was stirred at 0° C. for 90 min and then diluted with 600 ml of ethyl acetate, and the aqueous phase was separated off. The aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with saturated aqueous sodium bicarbonate solution, dried and concentrated. The residue was dissolved in dichloromethane and chromatographed on silica gel (petroleum ether/ethyl acetate gradient as mobile phase). This gave 24 g (55% of theory) of the title compound.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[C:4]#[N:5].[NH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>CN(C=O)C>[F:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:2]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:3]=1[C:4]#[N:5]
Reactant: C1CCNCC1
Reactant: N#Cc1c(F)cccc1F
Solvent: CN(C)C=O
Product: N#Cc1c(F)cccc1N1CCCCC1
Yield: 43.8 %

Procedure:
2,6-Difluorobenzonitrile (250 mg; 1.8 mmol) and piperidine (145 mg; 1.7 mmol) were mixed in DMF (5 mL) for 3 hours at RT. The solvent is removed under vacuum, and the resulting oil is dried under vacuum at 30° C. overnight to yield 152 milligrams of 2-fluoro-6-(piperidin-1-yl)benzonitrile.
Reaction SMILES: Br[CH:2]([C:4](=[O:7])[CH2:5][CH3:6])[CH3:3].[C:8]1(=[O:18])[NH:12][C:11](=[O:13])[C:10]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:9]12.[K].C(OCC)(=O)C>CN(C=O)C>[CH3:3][CH:2]([N:12]1[C:8](=[O:18])[C:9]2[C:10](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:11]1=[O:13])[C:4](=[O:7])[CH2:5][CH3:6]
Reactant: CCC(=O)C(C)Br
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCC(=O)C(C)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 10 h
Yield: 79 %

Procedure:
2-Bromo-pentan-3-one obtained in Example (15a) (8.47 g, 35.57 mmol) was dissolved in DMF (120 mL). Potassium phthalimide (6.9 g, 37.25 mmol) was added, and the mixture was stirred at room temperature for 10 hours. Ethyl acetate was added to the reaction solution, and the organic layer was washed with 1 N hydrochloric acid and brine, and dried over anhydrous sodium sulfate. Following concentration under reduced pressure, the residue was washed with hexane to obtain 6.5 g of the title compound as a white solid (79%).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:17]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16]2[CH2:20][CH2:19][N:18]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:17]=2)=[CH:13][CH:14]=1
Reactant: c1ccc(COc2ccc(NC3=NN(c4ccccc4)CC3)cc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Oc1ccc(NC2=NN(c3ccccc3)CC2)cc1
Yield: 65.2 %

Procedure:
A suspension of N-(4-benzyloxyphenyl)-4,5-dihydro-1-phenyl-1H-pyrazol-3-amine (6.9 g) in ethanol (350 ml) was hydrogenated at atmospheric pressure over 10% palladium on carbon until hydrogen uptake ceased. The mixture was filtered and the filtrate evaporated to small volume. The resulting precipitate was collected, washed with ethanol and dried to give the title compound, (3.32 g) mp 211°-14° (dec).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])[CH2:7][CH2:6]1)=[O:4].[Cl:21][S:22](O)(=[O:24])=[O:23]>ClCCl>[CH3:18][O:17][C:12]1[CH:13]=[CH:14][C:15]([S:22]([Cl:21])(=[O:24])=[O:23])=[CH:16][C:11]=1[N:8]1[CH2:7][CH2:6][N:5]([C:3](=[O:4])[C:2]([F:1])([F:19])[F:20])[CH2:10][CH2:9]1
Reactant: O=S(=O)(O)Cl
Reactant: COc1ccccc1N1CCN(C(=O)C(F)(F)F)CC1
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)Cl)cc1N1CCN(C(=O)C(F)(F)F)CC1
Reaction time: 0.17 h

Procedure:
A solution of 2,2,2-trifluoro-1-[4-(2-methoxy-phenyl)-piperazin-1-yl]-ethanone (14 g; 0.48 mol) in dichloromethane (20 mL) was added to chlorosulfonic acid (75 mL) in such a rate that the inner temperature did not exceed −5° C. After 10 min at this temperature, the solution was poured slowly onto ice-water (500 g), the precipitate was filtered and washed with cold water (2×200 mL) and cold diethyl ether (200 mL). The resulting solid was recrystallized from diethyl ether to give 4-methoxy-3-[4-(2,2,2-trifluoro-acetyl)-piperazin-1-yl]-benzenesulfonyl chloride as white powder (7.7 g; 41%), MS, MH+ 387, m. p. 125-127.3° C.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[F:11])[OH:4].[F:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([C:34](O)=[O:35])=[CH:26][CH:25]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([C:34]([NH:1][CH:2]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][CH:14]=2)[CH:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[F:11])[OH:4])=[O:35])=[CH:26][CH:25]=1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccccc1F
Reactant: O=C(O)c1ccc(F)c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: O=C(NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccccc1F)c1ccc(F)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.5 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(2-fluorophenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol (450 mg, 1.44 mmol) in acetonitrile (20 ml) were added 4-fluoronaphthalenecarboxylic acid (274 mg, 1.44 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (412 mg, 2.15 mmol) and 1-hydroxy-1H-benzotriazole (221 mg, 1.44 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1). Recrystallization from ethyl acetate-hexane gave the title compound (465 mg, 67%).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:13])[C:9]([O:11][CH3:12])=[O:10])=[C:4]([F:14])[CH:3]=1.C(OC([S-])=[S:19])C.[K+]>>[F:14][C:4]1[CH:3]=[C:2]([SH:19])[CH:7]=[CH:6][C:5]=1[CH:8]([CH3:13])[C:9]([O:11][CH3:12])=[O:10]
Reactant: CCOC(=S)[S-]
Reactant: COC(=O)C(C)c1ccc(N)cc1F
Agent: [K+]
Product: COC(=O)C(C)c1ccc(S)cc1F
Yield: 92 %

Procedure:
Compound (7) obtained above was diazotized and subsequently treated with potassium ethylxanthate to give compound (9) of interest as colorless oil at a yield of 92%.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]([CH:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[C:7]([CH2:9]Cl)=[N:8][C:4]=2[CH:3]=1.[CH3:19][S:20]([C:23]1[C:31]2[C:26](=[CH:27][N:28]=[CH:29][CH:30]=2)[NH:25][N:24]=1)(=[O:22])=[O:21]>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]([CH:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[C:7]([CH2:9][N:25]3[C:26]4=[CH:27][N:28]=[CH:29][CH:30]=[C:31]4[C:23]([S:20]([CH3:19])(=[O:21])=[O:22])=[N:24]3)=[N:8][C:4]=2[CH:3]=1
Reactant: ClCc1nc2cc(Cl)ccc2n1C1CCOCC1
Reactant: CS(=O)(=O)c1n[nH]c2cnccc12
Product: CS(=O)(=O)c1nn(Cc2nc3cc(Cl)ccc3n2C2CCOCC2)c2cnccc12

Procedure:
The title compound was prepared in analogy to Example 2-1 by using 5-chloro-2-chloromethyl-1-(tetrahydro-pyran-4-yl)-1H-benzoimidazole and 3-methanesulfonyl-1H-pyrazolo[3,4-c]pyridine instead of 5-chloro-2-chloromethyl-1-((S)-1,1-dioxo-tetrahydro-1λ6-thiophen-3-yl)-1H-benzoimidazole and 3-(methylsulfonyl)-1H-pyrazolo[3,4-c]pyridine.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:9])[NH:4][N:5]=[C:6]([Cl:8])[CH:7]=1.[H-].[Na+].I[CH3:13]>CN(C=O)C>[Br:1][C:2]1[C:3](=[O:9])[N:4]([CH3:13])[N:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CI
Reactant: O=c1[nH]nc(Cl)cc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1nc(Cl)cc(Br)c1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 68 %

Procedure:
A 250-mL single-necked round bottomed flask equipped with a magnetic stirrer was purged with nitrogen and charged with 4-bromo-6-chloropyridazin-3(2H)-one (1.00 g, 4.77 mmol) and DMF (15 mL). Sodium hydride (60% by weight in oil, 229 mg, 5.73 mmol) was added in one portion. After stirring at room temperature for 10 minutes, iodomethane (1.02 g, 7.16 mmol) was added and the reaction stirred at room temperature for 1.5 h. The reaction was then quenched with aqueous saturated sodium bicarbonate (10 mL) and the resulting solution poured into water (150 mL). The mixture was then extracted with ethyl acetate (250 mL). The organic layer was dried over sodium sulfate. The drying agent was then removed by filtration, and the filtrate was concentrated under reduced pressure to residue. Purification by column chromatography afforded 103e in a 68% yield (722 mg) as a white solid: mp 107-108° C.; 1H NMR (300 MHz, CDCl3) δ 7.62 (s, 1H), 3.81 (s, 3H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH2:10]O.CS(OS(C)(=O)=O)(=O)=O.CCN(C(C)C)C(C)C.[N:30]1([C:36]2[CH:43]=[CH:42][CH:41]=[CH:40][C:37]=2[C:38]#[N:39])[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>C(Cl)Cl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH2:10][N:33]1[CH2:32][CH2:31][N:30]([C:36]2[CH:43]=[CH:42][CH:41]=[CH:40][C:37]=2[C:38]#[N:39])[CH2:35][CH2:34]1
Reactant: OCc1cc2ccccc2s1
Reactant: N#Cc1ccccc1N1CCNCC1
Agent: CS(=O)(=O)OS(C)(=O)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccccc1N1CCN(Cc2cc3ccccc3s2)CC1

Procedure:
The product from Example 8A (150 mg 0.9 mmol), methane sulfonic anhydride (159 mg, 0.9 mmol), and DIEA (475 μL 2.7 mmol) were combined. After stirring, 2-(1-piperazinyl)benzonitrile (181 mg, 1.0 mmol) in 2 ml DCM was also combined and stirred at room temperature for 18 hours. The mixture was concentrated and the residue was taken up in hot methanol. The methanol was filtered and the filter cake washed with cold methanol to provide the title compound. 1H NMR (300 MHz, CDCl3) δ 2.69 (m, 4H) 3.04 (s, 4H) 3.76 (m, 4H) 3.86 (s, 1H) 6.74 (m, 2H) 7.29 (m, 3H) 7.75 (m, 1H); (ESI) m/z 334 (M+H)+.
Reaction SMILES: ClC1C=C(CN2C(=O)C3=CC=CC=C3C2=O)N=C(OC)N=1.COC1N=C(OC)C=C(CN2C(=O)C3=CC=CC=C3C2=O)N=1.Cl[C:45]1[CH:50]=[C:49]([CH2:51][N:52]2[C:56](=[O:57])[C:55]3=[CH:58][CH:59]=[CH:60][CH:61]=[C:54]3[C:53]2=[O:62])[N:48]=[C:47]([S:63][CH3:64])[N:46]=1.[CH3:65][S-:66].[Na+]>>[CH3:64][S:63][C:47]1[N:46]=[C:45]([S:66][CH3:65])[CH:50]=[C:49]([CH2:51][N:52]2[C:56](=[O:57])[C:55]3=[CH:58][CH:59]=[CH:60][CH:61]=[C:54]3[C:53]2=[O:62])[N:48]=1
Reactant: C[S-]
Reactant: CSc1nc(Cl)cc(CN2C(=O)c3ccccc3C2=O)n1
Agent: COc1cc(CN2C(=O)c3ccccc3C2=O)nc(OC)n1
Agent: COc1nc(Cl)cc(CN2C(=O)c3ccccc3C2=O)n1
Agent: [Na+]
Product: CSc1cc(CN2C(=O)c3ccccc3C2=O)nc(SC)n1

Procedure:
Using the above method, 4-chloro-2-methoxy-6-phthalimidomethylpyrimidine could be converted to 2,4-dimethoxy-6-phthalimidomethylpyrimidine. Similarly, 4-chloro-2-methlythio-6-phthalimidomethylpyrimidine was reacted with sodium methanethiolate to provide 2,4-bis(methylthio)-6-phthalimidomethylpyrimidine, identical in all respects with the compound prepared in Example 1, part D.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[C:5]([CH3:32])([CH3:31])[CH2:6][C:7]1[N:8]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][CH:25]=2)[C:9]2[C:14]([C:15]=1[S:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:13][C:12]([O:21]C)=[CH:11][CH:10]=2)[CH3:2].CC(S)(C)C.[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:33])[C:5]([CH3:32])([CH3:31])[CH2:6][C:7]1[N:8]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([Br:30])=[CH:28][CH:29]=2)[C:9]2[C:14]([C:15]=1[S:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:13][C:12]([OH:21])=[CH:11][CH:10]=2)[CH3:2]
Reactant: CCOC(=O)C(C)(C)Cc1c(SC(C)(C)C)c2cc(OC)ccc2n1Cc1ccc(Br)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CC(C)(C)S
Product: CCOC(=O)C(C)(C)Cc1c(SC(C)(C)C)c2cc(O)ccc2n1Cc1ccc(Br)cc1
Temperature: -2.5 °C
Reaction time: 2 h

Procedure:
To a reaction vessel containing CH2Cl2 (3.3-fold, V/W of starting material) was added 3-[1-(4-bromo-benzyl)-3-tert-butylsulfanyl-5-methoxy-1H-indol-2-yl]-2,2-dimethyl-propionic acid ethyl ester (1.0 eq). 2-Methyl-2-propanethiol (7.80 eq) was subsequently added to the reaction mixture and the reaction was cooled down to a temperature of −5 to 0° C. While maintaining the reaction mixture at this temperature, AlCl3 (3.30 eq) was added portion-wise to the reaction. The reaction was stirred at a temperature of 0 to 5° C. for about 2 hours, then subsequently warmed to 20-25° C. The reaction was then quenched with water (6.5 fold; v/w of starting material) and the mixture acidified to a pH of 2 with 2.0M HCl. The organic layer was then collected and the aqueous layer washed with CH2Cl2 to recover remaining product. The organic layers were combined and washed with 1.0M HCl and water followed by a brine wash and concentrated in vacuo. Ethyl acetate (1.0 fold; v/w of starting material) was added to the solid and heated to dissolve the product. The flask was gradually cooled to 0-2° C. followed by the slow addition of hexanes. The mixture was agitated for a period of about 2 hours, followed by filtration to collect the solid. The solid was subsequently dried under vacuum.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[CH2:4]Br.[C-:11]#[N:12].[K+]>C(O)C.O>[Cl:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[CH2:4][C:11]#[N:12]
Reactant: [C-]#N
Reactant: Clc1ccc(Cl)c(CBr)c1
Agent: [K+]
Solvent: O
Solvent: CCO
Product: N#CCc1cc(Cl)ccc1Cl
Temperature: 80 °C
Yield: 83.6 %

Procedure:
A mixture of 2,5-dichlorobenzyl bromide (5.4 g, 22.5 mmol) in 16 mL of ethanol and potassium cyanide (1.63 g, 25 mmol) in 4 mL of water was heated at 80° C. overnight, then cooled, and the solids were filtered and washed with ethanol to give 3.5 g of 2,5-dichlorophenylacetonitrile as a white powder melting at 89-91° C. The nitrile was suspended in 20 red, of ethanol, and 20 mL of a 25% aqueous NaOH solution was added. The mixture was heated in a CEM Explore™ microwave reactor at 140° C. for 30 minutes, then cooled, poured into ice water and acidified to pH 1 with concentrated HCl to give a precipitate. The precipitate was filtered, washed with water and dried in a vacuum oven at 90° C. for 5 h to give the title compound as a white powder.