Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]2[CH2:11][C:10](=[O:12])[NH:9][C:8]2=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:14]([C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>N1C=CC=CC=1>[O:14]([C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([N:9]1[C:10](=[O:12])[CH2:11][N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]1=[O:13])=[O:24])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C(Cl)c1ccccc1Oc1ccccc1
Reactant: O=C1CN(c2ccccc2)C(=O)N1
Solvent: c1ccncc1
Product: O=C1CN(c2ccccc2)C(=O)N1C(=O)c1ccccc1Oc1ccccc1
Yield: 34.5 %

Procedure:
In a similar manner to Example 8, 500 mg (2.80 mmol) of 1-phenyl-imidazolidin-2,4-dione were reacted with 700 mg (3.00 mmol) of 2-phenoxybenzoyl chloride. After completion of the reaction, pyridine was distilled off under reduced pressure, and the resultant residue was subjected to extraction with ethyl acetate. The organic layer was washed with dilute hydrochloric acid and with saturated saline. The thus-washed organic layer was dried over anhydrous magnesium sulfate, and the solvent was then distilled off. The resultant residue was purified by column chromatography on silica gel (developing solvent: n-hexane/ethyl acetate) and subjected to crystallization from n-hexane/ethyl acetate to obtain 360 mg (yield: 32.8%) of the title compound.
Reaction SMILES: Br[C:2]1[C:7]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:14][NH2:15]>N1C=CC=CC=1>[NH:14]([C:2]1[C:7]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:5]=[CH:4][N:3]=1)[NH2:15]
Reactant: NN
Reactant: Brc1ncccc1-c1cccnc1
Solvent: c1ccncc1
Product: NNc1ncccc1-c1cccnc1
Temperature: 100 °C

Procedure:
A mixture of 16.46 g of 2'-bromo-3,3'-bipyridine, 24 ml of anhydrous hydrazine and 500 ml of dry pyridine was heated at 100° C. for 3 days. The solvent was removed under vacuum, toluene was added and removed and the residue was partitioned between saturated aqueous sodium carbonate and methylene chloride. The organic layer was dried, the solvent removed under vacuum and the residue crystallized from methylene chloride-hexane, giving 2'-hydrazino-3,3'-bipyridine as tan crystals.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]O)=[C:18]([CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[CH:17]=1>>[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)=[C:18]([CH2:24][CH2:25][C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)[CH:17]=1
Reactant: OCc1ccc(F)cc1CCc1ccc(F)cc1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Product: N#Cc1ccnc(-n2nccc2OCc2ccc(F)cc2CCc2ccc(F)cc2)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and [4-fluoro-2-[2-(4-fluorophenyl)ethyl]phenyl]methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 2.86-2.98 (4H, m), 5.05 (2H, s), 5.73 (1H, d, J=2.0 Hz), 6.90-78.01 (6H, m), 7.33-7.39 (2H, m), 7.59 (1H, d, J=1.6 Hz), 7.95 (1H, s), 8.56 (1H, d, J=4.4 Hz). [M+H] Calc'd for C24H18F2N4O, 417. Found, 417.
Reaction SMILES: [CH3:1][CH:2]([N:10]1[C:14]([NH2:15])=[C:13](C(O)=O)[CH:12]=[N:11]1)[CH:3](OCC)OCC.Cl.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[CH3:3][C:2]1[N:10]2[N:11]=[CH:12][CH:13]=[C:14]2[NH:15][CH:1]=1
Reactant: CCOC(OCC)C(C)n1ncc(C(=O)O)c1N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1c[nH]c2ccnn12
Temperature: 25 °C
Yield: 64.6 %

Procedure:
1-(1-Methyl-2,2-diethoxyethyl)-4-carboxy-5-aminopyrazole (9.9 g) was dissolved in tetrahydrofuran (200 ml) and thereto was added 3N-hydrochloric acid (52 ml). The mixture was refluxed for 3 hours. The reaction mixture was cooled at room temperature, adjusted to pH 6 with aqueous 30% potassium carbonate and extracted with ethyl acetate (100 ml). Further the separated aqueous layer was extracted with ethyl acetate (50 ml). The organic layer was combined and dried over magnesium sulfate. The solvent was distilled off in vacuo. The residue was pulverized with isopropyl ether and the powder was collected by filtration to give 3-methyl-1H-imidazo[1,2-b]pyrazole (3.01 g).
Reaction SMILES: CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.Cl.[NH2:35][N:36]([CH:45]([CH3:47])[CH3:46])[C:37]([NH:39][CH2:40][C:41]([F:44])([F:43])[F:42])=[O:38].[F:48][C:49]([F:76])([F:75])[C:50]1[CH:58]=[C:57](/[CH:59]=[CH:60]/[CH:61]([C:66]2[CH:71]=[C:70]([Cl:72])[C:69]([Cl:73])=[C:68]([Cl:74])[CH:67]=2)[C:62]([F:65])([F:64])[F:63])[CH:56]=[CH:55][C:51]=1[C:52](O)=[O:53]>CN(C=O)C.O>[CH:45]([N:36]([C:37]([NH:39][CH2:40][C:41]([F:43])([F:42])[F:44])=[O:38])[NH:35][C:52](=[O:53])[C:51]1[CH:55]=[CH:56][C:57](/[CH:59]=[CH:60]/[CH:61]([C:66]2[CH:67]=[C:68]([Cl:74])[C:69]([Cl:73])=[C:70]([Cl:72])[CH:71]=2)[C:62]([F:63])([F:64])[F:65])=[CH:58][C:50]=1[C:49]([F:75])([F:76])[F:48])([CH3:47])[CH3:46]
Reactant: CC(C)N(N)C(=O)NCC(F)(F)F
Reactant: O=C(O)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1C(F)(F)F
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N(NC(=O)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1C(F)(F)F)C(=O)NCC(F)(F)F
Reaction time: 4 h
Yield: 32.5 %

Procedure:
DIPEA (0.32 ml, 1.88 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU) (263 mg, 0.69 mmol) and 1-amino-1-isopropyl-3-(2,2,2-trifluoroethyl)urea hydrochloride (178 mg, 0.75 mmol) were added to a stirred solution of 2-(trifluoromethyl)-4-[(E)-4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl]benzoic acid (300 mg, 0.63 mmol) in DMF (2 mL) at ambient temperature and the reaction mixture was stirred for 4 h. Water was added to the reaction mixture and it was extracted with EtOAc. The organic layer was washed with brine followed by water, dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography on silica, eluting with 20% EtOAc in petroleum ether to afford the title compound as a brown gum (135 mg, 29%).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][N:9]=2)[CH:4]=[CH:3][C:2]1=[O:11].[H-].[Na+].Br[CH2:15][CH:16]1[O:20][CH2:19][CH2:18][O:17]1.O>CN(C)C=O.C(OCC)(=O)C>[O:17]1[CH2:18][CH2:19][O:20][CH:16]1[CH2:15][N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][N:9]=2)[CH:4]=[CH:3][C:2]1=[O:11]
Reactant: BrCC1OCCO1
Reactant: O=c1ccc2cccnc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=c1ccc2cccnc2n1CC1OCCO1
Temperature: 55 °C
Reaction time: 0.12 h

Procedure:
To a solution of 1.2 g of 1,8-naphthyridin-2(1H)-one in 18 mL of N,N-dimethylformamide, 0.36 g of 60% sodium hydride was added, and the mixture was stirred at 50 to 60° C. for 7 minutes. Thereto was added 0.94 mL of 2-bromomethyl-1,3-dioxolan, and the mixture was stirred at 95 to 105° C. for 3 hours. The reaction mixture was cooled to room temperature, water and ethyl acetate were then added thereto, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate and chloroform. The organic layer and the extract were combined, the resultant solution was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography using an eluent of hexane:ethyl acetate=1:1 to obtain 1.2 g of 1-(1,3-dioxolan-2-ylmethyl)-1,8-naphthyridin-2(1H)-one as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:19][CH3:20])=[CH:4][C:5]2[CH:9](O)[CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:7][C:6]=2[C:17]=1[Cl:18].B(F)(F)F.CCOCC.C(O)(=O)C>O.[OH-].[Na+]>[Cl:1][C:2]1[C:3]([O:19][CH3:20])=[CH:4][C:5]2[CH:9]=[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:7][C:6]=2[C:17]=1[Cl:18]
Reactant: COc1cc2c(c(Cl)c1Cl)SC(c1ccccc1)C2O
Agent: FB(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Solvent: CC(=O)O
Product: COc1cc2cc(-c3ccccc3)sc2c(Cl)c1Cl
Yield: 30.7 %

Procedure:
A mixture of 5.0 g of 6,7-dichloro-2,3-dihydro-3-hydroxy-5-methoxy-2-phenylbenzo[b]thiophene, 10 ml of boron trifluoride etherate and 20 ml of glacial acetic acid is refluxed for 1 hour. The mixture is cooled, diluted with water and basified with dil sodium hydroxide solution. Extraction with dichloromethane followed by column chromatography over silica (50% dichloromethane in hexane) gives 1.45 g of 6,7-dichloro-5-methoxy-2-phenylbenzo[b]thiophene, mp 144°-145°.
Reaction SMILES: [C:1]1([C:7]2[C:8]([CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])=[CH:9][N:10]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]4[N:22]=[C:23]([C:26]5[S:27][CH:28]=[CH:29][CH:30]=5)[S:24][CH:25]=4)=[CH:15][CH:14]=3)[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[C:1]1([C:7]2[C:8]([CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[CH:9][N:10]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][C:21]4[N:22]=[C:23]([C:26]5[S:27][CH:28]=[CH:29][CH:30]=5)[S:24][CH:25]=4)=[CH:17][CH:18]=3)[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3csc(-c4cccs4)n3)cc2)cc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)CCc1cn(Cc2ccc(OCc3csc(-c4cccs4)n3)cc2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.4 %

Procedure:
A mixture of ethyl 3-[4-phenyl-1-[4-[2-(2-thienyl)-4-thiazolylmethoxy]benzyl]-3-pyrrolyl]propionate (582 mg), 1N aqueous sodium hydroxide solution (2.5 ml), tetrahydrofuran (5 ml), and ethanol (5 ml) was stirred at room temperature overnight, and 1N hydrochloric acid (2.5 ml) was added to the mixture, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The colorless crystals obtained were collected by filtration to yield 3-[4-phenyl-1-[4-[2-(2-thienyl)-4-thiazolylmethoxy]benzyl]-3-pyrrolyl]propionic acid (421 mg, yield: 76%). This was recrystallized from ethyl acetate-hexane. Melting point: 106–107° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH2:9][CH2:10][CH3:11])[C:6](=[O:12])[NH:5][C:4](=[O:13])[CH:3]=1.[N:14]([O-])=[O:15].[Na+]>O>[NH2:1][C:2]1[N:7]([CH2:8][CH2:9][CH2:10][CH3:11])[C:6](=[O:12])[NH:5][C:4](=[O:13])[C:3]=1[N:14]=[O:15]
Reactant: O=N[O-]
Reactant: CCCCn1c(N)cc(=O)[nH]c1=O
Agent: [Na+]
Solvent: O
Product: CCCCn1c(N)c(N=O)c(=O)[nH]c1=O

Procedure:
To 50.6 g (0.276 mol) of 6-amino-1-butyl-2,4-(1H,3H)-pyrimidinedione (VIII) dissolved in 1.8 l of wate at 80° C. was added 60 ml of 5N NCl and 20 g (0.29 mol) of NaNO2 which were dissolved in water. After cooling the red crystals were filtered off and washed with water. Yield 52.8 g (97%) (IX), NMR.
Reaction SMILES: [C:1]([C:6]1[N:7]=[C:8]([CH2:13][CH2:14][CH3:15])[NH:9][C:10]=1[C:11]#[N:12])(=[O:5])[CH2:2][CH2:3][CH3:4].Br[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:25]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[CH:26][CH:27]=[CH:28][CH:29]=2)=[CH:20][CH:19]=1.[H-].[Na+]>CN(C)C(=O)C>[C:33]([O:32][C:30]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:21]1[CH:22]=[CH:23][C:18]([CH2:17][N:9]2[C:10]([C:11]#[N:12])=[C:6]([C:1](=[O:5])[CH2:2][CH2:3][CH3:4])[N:7]=[C:8]2[CH2:13][CH2:14][CH3:15])=[CH:19][CH:20]=1)=[O:31])([CH3:36])([CH3:35])[CH3:34]
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)cc1
Reactant: CCCC(=O)c1nc(CCC)[nH]c1C#N
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCCC(=O)c1nc(CCC)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c1C#N
Yield: 72.1 %

Procedure:
Following a procedure similar to that described in Example 45(a), but using 1.026 g of 4-butyryl-2-propylimidazole-5-carbonitrile (prepared as described in Preparation 28), 1.91 g of t-butyl 4'-(bromomethyl)biphenyl-2-carboxylate and 0.209 g of sodium hydride (as a 55% w/w dispersion in mineral oil) in 20 ml of N,N-dimethylacetamide, 1.70 g of the title compound were obtained as a viscous oil.
Reaction SMILES: [CH2:1]([Li])CCC.[NH:6]([C:13]1[N:18]=[C:17]([C:19]2[N:23]3[CH2:24][CH2:25][CH2:26][CH2:27][C:22]3=[N:21][CH:20]=2)[CH:16]=[CH:15][N:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.IC>CCCCCC.C1COCC1>[NH:6]([C:13]1[N:18]=[C:17]([C:19]2[N:23]3[CH2:24][CH2:25][CH2:26][CH:27]([CH3:1])[C:22]3=[N:21][CH:20]=2)[CH:16]=[CH:15][N:14]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: [Li]CCCC
Reactant: c1ccc(Nc2nccc(-c3cnc4n3CCCC4)n2)cc1
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CI
Product: CC1CCCn2c(-c3ccnc(Nc4ccccc4)n3)cnc21
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 16 %

Procedure:
n-Butyllithium (1.2 ml of a 1.6M solution in hexane, 1.92 mmol) was added slowly to a stirred solution of 2-anilino-4-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-3-yl)pyrimidine (Example 2; 200 mg, 0.69 mmol) in dry THF (10 ml) cooled to −78° C. under nitrogen making sure that the reaction temperature remained below −65° C. The mixture was stirred at −70° C. for 15 minutes, then iodomethane (45 μl, 0.72 mmol) was added and the reaction stirred at −70° C. for 10 minutes and then allowed to warm and stirred at ambient temperature for 20 hours. The reaction mixture was partitioned between EtOAc and water and the layers separated. The organic layer was washed with saturated brine, dried (Na2SO4) and the volatiles removed by evaporation. The residue was purified by chromatography eluting with DCM/MeOH (98:2). The purified product was twice triturated with diethyl ether, collected by filtration and dried to give the title compound (33 mg, 16%) as a pale yellow solid. NMR: 1.37 (d, 3H), 1.57 (m, 1H), 1.92 (m, 1H), 2.07 (m, 2H), 2.97 (m, 1H), 4.25 (m, 1H), 4.65 (m, 1H), 7.02 (t, 2H), 7.15 (d, 1H), 7.33 (t, 2H), 7.72 (m, 3H), 8.38 (d, 1H), 9.42 (s. 1H); m/z 306.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[NH:10][C:9]3[N:17]=[CH:18][CH:19]=[CH:20][C:8]=3[N:7]=2)=[CH:2]1.[H-].[Na+].[CH3:23][N:24]([CH3:29])[CH2:25][CH2:26][CH2:27]Cl>>[CH3:23][N:24]([CH3:29])[CH2:25][CH2:26][CH2:27][N:10]1[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:6]([C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)=[N:7][C:8]2[CH:20]=[CH:19][CH:18]=[N:17][C:9]1=2
Reactant: c1cnc2c(c1)N=C(c1ccsc1)c1ccccc1N2
Reactant: CN(C)CCCCl
Agent: [H-]
Agent: [Na+]
Product: CN(C)CCCN1c2ccccc2C(c2ccsc2)=Nc2cccnc21

Procedure:
Following the procedure of Example 23, 6-(3-thienyl)-11H-pyrido[2,3-b][1,4]benzodiazepine is reacted with sodium hydride followed by reaction with 3-dimethylaminoproyl chloride to give the title compound.
Reaction SMILES: [C:1]1(=[O:8])O[C:5](=[O:6])[CH:4]=[C:2]1[CH3:3].[CH2:9]([NH2:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>N1C=CC=CC=1>[CH3:3][C:2]1[C:1](=[O:8])[N:17]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:5](=[O:6])[CH:4]=1
Reactant: CCCCCCCCN
Reactant: CC1=CC(=O)OC1=O
Solvent: c1ccncc1
Product: CCCCCCCCN1C(=O)C=C(C)C1=O
Temperature: 90 °C

Procedure:
A solution of citraconic anhydride (0.1 M) in pyridine (20 ml)was treated with octylamine (0.1 M). The reaction mixture was heated to 90° C. for six hours. The reaction mixture was then concentrated in vacuo and the residue was extracted into ethyl acetate. The ethyl acetate layer was washed with water and with cold aqueous hydrochloric acid, then dried over sodium sulphate and finally concentrated in vacuo. The residue obtained was chromatographed over silica gel to afford the desired product.
Reaction SMILES: CC1C=CC(S(NC2C=C(C3C=CC4N(C=C(NC(=O)C)N=4)N=3)C=CC=2)(=O)=O)=CC=1.Cl[C:32]1[CH:33]=[CH:34][C:35]2[N:36]([CH:38]=[C:39]([NH:41][C:42](=[O:44])[CH3:43])[N:40]=2)[N:37]=1.[CH3:45][S:46][C:47]1[CH:48]=[C:49](B(O)O)[CH:50]=[N:51][CH:52]=1>>[CH3:45][S:46][C:47]1[CH:48]=[C:49]([C:32]2[CH:33]=[CH:34][C:35]3[N:36]([CH:38]=[C:39]([NH:41][C:42](=[O:44])[CH3:43])[N:40]=3)[N:37]=2)[CH:50]=[N:51][CH:52]=1
Reactant: CSc1cncc(B(O)O)c1
Reactant: CC(=O)Nc1cn2nc(Cl)ccc2n1
Agent: CC(=O)Nc1cn2nc(-c3cccc(NS(=O)(=O)c4ccc(C)cc4)c3)ccc2n1
Product: CSc1cncc(-c2ccc3nc(NC(C)=O)cn3n2)c1

Procedure:
Following the procedure described for N-(6-(3-(4-methylphenylsulfonamido)phenyl)imidazo[1,2-b]pyridazin-2-yl)acetamide (Example 1), N-(6-chloroimidazo[1,2-b]pyridazin-2-yl)acetamide (Example 1, Step 4) (0.075 g, 0.36 mmol) was reacted with 5-(methylthio)pyridin-3-ylboronic acid (0.11 g, 0.64 mmol, Combi-Blocks, San Diego, Calif.) to afford the title compound as a white solid. MS (ESI positive ion) m/z: 300 (M+1). 1H NMR (400 MHz, DMSO-d6): δ ppm 10.94 (s, 1H), 9.00 (d, J=2.0 Hz, 1H), 8.60 (d, J=2.2 Hz, 1H), 8.34 (s, 1H), 8.27 (t, J=2.2 Hz, 1H), 8.12 (d, J=9.4 Hz, 1H), 7.90 (d, J=9.4 Hz, 1H), 2.64 (s, 3H), 2.12 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([NH:17][C:18](=[O:33])[C:19]1[CH:24]=[CH:23][C:22]([C:25]([N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[O:26])=[C:21]([CH3:32])[CH:20]=1)[C:7]1[NH:11][C:10]2[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:9]=2[N:8]=1.[C:34](Cl)(=[O:36])[CH3:35].C(N(CC)CC)C.ClCl>O1CCCC1.ClCCl.CO>[C:34]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([NH:17][C:18](=[O:33])[C:19]1[CH:24]=[CH:23][C:22]([C:25]([N:27]2[CH2:28][CH2:29][CH2:30][CH2:31]2)=[O:26])=[C:21]([CH3:32])[CH:20]=1)[C:7]1[NH:11][C:10]2[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:9]=2[N:8]=1)(=[O:36])[CH3:35]
Reactant: CC(=O)Cl
Reactant: Cc1cc(C(=O)N[C@@H](CCCCN)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Agent: ClCl
Solvent: CO
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(=O)NCCCC[C@H](NC(=O)c1ccc(C(=O)N2CCCC2)c(C)c1)c1nc2cc(Cl)ccc2[nH]1
Yield: 55 %

Procedure:
Prepared analogously to Example 23a from N-[(1S)-5-amino-1-(5-chloro-1H-benzimidazol-2-yl)pentyl]-3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzamide, acetyl chloride, and triethylamine in tetrahydrofuran. Yield: 55%; Rf value: 0.2 (silica gel; dichloromethane/methanol=9:1); C27H32ClN5O3 (510.04); mass spectrum: (M−H)−=510/512 (chlorine isotope).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH2:16][CH:17]([CH2:23][NH2:24])[CH2:18]3)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH2:25](Br)[CH:26]=[CH2:27].C(N(CC)CC)C>CN(C=O)C>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH2:16][CH:17]([CH2:23][NH:24][CH2:27][CH:26]=[CH2:25])[CH2:18]3)(=[O:12])=[O:11])=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: C=CCBr
Reactant: CC(C)c1ccc(S(=O)(=O)Nc2cccc3c2CC(CN)C3)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=CCNCC1Cc2cccc(NS(=O)(=O)c3ccc(C(C)C)cc3)c2C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 11.3 %

Procedure:
4-Isopropyl-N-(2-aminomethyl-indan-4-yl)-benzenesulfonamide (80 mg, 0.23 mmol), allyl bromide (30 mg, 0.23 mmol) and triethylamine (20 mg, 0.23 mmol) were dissolved in 2 mL of DMF and stirred at room temperature for 18 h. The solution was concentrated, water added and extracted with ethyl acetate. The organic phase was dried over MgSO4, filtered and the filtrate was evaporated in vacuo to give a residue which was purified by column chromatography using (dichloromethane-MeOH, 0-5%) to give a yellow oil (10 mg, 6%).
Reaction SMILES: C1C2N(C(=O)C[C@@H](CCC)C(O)=O)C3C(=CC=CC=3)C=2C=CC=1.C([O:28][C:29](=[O:59])[CH2:30][CH:31]([NH:36][C:37](=[O:58])[CH:38]([CH2:42][C:43]([N:45]1[C:57]2[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=2[C:51]2[C:46]1=[CH:47][CH:48]=[CH:49][CH:50]=2)=[O:44])[CH2:39][CH2:40][CH3:41])[C:32](=[O:35])[CH2:33][F:34])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:56]1[C:57]2[N:45]([C:43](=[O:44])[CH2:42][CH:38]([CH2:39][CH2:40][CH3:41])[C:37]([NH:36][CH:31]([C:32](=[O:35])[CH2:33][F:34])[CH2:30][C:29]([OH:59])=[O:28])=[O:58])[C:46]3[C:51](=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:52]=2[CH:53]=[CH:54][CH:55]=1
Reactant: CCCC(CC(=O)n1c2ccccc2c2ccccc21)C(=O)NC(CC(=O)OC(C)(C)C)C(=O)CF
Agent: CCC[C@H](CC(=O)n1c2ccccc2c2ccccc21)C(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCC(CC(=O)n1c2ccccc2c2ccccc21)C(=O)NC(CC(=O)O)C(=O)CF
Reaction time: 2 h
Yield: 5.6 %

Procedure:
A solution of [3S/R, (2R)]-3-[2-(2-carbazol-9-yl-2-oxo-ethyl)-pentanoylamino]-5-fluoro-4-oxo-pentanoic acid tert-butyl ester (1.43 g, 2.88 mmol) in anhydrous DCM (20 ml) was treated with a solution of TFA (10 ml) in anhydrous DCM (10 ml) with stirring. The mixture was stirred at 0° C. for 2 h then at room temperature for 2 h. The mixture was concentrated under reduced pressure and then the residue was dissolved in dry DCM. This process was repeated several times in order to remove excess trifluoroacetic acid. The off-white solid was recrystallized from Et2O/40/60 hexanes to give the title compound as a white powder (71 mg): IR (solid, cm−1) 1746, 1689, 1641, 1541, 1436, 1374, 1284, 1207, 1160 cm-1; 1H NMR (400 MHz, d6-DMSO) δ 0.80-1.00 (3H, m), 1.20-1.76 (4H, m), 2.30-2.90 (2H, m), 2.95-3.24 (1H, m), 3.26-3.59 (2H, m), 4.25-4.79 (1.5H, m) 5.02-5.43 (1.5H, m), 7.36-7.58 (4H, m), 8.10-8.30 (4H, m), 8.54-8.91 (1H, m); 13C NMR (100 MHz, DMSO) δ 14.31, 20.03, 20.13, 21.92, 22.51, 34.36, 34.77, 41.20, 41.62, 44.06, 51.77, 52.84, 83.45, 85.22, 116.70, 120.54, 123.91, 124.01, 127.85, 126.01, 138.20, 172.15, 172.36, 172.96, 173.00, 175.32, 175.48, 202.60, 203.10; 19F (376 MHz, DMSO) δ −226.68, −226.73, −231.21, −232.95, −233.38, −233.52.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([CH2:8][N:9]2[CH:13]=[CH:12][N:11]=[C:10]2[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[N:15]=2)[C:3]=1[CH2:21][CH2:22][CH3:23].C[O-].[Na+].[C:27](O)(=[O:29])C>CO>[F:20][C:16]1[N:15]=[C:14]([C:10]2[N:9]([CH2:8][C:4]3[C:3]([CH2:21][CH2:22][CH3:23])=[C:2]([O:29][CH3:27])[N:7]=[CH:6][N:5]=3)[CH:13]=[CH:12][N:11]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: CCCc1c(Cl)ncnc1Cn1ccnc1-c1cccc(F)n1
Reactant: CC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCc1c(Cn2ccnc2-c2cccc(F)n2)ncnc1OC

Procedure:
A solution of 6-chloro-4-[2-(6-fluoro-pyridin-2-yl)-imidazol-1-ylmethyl]-5-propyl-pyrimidine (0.23 mmol), sodium methoxide (0.46 mmol) in methanol (5 mL) is stirred at ROOM TEMPERATURE under N2 overnight. Acetic acid (0.23 mmol) is added, followed by water/acetic acetate work-up. On drying, the solvent is removed in vacuo. Preparative TLC separation gives the title compound. LC-MS (M+1) 328.2 (retention time: 1.01 min).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([C:16](=[O:18])[CH3:17])[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[Br-:20].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1>O1CCCC1>[C:1]([O:5][C:6](=[O:19])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([C:16](=[O:18])[CH2:17][Br:20])[N:15]=1)([CH3:9])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: [Br-]
Reactant: CC(=O)c1csc(SC(C)(C)C(=O)OC(C)(C)C)n1
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(C(=O)CBr)cs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
2-{[4-Acetyl-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester (15.90 g) obtained in Example 8 was dissolved in tetrahydrofuran (150 mL), phenyltrimethylammonium tribromide (21.81 g) was added by small portions over 15 min, and the mixture was stirred at room temperature overnight. The precipitated solid was filtered off, the solvent was evaporated, and the residue was dissolved in ethyl acetate (200 mL). The solution was washed successively with water and saturated aqueous sodium chloride solution (each 100 mL) and dried over anhydrous sodium sulfate. The solvent was evaporated and the obtained residue was purified by column chromatography (Yamazen HI-FLASH™ COLUMN size 3 L, elution solvent: hexane/ethyl acetate-90/10-50/50, performed in 5 times) to give the title compound (12.28 g).