Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:18]=[CH:17][C:9]2[N:10]=[C:11]([NH:13][C:14](=[O:16])[CH3:15])[S:12][C:8]=2[C:7]=1[C:19]#[N:20].[F:24][C:25]([F:37])([F:36])[C:26]1[CH:27]=[C:28]([CH2:32][C:33](O)=[O:34])[CH:29]=[CH:30][CH:31]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.N1C=CC=CC=1>C(OCC)(=O)C>[C:14]([NH:13][C:11]1[S:12][C:8]2[C:7]([C:19]#[N:20])=[C:6]([O:5][C:4]3[CH:3]=[C:2]([NH:1][C:33](=[O:34])[CH2:32][C:28]4[CH:29]=[CH:30][CH:31]=[C:26]([C:25]([F:36])([F:24])[F:37])[CH:27]=4)[CH:23]=[CH:22][CH:21]=3)[CH:18]=[CH:17][C:9]=2[N:10]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)Nc1nc2ccc(Oc3cccc(N)c3)c(C#N)c2s1
Reactant: O=C(O)Cc1cccc(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Nc1nc2ccc(Oc3cccc(NC(=O)Cc4cccc(C(F)(F)F)c4)c3)c(C#N)c2s1
Temperature: 85 °C
Reaction time: 12 h
Yield: 69.2 %

Procedure:
A mixture of N-[6-(3-aminophenoxy)-7-cyano-1,3-benzothiazol-2-yl]acetamide (141 mg, 0.436 mmol) produced in Example 12(ii), [3-(trifluoromethyl)phenyl]acetic acid (176 mg, 0.872 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (331 mg, 0.872 mmol) and pyridine (3 mL) was stirred at 85° C. for 12 hr. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (5 mL), washed successively with saturated aqueous ammonium chloride solution (5 mL), saturated aqueous sodium hydrogen carbonate solution (5 ml) and saturated brine (5 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=40/60→100/0), and the obtained solution was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate/n-heptane (1/1) to give the title compound (154 mg, 69%) as a white powder.
Reaction SMILES: [Br:1][C:2]1[N:3]([C:12]2[N:13]=[CH:14][N:15]=[C:16]([NH2:19])[C:17]=2[N:18]=1)[C@@H:4]1[O:11][C@H:8]([CH2:9][OH:10])[C@@H:6]([OH:7])[CH2:5]1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](Cl)([C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:24][CH:23]=1.C[Si](C)(C)Cl.[C:49](Cl)(=[O:56])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>N1C=CC=CC=1>[C:49]([NH:19][C:16]1[C:17]2[N:18]=[C:2]([Br:1])[N:3]([C:12]=2[N:13]=[CH:14][N:15]=1)[C@@H:4]1[O:11][C@H:8]([CH2:9][O:10][C:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=2)[C:25]2[CH:26]=[CH:27][C:22]([O:21][CH3:20])=[CH:23][CH:24]=2)[C@@H:6]([OH:7])[CH2:5]1)(=[O:56])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1
Reactant: Nc1ncnc2c1nc(Br)n2[C@H]1C[C@H](O)[C@@H](CO)O1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: O=C(Cl)c1ccccc1
Agent: C[Si](C)(C)Cl
Solvent: c1ccncc1
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3c(Br)nc4c(NC(=O)c5ccccc5)ncnc43)C[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 41.6 %

Procedure:
8-Bromo-2′-Deoxyadenosine (7.7 gm. 22.17 mmol) was dried by co-evaporation with dry pyridine and the solid was suspended in 200 ml of dry pyridine followed by the addition of 4,4′-dimethoxytriphenylmethyl chloride (DMT-Cl) (9 gm, 26.6 mmol). After stirring for 4 hrs at RT, TLC on silica gel showed that a new product was formed and some starting material was unreacted. Another amount of DMT-Cl (3 gm) was added and stirred at RT for 2 hrs. When TLC showed that all starting material was converted to new product with higher Rf, the reaction mixture was cooled to 0 C and trimethylchlorosilane (12.042 gm., 14 ml, 110.85 mmol) was added dropwise while cooling and after 40 min. while stirring benzoyl chloride (15.58 gm, 12.88 ml, 110.85 mmol) was similarly added. The reaction was allowed to react at RT over 2 hrs. The reaction was quenched by slow addition of cold water (50 ml), followed by addition of concentrated ammonia (30%, 50 ml). After 30 min. the reaction mixture was evaporated to dryness. The residue was dissolved in water, and the solution was extracted with ethyl acetate three times, the organic layer washed with saturated sodium bicarbonate solution, and then brine. The organic phase was dried over sodium sulphate, evaporated to dryness. The product was purified on a silica column chromatography, to give a yellowish solid product (6.79 gm, 41.6%). The structure of this product was confirmed by H NMR and ES-MS.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][N:3]=1.[OH-].[K+].[N+:12]([CH2:14][C:15]([N:17]1[CH2:21][CH:20]=[CH:19][CH2:18]1)=[O:16])#[C-:13]>CO>[Cl:1][C:2]1[CH:7]=[C:6]([C@@H:8]2[O:9][CH:13]=[N:12][C@H:14]2[C:15]([N:17]2[CH2:21][CH:20]=[CH:19][CH2:18]2)=[O:16])[CH:5]=[CH:4][N:3]=1
Reactant: O=Cc1ccnc(Cl)c1
Reactant: [C-]#[N+]CC(=O)N1CC=CC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C([C@@H]1N=CO[C@H]1c1ccnc(Cl)c1)N1CC=CC1
Reaction time: 2 h
Yield: 84 %

Procedure:
SLA 07158 was prepared in accordance with method D using 2-chloropyridine-4-carbaldehyde SLA 07156 (0.47 g, 3.31 mmol), KOH (0.184 g, 3.33 mmol) in methanol (10 mL) and 2-Isocyano-1-(2H-pyrrol-1 (5H)-yl)ethanone SLA 07178 (0.410 g, 3.01 mmol). The solution was stirred 2 h with continued cooling. After work-up and column chromatography on florisil (EtOAc), trans-(5-(2-chloropyridin-4-yl)-4,5-dihydrooxazol-4-yl)(2H-pyrrol-1(5H)-yl)methanone SLA 07158 was obtained as a yellow solid (0.597 g, 84%).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]([NH:14][C:15](=[O:36])/[C:16](=[CH:21]/[C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH:32]=[C:31]([CH3:33])[N:30]=[CH:29]3)=[C:24]([O:34][CH3:35])[CH:23]=2)/[CH2:17][CH2:18][CH2:19]Cl)[CH3:13])=[CH:4]1.O.C(OCC)(=O)C>C1COCC1>[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]([N:14]2[CH2:19][CH2:18][CH2:17]/[C:16](=[CH:21]\[C:22]3[CH:27]=[CH:26][C:25]([N:28]4[CH:32]=[C:31]([CH3:33])[N:30]=[CH:29]4)=[C:24]([O:34][CH3:35])[CH:23]=3)/[C:15]2=[O:36])[CH3:13])=[CH:4]1
Reactant: COc1cc(/C=C(\CCCCl)C(=O)NC(C)c2c[nH]c3ccccc23)ccc1-n1cnc(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(/C=C2\CCCN(C(C)c3c[nH]c4ccccc34)C2=O)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
EDC (384 mg), HOBT (271 mg) and IPEA (0.582 mL) were sequentially added to a solution of (E)-5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valeric acid trifluoroacetate (300 mg) and 1-(1H-indol-3-yl)ethylamine (130 mg) in DMF (5 mL), and the reaction solution was stirred at room temperature for 12 hours. After confirming that the raw materials disappeared, ethyl acetate and water were added to the reaction solution and the organic layer was partitioned. The resulting organic layer was sequentially washed with a saturated aqueous solution of ammonium chloride and brine, and then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Carrier: Chromatorex™ NH, elution solvent:chloroform:methanol system) to obtain (E)-5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valeric acid (1-(1H-indol-3-yl)ethyl)amide (332 mg). Sodium hydride (containing mineral oil at 40%, 19.3 mg) was added to a solution of the resulting (E)-5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valeric acid (1-(1H-indol-3-yl)ethyl)amide (92 mg) in THF (3 mL) at 0° C., and the reaction solution was stirred at room temperature for 90 minutes. The reaction solution was cooled to 0° C., water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. The organic layer was washed sequentially with water and a saturated aqueous solution of sodium chloride. The organic layer was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (Carrier: Chromatorex™ NH, elution solvent:chloroform:methanol system) to obtain (E)-1-[1-(1H-indol-3-yl)ethyl]-3-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)piperidin-2-one as a racemate (37.3 mg). The compound (37 mg) was fractionated using CHIRALPAK™ AD-H manufactured by Daicel Chemical Industries, Ltd. (2 cm×25 cm: mobile phase: ethanol) to obtain the title optically active substance with a retention time of 10 minutes (15 mg; >99% ee) and the title optically active substance with a retention time of 14 minutes (14.2 mg; >99% ee).
Reaction SMILES: CC1C(C)=C(C)C(C)=C(C)C=1.CCCCCCC.B(Cl)(Cl)Cl.[S:23]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[CH:25]=[C:24]1[CH2:32][C:33]1[CH:34]=[C:35]([C@@H:40]2[O:69][C@H:68]([CH2:70][O:71]CC3C=CC=CC=3)[C@@H:59]([O:60]CC3C=CC=CC=3)[C@H:50]([O:51]CC3C=CC=CC=3)[C@H:41]2[O:42]CC2C=CC=CC=2)[CH:36]=[CH:37][C:38]=1[F:39]>ClCCl.CO>[S:23]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[CH:25]=[C:24]1[CH2:32][C:33]1[CH:34]=[C:35]([C@@H:40]2[O:69][C@H:68]([CH2:70][OH:71])[C@@H:59]([OH:60])[C@H:50]([OH:51])[C@H:41]2[OH:42])[CH:36]=[CH:37][C:38]=1[F:39]
Reactant: Fc1ccc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1Cc1cc2ccccc2s1
Agent: Cc1cc(C)c(C)c(C)c1C
Agent: ClB(Cl)Cl
Solvent: CCCCCCC
Solvent: CO
Solvent: ClCCl
Product: OC[C@H]1O[C@@H](c2ccc(F)c(Cc3cc4ccccc4s3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.2 %

Procedure:
Pentamethylbenzene (4.85 g) and a n-heptane solution (16.3 mL) containing 1.0 M of boron trichloride were added to a solution of (1s)-1,5-anhydro-1-[3-(1-benzothien-2-ylmethyl)-4-fluorophenyl]-2,3,4,6-tetra-O-benzyl-D-glucitol (2.5 g) dissolved in dichloromethane (50 mL, cooled to −78° C.) in an argon stream. The mixture was stirred at the same temperature for 2 hours. After the completion of the reaction, methanol (100 mL) was added for decomposition of the excessive reagent, and the solvents were removed by vacuum distillation. The residue was purified by silica gel column chromatography (chloroform-methanol). The obtained residue was suspended in a mixed solvent of ethanol and water and was refluxed with heating to dissolve. The resulting solution was slowly cooled to room temperature for recrystallization. The obtained crystal was collected by filtration and then dried under vacuum and heating to obtain (1S)-1,5-anhydro-1-[3-(1-benzothien-2-ylmethyl)-4-fluorophenyl]-D-glucitol (known compound A) (1.1 g) as a white crystal. The differential scanning calorimetry analysis chart (DSC analysis chart) of the known compound A obtained is shown in FIG. 1, and its X-ray powder diffraction chart is shown in FIG. 2.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][N:9]([C:15]1[CH:16]=[C:17]([CH:24]=[CH:25][C:26]=1[CH3:27])[C:18]([NH:20][CH:21]1[CH2:23][CH2:22]1)=[O:19])[C:8]2=[O:28].[CH3:29][S:30](Cl)(=[O:32])=[O:31].C(N(CC)CC)C>C(Cl)Cl.C(OCC)(=O)C>[CH:21]1([NH:20][C:18](=[O:19])[C:17]2[CH:24]=[CH:25][C:26]([CH3:27])=[C:15]([N:9]3[C:8](=[O:28])[C:7]4[C:12](=[CH:13][CH:14]=[C:5]([O:4][CH2:3][CH2:2][NH:1][S:30]([CH3:29])(=[O:32])=[O:31])[CH:6]=4)[N:11]=[CH:10]3)[CH:16]=2)[CH2:22][CH2:23]1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(OCCN)cc2c1=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(OCCNS(C)(=O)=O)cc2c1=O

Procedure:
3-[6-(2-Aminoethoxy)-4-oxoquinazolin-3(4H)-yl]-N-cyclopropyl-4-methylbenzamide (0.1 g), methanesulfonyl chloride (0.027 ml), and triethylamine (0.074 ml) were stirred in methylene chloride (2 ml) under an atmosphere of argon for 2 hours at room temperature. The reaction mixture was diluted with ethyl acetate and washed with water (2×), brine, dried (magnesium sulfate) and concentrated. Purification by column chromatography on a silica column eluting with 10% methanol/ethyl acetate gave the title compound (0.106 g) as a white solid; NMR Spectrum: (DMSOd6) 0.56 (m, 2H), 0.69 (m, 2H), 2.15 (s, 3H), 2.85 (m, 1H), 2.96 (s, 3H), 3.41 (m, 2H), 4.19 (t, 2H), 7.30 (t, 1H), 7.54 (m, 2H), 7.60 (s, 1H), 7.75 (d, 1H), 7.84 (s, 1H), 7.91 (d, 1H), 8.20 (s, 1H), 8.43 (d, 1H); Mass Spectrum: M+H+ 457.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([O:17][C:18]1[CH:33]=[CH:32][C:21]([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])=[C:20]([OH:34])[CH:19]=1)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[C:9]([O:17][C:18]1[CH:33]=[CH:32][C:21]([C:22]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:23])=[C:20]([O:34][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:19]=1)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: BrCc1ccccc1
Reactant: O=C(Oc1ccc(C(=O)OCc2ccccc2)c(O)c1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Oc1ccc(C(=O)OCc2ccccc2)c(OCc2ccccc2)c1)c1ccccc1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
Benzyl bromide (0.80 mL) was added to a mixture of benzyl 4-benzoyloxy-2-hydoxybenzoate (2.23 g) and cesium carbonate (2.29 g) in N,N-dimethylformamide (10 mL) at room temperature. The mixture was stirred at 50° C. for 3 hrs, and water was added. The resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by medium-pressure liquid silica gel column chromatography (eluent: n-hexane/ethyl acetate=6/1) to afford benzyl 4-benzoyloxy-2-benzyloxybenzoate (2.87 g).
Reaction SMILES: S(Cl)([Cl:3])=O.[NH2:5][C:6]1[CH:7]=[C:8]([OH:16])[C:9](=[CH:13][C:14]=1[Cl:15])[C:10]([OH:12])=[O:11].[CH3:17]O>>[ClH:3].[NH2:5][C:6]1[CH:7]=[C:8]([OH:16])[C:9](=[CH:13][C:14]=1[Cl:15])[C:10]([O:12][CH3:17])=[O:11]
Reactant: CO
Reactant: O=S(Cl)Cl
Reactant: Nc1cc(O)c(C(=O)O)cc1Cl
Product: COC(=O)c1cc(Cl)c(N)cc1O
Product: Cl
Temperature: 0 °C

Procedure:
To 300 ml of methanol is added 30 ml of thionylchloride and stirred at 0° C. To this is added 26 g (0.14 mol) of 4-amino-5-chlorosalicylic acid and refluxed for 18 hours. The mixture is clear and evaporated to dryness to obtain methyl 4-amino-5-chlorosalicylate hydrochloride which is then used directly in the next step.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]([CH3:25])[CH3:24])=[CH:18][CH:17]=1.[Cl:26][C:27]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[C:29]([Cl:42])[C:28]=1[OH:43]>ClCCl.CO>[Cl:26][C:27]1[CH:32]=[C:31]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][N:23]([CH3:24])[CH3:25])=[CH:18][CH:17]=2)[CH:30]=[C:29]([Cl:42])[C:28]=1[OH:43]
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1Nc1ccc(CN(C)C)cc1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Solvent: CO
Solvent: ClCCl
Product: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)cc2c1Nc1ccc(CN(C)C)cc1
Yield: 122.7 %

Procedure:
Following general procedure F, 1-(6-bromo-4-(4-((dimethylamino)methyl)phenylamino)quinolin-3-yl)ethanone (2.0 g, 5.09 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (2.2 g, 7.6 mmol) to obtain the free base. The purified product was suspended in dichloromethane/methanol (1:1, 40 mL) and HBr gas was bubbled through the suspension until a solution formed. The solution was concentrated to dryness and the resultant solid was triturated with diethyl ether. The mixture was filtered, washed with diethyl ether, and dried to obtain desired product (3.0 g, 94% over two steps) as a yellow solid: 1H NMR (300 MHz, DMSO) δ 11.93 (s, 1H), 10.59 (s, 1H), 9.81 (s, 1H), 9.24 (s, 1H), 8.37 (m, 2H), 8.11 (d, J=8.8 Hz, 1H), 7.66 (d, J=8.5 Hz, 2H), 7.56 (s, 2H), 7.51 (d, J=8.5 Hz, 2H), 4.39 (d, J=4.0 Hz, 2H), 2.74 (d, J=4.0 Hz, 6H), 2.54 (s, 3H). APCI MS m/z 480 [C26H23Cl2N3O2+H]+; HPLC>99% (AUC), tR=4.79 min.
Reaction SMILES: [F:1][C:2]1C=CC(C#N)=[N:6][C:7]=1[CH3:8].[CH2:11]1[CH2:15][O:14][CH2:13][CH2:12]1.[CH3:16][Mg+].[Br-].[BH4-].[Na+]>CCOCC>[F:1][C:2]1[CH:13]=[CH:12][C:11]([CH:15]([OH:14])[CH3:16])=[N:6][C:7]=1[CH3:8]
Reactant: C1CCOC1
Reactant: C[Mg+]
Reactant: Cc1nc(C#N)ccc1F
Agent: [BH4-]
Agent: [Br-]
Agent: [Na+]
Solvent: CCOCC
Product: Cc1nc(C(C)O)ccc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 22 %

Procedure:
A 250 ml round bottom flask containing 5-fluoro-6-methylpyridine-2-carbonitrile (Method 15; 2.24 g, 16.45 mmol) was charged with anhydrous THF (20 ml) under N2. The solution was cooled to 0° C., and a solution of MeMgBr (8.5 ml of a 3.0 M solution in ether, 25.5 mmol) was added dropwise. After 1 hour at 0° C., the reaction was quenched with saturated NH4Cl (10 ml, added drop wise), and the biphasic mixture was allowed to stir at 0° C. for 10 minutes. The layers were then separated, and the aqueous portion was extracted with EtOAc, and the combined organics were washed with brine, dried, filtered, and concentrated. The resulting oil was dissolved in MeOH (20 ml), and the solution was cooled to 0° C. NaBH4 (634 mg, 16.8 mmol) was added in portions over 5 minutes. The reaction was allowed to stir at room temperature for 1 hour, and was then concentrated. The residue was partitioned between EtOAc and H2O, and the aqueous layer was extracted with EtOAc. The combined organics were washed with brine, dried, filtered, and concentrated. The crude material was purified by silica gel chromatography (Rf in 60:40 hexanes:EtOAc=0.42) to afford the title compound as a pale yellow oil (550 mg, 22% over two steps). 1H NMR (400 MHz, CDCl3) δ 1.46 (d, J=6.6 Hz, 3H), 2.51 (d, J=3.0 Hz, 3H), 4.10 (s, 1H), 4.79-4.87 (m, 111), 7.08 (dd, J=8.5, 3.7 Hz, 1H), 7.31 (t, J=8.7 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([NH:7][C:8](=[O:23])[N:9]([C@H:16]2[CH2:21][CH2:20][C@H:19]([CH3:22])[CH2:18][CH2:17]2)[CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:4][CH:3]=1.[C:24]([NH:27][C:28]1[CH:37]=[CH:36][C:31]([S:32](Cl)(=[O:34])=[O:33])=[CH:30][CH:29]=1)(=[O:26])[CH3:25]>>[Cl:1][C:2]1[S:6][C:5]([NH:7][C:8](=[O:23])[N:9]([CH:10]2[CH2:11][CH2:12][N:13]([S:32]([C:31]3[CH:30]=[CH:29][C:28]([NH:27][C:24](=[O:26])[CH3:25])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[CH2:14][CH2:15]2)[C@H:16]2[CH2:21][CH2:20][C@H:19]([CH3:22])[CH2:18][CH2:17]2)=[N:4][CH:3]=1
Reactant: C[C@H]1CC[C@H](N(C(=O)Nc2ncc(Cl)s2)C2CCNCC2)CC1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Product: CC(=O)Nc1ccc(S(=O)(=O)N2CCC(N(C(=O)Nc3ncc(Cl)s3)[C@H]3CC[C@H](C)CC3)CC2)cc1

Procedure:
Prepared in a similar manner to Example 554 using 3-(5-chloro-thiazol-2-yl)-1-(trans-4-methyl-cyclohexyl)-1-piperidin-4-yl-urea and N-acetylsulfanilyl chloride.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16]2[N:15]=[C:14]([CH3:18])[CH:13]=[C:12]([CH3:19])[C:11]=2[C:10](=O)[CH2:9]1.[C:21]([NH:24][NH2:25])([NH2:23])=[NH:22].[ClH:26].Cl.O>C(O)C>[ClH:26].[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16]2[N:15]=[C:14]([CH3:18])[CH:13]=[C:12]([CH3:19])[C:11]=2[C:10](=[N:25][NH:24][C:21]([NH2:23])=[NH:22])[CH2:9]1
Reactant: N=C(N)NN
Reactant: Cc1cc(C)c2c(n1)CC(c1ccccc1F)CC2=O
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1cc(C)c2c(n1)CC(c1ccccc1F)CC2=NNC(=N)N
Yield: 74.4 %

Procedure:
A mixture of 7-(2-fluorophenyl)-2,4-dimethyl-5,6,7,8-tetrahydroquinolin-5-one (0.12 g), aminoguanidine hydrochloride (0.052 g), concentrated hydrochloric acid (0.067 ml), water (0.067 ml) and ethanol (10 ml) was refluxed for 7 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in water. The solution was washed with ethyl acetate. Under reduced pressure, the solvent was evaporated, and the residue was recrystallized from ethanol to give 7-(2-fluorophenyl)-5-guanidinoimino-2,4-dimethyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 85) (0.12 g).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:7]([C:9](=[CH:12]N(C)C)[C:10]#[N:11])=O)=[CH:5][CH:6]=1.Cl.[O:17]=[C:18]1[NH:22][CH2:21][CH2:20][N:19]1[CH2:23][CH2:24][NH:25][C:26]([NH2:28])=[NH:27].C(=O)([O-])[O-].[Cs+].[Cs+]>CN1CCCC1=O.CO>[Br:1][C:2]1[S:3][C:4]([C:7]2[C:9]([C:10]#[N:11])=[CH:12][N:28]=[C:26]([NH:25][CH2:24][CH2:23][N:19]3[CH2:20][CH2:21][NH:22][C:18]3=[O:17])[N:27]=2)=[CH:5][CH:6]=1
Reactant: CN(C)C=C(C#N)C(=O)c1ccc(Br)s1
Reactant: N=C(N)NCCN1CCNC1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: CO
Product: N#Cc1cnc(NCCN2CCNC2=O)nc1-c1ccc(Br)s1
Temperature: 100 °C

Procedure:
2-(2-Bromothiophene-5-carbonyl)-3-(dimethylamino)acrylonitrile) (3 g, 10 mmol) in N-methyl pyrrolidone (15 mL) was treated with 1-(2-(2-oxoimidazolidin-1-yl)ethyl)guanidine hydrochloride (1 M solution in N-methyl pyrrolidone, 15 mL, 15 mmol) and cesium carbonate (3.4 g, 10 mmol). The mixture was heated at 100° C. overnight. The reaction was then allowed to cool to room temperature and poured onto crushed ice. The resulting solid that formed was suspended in hot methanol to give a yellow solid (2.3 g). The filtrate was concentrated and purified by flash chromatography using a gradient of 3 to 10% methanol in dichloromethane to obtain an additional 0.9 g of the desired product. Total yield=3.2 g. MS (M+H)+ 394.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH2:14][CH3:15])=[C:9]([N+:16]([O-])=O)[CH:8]=1)=[O:5].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH2:31]([N:38]1[C:42](=[O:43])[C:41](=[C:44]2[N:48]([CH3:49])[C:47]3[CH:50]=[C:51]([O:54][CH2:55][CH2:56][Cl:57])[CH:52]=[CH:53][C:46]=3[S:45]2)[S:40][CH2+:39]1SC)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:31]([N:38]1[C:42](=[O:43])[C:41](=[C:44]2[N:48]([CH3:49])[C:47]3[CH:50]=[C:51]([O:54][CH2:55][CH2:56][Cl:57])[CH:52]=[CH:53][C:46]=3[S:45]2)[S:40][C:39]1=[N:16][C:9]1[CH:8]=[C:7]([NH:6][C:4](=[O:5])[CH2:3][N:2]([CH3:19])[CH3:1])[CH:12]=[CH:11][C:10]=1[NH:13][CH2:14][CH3:15])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CCNc1ccc(NC(=O)CN(C)C)cc1[N+](=O)[O-]
Reactant: CS[CH2+]1SC(=C2Sc3ccc(OCCCl)cc3N2C)C(=O)N1Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CCNc1ccc(NC(=O)CN(C)C)cc1N=C1SC(=C2Sc3ccc(OCCCl)cc3N2C)C(=O)N1Cc1ccccc1

Procedure:
In a manner similar to Example 30, intermediate 2-dimethylamino-4′-ethylamino-3′-nitroacetanilide was hydrogenated and then condensed with 3-benzyl-5-[5-(2-chloroethoxy)-3-methylbenzothiazol-2-ylidene]-2-methylthio-4-oxo-2-thiazolium p-toluenesulfonate to afford the title compound. MS(ESI): 651 (MH+).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[CH2:9]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CCN(C(C)C)C(C)C>CC1C=CC(C)=CC=1>[CH2:9]([N:16]1[CH2:21][CH2:20][N:19]([C:2]2[N:3]=[CH:4][N:5]=[C:6]([Cl:8])[CH:7]=2)[CH2:18][CH2:17]1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: c1ccc(CN2CCNCC2)cc1
Solvent: Cc1ccc(C)cc1
Solvent: CCN(C(C)C)C(C)C
Product: Clc1cc(N2CCN(Cc3ccccc3)CC2)ncn1
Temperature: 138 °C
Reaction time: 18 h

Procedure:
A mixture of 4,6-dichioropyrimidine (29.5 g), N-benzylpiperazine (44.0 g) and DIPEA (44 ml) was suspended in p-xylene (400 ml) and heated at 138° C. under reflux. After 18 hours the reaction mixture was allowed to cool to room temperature and filtered. The filtrate was evaporated using high vacuum pump apparatus to obtain 1-(benzyl)-4-(4-chloropyrimidin-6-yl)piperazine a brown solid, 60.5 g (105% based on 4,6-dichloropyrimidine);