Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3](=[O:16])[C:4]([CH3:15])([CH3:14])[CH2:5][S:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1.[NH:17]1[CH:21]=[CH:20][N:19]=[CH:18]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([S:6][CH2:5][C:4]([CH3:15])([CH3:14])[C:3](=[O:16])[CH2:2][N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)=[CH:8][CH:9]=1
Reactant: c1c[nH]cn1
Reactant: CC(C)(CSc1ccc(Cl)cc1)C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(CSc1ccc(Cl)cc1)C(=O)Cn1ccnc1
Yield: 81.7 %

Procedure:
199 g (0.618 mol) of 1-bromo-4-(4-chlorophenylsulphenyl)-3,3-dimethylbutan-2-one, 120 g (1.76 mols) of imidazole and 243.5 g (1.76 mols) of potassium carbonate in 3 liters of acetone are stirred under reflux for 5 hours. The mixture is then allowed to cool, the inorganic salts are filtered off with suction, and the filtrate is concentrated. The residue is taken up in methylene chloride, washed three times with water, dried over sodium sulphate, and concentrated. Recrystallizing from diisopropyl ether produces 156 g (82% of theory) of 4-(4-chlorophenylsulphenyl)-3,3-dimethyl-1-(imidazol-1-yl)-butan-2-one having a melting point of 50° C. ##STR118##
Reaction SMILES: [CH3:1][CH2:2][C@H:3]1[O:18][C:16](=[O:17])[C@H:15]([CH3:19])[C@@H:14]([O:20][C@@H:21]2[O:26][C@@H:25]([CH3:27])[C@H:24]([OH:28])[C@@:23]([O:30][CH3:31])([CH3:29])[CH2:22]2)[C@H:13]([CH3:32])[C@@H:12]([O:33][C@@H:34]2[O:39][C@H:38]([CH3:40])[CH2:37][C@H:36]([N:41]([CH3:43])[CH3:42])[C@H:35]2[OH:44])[C@@:11]([OH:46])([CH3:45])[CH2:10][C@@H:9]([CH3:47])[C:7](=[O:8])[C@H:6]([CH3:48])[C@@H:5]([OH:49])[C@@:4]1([OH:51])[CH3:50].O.[S-:53][C:54]#[N:55].[Na+]>C(O)(=O)C>[CH3:1][CH2:2][C@H:3]1[O:18][C:16](=[O:17])[C@H:15]([CH3:19])[C@@H:14]([O:20][C@@H:21]2[O:26][C@@H:25]([CH3:27])[C@H:24]([OH:28])[C@@:23]([O:30][CH3:31])([CH3:29])[CH2:22]2)[C@H:13]([CH3:32])[C@@H:12]([O:33][C@@H:34]2[O:39][C@H:38]([CH3:40])[CH2:37][C@H:36]([N:41]([CH3:42])[CH3:43])[C@H:35]2[OH:44])[C@@:11]([OH:46])([CH3:45])[CH2:10][C@@H:9]([CH3:47])[C:7](=[O:8])[C@H:6]([CH3:48])[C@@H:5]([OH:49])[C@@:4]1([OH:51])[CH3:50].[C:54]([SH:53])#[N:55]
Reactant: N#C[S-]
Agent: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(O)C[C@@H](C)C(=O)[C@H](C)[C@@H](O)[C@]1(C)O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: N#CS

Procedure:
Crude erythromycin (a mixture of erythromycin and other impurities) (30 g) was added into pure water (300 mL). The solution was stirred. Glacial acetic acid 20% (9.9 mL) was slowly added dropwise to the solution followed by stirring for 20 minutes. Then the mixture was filtered to remove the insoluble impurities in crude. Sodium thiocyanate solution 20% (18.4 mL, 0.038 mol) was added dropwise into the filtrate. The solution was stirred, adjusted to pH 7.2, and allowed to react for 1.5 h. After precipitation, the mixture was cooled for crystallization. The precipitate was filtered and washed with pure water for 3 times, and then dried to obtain erythromycin thiocyanate. The amount of the main component dried erythromycin A was 74.3% (detected by HPLC).
Reaction SMILES: [C:1]([O-])([O-])=O.[Na+].[Na+].Br[C:8]1[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1.B([C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1)(O)O.Cl>CC#N.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>[OH:14][C:10]1[CH:9]=[C:8]([C:18]2[CH:26]=[CH:25][C:21]([C:22]([O:24][CH3:1])=[O:23])=[CH:20][CH:19]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Oc1cccc(Br)c1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)c1ccc(-c2cccc(O)c2)cc1
Temperature: 90 °C
Yield: 57 %

Procedure:
An aqueous 0.4 M Na2CO3 solution (21.7 mL) was added to a solution of 3-bromophenol (500 mg, 2.89 mmol) and 4-boronobenzoic acid (480 mg, 2.89 mmol) in MeCN (14.5 mL). The mixture was degassed with argon (10 min) then Pd(PPh3)4 (168 mg, 0.14 mmol) was added. The reaction mixture was heated to 90° C. for 12 h. The cooled mixture was acidified with aqueous 1 N HCl solution and extracted with EtOAc. The organic layer was washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure. A solution of the residue in Et2O (150 mL) was treated with excess ethereal CH2N2 solution (ca. 0.6 M) then was concentrated under reduced pressure. The residue was purified by flash chromatography (Hexane:EtOAc, 85:15) to give the title compound (375 mg, 57% yield) as a yellow solid.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:10]([OH:19])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:21][C:22]1[CH:41]=[CH:40][C:25]([O:26][CH2:27][C:28]2[N:29]=[C:30]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[O:31][C:32]=2[CH3:33])=[C:24]([O:42][CH3:43])[CH:23]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:10]([O:19][CH2:21][C:22]2[CH:41]=[CH:40][C:25]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[O:31][C:32]=3[CH3:33])=[C:24]([O:42][CH3:43])[CH:23]=2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(CCl)ccc1OCc1nc(-c2ccccc2)oc1C
Reactant: CCOC(=O)Cc1cn(Cc2ccccc2)nc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1cn(Cc2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)c(OC)c1
Temperature: 60 °C
Reaction time: 5 h
Yield: 55.7 %

Procedure:
A mixture of ethyl (1-benzyl-3-hydroxy-1H-pyrazol-4-yl)acetate (521 mg), 4-(4-chloromethyl-2-methoxyphenoxymethyl)-5-methyl-2-phenyloxazole (687 mg), potassium carbonate (553 mg) and N,N-dimethylformamide (10 ml) was stirred at 60° C. for 5 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and ethyl [1-benzyl-3-[3-methoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxy]-1H-pyrazol-4-yl]acetate (632 mg, yield 56%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:2, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 86–87° C.
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC([I:28])(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F.O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[I:28][C:8]#[C:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C#Cc1ccccc1
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)I
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Product: IC#Cc1ccccc1
Yield: 55.3 %

Procedure:
In a 10 mL round-bottom flask, 1.02 g of phenylacetylene (10 mmol), 4.46 g of perfluoro-n-hexyl iodide (10 mmol), and 300 mg of tetra-n-butylammonium fluoride trihydrate (0.948 mmol) were mixed at 24° C. for 1 h. Gas chromatographic analysis of the resulting mixture showed that it contained 1.26 g of 1-iodo-2phenylacetylene (55% yield) and 0.45 g of unconverted phenylacetylene.
Reaction SMILES: C[Al](C)C.[CH:5]([NH2:8])([CH3:7])[CH3:6].C[O:10][C:11]([C:13]1[N:14]=[N:15][C:16]([O:19][CH2:20][C:21]2[C:22]([CH2:27][CH2:28][CH2:29][CH3:30])=[N:23][O:24][C:25]=2[CH3:26])=[CH:17][CH:18]=1)=O>C1(C)C=CC=CC=1.O1CCOCC1>[CH:5]([NH:8][C:11]([C:13]1[N:14]=[N:15][C:16]([O:19][CH2:20][C:21]2[C:22]([CH2:27][CH2:28][CH2:29][CH3:30])=[N:23][O:24][C:25]=2[CH3:26])=[CH:17][CH:18]=1)=[O:10])([CH3:7])[CH3:6]
Reactant: CC(C)N
Reactant: CCCCc1noc(C)c1COc1ccc(C(=O)OC)nn1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: CCCCc1noc(C)c1COc1ccc(C(=O)NC(C)C)nn1
Temperature: 90 °C
Reaction time: 1 h
Yield: 37.6 %

Procedure:
Trimethylaluminium (0.72 mL of a 2 M solution in toluene, 1.44 mmol) was added dropwise to a stirred solution of isopropylamine (85 mg, 1.44 mmol) in dioxane (3 mL) at room temperature under argon. After 1 h, a solution of 6-(3-butyl-5-methyl-isoxazol-4-ylmethoxy)-pyridazine-3-carboxylic acid methyl ester (110 mg, 0.36 mmol) in dioxane (3 mL) was added and the reaction mixture heated at 90° C. After 2 h the reaction mixture was cooled in an ice/water bath and quenched with Seignette salt solution (1 mL). The resultant mixture was filtered, the filter cake washed with dichloromethane, then the combined filtrates were concentrated then purified by chromatography (silica, 0 to 80% ethyl acetate in heptane) to give the title compound (45 mg, 38%) as a colourless oil. MS: m/e=333.4 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:11](N(OC)C)=[O:12])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[Mg][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=1>C1COCC1>[CH3:26][O:25][C:21]1[CH:20]=[C:19]([C:11](=[O:12])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH3:10])[CH:24]=[CH:23][CH:22]=1
Reactant: CON(C)C(=O)[C@H](C)NC(=O)OC(C)(C)C
Reactant: COc1cccc([Mg]Br)c1
Solvent: C1CCOC1
Product: COc1cccc(C(=O)[C@H](C)NC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a stirred solution of N2-(tert-butoxycarbonyl)-N-methoxy-N-methyl-L-alaninamide (777 mg, 3.3 mmol) in dry THF (50 ml) was added a solution of bromo(3-methoxyphenyl)magnesium (1M in THF, 10 ml, 10 mmol). The mixture was stirred at r.t. for 5 h, then quenched with saturated aqueous NH4Cl (50 ml). After stirring for 30 min, the layers were separated, the aqueous layer extracted with ethyl acetate (50 ml). The combined organic layers were dried with Na2SO4, and the solvent was removed in vacuo. The subtitle compound was isolated by flash chromatography on silica gel (n-heptane/ethyl acetate, gradient from 20 to 50% ethyl acetate). Yield 471 mg (94%).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([OH:13])=[O:12])[CH:6]=[CH:7][CH:8]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([OH:13])=[O:12])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(-c2ccccc2C(=O)O)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(O)c1ccccc1-c1cccc(O)c1
Temperature: -78 °C
Reaction time: 8 h

Procedure:
2-(3-Methoxyphenyl)benzoic acid from Step B (6.53 g, 28.6 mmol) was dissolved in dry CH2Cl2 (100 mL) under argon and cooled to −78° C. Boron tribromide (62.9 mL of a 1.0 M solution in CH2Cl2, 62.9 mmol) was added dropwise and the solution was stirred overnight and allowed to warm slowly to ambient temperature. The resulting mixture was cooled in an ice bath and quenched carefully with water (200 mL), then extracted with CH2Cl2 (3×250 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure to give the titled product which was sufficiently pure for use in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[CH:11]=1.[C:24]1([S:30](Cl)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])O.[Na+]>O1CCCC1>[C:24]1([S:30]([NH:1][C:2]2[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=2)[O:5][C:6]2[CH:7]=[CH:8][C:9]3[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]4[CH2:20][CH2:19]4)=[O:17])[N:14]=3)[CH:11]=2)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(Nc1cn2cc(Oc3cccc(NS(=O)(=O)c4ccccc4)c3)ccc2n1)C1CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 40.5 %

Procedure:
A mixture of N-[6-(3-aminophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (18.6 mg, 0.060 mmol), benzenesulfonyl chloride (12.8 μL, 0.100 mmol), tetrahydrofuran (3 mL) and aqueous sodium hydrogen carbonate solution (2 mL) was stirred at room temperature for 4 hr. The reaction mixture was extracted with ethyl acetate. The organic layer was concentrated, and the residue was purified by preparative HPLC to give the title compound (10.9 mg, 41%).
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:11])[C:4](=[O:10])[C@@H:5]1[CH2:9][CH2:8][CH2:7][NH:6]1.C(N(CC)CC)C.S=[C:20]1[CH2:24][S:23][C:22](=[O:25])[NH:21]1>C(O)C>[CH3:2][N:3]([CH3:11])[C:4](=[O:10])[C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:20]1[CH2:24][S:23][C:22](=[O:25])[N:21]=1
Reactant: O=C1NC(=S)CS1
Reactant: CN(C)C(=O)[C@@H]1CCCN1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CN(C)C(=O)[C@@H]1CCCN1C1=NC(=O)SC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of the crude product containing N,N-dimethyl-L-prolinamide hydrochloride obtained in B) (10.5 g) and triethylamine (13.6 g) in ethanol (100 mL) was added 4-thioxothiazolidin-2-one (6.0 g) at room temperature. The reaction mixture was stirred at room temperature for 3 hr, and the solvent was evaporated under reduced pressure. The obtained solid was suspended in THF, and the suspension was filtered through celite pad and silica gel pad. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate) to give the title compound (4.3 g).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[N:14]([C:15]=2[C:16]([CH3:18])=[O:17])[CH:13]=[CH:12][CH:11]=[CH:10]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[C:21](OCC)(=[O:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23]>C1C=CC=CC=1>[C:1]1([C:7]2[CH:8]=[C:9]3[N:14]([C:15]=2[C:16](=[O:17])[CH2:18][C:21](=[O:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:13]=[CH:12][CH:11]=[CH:10]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)c1c(-c2ccccc2)cc2ccccn12
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CCOC(=O)C(=O)CC(=O)c1c(-c2ccccc2)cc2ccccn12
Temperature: 60 °C
Yield: 81.9 %

Procedure:
To a solution of 25.7 g of methyl 2-phenyl-3-indolizinyl ketone in 360 ml of benzene were added 8.3 g of 50% sodium hydride and 28.2 g of diethyl oxalate, and the mixture was heated at 60° C. for 30 minutes. After cooling, the benzene was distilled off. To the residue was added 200 ml of water and the aqueous solution was acidified with acetic acid. Crystals precipitated were filtered off and washed with water, and then recerystallized from ethanol to give 30 g of ethyl 4-(2-phenyl-3-indolizinyl)-2,4-dioxobutyrate, melting at 100°-102° C.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[S:4].[OH:7][C:8]1[C:15]([O:16][CH3:17])=[CH:14][C:13]([CH3:18])=[CH:12][C:9]=1[CH:10]=[O:11].[OH-].[K+]>O1CCCC1.O>[CH3:1][N:2]([CH3:6])[C:3]([O:7][C:8]1[C:15]([O:16][CH3:17])=[CH:14][C:13]([CH3:18])=[CH:12][C:9]=1[CH:10]=[O:11])=[S:4]
Reactant: COc1cc(C)cc(C=O)c1O
Reactant: CN(C)C(=S)Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(C)cc(C=O)c1OC(=S)N(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
100 ml (0.8 mol) of dimethylthiocarbamoyl chloride in 150 ml of tetrahydrofuran are added at 5°-10° C. to 100 g (0.6 mol) of 2-hydroxy-3-methoxy-5-methylbenzaldehyde and 33.6 g (0.6 mol) of potassium hydroxide in 400 ml of water. The mixture is stirred at 25° C. for 15 min and, after adding 200 ml of 10% strength aqueous potassium hydroxide solution, extracted with ethyl acetate, the organic phase is washed with water and dried with sodium sulphate and, after concentrating in vacuo, the residue is recrystallised from ethanol.
Reaction SMILES: O.[NH2:2][NH2:3].[Br:4][C:5]1[C:12]([F:13])=[C:11]([F:14])[C:8]([C:9]#[N:10])=[C:7](F)[C:6]=1[F:16].O>C(O)C>[Br:4][C:5]1[C:6]([F:16])=[C:7]2[C:8]([C:9]([NH2:10])=[N:2][NH:3]2)=[C:11]([F:14])[C:12]=1[F:13]
Reactant: NN
Reactant: N#Cc1c(F)c(F)c(Br)c(F)c1F
Solvent: CCO
Solvent: O
Product: Nc1n[nH]c2c(F)c(Br)c(F)c(F)c12

Procedure:
1.14 cm3 of hydrazine monohydrate are added to 2.0 g of 4-bromo-2,3,5,6-tetrafluorobenzonitrile in 40 cm3 of absolute ethanol. The mixture is refluxed for 18 hours, 30 cm3 of distilled water are then added and the reaction medium is concentrated under reduced pressure (2 kPa; 50° C.). The residue is taken up in 100 cm3 of ethyl acetate and 10 cm3 of water, and the organic phase is separated out after settling of the phases has taken place, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2 kPa; 50° C.); after drying (90 Pa; 40° C.), 2.1 g of 6-bromo-4,5,7-trifluoro-1H-indazole-3-amine are obtained in the form of a beige-coloured solid.
Reaction SMILES: [C:1]([C:5]1[CH:23]=[CH:22][C:8]([CH2:9][NH:10][C:11](=O)[C:12]([F:20])([F:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>C1COCC1>[C:1]([C:5]1[CH:23]=[CH:22][C:8]([CH2:9][NH:10][CH2:11][C:12]([F:20])([F:19])[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(CNC(=O)C(F)(F)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(CNCC(F)(F)c2ccccc2)cc1
Yield: 38.7 %

Procedure:
Borane-tetrahydrofuran complex solution (1 M in THF, 1.89 mL, 1.89 mmol) was added at 0° C. to a solution of N-(4-tert-butyl-benzyl)-2,2-difluoro-2-phenyl-acetamide (200 mg, 0.63 mmol) in THF (3.2 mL), then the ice bath was removed and the solution heated to reflux over 16 h. After cooling, the reaction was quenched by careful addition of 1 M aq. hydrochloric acid solution. The reaction mixture was neutralized with aq. sodium hydroxide solution and extracted with DCM. The organic layer was washed with brine, dried (MgSO4), evaporated, and chromatographed (SiO2, heptane-ethyl acetate gradient). The fractions containing the product were concentrated, the residue dissolved in 5% ethanolic sulfuric acid solution (2 mL). This solution was heated at reflux for 2 h, neutralized with 2 M aq. sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4), and evaporated to produce the title compound (74 mg, 39%). Light yellow oil, MS (ISP) 304.3 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[C:6]([C:8]2(Cl)[NH:13][C:12]([NH2:14])=[N:11][CH:10]=[CH:9]2)[CH:7]=1.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[C:6]([C:8]2[N:13]=[C:12]([NH2:14])[N:11]=[C:10]([NH:34][C:31]3[CH:32]=[CH:33][C:28]([Cl:27])=[CH:29][CH:30]=3)[CH:9]=2)[CH:7]=1
Reactant: NC1=NC=CC(Cl)(c2cc(Br)ccc2OCc2ccc([N+](=O)[O-])cc2)N1
Reactant: Nc1ccc(Cl)cc1
Product: Nc1nc(Nc2ccc(Cl)cc2)cc(-c2cc(Br)ccc2OCc2ccc([N+](=O)[O-])cc2)n1
Yield: 82 %

Procedure:
Following the method described in Example 4, 6-[5-bromo-2-(4-nitro-benzyloxy)-phenyl]-6-chloro-pyrimidin-2-ylamine and 4-chloro-phenylamine provided the title compound (82% yield) as its hydrochloride salt. 1H NMR (DMSO-d6) δ 5.42 (s, 2H, CH2), 6.55 (s, 1H, Ar), 7.29 (d, 1H, J=9.4 Hz, Ar), 7.45 (d, 2H, J=8.8 Hz, Ar), 7.72-7.84 (m, 6H, Ar), 8.24 (d, 2H, J=8.7 Hz, Ar).
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:3]=1[N:4]([CH2:12][C:13]([CH3:15])=O)[C:5]([C:7]1[O:8][CH:9]=[CH:10][CH:11]=1)=[O:6].[Cl-].[OH:22][NH3+:23].C(N(CC)CC)C>C(O)C.C(Cl)Cl>[CH3:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:3]=1[N:4]([C:5]([C:7]1[O:8][CH:9]=[CH:10][CH:11]=1)=[O:6])[CH2:12][C:13](=[N:23][OH:22])[CH3:15]
Reactant: CC(=O)CN(C(=O)c1ccco1)c1c(C)cccc1C
Reactant: [NH3+]O
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: ClCCl
Product: CC(CN(C(=O)c1ccco1)c1c(C)cccc1C)=NO
Yield: 85.2 %

Procedure:
27.1 g (0.1 mol) of 2,6-dimethyl-N-acetonyl-N-(2-furoyl)-aniline, 14 g (0.2 mol) of hydroxyammonium chloride and 15 ml of triethylamine in 150 ml of ethanol were heated under reflux for 3 hours. The reaction mixture was then largely freed from solvent in vacuo, the residue was taken up in methylene chloride and the methylene chloride mixture was washed with water, dried over sodium sulphate and concentrated. The crystalline residue was triturated with ether and the solid was filtered off. 24.4 g (85% of theory) of 2,6-dimethyl-N-(2-furoyl)-N-(2-hydroxyimino-prop-1-yl)-aniline of melting point 155°-156° C. were obtained.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][N:15]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[NH:17][C:16]3=[O:24])[CH2:8][CH2:7]2)[N:5]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:4][N:3]1[CH2:31][C:32]1[CH:33]=[C:34]([CH:42]=[CH:43][CH:44]=1)[C:35]([O:37]C(C)(C)C)=[O:36].Cl>O1CCOCC1>[O:1]=[C:2]1[C:6]2([CH2:7][CH2:8][N:9]([CH2:12][CH2:13][CH2:14][N:15]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[NH:17][C:16]3=[O:24])[CH2:10][CH2:11]2)[N:5]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:4][N:3]1[CH2:31][C:32]1[CH:33]=[C:34]([CH:42]=[CH:43][CH:44]=1)[C:35]([OH:37])=[O:36]
Reactant: CC(C)(C)OC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCN(CCCn4c(=O)[nH]c5ccccc54)CC3)C2=O)c1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)c1cccc(CN2CN(c3ccccc3)C3(CCN(CCCn4c(=O)[nH]c5ccccc54)CC3)C2=O)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To tert-butyl 3-((4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (0.86 g, 1.44 mmol) was added 4M solution of HCl in dioxane (10 mL). After stirring at room temperature for 4 hours, the reaction mixture was concentrated in vacuo and lyophilized in acetonitrile/water (1:1) to obtain the title compound as a hydrochloride salt (0.8 g); 1H NMR (DMSO-d6): δ 1.89 (d, 2H, J=14.4 Hz), 2.15 (t, 2H, J=6.4 Hz), 2.90-2.96 (m, 2H), 3.19-3.22 (m, 2H), 3.50-3.66 (m, 6H), 3.90 (t, 2H, J=7.2 Hz), 4.63-4.66 (m, 4H), 6.76 (t, 1H, J=7.2 Hz), 6.99-7.04 (m, 5H), 7.18-7.24 (m, 3H), 7.50-7.57 (m, 2H), 10.77 (br, 1H), 10.91 (s, 1H), 13.01 (br, 1H); MS for C31H33N5O4 m/z 540.07 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[C:9]3[CH:15]=[CH:14][NH:13][C:10]3=[N:11][CH:12]=2)[CH:4]=[N:3]1.[CH3:16][C:17]1[CH:18]=[CH:19][C:20]2[N:21]([C:23]([SH:26])=[N:24][N:25]=2)[N:22]=1.II>CN(C=O)C>[CH3:16][C:17]1[CH:18]=[CH:19][C:20]2[N:21]([C:23]([S:26][C:15]3[C:9]4[C:10](=[N:11][CH:12]=[C:7]([C:5]5[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=5)[CH:8]=4)[NH:13][CH:14]=3)=[N:24][N:25]=2)[N:22]=1
Reactant: Cn1cc(-c2cnc3[nH]ccc3c2)cn1
Reactant: Cc1ccc2nnc(S)n2n1
Agent: II
Solvent: CN(C)C=O
Product: Cc1ccc2nnc(Sc3c[nH]c4ncc(-c5cnn(C)c5)cc34)n2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 11.2 %

Procedure:
To a solution of 5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine (28 mg, 0.141 mmol) and 6-methyl-[1,2,4]triazolo[4,3-b]pyridazine-3-thiol (35.3 mg, 0.212 mmol) in DMF (700 μL) was added iodine (72 μL, 0.283 mmol). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was then filtered and purified by mass-triggered HPLC (5-95% CH3CN/H2O, 0.1% HCOOH modifier) to provide 5.7 mg of 6-methyl-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-ylsulfanyl]-[1,2,4]triazolo[4,3-b]pyridazine (11% yield).
Reaction SMILES: [CH3:1][C:2]([N:11]1[CH:15]=[C:14]([N+:16]([O-])=O)[N:13]=[CH:12]1)([CH3:10])[CH2:3][NH:4][CH2:5][C:6]([CH3:9])([CH3:8])[CH3:7].[F:19][C:20]1[CH:21]=[C:22]([CH2:27][C:28]([NH:30][C@@H:31]([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)[C:32](O)=[O:33])=[O:29])[CH:23]=[C:24]([F:26])[CH:25]=1>>[F:19][C:20]1[CH:21]=[C:22]([CH2:27][C:28]([NH:30][CH:31]([C:35]2[CH:36]=[CH:37][C:38]([F:41])=[CH:39][CH:40]=2)[C:32]([NH:16][C:14]2[N:13]=[CH:12][N:11]([C:2]([CH3:10])([CH3:1])[CH2:3][NH:4][CH2:5][C:6]([CH3:9])([CH3:8])[CH3:7])[CH:15]=2)=[O:33])=[O:29])[CH:23]=[C:24]([F:26])[CH:25]=1
Reactant: O=C(Cc1cc(F)cc(F)c1)N[C@H](C(=O)O)c1ccc(F)cc1
Reactant: CC(C)(C)CNCC(C)(C)n1cnc([N+](=O)[O-])c1
Product: CC(C)(C)CNCC(C)(C)n1cnc(NC(=O)C(NC(=O)Cc2cc(F)cc(F)c2)c2ccc(F)cc2)c1

Procedure:
2-methyl-N-neopentyl-2-(4-nitro-1H-imidazol-1-yl)propan-1-amine (U.S. Ser. No. 11/078,898 filed Mar. 11, 2005) was reduced and coupled with (S)-2-(2-(3,5-difluorophenyl)acetamido)-2-(4-fluorophenyl)acetic acid to afford the title compound: MS 530 m/z (M+1).