Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][N:12]([C:15]3[CH:16]=[CH:17][C:18]4[N:22]=[C:21]([CH:23]5[CH2:25][CH2:24]5)[N:20]([CH3:26])[C:19]=4[CH:27]=3)[C:11](=[O:28])[CH:10]=2)[S:5][CH:6]=1.[CH:29]1(B(O)O)[CH2:31][CH2:30]1.C(=O)([O-])[O-].[K+].[K+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH:23]1([C:21]2[N:20]([CH3:26])[C:19]3[CH:27]=[C:15]([N:12]4[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:4]5[S:5][CH:6]=[C:2]([CH:29]6[CH2:31][CH2:30]6)[N:3]=5)=[CH:10][C:11]4=[O:28])[CH:16]=[CH:17][C:18]=3[N:22]=2)[CH2:25][CH2:24]1
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(OCc4nc(Br)cs4)cc3=O)cc21
Reactant: OB(O)C1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: Cn1c(C2CC2)nc2ccc(-n3ccc(OCc4nc(C5CC5)cs4)cc3=O)cc21
Temperature: 150 °C
Yield: 30.8 %

Procedure:
A mixture of 4-((4-bromo-1,3-thiazol-2-yl)methoxy)-1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one (50 mg), cyclopropylboronic acid (10.3 mg), tetrakis(triphenylphosphine)palladium (6.3 mg), potassium carbonate (60.4 mg), DME (1 ml) and water (0.3 ml) was heated at 150° C. for 15 min under microwave irradiation. Additional cyclopropylboronic acid (14.1 mg) was added to the mixture, and the mixture was heated 150° C. for further 15 min under microwave irradiation. The reaction mixture was poured into water and extracted with EtOAc. The extract was washed with brine, dried over MgSO4, concentrated and purified by silica gel column chromatography (hexane/EtOAc then EtOAc/MeOH). The resulting solid was recrystallized from EtOH-water to give the title compound (14.1 mg) as a white solid.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8]2[CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[O:11][CH:12]=2)=[CH:6][CH:5]=[N:4]1)[CH3:2].C1C(=O)N([Cl:24])C(=O)C1>C1COCC1>[Cl:24][C:6]1[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]=1[C:8]1[CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[O:11][CH:12]=1
Reactant: CCn1nccc1-c1coc(C(=O)OC)c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: C1CCOC1
Product: CCn1ncc(Cl)c1-c1coc(C(=O)OC)c1
Temperature: 70 °C
Reaction time: 5 h
Yield: 75.1 %

Procedure:
A mixture of methyl 4-(1-ethyl-1H-pyrazol-5-yl)-2-furancarboxylate (300 mg, 1.36 mmol) and NCS (218 mg, 1.63 mmol) in THF (5 mL) was heated to 70° C. in a sealed tube. After 5 h, the reaction mixture was concentrated and purified via column chromatography (silica, 10-20% EtOAc/Hexane) affording the title compound (260 mg, 75%) as a white solid: LC-MS (ES) m/z 255 (M+H)+.
Reaction SMILES: [F:1][P-:2]([F:7])([F:6])([F:5])([F:4])[F:3].[C:8]1([CH3:27])[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S+:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C[O-].[Na+].FC(F)(F)C(OC(=O)C(F)(F)F)=[O:34]>CO>[F:1][P-:2]([F:7])([F:6])([F:5])([F:4])[F:3].[C:8]1([CH3:27])[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S+:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:34]
Reactant: Cc1ccccc1[S+](c1ccccc1)c1ccccc1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: C[O-]
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CO
Product: Cc1ccccc1[S+](=O)(c1ccccc1)c1ccccc1
Yield: 15.5 %

Procedure:
(Tolyl)diphenylsulphonium hexafluorophosphate (1.08 g, 2.57 mol) is dissolved with stirring in methanol (40 ml) with cooling in an ice-water bath. Sodium methoxide (2.42 g, 31 mmol) is added slowly. After 15 mins a solution of trifluoroacetic anhydride (1.8 ml, 12.5 mmol) in methanol (30 ml) is added dropwise over 25 min. After 30 min the reaction mixture is filtered and evaporated under reduced pressure. Water is added and the resulting solid is collected and washed with water and ether, to give (tolyl)diphenylsulphoxonium hexafluorophosphate (0.85 g, 76%) identical to authentic material.
Reaction SMILES: [OH:1][CH:2]([C:29]([F:32])([F:31])[F:30])[CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:14][N:13]=2)=[CH:8][CH:7]=1.[H-].[K+].C1(C)C=CC(S(O[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])(=O)=O)=CC=1.O>O1CCCC1.C1(C)C=CC=CC=1>[CH2:45]([O:1][CH:2]([C:29]([F:31])([F:32])[F:30])[CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:14][N:13]=2)=[CH:10][CH:11]=1)[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52]
Reactant: CCCCCCCCOS(=O)(=O)c1ccc(C)cc1
Reactant: CCCCCCCCCCOc1cnc(-c2ccc(CCCC(O)C(F)(F)F)cc2)nc1
Agent: [H-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCCCOc1cnc(-c2ccc(CCCC(OCCCCCCCC)C(F)(F)F)cc2)nc1
Reaction time: 0.33 h
Yield: 56.7 %

Procedure:
1.1 g (2.5 mmol) of (-)-2-(4-(4-hydroxy-5,5,5-trifluoro-1-pentyl)phenyl)-5-decyloxypyrimidine was dissolved in 10 ml of tetrahydrofuran. This solution was added with 0.12 g (3 mmol) of potassium hydride, stirred at 10°-20° C. for 20 minutes, further added with 0.85 g (3 mmol) of octyl p-toluenesulfonate and reacted at 20°-30° C. for 2 hours. The reaction mixture was poured into 100 ml of water and 100 ml of toluene, and the toluene layer was washed with water and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using toluene/ethyl acetate as eluent to obtain 0.80 g of (-)-2-(4-(4-octyloxy-5,5,5-trifluoro-1-pentyl)phenyl)-5-decyloxypyrimidine
Reaction SMILES: [C:1]1([C:7]2[C:14]3[S:13][C:12]([NH2:15])=[N:11][C:10]=3[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.Cl.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1.[OH-].[Na+].Cl>C1COCC1.CO>[C:1]1([C:7]2[C:14]3[S:13][C:12]([NH:15][C:23](=[O:30])[C:24]4[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=4)=[N:11][C:10]=3[NH:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: Nc1nc2[nH]nc(-c3ccccc3)c2s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: CO
Solvent: C1CCOC1
Product: O=C(Nc1nc2[nH]nc(-c3ccccc3)c2s1)c1ccncc1
Temperature: 70 °C
Reaction time: 22 h
Yield: 42.3 %

Procedure:
To a stirring solution of 3-phenyl-1H-pyrazolo[3,4-d]thiazol-5-ylamine (20 mg, 0.092 mmol) and pyridine (52 μL, 0.65 mmol) in THF (0.5 mL) was added isonicotinoyl chloride hydrochloride (82 mg, 0.46 mmol). The reaction mixture was stirred at 70° C. for 22 h, then cooled to room temperature and treated with MeOH (1 mL) and a 4N aqueous solution of NaOH (0.25 mL). The reaction mixture was further stirred at room temperature for 4 h, then a 1N aqueous solution of HCl was added to adjust the pH to 7, and the mixture was extracted with 10% MeOH in CH2Cl2 (3×). Purification on silica gel with 0-10% MeOH in CH2Cl2 as eluent provided 12.5 mg (42%) of N-(3-phenyl-1H-pyrazolo[3,4-d]thiazol-5-yl)-isonicotinamide as a beige solid. 1H-NMR (d6-DMSO) δ: 13.5 and 13.7 (2 broad s, 1H, NH+tautomer), 13.2 (broad s, 1H, NH), 8.83 (d, 2H), 7.99 (d, 2H), 7.80 (m, 2H, tautomers), 7.55 (m, 2H, tautomers), 7.40 (m, 1H, tautomers; HPLC/MS m/z: 322 [MH]+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[CH:18][NH:17][N:16]=2)[N:3]=1.[CH3:20][C:21]1[C:22](B(O)O)=[CH:23][S:24][CH:25]=1>>[CH3:13][O:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([C:22]1[C:21]([CH3:20])=[CH:25][S:24][CH:23]=1)=[N:3][C:4]([NH:14][C:15]1[CH:19]=[CH:18][NH:17][N:16]=1)=[CH:5]2
Reactant: Cc1cscc1B(O)O
Reactant: COc1ccc2c(Cl)nc(Nc3cc[nH]n3)cc2c1
Product: COc1ccc2c(-c3cscc3C)nc(Nc3cc[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 4-methyl-3-thiopheneboronic acid to give [6-methoxy-1-(4-methyl-thiophen-3-yl)-isoquinolin-3-yl]-(1H-pyrazol-3-yl)-amine. LC-MS m/e 337(MH+).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]2[CH:13]=[C:12]([O:14][CH:15]3[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]3)[CH:11]=[CH:10][N:9]=2)[S:5][CH:6]=1.[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31]>ClCCl>[OH:32][C:30]([C:29]([F:34])([F:33])[F:28])=[O:31].[CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]2[CH:13]=[C:12]([O:14][CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[CH:11]=[CH:10][N:9]=2)[S:5][CH:6]=1
Reactant: Cc1csc(Nc2cc(OC3CCN(C(=O)OC(C)(C)C)CC3)ccn2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1csc(Nc2cc(OC3CCNCC3)ccn2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 103 %

Procedure:
A 100 mL round bottom flask was charged with tert-butyl 4-(2-(4-methylthiazol-2-ylamino)pyridin-4-yloxy)piperidine-1-carboxylate (1.50 g, 3.84 mmol) in dichloromethane (10 mL) and added 2,2,2-trifluoroacetic acid (0.888 mL, 11.5 mmol). The reaction mixture was stirred at room temperature for 2 hours, then concentrated to provide 4-methyl-N-(4-(piperidin-4-yloxy)pyridin-2-yl)thiazol-2-amine TFA salt (1.6 g, 100%) as a light yellow solid. 1H NMR (DMSO) δ 8.53 (bs, 2H), 8.15 (d, 1H), 6.67 (dd, 1H), 6.61 (m, 1H), 6.56 (d, 1H), 4.74 (m, 1H), 3.25 (bm, 2H), 3.11 (bm, 2H), 2.23 (d, 3H), 2.10 (bm, 2H), 1.84 (bm, 2H); Mass spectrum (apci) m/z=291 (100) (M+H).
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([C:15]([O:17][CH3:18])=[O:16])[CH:8]=[C:9]([CH:14]=1)[C:10]([O:12][CH3:13])=[O:11])C=C.CN(C)[C:21]1[CH:26]=CC=C[CH:22]=1>CCOC(C)=O>[CH2:26]([C:14]1[C:5]([OH:4])=[CH:6][C:7]([C:15]([O:17][CH3:18])=[O:16])=[CH:8][C:9]=1[C:10]([O:12][CH3:13])=[O:11])[CH:21]=[CH2:22]
Reactant: CN(C)c1ccccc1
Reactant: C=CCOc1cc(C(=O)OC)cc(C(=O)OC)c1
Solvent: CCOC(C)=O
Product: C=CCc1c(O)cc(C(=O)OC)cc1C(=O)OC
Temperature: 25 °C
Yield: 70 %

Procedure:
A solution of dimethyl 5-(allyloxy)isophthalate (1.5 g, 5.994 mmol) in N,N-dimethylaniline (15 mL) was heat at 200° C. for 14 hours. After it was cooled to room temperature, the reaction was diluted with EtOAc, washed with 0.5 N HCl, brine, and dried with Na2SO4. The solvent was evaporated under reduced pressure. The desired product was purified via silica gel gradient column chromatography with EtOAc/Hex (10-25%) to afford the title compound (750 mg, yield 70%) as a white solid. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 3.82 (d, J=6.22 Hz, 2 H) 3.92 (d, J=5.84 Hz, 6 H) 5.02-5.11 (m, 1 H) 5.10-5.17 (m, 1 H) 5.81 (s, 1 H) 5.90-6.13 (m, 1 H) 7.70 (d, J=1.70 Hz, 1 H) 8.11 (d, J=1.51 Hz, 1 H); LC-MS (ESI)+m/z=251.00 (M+H)+.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[F:11][C:12]1[CH:20]=[CH:19][C:18]2[C:14](=[CH:15][N:16]([CH3:21])[N:17]=2)[C:13]=1[CH2:22][OH:23].C(N(CC)CC)C>ClCCl>[F:11][C:12]1[CH:20]=[CH:19][C:18]2[C:14](=[CH:15][N:16]([CH3:21])[N:17]=2)[C:13]=1[CH:22]=[O:23]
Reactant: Cn1cc2c(CO)c(F)ccc2n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: Cn1cc2c(C=O)c(F)ccc2n1
Reaction time: 0.5 h
Yield: 94.6 %

Procedure:
To a solution of dimethyl sulfoxide (7.56 mL, 107 mmol) in dichloromethane (100 mL) was added oxalyl chloride (4.86 mL, 53.3 mmol) at −78° C., and the mixture was stirred for 30 min. To the reaction mixture was added a solution of (5-fluoro-2-methyl-2H-indazol-4-yl)methanol (3.20 g, 17.8 mmol) in dichloromethane (78.0 mL), and the mixture was stirred for 2 hr. To the reaction mixture was added triethylamine (22.5 mL, 160 mmol) at −78° C., and the mixture was stirred for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by flash silica gel column chromatography (ethyl acetate/hexane=1/3) to give the title compound (3.00 g, yield 95%).
Reaction SMILES: Cl.Cl.[CH:3]1([NH:6][C:7]([C:9]2[C:17]3[CH:16]=[C:15]([C:18]4[C:23]([Cl:24])=[CH:22][N:21]=[C:20]([NH:25][CH2:26][CH2:27]C5CCNCC5)[N:19]=4)[S:14][C:13]=3[CH:12]=[CH:11][CH:10]=2)=[O:8])[CH2:5][CH2:4]1.C1(NC([C:40]2[C:48]3[CH:47]=[C:46]([C:49]4C([Cl:55])=CN=[C:51](Cl)[N:50]=4)SC=3C=CC=2)=O)CC1.C(OC(N1CCCC(CCCN)C1)=O)(C)(C)C>>[ClH:24].[ClH:55].[CH:3]1([NH:6][C:7]([C:9]2[C:17]3[CH:16]=[C:15]([C:18]4[C:23]([Cl:24])=[CH:22][N:21]=[C:20]([NH:25][CH2:26][CH2:27][CH2:40][CH:48]5[CH2:47][CH2:46][CH2:49][NH:50][CH2:51]5)[N:19]=4)[S:14][C:13]=3[CH:12]=[CH:11][CH:10]=2)=[O:8])[CH2:5][CH2:4]1
Reactant: O=C(NC1CC1)c1cccc2sc(-c3nc(NCCC4CCNCC4)ncc3Cl)cc12
Reactant: O=C(NC1CC1)c1cccc2sc(-c3nc(Cl)ncc3Cl)cc12
Agent: CC(C)(C)OC(=O)N1CCCC(CCCN)C1
Agent: Cl
Product: O=C(NC1CC1)c1cccc2sc(-c3nc(NCCCC4CCCNC4)ncc3Cl)cc12

Procedure:
Using the method of 2-[5-chloro-2-(2-piperidin-4-yl-ethylamino)-pyrimidin-4-yl]-benzo[b]thiophene-4-carboxylic acid cyclopropylamide di-hydrochloride, the title compound is synthesized as a di-hydrochloride salt from 2-(2,5-dichloropyrimidin-4-yl)-benzo[b]thiophene-4-carboxylic acid cyclopropylamide and racemic 3-(3-aminopropyl)-piperidine-1-carboxylic acid tert-butyl ester. ES+(m/z) 470 (35Cl) and 472 (37Cl) [M(free base)+H].
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][OH:12])=[CH:6][CH:5]=1.Cl[C:14]1[C:23]2[C:18](=[C:19]([F:24])[CH:20]=[CH:21][CH:22]=2)[N:17]=[CH:16][CH:15]=1>CN(C=O)C>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][O:12][C:14]2[C:23]3[C:18](=[C:19]([F:24])[CH:20]=[CH:21][CH:22]=3)[N:17]=[CH:16][CH:15]=2)=[CH:6][CH:5]=1
Reactant: Fc1cccc2c(Cl)ccnc12
Reactant: OCCc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1cccc2c(OCCc3ccc(Cl)cc3)ccnc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 11.2 %

Procedure:
To 1.2 g of sodium hydride in 50 mL of DMF was added 3.9 g of 2-(4-chlorophenyl)ethyl alcohol. The mixture was stirred at room temperature for one hour, then 4.5 g of 4-chloro-8-fluoroquinoline in 10 mL of DMF was added, the the mixture was heated to reflux for two hours. Then the mixture was allowed to cool to room temperature while it was stirred for four hours, after which it was poured into an ice/water mixture. The mixture was filtered, and the filter cake was washed with H2O. Recrystallization from pentane/ethyl acetate gave 0.840 g of the title product. Yield 11.2%. M.P. 139°-140° C.
Reaction SMILES: C1C([C:7]2[NH:23][C:21](=O)[C:9]3=[C:10](C4C=CC(Cl)=CC=4)[NH:11][C:12](=[O:13])[C:8]=23)=CC=C(Cl)C=1.S(=O)(=O)(O)[OH:26]>O>[O:26]=[C:8]1[C:7]2[C:10]([CH:9]=[CH:21][N:23]=2)=[N:11][C:12]1=[O:13]
Reactant: O=S(=O)(O)O
Reactant: O=C1NC(c2ccc(Cl)cc2)=C2C(=O)NC(c3ccc(Cl)cc3)=C12
Solvent: O
Product: O=c1nc2ccnc-2c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The pigment dispersant A1 of Synthesis Example A1 (3.75 parts) and C.I. Pigment Red 254 (6.25 parts) were added to 95% sulfuric acid (100 parts), followed by stirring at room temperature for 1 hour. Subsequent to cooling, the resulting concentrated sulfuric acid solution was poured into iced water (1,000 parts); its pouring led the precipitation of a composite according to the present invention. The formed precipitate was collected by filtration and then washed with water to obtain a water-based paste (39 parts, true amount: 10 parts). The water-based paste was dried to obtain a diketopyrrolopyrrole (a pigment dispersant A3, 10 parts), which was determined to contain on average 0.3 sulfonic group introduced per molecule from the results of an elemental analysis for sulfur.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=2)[N:8]=1)=O.[CH3:26][S:27]([C:30]1[CH:31]=[C:32]([NH:36]N)[CH:33]=[CH:34][CH:35]=1)(=[O:29])=[O:28]>>[CH3:26][S:27]([C:30]1[CH:31]=[C:32]([N:36]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)[CH:33]=[CH:34][CH:35]=1)(=[O:28])=[O:29]
Reactant: CS(=O)(=O)c1cccc(NN)c1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(OC(F)(F)F)c2)ccc1=O
Product: CS(=O)(=O)c1cccc(-n2nccc2-c2nn(-c3cccc(OC(F)(F)F)c3)ccc2=O)c1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-6) and (3-methanesulfonyl-phenyl)-hydrazine according to the method described for example 43. MS: M=477.2 (M+H)+
Reaction SMILES: [NH2:1][C@@H:2]1[C:31]([CH3:33])([CH3:32])[C@H:30]2[C@@:5]3([O:26][C:9]4[C:10]5[CH2:11][NH:12][C:13](=[O:25])[C:14]=5[CH:15]=[C:16]([O:17]CC5C=CC=CC=5)[C:8]=4[CH2:7][C@:6]3([CH3:35])[C@@H:27]([CH3:34])[CH2:28][CH2:29]2)[CH2:4][CH2:3]1>CO.[C].[Pd]>[NH2:1][C@@H:2]1[C:31]([CH3:33])([CH3:32])[C@H:30]2[C@@:5]3([O:26][C:9]4[C:10]5[CH2:11][NH:12][C:13](=[O:25])[C:14]=5[CH:15]=[C:16]([OH:17])[C:8]=4[CH2:7][C@:6]3([CH3:35])[C@@H:27]([CH3:34])[CH2:28][CH2:29]2)[CH2:4][CH2:3]1
Reactant: C[C@H]1CC[C@H]2C(C)(C)[C@@H](N)CC[C@]23Oc2c(c(OCc4ccccc4)cc4c2CNC4=O)C[C@]13C
Agent: [Pd]
Solvent: CO
Product: C[C@H]1CC[C@H]2C(C)(C)[C@@H](N)CC[C@]23Oc2c(c(O)cc4c2CNC4=O)C[C@]13C
Temperature: 25 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
To Compound (46a) (30 mg, 0.063 mmol) dissolved in 4.0 ml of methanol was added 6 mg of 10% palladium-carbon, and the mixture stirred under hydrogen atmosphere for 1 hour at room temperature. After the palladium-carbon was removed by filtration, the filtrate was concentrated under reduced pressure. The residue was crystallized from diethyl ether, and recrystallized from diethyl ether-methanol to give 16 mg (48%) of Compound (47a).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[Cl:13]N1C(=O)CCC1=O>CN(C)C=O>[NH2:1][C:2]1[C:3]([CH3:12])=[C:4]([C:9]([Cl:13])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)c1cccc(N)c1C
Solvent: CN(C)C=O
Product: COC(=O)c1c(Cl)ccc(N)c1C
Reaction time: 72 h
Yield: 44.8 %

Procedure:
To a solution of methyl 3-amino-2-methylbenzoate (25.0 g, 151 mmol) in N,N-dimethylformamide (757 mL) was added N-chlorosuccinimide (20.2 g, 151 mmol) at room temperature, and the mixture was stirred for 3 days. The reaction mixture was concentrated under reduced pressure to a half volume, and the mixture was extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by flash silica gel column chromatography (ethyl acetate/hexane=1/5) to give the title compound (13.5 g, yield 45%).
Reaction SMILES: [CH3:1][N:2]([CH3:34])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([NH:12][C:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[N:31]=[C:30]([CH3:32])[O:29][N:28]=4)=[CH:23][C:22]=3[CH3:33])=[CH:17][CH:16]=2)=[O:14])[CH:9]=[CH:10][CH:11]=1.[Cl:35]N1C(=O)CCC1=O>ClCCl>[CH3:1][N:2]([CH3:34])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:35])=[C:8]([NH:12][C:13]([C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[N:31]=[C:30]([CH3:32])[O:29][N:28]=4)=[CH:23][C:22]=3[CH3:33])=[CH:19][CH:20]=2)=[O:14])[CH:7]=1
Reactant: Cc1nc(-c2ccc(-c3ccc(C(=O)Nc4cccc(OCCN(C)C)c4)cc3)c(C)c2)no1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: Cc1nc(-c2ccc(-c3ccc(C(=O)Nc4cc(OCCN(C)C)ccc4Cl)cc3)c(C)c2)no1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of N-[3-(2dimethylaminoethoxy)phenyl]-2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-carboxamide (E13) (200 mg) in dichloromethane (10 ml) was treated with N-chlorosuccinimide (64 mg) and the mixture stirred at room temperature overnight. The reaction mixture was evaporated under reduced pressure, and the residue triturated with diethyl ether and the precipitated succinimide was removed by filtration. The filtrate was evaporated under reduced pressure and flash column chromatographed on silica gel, eluting with dichloromethane, then chloroform and methanol to give the title compound. (77 mg, 36%). Mp 101°-2° C.
Reaction SMILES: [CH:1]1([CH:6]([N:10]2[CH:14]=[C:13]([C:15]3[C:16]4[CH:23]=[CH:22][N:21](COCC[Si](C)(C)C)[C:17]=4[N:18]=[CH:19][N:20]=3)[CH:12]=[N:11]2)[CH2:7][C:8]#[CH:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:32]([OH:38])([C:34]([F:37])([F:36])[F:35])=[O:33]>C(Cl)Cl>[F:35][C:34]([F:37])([F:36])[C:32]([OH:38])=[O:33].[CH:1]1([CH:6]([N:10]2[CH:14]=[C:13]([C:15]3[C:16]4[CH:23]=[CH:22][NH:21][C:17]=4[N:18]=[CH:19][N:20]=3)[CH:12]=[N:11]2)[CH2:7][C:8]#[CH:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C#CCC(C1CCCC1)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C#CCC(C1CCCC1)n1cc(-c2ncnc3[nH]ccc23)cn1
Reaction time: 1 h
Yield: 60 %

Procedure:
A solution of 4-[1-(1-cyclopentylbut-3-yn-1-yl)-1H-pyrazol-4-yl]-7-[2-(trimethylsilyl)-ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (52 mg, 0.12 mmol) in DCM (3 mL) and TFA (1 mL) was stirred for 2 hours. The solvents were removed in vacuo. The resulting residue was dissolved in THF (3 mL) and 6N NaOH (2 mL) was added. After stirring for 1 hour, the mixture was partitioned between water and ethyl acetate. The organic layer was dried over sodium sulfate and the solvent was removed in vacuo. Purification via preparative-HPLC/MS (C18 eluting with a gradient of H2O and ACN containing 0.1% TFA) afforded product (30 mg, 60%).
Reaction SMILES: [CH2:1]([NH:4][C:5](=[O:15])[NH:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[C:9]#[N:10])[CH:2]=[CH2:3].O>C(O)C.O.N>[NH:10]=[C:9]1[C:8]2[C:7](=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:6][C:5](=[O:15])[N:4]1[CH2:1][CH:2]=[CH2:3]
Reactant: C=CCNC(=O)Nc1ccccc1C#N
Agent: N
Solvent: CCO
Solvent: O
Product: C=CCn1c(=O)[nH]c2ccccc2c1=N
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83.5 %

Procedure:
A mixture of 2-(3-allylureido)benzonitrile (10.0 g, 50 mmol) in ethanol (70 mL) and 28% of ammonia water (50 mL) was heated on a steam bath with occasional stirring for 15 minutes. The mixture was then cooled to room temperature and to the mixture was added water (100 mL). The solid was collected by filtration and was recrystallized from methanol with a few drops of ammonia water to give 8.4 g (84%) of 3,4-dihydro-4-imino-3-allyl-2(1H)-quinazolinone, mp 223°-224° C. IR (KBr): 3284, 3203, 3147, 1691, 1582 cm-1. 1H NMR (300 MHz, DMSO-d6): δ4.61 (d, 2H, =CH2), 5.08 (q, 2H, CH2), 5.85 (m, 1H, =CH), 7.07 (m, 2H, Ar--H), 7.46 (t, 1H, Ar--H), 8.04 (d, 1H, Ar--H), 8.85 (br s, 1H, NH), 10.74 (s, 1H, NH). 13C NMR (75 MHz, DMSO-d6): δ42.54, 115.08, 115.81, 122.09, 126.13, 132.77, 133.15, 137.01, 149.76. Anal. Calcd for C11H11N3O; C, 65.63; H, 5.56; N, 20.87. Found: C, 65.67; H, 5.51; N, 20.86.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1)=[O:4].C(N(C(C)C)C(C)C)C.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.[N:56]12[CH2:63][CH2:62][CH:59]([CH2:60][CH2:61]1)[C@@H:58](O)[CH2:57]2>C1COCC1>[CH3:1][O:2][C:3](=[O:4])[C:5]1[CH:6]=[CH:7][C:8]([CH:11]([C:12]([O:14][C@@H:58]2[CH:59]3[CH2:62][CH2:63][N:56]([CH2:61][CH2:60]3)[CH2:57]2)=[O:13])[NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:9][CH:10]=1
Reactant: COC(=O)c1ccc(C(Nc2ccccc2)C(=O)O)cc1
Reactant: O[C@H]1CN2CCC1CC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(Nc2ccccc2)C(=O)O[C@H]2CN3CCC2CC3)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 20.9 %

Procedure:
N-Ethyl-N-isopropylpropan-2-amine 2-(4-(methoxycarbonyl)phenyl)-2-(phenylamino)acetate (I94) (212 mg, 0.51 mmol), DCC (158 mg, 0.77 mmol), and HOBT (117 mg, 0.77 mmol) are dissolved in dry THF (5 mL). (R)-Quinuclidin-3-ol (195 mg, 1.53 mmol) is added and the mixture is stirred at RT for 2 days. A second portion of DCC (79 mg, 0.38 mmol), HOBT (58.7 mg, 0.38 mmol) and (R)-quinuclidin-3-ol (98 mg, 0.77 mmol) are added and the mixture is further stirred for 24 hours. Then THF is evaporated, the residue is dissolved in EtOAc and washed with NaHCO3, water and brine. The organic phase is dried (Na2SO4), filtered and evaporated. The crude is purified by preparative HPLC. The recovered fractions are evaporated, dissolved in EtOAc and washed with sat. NaHCO3. The organic phase is dried (Na2SO4), filtered and evaporated to afford the desired compound as a colorless oil (42 mg, 21% yield, mixture of diastereoisomers).