Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:3]2([CH2:7][CH:6](CS([O-])(=O)=O)[CH2:5][O:4]2)[CH2:2]1.[OH:13][C:14]1[CH:23]=[C:22]2[C:17]([C:18]([O:24][C:25]3[CH:30]=[CH:29][C:28]([N:31]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[C:32]([C:34]4([C:37]([NH2:39])=[O:38])[CH2:36][CH2:35]4)=[O:33])=[CH:27][C:26]=3[F:46])=[CH:19][CH:20]=[N:21]2)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C>[CH2:2]1[C:3]2([CH2:7][CH:6]([O:13][C:14]3[CH:23]=[C:22]4[C:17]([C:18]([O:24][C:25]5[CH:30]=[CH:29][C:28]([N:31]([C:40]6[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=6)[C:32]([C:34]6([C:37]([NH2:39])=[O:38])[CH2:36][CH2:35]6)=[O:33])=[CH:27][C:26]=5[F:46])=[CH:19][CH:20]=[N:21]4)=[CH:16][CH:15]=3)[CH2:5][O:4]2)[CH2:1]1
Reactant: O=S(=O)([O-])CC1COC2(CC2)C1
Reactant: NC(=O)C1(C(=O)N(c2ccccc2)c2ccc(Oc3ccnc4cc(O)ccc34)c(F)c2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: NC(=O)C1(C(=O)N(c2ccccc2)c2ccc(Oc3ccnc4cc(OC5COC6(CC6)C5)ccc34)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 36 h
Yield: 20.1 %

Procedure:
To a mixture of (4-oxaspiro[2.4]heptane-6-yl)methanesulfonate (168 mg, 0.877 mmol, from example 6) and N-(4-(7-hydroxyquinolin-4-yloxy)-3-fluorophenyl)-N-phenylcyclopropane-1,1-dicarboxamide (300 mg, 0.584 mmol) in 5 mL of N,N-dimethylacetamide was added cesium carbonate (893 mg, 2.74 mmol). After stirring at room temperature for 36 hrs, the reaction mixture was warmed up to 40° C. and continued to stir for 8 hrs. The reaction mixture was concentrated in vacuo and the residue was chromatographed with a silica gel column (1:1 (v/v) EtOAc/n-hexane) to afford the title compound as a white solid (65 mg, 18%).
Reaction SMILES: [C:1]([C:4](=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=1)[C:5]([CH3:7])=[O:6])(=O)[CH3:2].Cl.[C:19]([NH2:27])(=[NH:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C.C(OCC)(=O)C>C(O)CCC>[C:5]([C:4]1[CH:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[NH:27][C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:26][C:1]=1[CH3:2])(=[O:6])[CH3:7]
Reactant: N=C(N)c1ccccc1
Reactant: CC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(C)=O
Agent: Cl
Solvent: CCCCO
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(=O)C1=C(C)N=C(c2ccccc2)NC1c1cccc([N+](=O)[O-])c1
Reaction time: 1 h
Yield: 31 %

Procedure:
A mixture of 1-acetyl-1-(3-nitrobenzyliden)acetone (10 g), benzamidine hydrochloride (8.06 g) and triethylamine (8.4 ml) in n-butanol (100 ml) was refluxed for 2 hours. The reaction mixture was added ethyl acetate (100 ml), washed with water (100 ml) and 5% hydrochloric acid (100 ml) successively. The solvent was evaporated and the residue was stirred with ethyl acetate (100 ml) for 1 hour. The crystals were collected by filtration, added a mixture of chloroform (100 ml) and water (100 ml) and adjusted to pH 8.5 by saturated potassium carbonate. The organic layer was evaporated in vacuo to give 5-acetyl-4-methyl-6-(3-nitrophenyl)-2-phenyl-1,6-dihydropyrimidine (4.46 g).
Reaction SMILES: FS([O-])(=O)=[O:3].Cl[C:7]1[C:11]([Cl:12])=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[S:9][N+:8]=1[CH3:18]>C([O-])([O-])=O.[K+].[K+]>[Cl:12][C:11]1[C:7](=[O:3])[N:8]([CH3:18])[S:9][C:10]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: O=S(=O)([O-])F
Reactant: CCOC(=O)c1s[n+](C)c(Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)c1sn(C)c(=O)c1Cl
Yield: 37.6 %

Procedure:
3,4-Dichloro-5-ethoxycarbonyl-2-methylisothiazolium fluorosulfonate (4.2 g, 0.012 mol) was added to 50 ml of saturated K2CO3 solution. The aqueous phase was extracted wih 3×50 ml of CH2Cl2. The combined extracts were dried (MgSO4), filtered and conc. to yield a solid. Recrystallization from heptane yielded 1.0 g (35%) of 4-chloro-5-ethoxycarbonyl-2-methyl-4-isothiazolin-3-one, mp 142-147. Analysis: Calculated for C7H8ClNO3S; C, 37.92; H, 3.65; Cl, 16.01; N, 6.31; S, 14.47. Found: C, 38.39; H, 3.81; Cl, 15.49; N, 6.31; S, 14.56.
Reaction SMILES: [Cl:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]2[NH:6][C:7](=[O:15])[C:8]3[CH2:14][S:13][CH2:12][C:9]=3[N:10]([CH3:11])[C:4]=2[CH:3]=1.N1C=CC=CC=1.ClN1C(=O)CCC1=O>O>[Cl:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]2[NH:6][C:7](=[O:15])[C:8]3[C:9](=[CH:12][S:13][CH:14]=3)[N:10]([CH3:11])[C:4]=2[CH:3]=1
Reactant: CN1C2=C(CSC2)C(=O)Nc2cc(Cl)c(Cl)cc21
Agent: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: c1ccncc1
Product: CN1c2cc(Cl)c(Cl)cc2NC(=O)c2cscc21

Procedure:
To a suspension of 0.40 g. of 6,7-dichloro-1,3,4,9-tetrahydro-4-methyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one in 2.7 ml. of dry pyridine is added, in portions. a total of 0.18 g. of N-chlorosuccinimide. The resulting solution is heated on a steam bath for 15 minutes, cooled and diluted with water. The solid which separates is collected and recrystallized from methanol-water to give off-white crystals, m.p. 270°-272° C. (dec.).
Reaction SMILES: [CH:1](Br)([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[O:11]=[CH:12][C:13]1[CH:21]=[CH:20][C:18]([OH:19])=[C:15]([O:16][CH3:17])[CH:14]=1>CN(C=O)C.C(OCC)C>[CH:1]([O:19][C:18]1[CH:20]=[CH:21][C:13]([CH:12]=[O:11])=[CH:14][C:15]=1[O:16][CH3:17])([CH3:3])[CH3:2]
Reactant: CC(C)Br
Reactant: COc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COc1cc(C=O)ccc1OC(C)C
Temperature: 80 °C

Procedure:
Isopropyl bromide (40.0 mL, 421 mmol) was added to a suspension of K2CO3 (48.0 g, 348 mmol) and vanillin (40 g, 263 mmol) in DMF (150 mL) and the stirring slurry heated to 80° C. for 15 h. The reaction mixture was then cooled to room temperature, diluted with diethyl ether (200 mL) and washed with H2O (4×200 mL), dried (MgSO4) and concentrated under reduced pressure giving the title compound as a slightly tan oil (51.0 g, 100%) which required no further purification. The spectra of this material are identical with that previously reported (M. F. Comber and M. V. Sargent, J. Chem. Soc., Perkin Trans. 1, 1991, 2783).
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=O)[C:10]([OH:12])=[O:11])[N:8]=1)=[O:2].[OH-].[Na+].Cl.[F:17][C:18]([F:23])([F:22])[CH2:19][O:20][NH2:21]>CO.O>[F:17][C:18]([F:23])([F:22])[CH2:19][O:20][N:21]=[C:9]([C:7]1[N:8]=[C:4]([NH:3][CH:1]=[O:2])[S:5][CH:6]=1)[C:10]([OH:12])=[O:11]
Reactant: O=CNc1nc(C(=O)C(=O)O)cs1
Reactant: NOCC(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=CNc1nc(C(=NOCC(F)(F)F)C(=O)O)cs1
Yield: 54.6 %

Procedure:
A suspension of 2-(2-formylaminothiazol-4-yl)-glyoxylic acid (3.0 g) in methanol (60 ml) and water (60 ml) was adjusted to pH 8 with 1 N aqueous solution of sodium hydroxide under stirring. To the solution was added 2,2,2-trifluoroethoxyamine hydrochloride (2.24 g) and then adjusted to pH 2.5 to 3 with 1 N aqueous solution of sodium hydroxide. After the solution was stirred at ambient temperature for 1.5 hours, methanol was removed from the resultant solution under reduced pressure. The remaining aqueous solution was adjusted to pH 7 with 1 N aqueous solution of sodium hydroxide and then washed with ethyl acetate. To the aqueous solution was added ethyl acetate and then adjusted to pH 1.5 with 10% hydrochloric acid, and then extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and then evaporated under reduced pressure to give 2-(2,2,2-trifluoroethoxyimino)-2-(2-formylaminothiazol-4-yl)acetic acid (syn isomer) (2.4 g), mp 162° to 163° C. (dec.).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:10][C:11]([N:13]2[CH2:18][CH2:17][CH2:16][C@@H:15]([C:19]3[N:23]([CH2:24][CH2:25][CH2:26][O:27][CH3:28])[C:22]4[CH:29]=[CH:30][CH:31]=[CH:32][C:21]=4[N:20]=3)[CH2:14]2)=[O:12])=[CH:4][CH:3]=1.[CH:41]1([NH2:47])[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1.N12CCCN=C1CCCCC2.N1C=CN=C1.C1C[O:67][CH2:66]C1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:41]1([NH:47][C:66]([C:2]2[CH:3]=[CH:4][C:5]([CH2:8][C@@H:9]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:10][C:11]([N:13]3[CH2:18][CH2:17][CH2:16][C@@H:15]([C:19]4[N:23]([CH2:24][CH2:25][CH2:26][O:27][CH3:28])[C:22]5[CH:29]=[CH:30][CH:31]=[CH:32][C:21]=5[N:20]=4)[CH2:14]3)=[O:12])=[CH:6][CH:7]=2)=[O:67])[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1
Reactant: NC1CCCCC1
Reactant: COCCCn1c([C@@H]2CCCN(C(=O)C[C@@H](Cc3ccc(Br)cc3)NC(=O)OC(C)(C)C)C2)nc2ccccc21
Reactant: C1CCOC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1c[nH]cn1
Solvent: C1CCC2=NCCCN2CC1
Product: COCCCn1c([C@@H]2CCCN(C(=O)C[C@@H](Cc3ccc(C(=O)NC4CCCCC4)cc3)NC(=O)OC(C)(C)C)C2)nc2ccccc21
Temperature: 150 °C
Yield: 39 %

Procedure:
tert-Butyl (R)-1-(4-bromophenyl)-4-((R)-3-(1-(3-methoxypropyl)-11−1-benzo[d]imidazol-2-yl)piperidin-1-yl)-4-oxobutan-2-ylcarbamate (6A) (as prepared in Example 6, Step A) (0.098 mmol, 0.060 g) was added to a 5 mL microwave vessel equipped for stirring. Cyclohexanamine (0.293 moles, 0.034 mL), palladium(II) acetate (0.01 mmol, 0.002 g), Mo(CO)6 (0.098 mmol, 0.026 g), 1,8 diazabicyclo[5.4.0]undec-7-ene (0.293 mmol, 0.044 mL), imidazole (0.049 mmol, 0.003 g), and THF (2 mL) were then added. The flask was sealed and heated to 150° C. for 15 min in the microwave. The reaction mixture was filtered over celite and the solid rinsed with THF (20 mL). The filtrate was collected and concentrated in-vacuo. This crude oil was re-dissolved in methanol (3 mL), filtered, and then purified by preparative LC/MS (20-80% CH3CN in H2O). The resultant fractions were collected and the solvent was removed in-vacuo affording tert-butyl (R)-1-(4-(cyclohexylcarbamoyl)phenyl)-4-((R)-3-(1-(3-methoxypropyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-4-oxobutan-2-ylcarbamate (98A) as a clear colored oil (0.039 mmol, 0.025 g, 39% yield). ESI-MS: 660.4 m/z (M+H)+.
Reaction SMILES: [C:1]([NH:4][C@@H:5]([C:13]([OH:15])=[O:14])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:3])[CH3:2].[CH3:16][O:17][C:18](=[O:28])[CH:19]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[NH2:20]>CO>[C:1]([NH:4][C@@H:5]([C:13]([OH:15])=[O:14])[CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)(=[O:3])[CH3:2].[CH3:16][O:17][C:18](=[O:28])[C@H:19]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[NH2:20]
Reactant: COC(=O)C(N)Cc1ccccc1
Agent: CC(=O)N[C@H](Cc1ccccc1)C(=O)O
Solvent: CO
Product: COC(=O)[C@@H](N)Cc1ccccc1

Procedure:
10.35 Parts of N-acetyl-D-phenylalanine is dissolved in 40 parts of methanol, then treated with 17.9 parts of DL-phenylalanine methyl ester. A precipitate forms immediately and a additional 60 parts of methanol is added. The mixture then is filtered and the solid remaining is washed with additional methanol and dried. Recrystallization from methanol affords the crystalline salt of N-acetyl-D-phenylalanine and L-phenylalanine methyl ester, melting at about 170°-172° and displaying an [α]D in 0.5% water of about -33.3°.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]3[O:26][CH2:27][O:28][C:22]=3[CH:21]=2)[C:11]2[CH:16]=[C:15]([Cl:17])[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]4[O:26][CH2:27][O:28][C:22]=4[CH:21]=3)[C:11]3[CH:16]=[C:15]([Cl:17])[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1ncc[nH]1
Reactant: Clc1nc(NCc2ccc3c(c2)OCO3)c2cc(Cl)sc2n1
Product: Cc1nccn1-c1nc(NCc2ccc3c(c2)OCO3)c2cc(Cl)sc2n1

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2,6-dichloro-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-6-chloro-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH2:1]([P:8]([NH:17][C@H:18]([C:20]([N:22]1[CH2:29][CH2:28][CH2:27][C@H:23]1[C:24](O)=[O:25])=[O:21])[CH3:19])([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.Cl.[CH3:41][O:42][C:43](=[O:48])[C@H:44]([CH2:46][OH:47])[NH2:45].CCN=C=NCCCN(C)C>CN(C=O)C.C(OCC)(=O)C>[CH3:41][O:42][C:43](=[O:48])[C@H:44]([CH2:46][OH:47])[NH:45][C:24](=[O:25])[C@@H:23]1[CH2:27][CH2:28][CH2:29][N:22]1[C:20](=[O:21])[C@H:18]([CH3:19])[NH:17][P:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:9]
Reactant: C[C@H](NP(=O)(Cc1ccccc1)Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Reactant: COC(=O)[C@@H](N)CO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CO)NC(=O)[C@@H]1CCCN1C(=O)[C@H](C)NP(=O)(Cc1ccccc1)Cc1ccccc1
Temperature: -15 °C
Reaction time: 3 h
Yield: 87.1 %

Procedure:
Dibenzylphosphoryl-L-alanyl-L-proline (1.2 g, 2.5 m mole) as shown in the Japanese patent first publication No. 104863/1981, HOBt (338 mg, 2.5 m mole) and L-serine methylester hydrochloride (467 mg, 3 m mole) were suspended in DMF (10 ml), and WSC (0.5 ml) was added dropwise thereto while cooling to -15° C. and stirring. The reaction was carried out for 3 hours under cooling and next overnight at a room temperature. Ethyl acetate (100 ml) was added to the reaction solution, washed 1N hydrochloric acid and water in order, and dried with anhydrous sodium sulfate. The thus obtained solution was distilled under reduced pressure to give an oily dibenzylphosphoryl-L-alanyl-L-prolyl-L-serine methyl ester (1.3 g). The oily product gave a single spot with Rf 0.46 by thin layer chromatography (developing solvent; chloroform:methanol:acetic acid=95:5:3, colour forming method: spraying of 25% hydrobromic acid and 0.1% ninhydrine and heating). The oily material was dissolved in a mixture (20 ml) of acetone and methanol (1:1) and 1N sodium hydroxide (5 ml) was added thereto under cooling with ice. The mixture was stirred for 1.5 hours at room temperature and neutralized with 1N hydrochloric acid. The solution was distilled under reduced pressure to eliminate the organic solvent, and the residue was dissolved in ethyl acetate, washed with 1N hydrochloric acid and water in order, and dried with anhydrous sodium sulfate. The thus obtained solution was distilled under reduced pressure to give oily dibenzylphosphoryl-L-alanyl-L-prolyl-L-serine (1.2 g). The oily material gave a single spot with Rf 0.18 by thin layer chromatography (developing solvent: chloroform:methanol:acetic acid=95:5:3, colour forming method; spraying of 25% hydrobromic acid and 0.1% ninhydrine, and heating).
Reaction SMILES: C(O[C:4]1[C:5](=[O:19])[C:6](=[O:18])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=1[OH:17])C.[C:20]([NH2:24])([CH3:23])([CH3:22])[CH3:21].ClCl.C(O)C>CCCCCC.C(OCC)(=O)C>[C:20]([NH:24][C:4]1[C:5](=[O:19])[C:6](=[O:18])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=1[OH:17])([CH3:23])([CH3:22])[CH3:21]
Reactant: CCOc1c(Nc2ccc(C#N)cc2O)c(=O)c1=O
Reactant: CC(C)(C)N
Agent: ClCl
Solvent: CCCCCC
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)Nc1c(Nc2ccc(C#N)cc2O)c(=O)c1=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 3-ethoxy-4-(2-hydroxy-4-cyanophenyl)amino-3-cyclobutene-1,2-dione (0.395 g, 0.0015 mol) and tert-butylamine (4 ml, 0.038 mol) in enough CH2 Cl2 to form a solution (a small amount of dry ethanol was required) was stirred at room temperature for two days. During this time, a precipitate forms. TLC (2:1 ethyl acetate:hexane) indicates a loss of starting material. The reaction is evaporated to a solid on a rotary evaporator. The solid is taken up in ethyl acetate and extracted well with 0.25N HCl. The organic layer is washed once with distilled water, dried (Na2SO4), and evaporated to a solid. The solid is collected and washed with diethyl ether to give 3-(tert-butylamino)-4-(2-hydroxy-4-cyanophenyl)amino-3-cyclobutene-1,2-dione, 0.270 g (0.00095 mol, 62%).
Reaction SMILES: [CH:1]1([CH2:4][C:5](=O)/[C:6](/[C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[N:12]=2)=[CH:7]\N(C)C)[CH2:3][CH2:2]1.[OH:25][C@@H:26]([CH3:32])[CH2:27][NH:28][C:29]([NH2:31])=[NH:30].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:1]1([CH2:4][C:5]2[C:6]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)[N:12]=3)=[CH:7][N:31]=[C:29]([NH:28][CH2:27][C@@H:26]([OH:25])[CH3:32])[N:30]=2)[CH2:3][CH2:2]1
Reactant: C[C@H](O)CNC(=N)N
Reactant: CN(C)/C=C(\C(=O)CC1CC1)c1ccnc(Nc2ccncc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@H](O)CNc1ncc(-c2ccnc(Nc3ccncc3)n2)c(CC2CC2)n1
Temperature: 90 °C
Reaction time: 3 h
Yield: 45.5 %

Procedure:
To a solution of (Z)-1-cyclopropyl-4-(dimethylamino)-3-(2-(pyridin-4-ylamino)pyrimidin-4-yl)but-3-en-2-one (9) (50 mg, 0.155 mmol) in DMF (1288 μl), (S)-1-(2-hydroxypropyl)guanidine (18.11 mg, 0.115 mmol), and potassium carbonate (64.1 mg, 0.464 mmol) were added, and the reaction mixture was stirred at 90° C. for 3 hours. The crude product was purified by reverse-phase HPLC [30-90% organic phase over 15 minutes] followed by Biotage™ silica gel chromatography [10 g SNAP column, 100% DCM to 12% MeOH/DCM] to obtain the desired product (19.76 mg, 33%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH2:9])=[O:8].[Cu](C#N)[C:12]#[N:13].N>CN(C=O)C>[C:12]([C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH2:9])=[O:8])#[N:13]
Reactant: NC(=O)c1cncc(Br)c1
Reactant: N#C[Cu]C#N
Agent: N
Solvent: CN(C)C=O
Product: N#Cc1cncc(C(N)=O)c1
Temperature: 140 °C
Reaction time: 24 h
Yield: 16.6 %

Procedure:
5-Bromonicotinamide (905 mg) and copper cyanide (630 mg) were suspended in DMF (15 ml) and the mixture was stirred at 140° C. for 24 hrs. Aqueous ammonia was added to the reaction mixture at room temperature and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent, methanol:ethyl acetate=1:10) for purification to give the title compound (110 mg) as a colorless powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([C@@H:16]3[CH2:19][CH2:18][C@H:17]3[C:20]([O:22]C)=[O:21])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl[C:25]1[S:26][C:27]2[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:28]=2[N:29]=1.[OH-].[Na+]>C(O)CCC>[Cl:34][C:32]1[CH:31]=[CH:30][C:28]2[N:29]=[C:25]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([C:8]4[CH:13]=[CH:12][C:11]([C:14]([C@@H:16]5[CH2:19][CH2:18][C@H:17]5[C:20]([OH:22])=[O:21])=[O:15])=[CH:10][CH:9]=4)=[CH:4][CH:3]=3)[S:26][C:27]=2[CH:33]=1
Reactant: COC(=O)[C@@H]1CC[C@H]1C(=O)c1ccc(-c2ccc(N)cc2)cc1
Reactant: Clc1ccc2nc(Cl)sc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCO
Product: O=C(O)[C@@H]1CC[C@H]1C(=O)c1ccc(-c2ccc(Nc3nc4ccc(Cl)cc4s3)cc2)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 10.8 %

Procedure:
To a solution of methyl trans-2-[(4′-amino-1,1′-biphenyl-4-yl) carbonyl]cyclobutane-carboxylate (100 mg, 0.32 mmol) in n-butanol (15 mL) was added 2,6-dichloro-1,3-benzothiazole (396 mg, 1.94 mmol), and the resulting reaction mixture was heated at 90° C. overnight. The mixture was evaporated to dryness and the residue was brought up in MeOH. Then 1 N aqueous NaOH (1.0 mL, 1.0 mmol) was added to the suspension, and the reaction mixture was stirred at 50° C. overnight. The reaction mixture was concentrated, and the residue was suspended in water. Concentrated HCl was added to adjust the acidity to pH 1, and the precipitate that formed was collected by filtration, washed with water and MeOH, and dried in a vacuum oven to give trans-2-({4′-[(6-chloro-1,3-benzothiazol-2-yl) amino]-1,1′-biphenyl-4-yl}carbonyl)cyclobutanecarboxylic acid (16 mg, 10%). LC-MS ret. time 3.69; m/z 463.1 (MH+); 1H NMR (400 MHz, DMSO-d6) δ 2.01–2.23 (m, 3 H), 2.32 (m, 1H), 3.43 (m, 1H), 4.32 (m, 1H), 7.35 (m, 1H), 7.31 (m, 1H), 7.62 (d, 1H), 7.81 (m, 4H), 7.90 (d, 2H), 7.98 (m, 3H), 10.77 (s, 1H), 12.29 (s, 1H).
Reaction SMILES: Br.C(O)(=O)C.CS(C)=O.[CH2:10]([S:13]([NH:16][CH2:17][CH:18]1[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:27]3[CH2:28][CH2:29][C:30](=[O:33])[NH:31][N:32]=3)[CH:24]=2)[CH2:19]1)(=[O:15])=[O:14])[CH2:11][CH3:12].C(OC(C)C)(C)C>C(O)(=O)C>[CH2:10]([S:13]([NH:16][CH2:17][CH:18]1[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:27]3[CH:28]=[CH:29][C:30](=[O:33])[NH:31][N:32]=3)[CH:24]=2)[CH2:19]1)(=[O:15])=[O:14])[CH2:11][CH3:12]
Reactant: CCCS(=O)(=O)NCC1Cc2ccc(C3=NNC(=O)CC3)cc2C1
Agent: Br
Solvent: CS(C)=O
Solvent: CC(=O)O
Solvent: CC(C)OC(C)C
Product: CCCS(=O)(=O)NCC1Cc2ccc(-c3ccc(=O)[nH]n3)cc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.5 %

Procedure:
25 ml of 30% hydrogen bromide-acetic acid and 1.3 ml of dimethyl sulfoxide were added to 5.24 g of 2-(propylsulfonylaminomethyl)-5-[4,5-dihydropyridazin-3(2H)-on-6-yl]indane suspended in 60 ml of acetic acid. The mixture was stirred at room temperature for 2 hours. 150 ml of isopropyl ether was added to the mixture, and crystals precipitated were collected by filtration, washed with water, dried and then recrystallized from methanol to obtain 4.82 g of 2-(propylsulfonylaminomethyl)-5-[pyridazin-3(2H)-on-6-yl]indane. This compound had the same physical properties as those of the compound obtained in Example 2.
Reaction SMILES: C([NH:4][CH2:5][C:6]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:9]=[C:8]([S:16]([Cl:19])(=[O:18])=[O:17])[C:7]=1[OH:20])(=O)C.[CH3:21][NH:22][CH3:23]>>[ClH:19].[NH2:4][CH2:5][C:6]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:9]=[C:8]([S:16](=[O:18])(=[O:17])[N:22]([CH3:23])[CH3:21])[C:7]=1[OH:20]
Reactant: CC(=O)NCc1cc(C(C)(C)C)cc(S(=O)(=O)Cl)c1O
Reactant: CNC
Product: CN(C)S(=O)(=O)c1cc(C(C)(C)C)cc(CN)c1O
Product: Cl

Procedure:
This compound is prepared analogously to Examples 11c and 11d from 2-acetamidomethyl-6-chlorosulfonyl-4-(1,1-dimethylethyl)-phenol and dimethylamine.
Reaction SMILES: C[Al](C)C.[F:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][NH2:11])=[CH:8][CH:7]=1.C([O:16][C:17]([C:19]1[C:20]([S:35][CH2:36][CH3:37])=[N:21][C:22]2[C:27]([C:28]=1[CH3:29])=[CH:26][CH:25]=[C:24]([O:30][C:31]([F:34])([F:33])[F:32])[CH:23]=2)=O)C.CCCCCC.C(Cl)Cl>C1(C)C=CC=CC=1.Cl>[CH2:36]([S:35][C:20]1[C:19]([C:17]([NH:11][CH2:10][C:9]2[CH:12]=[CH:13][C:6]([F:5])=[CH:7][CH:8]=2)=[O:16])=[C:28]([CH3:29])[C:27]2[C:22](=[CH:23][C:24]([O:30][C:31]([F:34])([F:32])[F:33])=[CH:25][CH:26]=2)[N:21]=1)[CH3:37]
Reactant: CCOC(=O)c1c(SCC)nc2cc(OC(F)(F)F)ccc2c1C
Reactant: NCc1ccc(F)cc1
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: ClCCl
Product: CCSc1nc2cc(OC(F)(F)F)ccc2c(C)c1C(=O)NCc1ccc(F)cc1
Temperature: 90 °C
Yield: 60.7 %

Procedure:
1.12 ml (2.24 mmol, 2M in toluene)trimethyl aluminium and 260 μl (2.24 mmol) 4-fluorobenzylamine were added in succession to a solution of 200 mg (0.56 mmol) 2-ethylsulfanyl-4-methyl-7-(trifluoromethyloxy)-quinoline-3-carboxylic acid ethyl ester (VVV25) in toluene (7 ml) and the mixture was then heated for 3 h at 90° C. Then it was diluted with 0.5M hydrochloric acid and extracted with EE. The organic phase was washed with water and brine, dried over Na2SO4, filtered and concentrated to small volume under vacuum. Column chromatography (hexane/DCM 3:2) of the residue yielded 150 mg (0.34 mmol, 61%) 2-ethylsulfanyl-N-[(4-fluorophenyl)-methyl]-4-methyl-7-(trifluoromethyloxy)-quinoline-3-carboxamide. MS: m/z 439.1 [M+H]+.