Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH2:16]([NH2:23])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].C(N(CC)C(C)C)(C)C>C(Cl)(Cl)Cl.C(Cl)Cl.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([NH:23][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:11])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(Br)cc1
Reactant: CCCCCCCN
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: CCCCCCCNC(=O)Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A stirred solution of (4-bromo-phenyl)-acetic acid (0.186 mol, 40.0 g) and thionyl chloride (0.558 mol, 40.0 mL) in chloroform (500 mL) under a N2 atmosphere was heated under reflux for 20 hours. The mixture was cooled to room temperature and evaporated under vacuum to give an oil. This was dissolved in anhydrous methylene chloride (150 mL) and added dropwise to a solution of heptylamine (0.20 mol, 30.3 mL) and N,N-diisopropylethylamine (0.37 mol, 64.7 mL) in anhydrous methylene chloride cooled to 0° C. The mixture was stirred at room temperature for 45 minutes then poured into water and extracted with methylene chloride. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and the solvent was removed under vacuum. The solid residue was purified by crystallization from ethyl acetate/hexanes to give 2-(4-bromo-phenyl)-N-heptyl-acetamide as a white solid. (37 g, 64%)
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][O:14][CH2:15][CH:16]=[C:17]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)[C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)[CH2:7]1)=[O:5])C.[OH-].[Na+]>C(O)C>[F:37][C:34]([F:35])([F:36])[C:31]1[CH:32]=[CH:33][C:28]([C:17]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)=[CH:16][CH2:15][O:14][CH2:13][CH2:12][N:8]2[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4]([OH:5])=[O:3])[CH2:7]2)=[CH:29][CH:30]=1
Reactant: CCOC(=O)[C@@H]1CCCN(CCOCC=C(c2ccc(C(F)(F)F)cc2)c2ccc(C(F)(F)F)cc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)[C@@H]1CCCN(CCOCC=C(c2ccc(C(F)(F)F)cc2)c2ccc(C(F)(F)F)cc2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 105 %

Procedure:
(R)-N-(2-(3,3-bis(4-(trifluoromethyl)phenyl)-2-propen-1-yloxy)ethyl)-3-piperidinecarboxylic acid ethyl ester (2.0 g, 3.8 mmol) was dissolved in ethanol (30 ml) and a 1 M sodium hydroxide solution (17 ml) was added. The reaction mixture was stirred at room temperature for 3 h. The solvent was evaporated in vacuo and dichloromethane (100 ml) was added. A concentrated hydrochloric acid solution was added (1.9 ml) and the phases were separated. Ethyl acetate was added to the organic phase which was then dried over sodium sulphate. The solvent was evaporated in vacuo to give 2.0 g (99%) of the title compound as a solid.
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:10]([C:19]2[C:24]([CH2:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:20]=2[CH2:27][CH3:28])[C:11]([C:14]([O:16]CC)=[O:15])=[CH:12][N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>>[CH2:1]([S:8][C:9]1[N:10]([C:19]2[C:24]([CH2:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:20]=2[CH2:27][CH3:28])[C:11]([C:14]([OH:16])=[O:15])=[CH:12][N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cnc(SCc2ccccc2)n1-c1c(CC)cccc1CC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCc1cccc(CC)c1-n1c(C(=O)O)cnc1SCc1ccccc1
Yield: 90 %

Procedure:
31.5 g (0.08 mol) of ethyl 2-benzylthio-1-(2,6-diethylphenyl)-imidazole-5-carboxylate (cf. Example 2) were stirred with 30 g of 33% strength sodium hydroxide solution at 80° C. until a homogeneous solution was formed. The solution was allowed to cool and acidified to pH 3 with dilute hydrochloric acid, and the product was filtered off under suction and dried in vacuo. 26.4 g (90% of theory) of 2-benzylthio-1-(2,6-diethylphenyl)-imidazole-5-carboxylic acid, solid at melting point 152°-154° C., were obtained.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[N:10][S:11]([CH2:13][CH:14]([CH3:16])[CH3:15])=[O:12])=[CH:5][C:4]=1[F:23])#[N:2].[CH3:24][Mg+].[Br-]>C1COCC1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:10][S:11]([CH2:13][CH:14]([CH3:16])[CH3:15])=[O:12])([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[CH3:24])=[CH:5][C:4]=1[F:23])#[N:2]
Reactant: C[Mg+]
Reactant: CC(C)CS(=O)N=C(c1cccnc1)c1ccc(C#N)c(F)c1
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(C)CS(=O)NC(C)(c1cccnc1)c1ccc(C#N)c(F)c1
Reaction time: 0.25 h

Procedure:
N-[(4-cyano-3-fluoro-phenyl)-(3-pyridyl)-methylene]-2-methylpropanesulfinamide (0.315 g, 0.956 mmol) was dissolved in anhydrous THF (10 mL), cooled in a ice bath, and treated with a 3.0 M ethereal solution of MeMgBr (0.96 mL, 2.87 mmol). After 15 min, the reaction was quenched with H2O, diluted with CH2Cl2 and saturated NaHCO3 solution and separated. The aqueous layer was extracted with CH2Cl2 (2×), the organic layers combined, dried (Na2SO4), filtered and concentrated to give the title compound after chromatography on a Waters Prep Pak column eluting with 0.1% TFA/H2O: 0.1% TFA/CH3CN, 95:5 to 5:95.
Reaction SMILES: CN(CN(C)C)C.C(Cl)(=O)C.[CH3:12][C:13]1[CH:28]=[CH:27][C:16]([O:17][C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[NH:23][CH:22]=[CH:21]3)=[CH:15][CH:14]=1.C[N:30]([CH2:32][C:33]1C2C(=CC=C(OC3C=CC(C)=CC=3)C=2)NC=1)C.[C-]#N.[K+].CI>C(Cl)Cl.CN(C=O)C>[C:32]([CH2:33][C:21]1[C:20]2[C:24](=[CH:25][CH:26]=[C:18]([O:17][C:16]3[CH:27]=[CH:28][C:13]([CH3:12])=[CH:14][CH:15]=3)[CH:19]=2)[NH:23][CH:22]=1)#[N:30]
Reactant: Cc1ccc(Oc2ccc3[nH]cc(CN(C)C)c3c2)cc1
Reactant: Cc1ccc(Oc2ccc3[nH]ccc3c2)cc1
Agent: CN(C)CN(C)C
Agent: [C-]#N
Agent: [K+]
Solvent: CI
Solvent: CC(=O)Cl
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2ccc3[nH]cc(CC#N)c3c2)cc1

Procedure:
Treatment of a cooled solution of N,N,N',N'-tetramethyldiaminomethane (0.24 g, 0.32 mL, 2.35 mmol) in CH2Cl2 (7 mL) with acetyl chloride (0.19 g, 0.17 mL, 2.39 mmol) followed by a solution of 5-(4-methylphenoxy)indole (0.39 g, 1.74 mmol) in CH2Cl2 (6 mL), gave after work-up: 3-(N,N-dimethylaminomethyl)-5-(4-methylphenoxy)indole as a gum. This was treated with potassium cyanide (0.43 g, 6.6 mmol) and methyl iodide (0.98 g, 0.43 mL, 6.9 mmol) in DMF (6 mL) for 16 hr, and after appropriate work-up, 3-cyanomethyl-5-(4-methylphenoxy)indole was obtained as an off-white crystalline solid 0.338 g (74%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:28])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[NH:17][C:18]([C:20]2[S:21][C:22]([CH2:26]Br)=[CH:23][C:24]=2[Cl:25])=[O:19])=[CH:4][CH:3]=1.C([O-])([O-])=[O:30].[Ca+2]>O1CCOCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:28])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[NH:17][C:18]([C:20]2[S:21][C:22]([CH2:26][OH:30])=[CH:23][C:24]=2[Cl:25])=[O:19])=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccc(Cl)cc1)c1cc(Cl)ccc1NC(=O)c1sc(CBr)cc1Cl
Reactant: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: C1COCCO1
Solvent: O
Product: O=C(Nc1ccc(Cl)cc1)c1cc(Cl)ccc1NC(=O)c1sc(CO)cc1Cl
Temperature: 25 °C
Yield: 56.7 %

Procedure:
To a solution of N-(4-chlorophenyl)-2-[((5-bromomethyl-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide (0.3 g, 0.58 mmol) in dioxane (10 mL) and water (2 mL) was added CaCO3 (0.29 g, 2.89 mmol). The resulting turbid solution was heated to reflux for 64 hours, and then cooled to ambient temperature. The reaction mixture was concentrated to remove dioxane and purified by flash chromatography on silica followed by precipitation from CH2Cl2 and hexane to afford 0.15 g of N-(4-chlorophenyl)-2-[((5-hydroxymethyl-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide, as a yellow solid; NMR (DMSO-d6/TFA) 11.1 (s, 1), 10.7 (s, 1), 8.4 (d, 1), 7.9 (s, 1), 7.7 (d, 2), 7.5 (d, 1), 7.3 (d, 2), 7.0 (s, 1), 4.6(s, 2) ppm.
Reaction SMILES: C([O:3][C:4]([CH:6]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:7][S:8]([C:11]([CH3:16])([CH3:15])[C:12](Cl)=[O:13])(=[O:10])=[O:9])=[O:5])C.[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[CH3:15][C:11]([S:8]([CH2:7][C@@H:6]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:4]([OH:3])=[O:5])(=[O:9])=[O:10])([C:12]([N:28]1[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]1)=[O:13])[CH3:16]
Reactant: CN1CCNCC1
Reactant: CCOC(=O)C(Cc1ccccc1)CS(=O)(=O)C(C)(C)C(=O)Cl
Product: CN1CCN(C(=O)C(C)(C)S(=O)(=O)C[C@@H](Cc2ccccc2)C(=O)O)CC1

Procedure:
In an analogous manner to that described in Example 1, paragraphs (d) and (e), starting from 2-mercaptoisobutyric acid and ethyl 2-benzylacrylate there was obtained (RS)-2-[[2-[(ethoxy)carbonyl]-3-phenylpropyl]sulfonyl]-2-methylpropionyl chloride, reaction of which with 1-methylpiperazine analogously to Example 2, paragraph (a), and subsequent enzymatic hydrolysis analogously to Example 6, paragraph (c), yielded (S)-α-[[[1-methyl-1-[(4-methyl-1-piperazinyl)carbonyl]ethyl]sulfonyl]methyl]hydrocinnamic acid, MS: 396 (M)+, as a colourless solid.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[S:21][CH3:22].Cl.[NH2:24][OH:25].C(N(CC)CC)C.O>O1CCOCC1.C(Cl)(Cl)Cl.CCCCCC>[NH2:1][C:2]1[N:6]([C:7]2[C:8]([Cl:18])=[CH:9][C:10]([C:14]([F:17])([F:15])[F:16])=[CH:11][C:12]=2[Cl:13])[N:5]=[C:4]([C:19](=[N:24][OH:25])[NH2:20])[C:3]=1[S:21][CH3:22]
Reactant: NO
Reactant: CSc1c(C#N)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CSc1c(C(N)=NO)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Temperature: 25 °C
Reaction time: 29 h
Yield: 85.3 %

Procedure:
5-Amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-methylthiopyrazole (7.5 g, 20.4 mmol) and hydroxylamine hydrochloride (1.83 g, 25.5 mmol) were dissolved in 75 ml of dioxane, and then triethylamine (2.5 g, 24.5 mmol) was added at room temperature. After the mixture was stirred at room temperature for 29 hours, hydroxylamine hydrochloride (720 mg, 10.1 mmol) and triethylamine (1.0 g, 10.2 mmol) were further added, followed by stirring at room temperature for 22 hours. The reaction mixture was poured into 200 ml of iced water and extracted with 250 ml of ethyl acetate. The extract was dried over anhydrous magnesium sulfate and then concentrated to obtain a yellow crystal. The crystal was subjected to silica gel column chromatography [eluent: mixed solvent of n-hexane and chloroform (volume ratio=1:1)] to obtain 6.98 g (17.4 mmol) of the title compound as a colorless crystal. Yield 85%.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[CH:5]=1)=[O:3].C(N(CC)CC)C.[C:18](Cl)(=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20].O>C(Cl)(Cl)Cl>[C:2]([C:4]1[CH:5]=[C:6]([NH:10][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:1]
Reactant: CC(=O)c1cccc(N)c1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(=O)c1cccc(NC(=O)C(C)(C)C)c1
Reaction time: 0.25 h
Yield: 79.5 %

Procedure:
To a stirred solution of 3-aminoacetophenone (1.0 g, 7.4 mmol) in chloroform cooled to 0° C. was added triethylamine dropwise (1.44 g, 14.2 mmol). The mixture was stirred for 15 min at this temperature and then pivaloyl chloride (0.83 g, 7.4 mmol) was added dropwise and the mixture was stirred overnight. Water was added and the aqueous layer was extracted with DCM. The collected organic extracts were washed with sat. aq. NaHCO3 and brine, dried over anhydrous MgSO4, and filtered. The solvent was evaporated under reduced pressure to afford 8z as a white solid (1.29 g, 80%). Mp 130-133° C. 1H NMR (600 MHz, CDCl3): δ 8.07 (t, J=1.8 Hz, 1H), 7.90-7.88 (m, 1H), 7.76 (br s, 1H), 7.65-7.63 (m, 1H), 7.37 (t, J=1.8 Hz 1H), 2.57 (s, 3H), 1.31 (s, 9H). 13C NMR (150 MHz, CDCl3): δ 198.2, 177.2, 138.8, 137.7, 129.3, 124.9, 124.1, 119.7, 39.8, 27.6, 26.8.
Reaction SMILES: [CH3:1][C@H:2]1[C@@H:7]([N:8]([C:10]2[N:18]=[CH:17][N:16]=[C:15]3[C:11]=2[CH:12]=[CH:13][NH:14]3)[CH3:9])[CH2:6][N:5]([C:19]([CH2:21][C:22]#[N:23])=[O:20])[CH2:4][CH2:3]1.Br.[C:25]([O-:37])(=[O:36])[CH2:26][C:27]([CH2:32][C:33]([OH:35])=[O:34])([C:29]([OH:31])=[O:30])[OH:28].[Na+]>O>[CH3:1][C@H:2]1[C@@H:7]([N:8]([C:10]2[N:18]=[CH:17][N:16]=[C:15]3[C:11]=2[CH:12]=[CH:13][NH:14]3)[CH3:9])[CH2:6][N:5]([C:19]([CH2:21][C:22]#[N:23])=[O:20])[CH2:4][CH2:3]1.[CH2:32]([C:27]([OH:28])([C:29]([OH:31])=[O:30])[CH2:26][C:25]([OH:37])=[O:36])[C:33]([OH:35])=[O:34]
Reactant: O=C([O-])CC(O)(CC(=O)O)C(=O)O
Agent: Br
Agent: C[C@@H]1CCN(C(=O)CC#N)C[C@@H]1N(C)c1ncnc2[nH]ccc12
Agent: [Na+]
Solvent: O
Product: O=C(O)CC(O)(CC(=O)O)C(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Amorphous tofacitinib hydrobromide (0.55 g) was dissolved in water (6 mL). The solution was treated with solid monosodium citrate (0.40 g, 1.69 mmol) and the resulting white suspension was stirred for 16 hours at 25° C. The suspension was filtered, washed with water (2×5 mL) and air-dried for 16 hours at 25° C. to yield 0.63 g of tofacitinib citrate as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([Cl:14])=[N:10][CH:11]=[CH:12][CH:13]=2)[N:5]=[CH:4][N:3]=1.[CH3:15][NH2:16]>C(Cl)Cl.C1COCC1.CC(C)=O>[Cl:14][C:9]1[C:8]([C:6]2[N:5]=[CH:4][N:3]=[C:2]([NH:16][CH3:15])[N:7]=2)=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: Clc1ncnc(-c2cccnc2Cl)n1
Reactant: CN
Solvent: C1CCOC1
Solvent: CC(C)=O
Solvent: ClCCl
Product: CNc1ncnc(-c2cccnc2Cl)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To 2-chloro-4-(2-chloro-pyridin-3-yl)-[1,3,5]triazine (10.0 g, 44.0 mmol) in 55 ml of methylene chloride was added methylamine (45 ml, 88.0 mmol) as a 2.0 M solution in THF at 0° C. After stirring at room temperature for 18 h, the mixture was diluted with acetone and filtered through a plug of silica gel and concentrated to yield the desired product. MS m/z=222 [M+H]+. Calc'd for C9H8ClN5: 221.65.
Reaction SMILES: [F:1][C:2]([S:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)([F:4])[F:3].[CH3:13][N:14]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:15](Cl)=[O:16]>>[F:1][C:2]([S:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:15](=[O:16])[N:14]([CH3:13])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:8][CH:7]=1)([F:4])[F:3]
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: Oc1ccc(SC(F)(F)F)cc1
Product: CN(C(=O)Oc1ccc(SC(F)(F)F)cc1)c1ccccc1

Procedure:
The title compound was prepared from 4-trifluoromethylsulfanyl-phenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC (70%, clear oil). HPLC-MS m/z=328.0 (M+1), Rt: 5.16 min.
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:14]([O:15]CC2C=CC=CC=2)[C@H:13]([O:23]CC2C=CC=CC=2)[C@@H:12]([CH2:31][O:32]CC2C=CC=CC=2)[O:11][C@H:10]1[C:40]1[S:44][C:43]2[C:45]([CH2:49][C:50]3[CH:55]=[CH:54][C:53]([CH3:56])=[CH:52][CH:51]=3)=[CH:46][CH:47]=[CH:48][C:42]=2[CH:41]=1)C1C=CC=CC=1.C(S)C.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[C@@H:10]1([C:40]2[S:44][C:43]3[C:45]([CH2:49][C:50]4[CH:51]=[CH:52][C:53]([CH3:56])=[CH:54][CH:55]=4)=[CH:46][CH:47]=[CH:48][C:42]=3[CH:41]=2)[O:11][C@H:12]([CH2:31][OH:32])[C@@H:13]([OH:23])[C@H:14]([OH:15])[C@H:9]1[OH:8]
Reactant: Cc1ccc(Cc2cccc3cc([C@@H]4O[C@H](COCc5ccccc5)[C@@H](OCc5ccccc5)[C@H](OCc5ccccc5)[C@H]4OCc4ccccc4)sc23)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCS
Product: Cc1ccc(Cc2cccc3cc([C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)sc23)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 32 %

Procedure:
To a solution of 2-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)-7-(4-methylbenzyl)benzo[b]thiophene (0.95 g) and ethanethiol (1.8 mL) in dichloromethane (15 mL) was added boron trifluoride diethyl ether complex (2.1 mL) at room temperature. The reaction mixture was stirred at room temperature for 3 hours, and a saturated potassium carbonate aqueous solution was added to the mixture. The mixture was extracted with ethyl acetate. The organic layer washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1) to give the title compound (0.16 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][C:12]([NH:15][C:16]3[CH:17]=[N:18][C:19]([CH3:25])=[C:20]([CH:24]=3)[C:21](O)=[O:22])=[N:13][CH:14]=2)=[CH:5][CH:4]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:59][S:60]([N:63]1[CH2:68][CH2:67][NH:66][CH2:65][CH2:64]1)(=[O:62])=[O:61]>CN(C=O)C>[CH3:59][S:60]([N:63]1[CH2:68][CH2:67][N:66]([C:21]([C:20]2[C:19]([CH3:25])=[N:18][CH:17]=[C:16]([NH:15][C:12]3[N:13]=[CH:14][C:9]([C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=4)=[CH:10][N:11]=3)[CH:24]=2)=[O:22])[CH2:65][CH2:64]1)(=[O:62])=[O:61]
Reactant: COc1ccc(-c2cnc(Nc3cnc(C)c(C(=O)O)c3)nc2)cc1
Reactant: CS(=O)(=O)N1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2cnc(Nc3cnc(C)c(C(=O)N4CCN(S(C)(=O)=O)CC4)c3)nc2)cc1
Reaction time: 0.03 h

Procedure:
To a solution of 5-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]-2-methyl-nicotinic acid 10 (0.05 mmol) in DMF (1 mL) is added HATU (0.06 mmol) and DIEA (0.14 mmol) at rt. The resulting mixture is stirred for 2 min then 1-methanesulfonyl-piperazine (0.05 mmol) is added. The reaction mixture is stirred at rt for 4 h and then directly purified by preparative LCMS to give (4-methanesulfonyl-piperazin-1-yl)-{5-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]-2-methyl-pyridin-3-yl}-methanone B1. 1H NMR (400 MHz, d4-CH3OH) δ 9.30 (d, J=4.0 Hz, 1H), 8.81 (s, 2H), 8.50 (d, J=4.0 Hz, 1H), 7.60-7.758 (m, 2H), 7.07-7.05 (m, 2H), 3.96-3.94 (m, 2H), 3.85 (s, 3H), 3.54-352 (m, 2H), 3.42-3.39 (m, 2H), 3.27 (bs, 2H), 2.91 (s, 3H), 2.62 (s, 3H). MS (m/z) (M+1)+: 483.1.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[C:9]([O:12][C:13]([CH3:22])([CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])[CH:14]=[CH2:15])(=[O:11])[CH3:10].[C:23](Cl)(=[O:32])[C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1>C1COCC1>[CH3:31][O:30][C:27]1[CH:28]=[CH:29][C:24]([C:23](=[O:32])[CH2:10][C:9]([O:12][C:13]([CH3:22])([CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])[CH:14]=[CH2:15])=[O:11])=[CH:25][CH:26]=1
Reactant: C=CC(C)(CCC=C(C)C)OC(C)=O
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CC(C)(CCC=C(C)C)OC(=O)CC(=O)c1ccc(OC)cc1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
Lithium diisopropylamide (119.0 mL of a 2.0 M solution, 0.238 mol) is placed into a 500 mL three-necked round-bottomed flask fitted with a magnetic stirrer, internal thermometer, argon inlet, and addition funnel. The flask is cooled to -78° C. 3,7-dimethyl-1,6-octadien-3-yl acetate (22.04 g, 0.112 mol) is dissolved in THF (5 mL) and the resulting solution added to the flask over 45 min. Once addition is complete, the mixture is stirred for an additional 15 min. before being treated with a solution p-anisoyl chloride (35.00 g, 0.106 mol) dissolved in THF (30 mL) over 30 min. The mixture is warmed to -20° C. and stirred at that temperature for 18 h. After warming to 0° C., the mixture is quenched with 20% HCl (80 mL). The mixture is poured into a separatory funnel containing ether (150 mL) and water (250 mL). The aqueous layer is extracted with ether (50 mL). The mixture is poured into a separatory funnel containing ether (150 mL) and water (250 mL). The aqueous layer is extracted with ether (150 mL). The combined organic layers are washed with saturated NaHCO3 solution (2×100 mL), water (2×150 mL) and brine (150 mL), dried over MgSO4 and filtered. The solvent is removed by rotary evaporation to give an oil. The oil is purified by column chromatography (elution with 2% ethyl acetate/petroleum ether) to yield a colorless oil having 1H and 13C NMR spectra consistent with the desired product.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[C:15]2[CH:14]=[CH:13][C:12]3[N:16]=[C:17]([NH:20][C:21]4[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=4[Cl:28])[N:18]([CH3:19])[C:11]=3[C:10]=2[C:9](=[O:29])[NH:8][C:7]=1[CH3:30])C.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C.Cl>C1COCC1.O>[Cl:27][C:26]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:28])[C:21]=1[NH:20][C:17]1[N:18]([CH3:19])[C:11]2[C:10]3[C:9](=[O:29])[NH:8][C:7]([CH3:30])=[C:6]([CH2:5][CH2:4][OH:3])[C:15]=3[CH:14]=[CH:13][C:12]=2[N:16]=1
Reactant: CCOC(=O)Cc1c(C)[nH]c(=O)c2c1ccc1nc(Nc3c(Cl)cccc3Cl)n(C)c12
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Cc1[nH]c(=O)c2c(ccc3nc(Nc4c(Cl)cccc4Cl)n(C)c32)c1CCO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.9 %

Procedure:
To a stirred solution of the product of Example 9 (25 mg, 0.05 mmol), in THF (2 mL), under nitrogen, was added a solution of lithium aluminum hydride (1M in THF, 0.25 mL, 0.25 mmol). The mixture was stirred for 30min at room temperature. Ethyl acetate was added, followed by water, and then acidified with 1N HCl. The whole mixture was applied to a Varian SCX cartridge, and washed in turn with 1N HCl, water, acetone, MeOH, and MeOH/CH2Cl2 (1:1). The product was then eluted with MeOH/CH2Cl2/NH4OH (49:49:2). Evaporation of the eluent gave the title compound (15 mg, 72%). Mp >300° C.; MS(ES) 417, 419 (MH+).
Reaction SMILES: C[O:2][C:3]1[NH:4][C:5]([CH3:23])=[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[N:8]=1.N1C=CC=CC=1.[C:30](Cl)(=[O:33])[CH2:31][CH3:32]>ClCCl>[CH3:23][C:5]1[NH:4][C:3](=[O:2])[N:8]([C:30](=[O:33])[CH2:31][CH3:32])[CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[C:6]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)C1=C(C)NC(OC)=NC1c1cccc([N+](=O)[O-])c1
Reactant: CCC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)C1=C(C)NC(=O)N(C(=O)CC)C1c1cccc([N+](=O)[O-])c1
Reaction time: 2 h
Yield: 66.8 %

Procedure:
A solution of 1,4-dihydro-2-methoxy-6-methyl-4-(3-nitrophenyl)-5-pyrimidinecarboxylic acid, ethyl ester (750 mg., 2.35 mmole) and dry pyridine (0.57 ml., 7.05 mmole) in dichloromethane (5.0 ml.) at -20° (methanol/ice bath) under argon is treated dropwise via gas-tight syringe with propionyl chloride (0.26 ml., 2.82 mmole). The reaction mixture is stirred for 2.0 hours and evaporated. The solid yellow residue is dissolved in methanol (25 ml.) and tetrahydrofuran (15 ml.) and treated with 5N hydrochloric acid (6.0 ml.). After stirring at room temperature for 1.0 hour, the reaction mixture is evaporated. The residue is partitioned between ethyl acetate and sodium bicarbonate solution. The organic phase is washed with saturated sodium chloride, dried over magnesium sulfate, and evaporated. The residue is flash chromatographed to give the title compound as a white foam (567 mg.). This foam is combined with material from another batch (290 mg.) and recrystallized from dichloromethane/isopropyl ether to give large shiny white crystals (784 mg., m. p. 152°-154°). TLC(silica gel; 50% ethyl acetate:hexanes) Rf =0.57.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:15][C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[NH:21][CH:20]=[CH:19]3)=[C:6](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:7]=1.[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:15][C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[N:21]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:20]=[CH:19]3)=[C:6](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:7]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)/C=C/c1cc(F)ccc1Cc1ccc2[nH]ccc2c1
Product: CCOC(=O)/C=C/c1cc(F)ccc1Cc1ccc2c(ccn2Cc2ccccc2)c1

Procedure:
The indole of Step 1 (621 mg; 1.92 mmol) was coupled with benzyl bromide according to the procedure described in step 1 of example 2 to yield 678 mg of the title compound.