Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[N:7]2[CH:8]=[C:9]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[CH:10]=[C:11]([CH3:12])[C:6]2=[N:5][CH:4]=1)#[CH:2].[OH:23][CH2:24][C:25]([NH:28][S:29]([C:32]1[CH:33]=[N:34][CH:35]=[C:36](Br)[CH:37]=1)(=[O:31])=[O:30])([CH3:27])[CH3:26]>>[OH:23][CH2:24][C:25]([NH:28][S:29]([C:32]1[CH:33]=[N:34][CH:35]=[C:36]([C:2]#[C:1][C:3]2[N:7]3[CH:8]=[C:9]([C:13]4[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:22])[F:20])=[CH:15][CH:14]=4)[CH:10]=[C:11]([CH3:12])[C:6]3=[N:5][CH:4]=2)[CH:37]=1)(=[O:31])=[O:30])([CH3:27])[CH3:26]
Reactant: C#Cc1cnc2c(C)cc(-c3ccc(C(F)(F)F)cc3)cn12
Reactant: CC(C)(CO)NS(=O)(=O)c1cncc(Br)c1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cn2c(C#Cc3cncc(S(=O)(=O)NC(C)(C)CO)c3)cnc12

Procedure:
The title compound was prepared from 3-ethynyl-8-methyl-6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine (example C.20) (300 mg, 1 mmol) and 5-bromo-pyridine-3-sulfonic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (example B.2) (278 mg, 0.9 mmol) according to general procedure II. Obtained as a white solid (60 mg, 11%). MS (ISP) 529.1 [(M+H)+]; mp 189° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:13]([CH2:14][CH2:15][CH3:16])[CH2:12][N:11]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:10][CH:9]2[OH:24])=[CH:4][CH:3]=1.Cl[CH2:26][C:27]1[N:31]([CH2:32][CH3:33])[C:30]2[CH:34]=[CH:35][CH:36]=[CH:37][C:29]=2[N:28]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH:13]([CH2:14][CH2:15][CH3:16])[CH2:12][N:11]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:10][CH:9]2[O:24][CH2:26][C:27]2[N:31]([CH2:32][CH3:33])[C:30]3[CH:34]=[CH:35][CH:36]=[CH:37][C:29]=3[N:28]=2)=[CH:6][CH:7]=1
Reactant: CCn1c(CCl)nc2ccccc21
Reactant: CCCC1CN(C(=O)OC(C)(C)C)CC(O)C1c1ccc(Cl)cc1
Product: CCCC1CN(C(=O)OC(C)(C)C)CC(OCc2nc3ccccc3n2CC)C1c1ccc(Cl)cc1

Procedure:
In an analogous manner to that described in Example 62(h), by alkylating tert-butyl (3RS,4RS,5SR)-4-(4-chloro-phenyl)-3-hydroxy-5-propyl-piperidine-1-carboxylate with 2-chloromethyl-1-ethyl-1H-benzoimidazole [Acta Pol. Pharm. 1977, 34(4), 359-369] there was obtained tert-butyl (3RS,4RS,5SR)-4-(4-chloro-phenyl)-3-(1-ethyl-1H-benzimidazol-2-ylmethoxy)-5-propyl-piperidine-1-carboxylate as a colourless oil, MS: 495 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[C:8]=2[Cl:15])[N:5]=[CH:4][C:3]=1[C:16]([OH:18])=O.S(Cl)([Cl:21])=O>>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[C:8]=2[Cl:15])[N:5]=[CH:4][C:3]=1[C:16]([Cl:21])=[O:18]
Reactant: O=S(Cl)Cl
Reactant: Nc1c(C(=O)O)cnn1-c1ccc(Cl)c(Cl)c1Cl
Product: Nc1c(C(=O)Cl)cnn1-c1ccc(Cl)c(Cl)c1Cl

Procedure:
5-Amino-1-(2,3,4-trichlorophenyl)pyrazol-4-yl carboxylic acid (54 g) and thionyl chloride (75 ml) were heated together under reflux for one hour. The reaction mixture was then evaporated to dryness and residual thionyl chloride was removed by evaporation in the presence of toluene (3×200 ml) to give 5-amino-1-(2,3,4-trichlorophenyl)pyrazol-4-yl carbonyl chloride, in the form of a dark coloured oil which was used in the preparation described in Example 11 without further purification.
Reaction SMILES: [CH3:1][CH:2]([NH:4][C:5]([NH:7][S:8]([C:11]1[C:12]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=2)=[N:13][C:14](S(C)=O)=[N:15][CH:16]=1)(=[O:10])=[O:9])=[O:6])[CH3:3].[CH3:28][NH2:29].[OH-].[Na+].C(O)(=O)C>O.C(O)C>[CH3:28][NH:29][C:14]1[N:13]=[C:12]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=2)[C:11]([S:8]([NH:7][C:5]([NH:4][CH:2]([CH3:3])[CH3:1])=[O:6])(=[O:10])=[O:9])=[CH:16][N:15]=1
Reactant: CN
Reactant: Cc1cccc(Nc2nc(S(C)=O)ncc2S(=O)(=O)NC(=O)NC(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: CNc1ncc(S(=O)(=O)NC(=O)NC(C)C)c(Nc2cccc(C)c2)n1
Temperature: 45 °C
Reaction time: 5 h
Yield: 88 %

Procedure:
N-[[(1-Methylethyl)amino]carbonyl]-4-[(3-methylphenyl)amino]-2-(methylsulfinyl)-5-pyrimidinesulfonamide (1.39 g, 3.38 mmol) was suspended in water (20 mL) and aqueous methylamine (6 mL, 40 wt % in H2O) was added to form a homogeneous solution. The mixture was stirred for five hours at 45° C., then diluted with an equal volume of ethanol and the solvents removed under reduced pressure to give a solid residue. The residue was suspended in water (20 mL) and 1.0N sodium hydroxide was added until the solution became homogeneous. Aqueous acetic acid 10% was added dropwise to form a white solid precipitate. The solid was filtered, washed three times, and dried in a vacuum oven at 75° C. overnight to yield 1.12 g (2.96 mmol, 88%) of pure product, m.p. 206°-207° C., as a white solid.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[C:11]([O:15][C:16]([NH:18][C@H:19]1[CH2:23][C@@H:22]([C:24]([O:26][CH3:27])=[O:25])[CH:21]=[CH:20]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].Cl[CH2:29][O:30][CH2:31][CH3:32]>O1CCCC1>[C:11]([O:15][C:16]([NH:18][C@H:19]1[CH2:23][C@@:22]([CH2:29][O:30][CH2:31][CH3:32])([C:24]([O:26][CH3:27])=[O:25])[CH:21]=[CH:20]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CCOCCl
Reactant: COC(=O)[C@H]1C=C[C@@H](NC(=O)OC(C)(C)C)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC[C@]1(C(=O)OC)C=C[C@@H](NC(=O)OC(C)(C)C)C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 662 %

Procedure:
To a 1.0 M solution of lithium hexamethyldisilazide in tetrahydrofuran (36.7 mL, 36.7 mmol) was added a solution of methyl (1R,4S)-4-[(tert-butoxycarbonyl)amino]cyclopent-2-ene-1-carboxylate (4.00 g, 1.66 mmol) in tetrahydrofuran (6.0 mL) at −78° C. The resulting light brown solution was stirred at −78° C. for 30 min before (chloromethoxy)ethane (1.88 g, 19.9 mol) was added in one portion. The mixture was stirred at −78° C. for 1 h and then kept in a freezer reading at −25° C. overnight. The reaction was then quenched with saturated NH4Cl (50 mL). The organic layer was separated and the aqueous layer was extracted with CH2Cl2 three times. The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated, and purified by flash chromatography (0 to 15% EtOAC in hexanes) to provide the desired product (3.29 g, 66%) as a cis/trans (3:2) mixture based on the analysis on reverse phase HPLC. MS calculated for C15H26NO5: (M+H) 300.2; found 200.2 (M+H-Boc).
Reaction SMILES: C1(C[N:8]([CH2:16][C@@H:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][C@H:18]2[OH:27])CC2C=CC=CC=2)C=CC=CC=1.[H][H]>CO.[Pd]>[NH2:8][CH2:16][C@@H:17]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][C@H:18]1[OH:27]
Reactant: [H][H]
Reactant: CCCCN1CC[C@@H](CN(Cc2ccccc2)Cc2ccccc2)[C@H](O)C1
Agent: [Pd]
Solvent: CO
Product: CCCCN1CC[C@@H](CN)[C@H](O)C1
Yield: 93.8 %

Procedure:
A mixture of intermediate (29) (0.079 mol) in methanol (250 ml) was hydrogenated with palladium-on-carbon (10%) (2 g) as a catalyst. After uptake of hydrogen (2 equivalents), the catalyst was filtered over celite and the filtrate was evaporated, yielding 13.8 g of (trans)-4-(aminomethyl)-1-butyl-3-piperidinol (intermediate 30).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10]([S:13][C:14]3[CH:15]=[C:16]([C:20]4([C:26]#[N:27])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[CH:17]=[CH:18][CH:19]=3)=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1.[OH-:28].[K+].O>CC(O)(C)C>[CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10]([S:13][C:14]3[CH:15]=[C:16]([C:20]4([C:26]([NH2:27])=[O:28])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[CH:17]=[CH:18][CH:19]=3)=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1
Reactant: [OH-]
Reactant: Cc1nccn1-c1ccc(Sc2cccc(C3(C#N)CCOCC3)c2)cc1
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: Cc1nccn1-c1ccc(Sc2cccc(C3(C(N)=O)CCOCC3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.1 %

Procedure:
4-{3-[4-(2-Methyl-imidazol-1-yl)-phenyl sulfanyl]-phenyl}-tetrahydro-pyran-4-carbonitrile (27.35 g) were dissolved in t-BuOH (280 mL) at 50° C. To the solution, KOH (12.28 g) was added and the mixture was stirred overnight. The suspension was cooled to room temperature and water (180 mL) was added. The suspension obtained was filtered and the filtercake was dried at 50° C. to yield 4-{3-[4-(2-Methyl-imidazol-1-yl)-phenyl sulfanyl]-phenyl}tetrahydro-pyran-4-carboxylic acid amide (17.52 g, 55% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][C:13](Cl)=[O:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(=S)=S.O>[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:13](=[O:14])[CH2:12][CH2:11][CH2:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[CH:19][CH:18]=1
Reactant: Fc1ccccc1
Reactant: O=C(Cl)CCCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: S=C=S
Product: O=C(CCCc1ccc([N+](=O)[O-])cc1)c1ccc(F)cc1
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
A solution of 4-(4-nitrophenyl)butyryl chloride (5.4 g, 23.7 mmol) and 4-fluorobenzene (2.6 mL, 26.2 mmol) dissolved in carbon disulfide (25 mL) was treated in portions with aluminum chloride (4.1 g, 30.75 mmol) under a nitrogen atmosphere. After the addition was complete, the reaction mixture was heated to 60-70° C. for about 12 hours. The resulting mixture was cooled in an ice bath, treated with concentrated hydrochloride acid (12 mL), and stirred for 30 minutes. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was separated, washed with 1 N aqueous sodium hydroxide, water, and brine, dried and evaporated in vacuo. Purification by silica gel chromatography, eluting with 5% ethyl acetate/hexane gave the title compound as a white solid (3.81 g, 56%). The product was used in the next step.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[C:5]2[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=2[N:3]=1.[F:12][CH:13]([F:31])[N:14]1[C:22]2[C:17](=[N:18][CH:19]=[CH:20][CH:21]=2)[N:16]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)[C:15]1=[O:30].[H-].[Na+]>CN(C=O)C.CO>[F:31][CH:13]([F:12])[N:14]1[C:22]2[C:17](=[N:18][CH:19]=[CH:20][CH:21]=2)[N:16]([C:23]2[CH:28]=[CH:27][C:26]([O:29][C:2]3[N:6]([CH3:7])[C:5]4[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=4[N:3]=3)=[CH:25][CH:24]=2)[C:15]1=[O:30]
Reactant: O=c1n(-c2ccc(O)cc2)c2ncccc2n1C(F)F
Reactant: Cn1c(Cl)nc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: Cn1c(Oc2ccc(-n3c(=O)n(C(F)F)c4cccnc43)cc2)nc2ccccc21
Temperature: 180 °C
Yield: 46.7 %

Procedure:
2-Chloro-1-methyl-1H-benzimidazole (70 mg) was added to a solution of 1-(difluoromethyl)-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (122 mg) and NaH (25.2 mg) in DMF (3 mL) at 100° C. The mixture was heated at 180° C. for 1 h under microwave irradiation. The reaction mixture was diluted with MeOH and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 0%-50% EtOAc in hexane) to give 1-(difluoromethyl)-3-{4-[(1-methyl-1H-benzimidazol-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (80 mg) as white crystals.
Reaction SMILES: [O:1]1[C:6]([C:7](=[N:13][O:14][CH2:15][CH2:16][CH3:17])[C:8]([O:10]CC)=[O:9])=[CH:5][S:4][CH2:3][CH2:2]1.[OH-].[Na+]>CO>[O:1]1[C:6]([C:7](=[N:13][O:14][CH2:15][CH2:16][CH3:17])[C:8]([OH:10])=[O:9])=[CH:5][S:4][CH2:3][CH2:2]1
Reactant: CCCON=C(C(=O)OCC)C1=CSCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCON=C(C(=O)O)C1=CSCCO1
Temperature: 25 °C
Reaction time: 18 h
Yield: 33.6 %

Procedure:
Ethyl 2-(2,3-dihydro-1,4-oxathiin-6-yl)-2-n-propoxyiminoacetate (mixture of syn isomer and anti isomer, 1 g.) was added to a mixture of methanol (10 ml.) and 1N aqueous solution of sodium hydroxide (6 ml.), and stirred at room temperature for 18 hours. After distilling off the methanol from the resultant solution in vacuo, a saturated aqueous solution of sodium bicarbonate (15 ml.) and ethyl acetate (15 ml.) were added to the residue and shaken sufficiently. The aqueous layer was separated, adjusted to pH 1.0 with 10% hydrochloric acid and extracted with ethyl acetate (20 ml.). The extract was washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was triturated with a mixture of n-hexane and diethyl ether (1:1). The precipitates were collected by filtration and washed with the same mixture to give 2-(2,3-dihydro-1,4-oxathiin-6-yl)-2-n-propoxyiminoacetic acid (syn isomer, 0.30 g.).
Reaction SMILES: Br[Zn][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.Br[C:10]1[S:11][C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][N:14]=1>O1CCOCC1.O.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>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:10]1[S:11][C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][N:14]=1
Reactant: Br[Zn]c1ccccn1
Reactant: CCOC(=O)c1cnc(Br)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1cnc(-c2ccccn2)s1
Reaction time: 0.17 h

Procedure:
A mixture of bromo(pyridine-2-yl)zinc (0.5 M in THF, 1.27 mL), ethyl 2-bromo-1,3-thiazole-5-carboxylate (0.063 mL, 0.42 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.02 g, 0.02 mmol) in 1,4-dioxane (3 mL) and water (0.03 mL) was subjected to MWI at 120° C. for 10 min. The reaction mixture was diluted with water and extracted with EtOAc. The organic solutions were combined, dried over Na2SO4, filtered, and concentrated to give ethyl 2-pyridin-2-yl-1,3-thiazole-5-carboxylate (0.12 g) which was used without further purification. LCMS: (FA) ES+ 235.
Reaction SMILES: [C:1]1([CH3:11])[C:2]([C:7]([O:9][CH3:10])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[Br:12]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:12][CH2:11][C:1]1[C:2]([C:7]([O:9][CH3:10])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccccc1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccccc1CBr
Temperature: 25 °C

Procedure:
To a solution of methyl o-toluate (15.0 g, 0.1 mol) in carbon tetrachloride (200 ml) were added N-bromosuccinimide (18.7 g, 0.1 mol) and benzoyl peroxide (catalytic amount) and the mixture was refluxed under heating for 2 hr. The reaction mixture was cooled to room temperature and the resulting precipitate was filtered off. The filtrate was concentrated under reduced pressure to give methyl α-bromo-o-toluate (yellow oil). The obtained oil was used in the next reaction without purification.
Reaction SMILES: [Br:1]Br.[NH:3]1[C:7]2=[N:8][CH:9]=[C:10]([N:12]3[C:20](=[O:21])[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]3=[O:22])[CH:11]=[C:6]2[CH:5]=[CH:4]1.N1C=CC=CC=1.C([O-])(O)=O.[Na+].[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl>[Br:1][C:5]1[C:6]2[C:7](=[N:8][CH:9]=[C:10]([N:12]3[C:13](=[O:22])[C:14]4[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=4)[C:20]3=[O:21])[CH:11]=2)[NH:3][CH:4]=1
Reactant: BrBr
Reactant: O=C1c2ccccc2C(=O)N1c1cnc2[nH]ccc2c1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C1c2ccccc2C(=O)N1c1cnc2[nH]cc(Br)c2c1
Reaction time: 0.5 h
Yield: 100.1 %

Procedure:
A solution of Br2 (30.2 mg, 0.189 mmol) in CH2Cl2 (2.0 mL) was added dropwise over a period of 4 min. to a stirred and cooled (0° C.) solution of 41 (50 mg, 0.189 mmol) and pyridine (18.0 mg, 0.23 mmol) in CH2Cl2 (2 mL). After additional stirring at 0° C. for 26 min. the reaction mixture was treated with a 1:1 (v/v) solution of saturated aqueous NaHCO3 and saturated aqueous Na2S2O3. Stirring continued for 30 min at 0° C. and the organic phase was separated. The aqueous layer was extracted with CH2Cl2. The combined organic solutions were dried (MgSO4), concentrated and the residue was separated by LCMS (column LUNA 10 μ C18(2) 00G-4253-V0 250×50 mm) using water—MeCN (0.1% AcOH) as eluent (in gradient; flow 80 mL/min) to afford 42 (64.7 mg, quant.). 1H NMR (400 MHz; CDCl3+3 drops of CD3OD) δ 7.40 (s, 1H), 7.81 (dd, J=3.1, 5.4 Hz, 2H), 7.94 (d, J=2.3 Hz, 1H), 7.96 (dd, J=5.5, 3.1 Hz, 2H), 8.29 (d, J=2.3 Hz, 1H); MS (ES) m/z 383 (MH++MeCN).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][N:13]2[C:17](=[O:18])[CH2:16][CH2:15][CH:14]2[CH2:19][CH2:20][CH:21]([O:29][Si](C(C)(C)C)(C)C)[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:6][CH:5]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH3:1][O:2][C:3](=[O:37])[C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][CH2:12][N:13]2[C:17](=[O:18])[CH2:16][CH2:15][CH:14]2[CH2:19][CH2:20][CH:21]([OH:29])[CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(CCCN2C(=O)CCC2CCC(Cc2ccccc2)O[Si](C)(C)C(C)(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CCCN2C(=O)CCC2CCC(O)Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.6 %

Procedure:
To a solution of 4-(3-{2-[3-(tert-butyl-dimethyl-silanyloxy)-4-phenyl-butyl]-5-oxo-pyrrolidin-1-yl}-propyl)-benzoic acid methyl ester (3.37 g, 6.43 mmol) in THF (40 mL) at 0° C. was added tetra-butylammonium fluoride (1M in THF, 9.6 mL, 9.6 mmol). The reaction mixture was stirred at room temperature for 18 h and the volatiles were removed in vacuo. EtOAc was added and the organic solution was washed with saturated aqueous NaHCO3 (2×), water (1×), and brine (1×). The organic solution was dried (MgSO4), filtered and concentrated. The residue was purified by medium pressure chromatography eluting with EtOAc to yield 2.28 g of 4-{3-[2-(3-hydroxy-4-phenyl-butyl)-5-oxo-pyrrolidin-1-yl]-propyl}-benzoic acid methyl ester. 1H NMR (CDCl3) (selected peaks) δ 7.91 (d, 2H), 7.32-7.15 (m, 7H), 3.86 (s, 3H), 3.75 (m, 1H), 3.63 (m, 1H), 3.54 (m, 1H), 2.94 (m, 1H), 2.78 (m, 1H), 2.61 (m, 3H); MS 410.1 (M+1).
Reaction SMILES: O.[NH2:2][NH2:3].F[C:5]1[CH:12]=[CH:11][CH:10]=[C:9]([I:13])[C:6]=1[C:7]#[N:8].O>C(O)C>[I:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:5]2[C:6]=1[C:7]([NH2:8])=[N:2][NH:3]2
Reactant: N#Cc1c(F)cccc1I
Reactant: NN
Solvent: O
Solvent: CCO
Product: Nc1n[nH]c2cccc(I)c12
Temperature: 78 °C

Procedure:
1.2 cm3 of hydrazine monohydrate are added to 2 g of 2-fluoro-6-iodobenzonitrile in 25 cm3 of ethanol. The reaction medium is then refluxed at about 78° C. for 12 hours. The medium is allowed to return to about 20° C. and 20 cm 3 of distilled water are then added in order to precipitate the product. The insoluble material is filtered on a sinter funnel, rinsed with 20 cm3 of distilled water and then taken up in 20 cm3 of dichloromethane. The organic phase is then dried over magnesium sulphate and evaporated under reduced pressure (2 kPa; 45° C.). After drying (90 Pa; 50° C.), 1.65 g of 4-iodo-1H-indazole-3-amine are obtained in the form of a yellow solid melting at 157° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[N:5]([NH:14][C:15](=[O:24])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:4]=1.[CH3:25][O:26][C:27]([NH:29][C@@H:30]([CH:34]([CH3:36])[CH3:35])[C:31](O)=[O:32])=[O:28]>>[CH3:25][O:26][C:27](=[O:28])[NH:29][C@@H:30]([CH:34]([CH3:35])[CH3:36])[C:31]([NH:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[N:5]([NH:14][C:15](=[O:24])[CH2:16][C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:4]=1)=[O:32]
Reactant: NCc1nn(NC(=O)Cc2ccc(Cl)cc2)c(=O)c2ccccc12
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Product: COC(=O)N[C@H](C(=O)NCc1nn(NC(=O)Cc2ccc(Cl)cc2)c(=O)c2ccccc12)C(C)C

Procedure:
The product of Example 42 and (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid were treated using a method similar to that described in Example 56 to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 11.59-11.62 (bs, 1H), 8.53 (d, J=5.5 Hz, 1H), 8.32 (dd, J=7.5, 1.7 Hz, 1H), 8.03 (d, J=7.1 Hz, 1H), 7.88-7.99 (m, 2H), 7.37-7.45 (m, 4H), 7.09-7.13 (m, 1H), 4.52-4.67 (m, 2H), 3.78-3.86 (m, 1H), 3.67 (s, 2H), 3.51 (s, 3H), 1.85-1.96 (m, 1H), 0.71-0.83 (d, 6H); MS (ESI+) M/Z 500 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([Cl:9])[N:3]=1.Cl.[CH3:11][C:12]1([NH2:15])[CH2:14][CH2:13]1.C[O-].[Na+]>CN1C(=O)CCC1.O>[Cl:9][C:4]1[N:3]=[C:2]([NH2:1])[N:7]=[C:6]([NH:15][C:12]2([CH3:11])[CH2:14][CH2:13]2)[CH:5]=1
Reactant: CC1(N)CC1
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CC1(Nc2cc(Cl)nc(N)n2)CC1
Temperature: 90 °C
Yield: 45.5 %

Procedure:
2-amino-4,6-dichloropyrimidine (508 mg, 3.1 mmol) was added to a suspension of 1-methylcyclopropylamine hydrochloride (1.0 g, 9.3 mmol) and sodium methoxide (502mg, 9.30 mmol) in NMP (3 ml). The resulting mixture was heated at 90° C. for 16 hours and then cooled to room temperature. The reaction mixture was diluted with water (20 ml) and the resulting precipitate filtered off, washed with further water (20 ml) and dried in vacuo to give the title compound as a colourless solid (280 mg, 15%).
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:12]3([CH:25]=[CH:24][C:23](=[O:26])[CH:22]=[CH:21]3)[N:11]=2)[CH2:6][CH2:5]1)[CH:2]=[CH2:3].C(OCC)(=O)C>C(Cl)Cl>[CH2:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[N:11]3[CH:25]=[CH:24][C:23](=[O:26])[CH:22]=[CH:21][C:12]3=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:14]=2)[CH2:8][CH2:9]1)[CH:2]=[CH2:3]
Reactant: C=CCN1CCN(C2=NC3(C=CC(=O)C=C3)C(c3ccccc3)=C2)CC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C=CCN1CCN(c2cc(-c3ccccc3)c3ccc(=O)ccn23)CC1
Temperature: 20 °C
Yield: 70 %

Procedure:
2-(4-Allyl-1-piperazinyl)-4-phenyl-1-azaspiro[4.5]deca-1,3,6,9-tetraen-8-one (40 g) is heated for 10 minutes to a temperature of about 220° C. After being cooled to a temperature of about 20° C., the residue is dissolved in methylene chloride (500 cc) and poured into silica (1 kg) contained in a column 6.5 cm in diameter. Successive elutions are performed with pure methylene chloride (1 liter), a mixture of methylene chloride and ethyl acetate (90:10 by volume) (1 liter) and a mixture of methylene chloride and ethyl acetate (80:20 by volume) (1 liter); the corresponding eluates are discarded. Elution is then performed with a mixture of methylene chloride and ethyl acetate (70:30 by volume) (3 liters) and the corresponding eluate is evaporated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. After recrystallization of the residue in acetonitrile (200 cc), 3-(4-allyl-1-piperazinyl)-1-phenyl-7H-pyrrolo[1,2-a]azepin-7-one (28 g), m.p. 125° C., is obtained.
Reaction SMILES: [C:1]1(=[O:7])O[C:4](=[O:5])[CH2:3][CH2:2]1.[NH2:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1>C1(C)C(C)=CC=CC=1>[N:12]1[CH:13]=[CH:14][C:9]([N:8]2[C:4](=[O:5])[CH2:3][CH2:2][C:1]2=[O:7])=[CH:10][CH:11]=1
Reactant: Nc1ccncc1
Reactant: O=C1CCC(=O)O1
Solvent: Cc1ccccc1C
Product: O=C1CCC(=O)N1c1ccncc1
Temperature: 25 °C

Procedure:
The starting material is prepared as follows: The mixture of 20 g of succinic anhydride, 19 g of 4-amino-pyridine, and 450 ml of xylene is refluxed for 24 hours with stirring. It is allowed to cool to room temperature and the solids are collected. They are extracted 3 times with 200 ml of methylene chloride at reflux and the combined extracts are evaporated and the residue recrystallized from ethanol, to yield the 1-(4-pyridyl)-pyrrolidin-2,5-dione.