Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[OH:11].Cl[C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[C:16]([C:23]3[NH:31][C:30]4[CH2:29][CH2:28][NH:27][C:26](=[O:32])[C:25]=4[CH:24]=3)[CH:17]=[CH:18][CH:19]=2)[N:14]=1>CN(C=O)C>[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[O:11][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[C:16]([C:23]3[NH:31][C:30]4[CH2:29][CH2:28][NH:27][C:26](=[O:32])[C:25]=4[CH:24]=3)[CH:17]=[CH:18][CH:19]=2)[N:14]=1
Reactant: Oc1ccc(F)cc1F
Reactant: O=C1NCCc2[nH]c(-c3cccc4ccc(Cl)nc34)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1NCCc2[nH]c(-c3cccc4ccc(Oc5ccc(F)cc5F)nc34)cc21
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 36.5 %

Procedure:
To NaH (60 wt % in mineral oil; 0.071 g, 1.763 mmol) in 1 mL DMF was added 2,4-difluorophenol (0.229 g, 1.76 mmol). After 10 min, a clear/colorless solution resulted. 2-(2-Chloroquinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 1; 0.075 g, 0.252 mmol) was added and the reaction became dark red. The reaction was sealed and heated to 90° C. for 4 h, then cooled to RT and stirred overnight. The reaction was cooled and partitioned between saturated aq. NH4Cl and EtOAc. The organic layer was washed with saturated aq. NaHCO3 (1×), water (1×), saturated aq. NaCl (1×), and the organics were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The material was treated with DCM and purified by silica gel chromatography using 0-50% 90/10 DCM/MeOH in DCM. The product-containing fractions were concentrated to afford 2-(2-(2,4-difluorophenoxy)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (0.036 g, 0.092 mmol, 37% yield) as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 10.99 (1H, br. s), 8.52 (1H, d, J=9.0 Hz), 8.09 (1H, dd, J=7.6, 1.4 Hz), 7.79-7.85 (1H, m), 7.55-7.69 (2H, m), 7.51 (1H, t, J=7.7 Hz), 7.47 (1H, d, J=9.0 Hz), 7.30 (1H, dddd, J=9.2, 7.9, 3.1, 1.5 Hz), 6.91-6.94 (1H, m), 6.90 (1H, d, J=2.3 Hz), 3.34-3.40 (2H, m), 2.52-2.57 (2H, m). m/z (ESI, +ve) 392.1 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][N:15]=[CH:14]3)=[O:9])[CH:3]=1.[CH2:20]([NH:23][CH:24]([CH3:26])[CH3:25])[CH2:21][CH3:22]>>[NH:16]1[C:17]2[C:13](=[CH:12][C:11]([NH:10][C:8]([C:4]3[CH:3]=[C:2]([N:23]([CH:24]([CH3:26])[CH3:25])[CH2:20][CH2:21][CH3:22])[N:7]=[CH:6][N:5]=3)=[O:9])=[CH:19][CH:18]=2)[CH:14]=[N:15]1
Reactant: O=C(Nc1ccc2[nH]ncc2c1)c1cc(Cl)ncn1
Reactant: CCCNC(C)C
Product: CCCN(c1cc(C(=O)Nc2ccc3[nH]ncc3c2)ncn1)C(C)C

Procedure:
Following the general method as outlined in Example 20, starting from 6-chloro-pyrimidine-4-carboxylic acid (1H-indazol-5-yl)-amide (Intermediate 16) and propyl-isopropylamine (Matrix), the title compound was obtained as a white solid.
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13](=[O:30])[C:14]1[CH:19]=[C:18]([S:20]([CH:23]2[CH2:25][CH2:24]2)(=[O:22])=[O:21])[N:17]=[C:16]([NH:26][CH:27]2[CH2:29][CH2:28]2)[CH:15]=1)(C)(C)C>ClCCl>[CH:27]1([NH:26][C:16]2[CH:15]=[C:14]([CH:19]=[C:18]([S:20]([CH:23]3[CH2:24][CH2:25]3)(=[O:22])=[O:21])[N:17]=2)[C:13]([OH:30])=[O:12])[CH2:28][CH2:29]1
Reactant: CC(C)(C)OC(=O)c1cc(NC2CC2)nc(S(=O)(=O)C2CC2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1cc(NC2CC2)nc(S(=O)(=O)C2CC2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Add trifluoroacetic acid (2 mL) to a solution of 2-cyclopropylamino-6-cyclopropanesulfonyl-isonicotinic acid tert-butyl ester (0.120 g, 0.355 mmol) in dichloromethane (2 mL) at 0° C. Stir the solution at room temperature for 3 h, concentrate and dry the title compound (0.076 g, 54%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O.C(=O)([O-])[O-].[K+].[K+].Br[CH:19](C(OCC)=O)[C:20]([O:22]CC)=[O:21].Cl>O>[CH3:11][O:10][C:8]1[CH:7]=[CH:6][C:3]2[CH:4]=[C:19]([C:20]([OH:22])=[O:21])[O:1][C:2]=2[CH:9]=1
Reactant: CCOC(=O)C(Br)C(=O)OCC
Reactant: COc1ccc(C=O)c(O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COc1ccc2cc(C(=O)O)oc2c1
Yield: 46.7 %

Procedure:
To a suspension of 2-hydroxy-4-methoxybenzaldehyde (20.0 g) and potassium carbonate (20.0 g) in2-butanone (80 ml) was added diethyl bromomalonate (39.3 g), and the mixture was refluxed under nitrogen atmosphere for 7 hours and cooled. To the mixture was added water, and the mixture was made acidic with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the resulting dark brown oil was suspended in a solution of potassium hydroxide (20.0 g) in ethanol (200 ml). The suspension was refluxed for 1 hour and cooled, and to the mixture was added water. The mixture was made acidic with 1N hydrochloric acid and extracted with ethylacetate(twice). The organic layer was washed with water and saturated brine, and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the resulting solid was washed with hexane to give yellow solid of 6-methoxybenzofuran-2-carboxylic acid (11.8 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.[CH3:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>>[CH3:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([NH:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1)=[O:22]
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Reactant: Cc1ccccc1C(=O)Cl
Product: Cc1ccccc1C(=O)Nc1ccc2[nH]c3c(c2c1)CC(N(C)C)CC3
Yield: 70.7 %

Procedure:
Beginning with 10.4 mg (0.046 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 8.9 μL (0.051 mMol) 2-methylbenzoyl chloride, 11.3 mg (71%) of the title compound were recovered as a beige solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7]1[S:11][N:10]=[C:9]([CH2:12][C:13]([OH:15])=[O:14])[N:8]=1)=[O:5])[CH3:2].[CH3:16]O>>[CH3:16][O:14][C:13](=[O:15])[CH2:12][C:9]1[N:8]=[C:7]([NH:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[S:11][N:10]=1
Reactant: CO
Reactant: CCOC(=O)Nc1nc(CC(=O)O)ns1
Product: CCOC(=O)Nc1nc(CC(=O)OC)ns1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Into a 3 L round bottom flask equipped with mechanical stirrer, thermometer and nitrogen purge was charged 2-(5-ethoxycarbonylamino-1,2,4-thiadiazol-3-yl)acetic acid (185 g, 0.80 mol, 1.0 eq.) followed by methanol (925 mL) and the resulting solution was cooled to 0° C. To the solution was bubbled in HCl gas for 30 minutes and the thinning slurry was allowed to stir overnight at 20° C. Proton NMR analysis shows complete conversion to the title compound. The solvent was removed by rotary evaporation to 400 mL and then cooled to 0° C. and seeded with pure title compound. The thickening reaction mixture was stirred at 0° C. for two hours and the white solid was collected by vacuum filtration. The solid was dried under high vacuum for 12 hours at 20° C. to give 172.2 grams of the title compound as an off white solid. 1H NMR (CD3OD): δ 1.47 (t, 3H); 3.83 (s, 3H); 3.97 (s, 2H); 4.45 (q, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10].[F:17][C:18]1[CH:19]=[C:20]([S:24](Cl)(=[O:26])=[O:25])[CH:21]=[CH:22][CH:23]=1>>[C:9]([C:3]1[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=1[NH:1][S:24]([C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([F:17])[CH:19]=1)(=[O:26])=[O:25])(=[O:10])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Product: O=C(c1ccccc1)c1cc(Cl)ccc1NS(=O)(=O)c1cccc(F)c1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using (2-amino-5-chloro-phenyl)-phenyl-methanone and 3-fluoro-benzenesulfonyl chloride. 1H NMR (CDCl3): δ (ppm): 7.00–7.05 (m, 1H), 7.35 (m, 1H), 7.37 (m, 1H), 7.39–7.44 (m, 4H), 7.37–7.43 (m, 4H), 7.45–7.46 (m, 1H), 7.49–7.50 (m, 1H), 7.51–7.52 (m, 2H), 7.58–7.62 (m, 1H), 9.80 (s, 1H). MS: m/z 390.0 (M++1).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:19]=[CH:18][C:13]([C:14](=[N:16][OH:17])[NH2:15])=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[C:20](Cl)(=O)[CH2:21][CH3:22].C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1>[N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]3[N:15]=[C:20]([CH2:21][CH3:22])[O:17][N:16]=3)=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCC(=O)Cl
Reactant: NC(=NO)c1ccc(OCCCn2ccnc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: CCc1nc(-c2ccc(OCCCn3ccnc3)cc2)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.2 %

Procedure:
There was suspended, in 5 ml of dry pyridine, 521 mg of 4-[3-(1H-imidazol-1-yl)propoxy]benzamidoxime. After gradual and dropwise addition of 194 mg of propionyl chloride and stirring at room temperature for one hour, the suspension was heated to a temperature ranging from 80° to 90° C. for 3.5 hours with stirring. The suspension was added to ice water and the pH thereof was adjusted to 9 to 10 by the addition of potassium carbonate. Then the suspension was extracted with ether and the extract was washed with water and then dried. After concentration of the extract, the resulting residue was purified by silica gel column chromatography (eluent: 98% chloroform-ethanol). n-Hexane was added to the resulting fraction to crystallize the product, followed by filtration to give 431 mg (yield 72.2%) of 3-[4 -[3-(1H-imidazol-1-yl)propoxy]phenyl]-5-ethyl-1,2,4-oxadiazole having a melting point of 74.0°-75.5 ° C.
Reaction SMILES: O.NN.[OH-].[K+].O=[C:7]([C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)[CH2:8][CH2:9][C:10]([OH:12])=[O:11]>C(O)CO.O>[S:14]1[CH:15]=[CH:16][CH:17]=[C:13]1[CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11]
Reactant: O=C(O)CCC(=O)c1cccs1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: O=C(O)CCCc1cccs1
Temperature: 180 °C
Yield: 84.7 %

Procedure:
Hydrazine hydrate (99%) (2.2 MI, 45.9 mmol) and KOH pellets (2.37 g, 42.4 mmol) were added to a solution of 4-oxo-4-(thiophen-2-yl)butanoic acid (2.3 g, 12.48 mmol) in ethylene glycol (30 MI), and the reaction mixture was heated to 180° C. for 10 h. The reaction mixture was cooled to room temperature and diluted with water. The aqueous layer was washed with diethyl ether, acidified with 6N HCl and then extracted with diethyl ether. The organic layer was then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica 60-120 mesh, eluant 2% MeOH in CH2Cl2), to get 4-(thiophen-2-yl)butanoic acid (1.8 g, yield 85%). 1H NMR (300 MHz, DMSO-d6) δ 12.06 (s, 1H), 7.31-7.29 (m, 1H), 6.94-6.91 (m, 1H), 6.84-6.82 (m, 1H), 2.82-2.77 (t, J=7.7 Hz, 2H), 2.27-2.22 (t, J=7.3 Hz, 2H), 1.86-1.76 (m, 2H). MS (ESI) m/z: Calculated for C8H10O2S: 170.04. found: 170.8 (M+H)+
Reaction SMILES: O=[C:2]1[C:10]2[CH:9]=[CH:8][O:7][C:6]=2[CH2:5][CH2:4][CH2:3]1.[CH2:11]1[CH2:15]O[CH2:13][CH2:12]1.C([Mg]Br)CCC.[NH4+].[Cl-]>CCOC(C)=O>[CH:15](=[C:2]1[C:10]2[CH:9]=[CH:8][O:7][C:6]=2[CH2:5][CH2:4][CH2:3]1)[CH2:11][CH2:12][CH3:13]
Reactant: O=C1CCCc2occc21
Reactant: C1CCOC1
Agent: CCCC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: CCCC=C1CCCc2occc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-oxo-4,5,6,7-tetrahydrobenzo[b]furan (20.06 g) and THF (200 ml) was added dropwise 2M n-butylmagnesium bromide with ice-water cooling over 15 minutes. The mixture was stirred at r.t. overnight. The reaction mixture was poured into a mixture of a saturated aqueous solution of NH4Cl and AcOEt. The separated organic layer was washed with water and brine, and dried over MgSO4, and evaporated. The resulting oil was purified by chromatography on SiO2 (CHCl3 as eluent) to give 4-n-butylidene-4,5,6,7-tetrahydrobenzo[b]furan as a yellow oil (12.06 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])=[CH:6][N:5]=[C:4](S(C)=O)[N:3]=1.FC(F)(F)C(O)=O.[CH3:26][S:27]([N:30]1[CH2:35][CH2:34][CH:33]([NH2:36])[CH2:32][CH2:31]1)(=[O:29])=[O:28].C(N(CC)CC)C>C(O)C>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:9])=[CH:6][N:5]=[C:4]([NH:36][CH:33]2[CH2:34][CH2:35][N:30]([S:27]([CH3:26])(=[O:29])=[O:28])[CH2:31][CH2:32]2)[N:3]=1
Reactant: CS(=O)c1ncc(C(=O)c2ccccc2)c(N)n1
Reactant: CS(=O)(=O)N1CCC(N)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCC(Nc2ncc(C(=O)c3ccccc3)c(N)n2)CC1

Procedure:
Treatment of the material prepared in Example 282 with material prepared in Example 162 in ethanol containing triethylamine at reflux for one hour, gave, after chilling and filtering, [4-amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl]-phenyl-methanone, as a colorless solid, MP 249-250° C. MS(ES) MH+376
Reaction SMILES: C[O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:16](=[O:17])[C:15]([Cl:18])=[C:14]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=3)[N:13]=[C:12]2[CH3:28])[CH:5]=1.[OH-].[Na+]>O1CCCC1>[Cl:18][C:15]1[C:16](=[O:17])[N:11]([C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=2[CH3:10])[C:3]([OH:29])=[O:2])[C:12]([CH3:28])=[N:13][C:14]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=1
Reactant: COC(=O)c1ccc(C)c(-n2c(C)nc(OCc3cccc(C)c3)c(Cl)c2=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cccc(COc2nc(C)n(-c3cc(C(=O)O)ccc3C)c(=O)c2Cl)c1
Temperature: 25 °C
Yield: 107.5 %

Procedure:
To a solution of 3-[5-chloro-2-methyl-4-(3-methyl-benzyloxy)-6-oxo-6H-pyrimidin-1-yl]-4-methyl-benzoic acid methyl ester from Step B (230 mg, 0.56 mmol) in tetrahydrofuran (1 mL) was added 1N sodium hydroxide (1 mL) and the solution was stirred at ambient temperature for eighteen hours. The solution was concentrated in vacuo and the aqueous residue was acidified to pH=2 using 1M HCl. The solution was extracted with ethyl acetate, washed with water and dried over magnesium sulfate. The slurry was filtered and concentrated to an orange oil (240 mg, quantitative yield). MS (M+H): 399
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH2:28][CH3:29])=[C:11]([C:13]3[C:14](=[O:27])/[C:15](=[CH:20]/[CH:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)/[CH2:16][C:17]=3[O:18]C)[N:12]=2)=[CH:4][CH:3]=1.Cl>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH2:28][CH3:29])=[C:11]([CH:13]3[C:14](=[O:27])/[C:15](=[CH:20]/[CH:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)/[CH2:16][C:17]3=[O:18])[N:12]=2)=[CH:4][CH:3]=1
Reactant: CCc1sc(-c2ccc(Cl)cc2)nc1C1=C(OC)C/C(=C\C2CCOCC2)C1=O
Agent: Cl
Solvent: C1COCCO1
Product: CCc1sc(-c2ccc(Cl)cc2)nc1C1C(=O)C/C(=C\C2CCOCC2)C1=O
Temperature: 60 °C
Yield: 5.1 %

Procedure:
To a stirred solution of 2-[2-(4-Chloro-phenyl)-5-ethyl-thiazol-4-yl]-3-methoxy-5-[1-(tetrahydro-pyran-4-yl)-meth-(E)-ylidene]-cyclopent-2-enone (85 mg, 0.19 mmol) in 1,4-dioxane (3 ml) was added 12M hydrochloric acid (32 μl, 0.38 mmol) and the reaction heated to 60° C. for 12 hours. The solvent was removed under reduced pressure and the residue purified by mass-directed preparative HPLC to give 2-[2-(4-Chloro-phenyl)-5-ethyl-thiazol-4-yl]-4-[1-(tetrahydro-pyran-4-yl)-meth-(E)-ylidene]-cyclopentane-1,3-dione (4 mg).
Reaction SMILES: O[C:2]1([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[CH:16][CH:15]=2)[CH2:6][CH2:5][CH2:4][CH:3]1[NH:7][S:8]([CH:11]([CH3:13])[CH3:12])(=[O:10])=[O:9].CCN(S(F)(F)[F:34])CC>C(Cl)Cl>[F:34][C:2]1([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[CH:16][CH:15]=2)[CH2:6][CH2:5][CH2:4][CH:3]1[NH:7][S:8]([CH:11]([CH3:13])[CH3:12])(=[O:10])=[O:9]
Reactant: CC(C)S(=O)(=O)NC1CCCC1(O)c1ccc(OCCNS(C)(=O)=O)cc1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CC(C)S(=O)(=O)NC1CCCC1(F)c1ccc(OCCNS(C)(=O)=O)cc1
Temperature: -78 °C

Procedure:
Into a 50 mL 3 neck flask fitted with a stirrer and thermometer, [2-hydroxy-2-(4-{2-[(methylsulfonyl)amino]ethoxy}phenyl)cyclopentyl][(methylethyl)sulfonyl]amine (150 mg, 0.36 mmol) in CH2Cl2 (5 mL) is added dropwise to 0.01 mL DAST in CH2CL2 (15 mL) while stirring at −78° C. under a nitrogen atmosphere. The reaction is allowed to warm to room temperature and diluted with CH2Cl2 (20 mL). This organic layer is washed with H2O, dried over Na2SO4, filtered, and concentrated under reduced vacuum to yield the product. This material is purified via silica gel chromatography employing the Chromatotron® and using 2000 micron rotor while eluting with a suitable eluent, such as hexanes/ethyl acetate to provide the final title compound.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][C:8]([C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([F:20])[CH:18]=4)[NH:13][CH:12]=3)=[CH:7][CH2:6]2)OCC1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][N:32](C2CCC(=O)CC2)[CH2:31][CH2:30]1>>[F:20][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[C:8]1[CH2:9][CH2:10][CH:5]([N:32]2[CH2:31][CH2:30][N:29]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[O:22][CH3:21])[CH2:34][CH2:33]2)[CH2:6][CH:7]=1
Reactant: Fc1ccc2[nH]cc(C3=CCC4(CC3)OCCO4)c2c1
Reactant: COc1ccccc1N1CCN(C2CCC(=O)CC2)CC1
Product: COc1ccccc1N1CCN(C2CC=C(c3c[nH]c4ccc(F)cc34)CC2)CC1

Procedure:
This compound was prepared in the manner described above for intermediate 1c by replacing 1,4-cyclohexanedione monoethylene ketal with 4-[4-(2-methoxy-phenyl)-piperazin-1-yl]-cyclohexanone (1.44 g, 5 mmol). The crude mixture was used in next step without further purification.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C@H:11]1[CH2:14][C@H:13]([NH:15][C:16]2[C:21](I)=[CH:20][N:19]=[CH:18][N:17]=2)[CH2:12]1.C([O-])(=O)C.[Cs+].[NH3:28]>CS(C)=O.[Cu]>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C@H:11]1[CH2:14][C@H:13]([NH:15][C:16]2[C:21]([NH2:28])=[CH:20][N:19]=[CH:18][N:17]=2)[CH2:12]1
Reactant: Ic1cncnc1N[C@H]1C[C@H](Nc2nc3ccccc3s2)C1
Reactant: N
Agent: [Cu]
Agent: CC(=O)[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: Nc1cncnc1N[C@H]1C[C@H](Nc2nc3ccccc3s2)C1
Temperature: 80 °C
Reaction time: 14 h

Procedure:
Trans-N1-(benzo[d]thiazol-2-yl)-N3-(5-iodopyrimidin-4-yl)cyclobutane-1,3-diamine (synthesized analogous to intermediate 33 using 5-iodo-4-chloropyrimidine in place of 3-bromo-2-chloropyridine, 0.130 g, 0.307 mmol), copper (0.010 g, 0.157 mmol), and cesium acetate (0.250 g, 1.302 mmol) were suspended in dry dimethylsulfoxide (2 mL) in a microwave vessel. Ammonia (2.0 M solution in methanol, 1.0 ml, 2.000 mmol) was added and the mixture sealed under argon. It was heated at 80° C. in an oil bath for 4½ hours then cooled to 60° C. and stirred for another 14 hours. The reaction mixture was partitioned between ethyl acetate (200 mL), water (200 mL), and ammonium hydroxide (30 mL). The organic was dried with magnesium sulfate and evaporated to dryness under reduced pressure. Purification using silica chromatography (0-10% (2 N ammonia in methanol) in dichloromethane gradient) gave the desired N4-(trans-3-(benzo[d]thiazol-2-ylamino)cyclobutyl)pyrimidine-4,5-diamine (0.033 g, 0.106 mmol, 34.4% yield).
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:12]=[C:13]([C:23]([OH:25])=O)[C:14]3[CH:15]=[N:16][N:17]([CH:20]([CH3:22])[CH3:21])[C:18]=3[CH:19]=2)[CH2:7][CH2:6]1)[CH3:3].[NH2:26][CH2:27][C:28]1[C:29](=[O:38])[NH:30][C:31]([CH3:37])=[CH:32][C:33]=1[CH2:34][CH2:35][CH3:36]>>[CH3:1][N:2]([CH2:4][CH:5]1[CH2:6][CH2:7][N:8]([C:11]2[CH:12]=[C:13]([C:23]([NH:26][CH2:27][C:28]3[C:29](=[O:38])[NH:30][C:31]([CH3:37])=[CH:32][C:33]=3[CH2:34][CH2:35][CH3:36])=[O:25])[C:14]3[CH:15]=[N:16][N:17]([CH:20]([CH3:22])[CH3:21])[C:18]=3[CH:19]=2)[CH2:9][CH2:10]1)[CH3:3]
Reactant: CC(C)n1ncc2c(C(=O)O)cc(N3CCC(CN(C)C)CC3)cc21
Reactant: CCCc1cc(C)[nH]c(=O)c1CN
Product: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(N2CCC(CN(C)C)CC2)cc2c1cnn2C(C)C

Procedure:
The title compound was prepared using the procedure described for example 37 (step c) from 6-(4-((dimethylamino)methyl)piperidin-1-yl)-1-isopropyl-1H-indazole-4-carboxylic acid and 3-(aminomethyl)-6-methyl-4-propyl-2(1H)-pyridinone. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.89 (t, J=7.33 Hz, 3H), 1.14-1.32 (m, 2H), 1.42 (m, 6H), 1.45-1.55 (m, 2H), 1.57-1.68 (m, 1H), 1.72-1.89 (m, 3H), 2.03-2.21 (m, 12H), 2.63-2.79 (m, 2H), 3.54-3.66 (m, 1H), 3.81 (m, 2H), 4.37 (d, J=4.80 Hz, 2H), 4.94 (quin, J=6.63 Hz, 1H), 5.91 (s, 1H), 7.05 (s, 1H), 7.32 (d, J=1.77 Hz, 1H), 8.14 (s, 1H), 8.44 (t, J=5.05 Hz, 2H), 11.24-11.80 (m, 1H); LCMS: (M+H)+=507.1
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([F:10])[C:3]=1[N:11](C(OC(C)(C)C)=O)[NH:12]C(OC(C)(C)C)=O.O1CCOCC1.C(OCC)C.[ClH:38]>>[ClH:38].[F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([F:10])[C:3]=1[NH:11][NH2:12]
Reactant: COc1cc(F)c(N(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(F)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: COc1cc(F)c(NN)c(F)c1
Reaction time: 0.5 h

Procedure:
Di-tert-butyl 1-(2,6-difluoro-4-methoxyphenyl)hydrazine-1,2-dicarboxylate (616 mg, 1.64 mmol) was heated in 4 M HCl in dioxane (5 mL, 20 mmol) at reflux. The solution over time became a suspension. At 30 min, the reaction was cooled, diethylether was added, and the solid was collected with a medium frit, washing with diethylether. This gave (2,6-difluoro-4-methoxy-phenyl)-hydrazine hydrochloride (0.246 g, 86%) as a tan solid. 1H NMR (400 MHz, DMSO-d6, δ): 9.75 (br. s., 3H) 7.46 (s, 1H) 6.79-6.90 (m, 2H) 3.78 (s, 3H).
Reaction SMILES: [C:1](C1C2C(=CC=CC=2)C=CC=1C)#[CH:2].BrC1C2C(=CC=CC=2)C=CC=1C.Br[C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][C:28]=1[C:37]([O:39][CH2:40][CH3:41])=[O:38]>>[C:1]([C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][C:28]=1[C:37]([O:39][CH2:40][CH3:41])=[O:38])#[CH:2]
Reactant: C#Cc1c(C)ccc2ccccc12
Reactant: CCOC(=O)c1ccc2ccccc2c1Br
Agent: Cc1ccc2ccccc2c1Br
Product: C#Cc1c(C(=O)OCC)ccc2ccccc12

Procedure:
Ethyl 1-ethynyl-2-naphthoate was prepared in a similar manner to 1-ethynyl-2-methylnaphthalene, except that 1-bromo-2-methylnaphthalene was replaced by ethyl 1-bromo-2-naphthoate.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1Cl)=[CH:12][CH:11]=[CH:10][C:9]=2[O:16][CH2:17][CH2:18][S:19][CH3:20])(=[O:4])[CH2:2][CH3:3].[NH2:21][C:22]1[C:23]([CH3:28])=[CH:24][CH:25]=[CH:26][CH:27]=1>C(#N)C>[C:1]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1[NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH3:28])=[CH:12][CH:11]=[CH:10][C:9]=2[O:16][CH2:17][CH2:18][S:19][CH3:20])(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)c1cnc2c(OCCSC)cccc2c1Cl
Reactant: Cc1ccccc1N
Solvent: CC#N
Product: CCC(=O)c1cnc2c(OCCSC)cccc2c1Nc1ccccc1C
Temperature: 55 °C
Reaction time: 3.5 h
Yield: 62.2 %

Procedure:
A mixture of 3-propanoyl-4-chloro-8-(2-methylthioethoxy)quinoline (0.60 g, 1.9 mmol) and o-toluidine (0.25 g, 2.3 mmol) in acetonitrile was heated to 55° C. and stirred for 3.5 h. The solvent was evaporated and the residue was partitioned between methylene chloride and a 10% sodium carbonate solution. The organic layer was dried over sodium sulfate and evaporated. Chromatography (SiO2 ; CH2Cl2 :EtOAc 60:40) gave 0.45 g (61%) of the title compound.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][C:17]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:18])[CH:10]=2)=[CH:5][CH:4]=1)=O.[S:26]1[CH2:30][C:29](=[O:31])[NH:28][C:27]1=[O:32]>>[O:32]=[C:27]1[NH:28][C:29](=[O:31])[C:30](=[CH:1][C:3]2[CH:4]=[CH:5][C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][C:17]([NH:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:18])[CH:10]=3)=[CH:7][CH:8]=2)[S:26]1
Reactant: O=C1CSC(=O)N1
Reactant: O=Cc1ccc(-c2cccc(CNC(=O)Nc3ccccc3)c2)cc1
Product: O=C(NCc1cccc(-c2ccc(C=C3SC(=O)NC3=O)cc2)c1)Nc1ccccc1
Yield: 50.9 %

Procedure:
In a manner similar to that of Example 1(f), by reacting 2.1 g (6.4 mmol) of 1-(4′-formylbiphenyl-3-ylmethyl)-3-phenylurea with 750 mg (6.4 mmol) of 2,4-thiazolidine dione, 1.4 g (53%) of the expected product are obtained.