Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li].[N:2]([N:4]1[C:9]([CH3:11])([CH3:10])[CH2:8][O:7][CH2:6][C:5]1([CH3:13])[CH3:12])=O>O1CCCC1.C(OCCCC)CCC>[NH2:2][N:4]1[C:5]([CH3:13])([CH3:12])[CH2:6][O:7][CH2:8][C:9]1([CH3:11])[CH3:10]
Reactant: CC1(C)COCC(C)(C)N1N=O
Agent: [Li]
Solvent: CCCCOCCCC
Solvent: C1CCOC1
Product: CC1(C)COCC(C)(C)N1N
Temperature: 99 °C

Procedure:
About 20% of a solution of 5 g of lithium alanate in 50 ml of tetrahydrofuran is added dropwise to a heated solution of 17.2 g of 4-nitroso-3,3,5,5-tetramethylmorpholine in 50 ml of tetrahydrofuran and 100 ml of dibutyl ether. The tetrahydrofuran is distilled off and the internal temperature is increased to 99° C. The remainder of the lithium alanate solution is then added dropwise and the mixture is kept at 70° C. for a further hour. After the mixture has been cooled in an ice-bath, 10 ml of water and 10 ml of 15% strength sodium hydroxide solution are carefully added. After filtration with suction, the filtrate is extracted by shaking first with water and then with 100 ml of 1N hydrochloric acid. The aqueous HCl phase is then extracted by shaking once more with diethyl ether and used in the next stage.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Br[CH2:8][C:9]#[CH:10].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[CH:20][C:21]([C:24]#[C:25][C:26]3[CH:27]=[C:28]4[C:32](=[CH:33][CH:34]=3)[N:31]([CH2:35][CH2:36][NH:37][CH2:38][CH:39]3[CH2:41][CH2:40]3)[CH:30]=[CH:29]4)=[N:22][CH:23]=2)=[CH:14][CH:13]=1>CN(C=O)C>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH:19]=[CH:20][C:21]([C:24]#[C:25][C:26]3[CH:27]=[C:28]4[C:32](=[CH:33][CH:34]=3)[N:31]([CH2:35][CH2:36][N:37]([CH2:38][CH:39]3[CH2:40][CH2:41]3)[CH2:10][C:9]#[CH:8])[CH:30]=[CH:29]4)=[N:22][CH:23]=2)=[CH:16][CH:17]=1
Reactant: Clc1ccc(-c2ccc(C#Cc3ccc4c(ccn4CCNCC4CC4)c3)nc2)cc1
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CCN(CCn1ccc2cc(C#Cc3ccc(-c4ccc(Cl)cc4)cn3)ccc21)CC1CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
45 mg (0.33 mmol) K2CO3 and 13 μL (0.18 mmol) 3-bromo-propyne are added at RT to a solution of 70 mg (0.16 mmol) (2-{5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-indol-1-yl}-ethyl)-cyclopropylmethyl-amine in 2 mL DMF and the reaction mixture is stirred for 4 h at RT. The mixture is evaporated down i. vac., the residue is taken up in water, extracted exhaustively with DCM and the organic phase is dried over Na2SO4. After the desiccant and solvent have been eliminated the residue is purified by chromatography (Alox, cyc/EtOAc 4:1).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[F:19][CH2:20][CH2:21]I.CCOCC>CN(C=O)C.O>[F:19][CH2:20][CH2:21][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=1
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: FCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)c1ccc(OCCF)cc1
Temperature: 70 °C

Procedure:
A mixture of commercially available ethyl 4-hydroxybenzoate (2.500 g; 15.04 mmol), K2CO3 (4.158 g; 30.08 mmol), and 1-fluoro-2-iodoethane (2.617 g; 15.04 mmol) in anh. DMF (30 ml) was heated to 70° C., under nitrogen, for 2.5 h. After cooling to rt, Et2O (100 ml) and water (50 ml) were added. The separated organic layer was further washed with water (2×50 ml), dried over anh. MgSO4, filtered, concentrated to dryness under reduced pressure, and the residue was further dried under HV affording ethyl 4-(2-fluoroethoxy)benzoate as a colorless solid. LC-MS (conditions D): tR=0.96 min.; no ionisation.
Reaction SMILES: IC.[I:3][C:4]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH:15]([CH3:17])[CH3:16])=[CH:8][C:5]=1[CH:6]=[O:7].[NH4+].[Cl-].[CH3:20][CH2:21]OCC>>[I:3][C:4]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH:15]([CH3:17])[CH3:16])=[CH:8][C:5]=1[CH:6]([OH:7])[CH2:20][CH3:21]
Reactant: CCOCC
Reactant: COc1cc(I)c(C=O)cc1OC(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CI
Product: CCC(O)c1cc(OC(C)C)c(OC)cc1I
Temperature: 0 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
A mixture of Mg turnings (585 mg, 24.1 g·atom) in dry Et2O (8.0 mL) was stirred at 0° C. under a nitrogen atmosphere then treated, dropwise, with a solution of iodomethane (2.25 mL, 28.1 mmol) in dry Et2O (7.0 mL). After 0.5 h a solution of aldehyde 5 (3.00 g, 9.38 mmol) in dry Et2O (10 mL) was added, dropwise, to the mixture that was then allowed to warm to 18° C. Stirring was continued at this temperature for 3 h then the reaction mixture was treated with NH4Cl (10 mL of a 20% w/v aqueous solution) followed by Et2O (20 mL). The separated organic phase was washed with H2O (1×10 mL) then dried (MgSO4), filtered and concentrated under reduced pressure to afford the title compound 7 (3.19 g, 97%) as an orange oil.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]3[N:12]=[C:13]([NH2:15])[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)=[CH:2]1.[CH2:16]([C:20]1[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=1)[CH:17]([CH3:19])[CH3:18]>>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]3[N:12]=[C:13]([NH:15][C:24](=[O:25])[C:23]4[CH:27]=[CH:28][C:20]([CH2:16][CH:17]([CH3:18])[CH3:19])=[CH:21][CH:22]=4)[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)=[CH:2]1
Reactant: Nc1nc2cccc(-c3ccoc3)n2n1
Reactant: CC(C)Cc1ccc(C(=O)O)cc1
Product: CC(C)Cc1ccc(C(=O)Nc2nc3cccc(-c4ccoc4)n3n2)cc1

Procedure:
The title compound was prepared following procedure and work up described for example 2, but starting from 5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A2), 75 mg; 0.37 mmol; 1.0 eq.) and 4-isobutylbenzoic acid (80 mg; 0.45 mmol; 1.2 eq.) as a yellow foam (25.5 mg, 19%). HPLC, Rt: 4.39 min. (purity 93.6%). LC/MS, M+(ESI): 361.1, M−(ESI): 359.1.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:24])[NH:13][C:14](=[O:23])[C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=2)=[CH:3]1.[CH3:25][C:26]1([CH3:33])[O:30][CH:29]([CH:31]=O)[CH2:28][O:27]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCl>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:24])[NH:13][C:14](=[O:23])[C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][CH2:31][CH:29]3[CH2:28][O:27][C:26]([CH3:33])([CH3:25])[O:30]3)[CH:17]=2)=[CH:3]1
Reactant: CC1(C)OCC(C=O)O1
Reactant: Cn1cc(C2=C(c3cccc(N)c3)C(=O)NC2=O)c2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cn1cc(C2=C(c3cccc(NCC4COC(C)(C)O4)c3)C(=O)NC2=O)c2ccccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 23.6 %

Procedure:
A mixture of 3-(1-methylindol-3-yl)-4-(3-aminophenyl)-1H-pyrrole-2,5-dione (100 mg, 0.32 mmol) and 2,2-dimethyldioxolane-4-carboxaldehyde (0.38 mmol) (prepared as described in Kumont, von R., et al. Helv. Chim. Acta., 66, 814, (1983)) in dichloromethane (12 mL) was stirred at room temperature for 10 min., and then Na(OAc)3BH (120 mg, 0.57 mmol) was added. The reaction mixture was stirred overnight and then partition between EtOAc and H20. The organic layer was separated, washed with water and concentrated. The crude product was purified by preparatory TLC with 3/1 hexanes/EtOAc to give 3-(1-methylindol-3-yl)-4-[3-(2,2-dimethyldioxolan-4-ylmethylamino)phenyl]-1H-pyrrole-2,5-dione (32.6 mg, 24%).
Reaction SMILES: [O:1]=[C:2]1[N:7]([CH2:8][CH2:9][CH2:10][NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[C:6]2[CH:18]=[CH:19][C:20]([S:22][CH:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:24][C:25]([O:27]CC)=[O:26])=[CH:21][C:5]=2[O:4][CH2:3]1.[OH-].[Na+].Cl>C(O)C>[O:1]=[C:2]1[N:7]([CH2:8][CH2:9][CH2:10][NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[C:6]2[CH:18]=[CH:19][C:20]([S:22][CH:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:24][C:25]([OH:27])=[O:26])=[CH:21][C:5]=2[O:4][CH2:3]1
Reactant: CCOC(=O)CC(Sc1ccc2c(c1)OCC(=O)N2CCCNc1ccccn1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CC(Sc1ccc2c(c1)OCC(=O)N2CCCNc1ccccn1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of ethyl 3-({3-oxo-4-[3-(2-pyridinylamino)propyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}sulfanyl)-3-phenylpropanoate in ethanol is treated with an equimolar amount of 1N sodium hydroxide solution. The mixture is stirred at room temperature overnight. Then, the pH is brought to neutrality with 1N hydrochloric acid, the solvent is evaporated under reduced pressure and the residue is purified by filtration through a small pad of silica gel, eluting with a mixture of dichloromethane, methanol and acetic acid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]#[N:14].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(Cl)Cl>[CH3:22][S:23]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]#[N:14])(=[O:25])=[O:24]
Reactant: N#CCCCCCCCCCCCO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCCCCCCCCCCC#N
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 15 g. of 12-hydroxydodecanonitrile and 14 ml. of triethylamine in 320 ml. of methylene chloride is stirred at 0° C. while 5.7 ml. of methanesulfonylchloride is added dropwise. The mixture is stirred at 0° C. for 1 hour, diluted with methylene chloride and extracted with water; cold, dilute hydrochloric acid; saturated aqueous sodium bicarbonate; and brine. The solution is dried over anhydrous magnesium sulfate and eaporated to yield 12-(methanesulfonyloxy)dodecanonitrile as a yellow oil
Reaction SMILES: [CH:1]([C:4]1[N:8]2[CH:9]=[C:10]([S:13][C:14]3[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=3[CH2:16][NH2:17])[CH:11]=[CH:12][C:7]2=[N:6][N:5]=1)([CH3:3])[CH3:2].N1C=CC=CC=1.Cl[C:29]([O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:30]>ClCCl>[C:32]1([O:31][C:29](=[O:30])[NH:17][CH2:16][C:15]2[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=2[S:13][C:10]2[CH:11]=[CH:12][C:7]3[N:8]([C:4]([CH:1]([CH3:3])[CH3:2])=[N:5][N:6]=3)[CH:9]=2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(C)c1nnc2ccc(Sc3ccccc3CN)cn12
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)c1nnc2ccc(Sc3ccccc3CNC(=O)Oc3ccccc3)cn12
Reaction time: 0.33 h

Procedure:
To a solution of 2-(3-Isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-ylsulfanyl)-benzylamine (417 mg, 1.4 mmol) in dichloromethane (14 mL) at ambient temperature under nitrogen was added pyridine (226 μL, 2.8 mmol) and phenyl chloroformate (192 μL, 1.5 mmol). The reaction was stirred for 20 minutes, then quenched with saturated NaHCO3. The reaction mixture was extracted with dichloromethane, the combined organics washed with brine, dried over sodium sulfate, and concentrated in vacuo. Purification by flash chromatography (eluting with ethyl acetate), followed by ether/hexane trituration gave the above named compound as a white solid (526 mg, 90%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH2:12](N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.CNOC.C[Mg]Cl.BrC1C=CC(F)=C(C=1)C(N(OC)C)=O>ClCCl.CN(C)C1C=CN=CC=1.O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([C:7](=[O:9])[CH3:12])[CH:10]=1
Reactant: O=C(O)c1cc(Br)ccc1F
Reactant: CCN(CC)CC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: CNOC
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(=O)c1cc(Br)ccc1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 5-bromo-2-fluoro-benzoic acid (3.50 g, 16 mmol) in dichloromethane (70 ml) was cooled to 0° C. and treated with triethylamine (1.725 g, 17 mmol), N-(3-dimethylamino-propyl)-N′-ethyl-carbodiimide hydrochloride (3.032 g, 16 mmol), 4-dimethylamino-pyridine (0.097 g, 0.8 mmol), and N,O-dimethyl-hydroxylamine (1.774 g, 18 mmol). The reaction mixture was left to warm to room temperature and stirred for 16 hours. For the workup, the reaction mixture was diluted with dichloromethane (100 ml) and, consecutively, extracted with water (50 ml), citric acid (10%, 50 ml), and saturated sodium hydrogen carbonate solution (50 ml). The organic layer was dried over sodium sulphate, then evaporated. The crude 5-bromo-2-fluoro-N-methoxy-N-methyl-benzamidematerial (3.73 g, 91%) was sufficiently pure and was directly engaged in the next step. In a dried flask, a solution of methylmagnesium chloride (3M in tetrahydrofuran, 5.69 ml, 17 mmol) in tetrahydrofuran (24 ml) was treated at 12-16° C. with a solution of 5-bromo-2-fluoro-N-methoxy-N-methyl-benzamide (3.73 g, 14.2 mmol) in tetrahydrofuran (24 ml). After complete addition, the reaction mixture was heated to reflux. After 20 minutes, the white suspension was quenched under ice cooling with a saturated solution of ammonium chloride (25 ml). After dilution with ethyl acetate (50 ml), the aqueous layer was separated and re-extracted with ethyl acetate (50 ml). The combined organic layers were washed with brine (20 ml), dried over sodium sulphate, and evaporated at reduced pressure. 1-(5-bromo-2-fluoro-phenyl)-ethanone was obtained as a light yellow solid (2.6 g, 84%), which was directly engaged in the next step. Rf: 0.55 (silica gel; eluent: heptane/ethyl acetate=4/1).
Reaction SMILES: C(OC([N:8]1[CH2:15][CH2:14][C:11]2([CH2:13][CH2:12]2)[C@H:10]([OH:16])[CH2:9]1)=O)(C)(C)C.[ClH:17].COC(C)(C)C>C(O)C>[ClH:17].[CH2:12]1[C:11]2([CH2:14][CH2:15][NH:8][CH2:9][C@H:10]2[OH:16])[CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC2)[C@H](O)C1
Agent: Cl
Solvent: COC(C)(C)C
Solvent: CCO
Product: O[C@@H]1CNCCC12CC2
Reaction time: 1 h
Yield: 90 %

Procedure:
A solution of (S)-4-hydroxy-6-aza-spiro[2.5]octane-6-carboxylic acid tert-butyl ester (3.26 g, 14.3 mmol) in ethanol (10 ml) was treated at room temperature with hydrogen chloride solution (4 M in 1,4-dioxane, 30 ml), then after 1 h tert-butyl methyl ether (40 ml) was added. The suspension was stirred for 1 h, then the precipitate was collected by filtration to afford the title compound (2.11 g, 90%). White solid, MS: 128.1 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:25]=[CH:24][CH:23]=[CH:22][C:11]=2[C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])=[O:9])=[CH:4][C:3]=1[N+:26]([O-])=O.[CH2:29]([O:31][C:32]([N:34]=[C:35]=S)=[O:33])[CH3:30].C(Cl)CCl.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)(=O)C.C(OCC)(=O)C.[Fe]>[CH2:29]([O:31][C:32]([NH:34][C:35]1[O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]([C:10]3[CH:25]=[CH:24][CH:23]=[CH:22][C:11]=3[C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])=[O:9])=[CH:4][C:3]=2[N:26]=1)=[O:33])[CH3:30]
Reactant: CCOC(=O)N=C=S
Reactant: O=C(OCc1ccccc1)c1ccccc1C(=O)c1ccc(O)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)Nc1nc2cc(C(=O)c3ccccc3C(=O)OCc3ccccc3)ccc2o1
Temperature: 25 °C
Reaction time: 0.58 h

Procedure:
A solution of phenylmethyl 2-[(4-hydroxy-3-nitrophenyl)carbonyl]benzoate (5.78 g, 15.3 mmol) in acetic acid (50 mL) was treated with iron powder (8.5 g, 153 mmol) at 50° C. for 30 min. After cooling to rt, the mixture was diluted with ethyl acetate, and the solids were removed by filtration though celite. The organic filtrate was washed with saturated sodium bicarbonate, which lead to further precipitation of solid contaminants. These solids were removed by filtration. The resulting organic filtrate was dried over magnesium sulfate, filtered, and concentrated to a brown foam. This material was taken up in DMF (30 mL). To this solution was added ethoxycarbonyl isothiocyanate (2.6 mL, 23 mmol). After stirring for 35 min, EDC (4.4 g, 23 mmol) was added to the reaction mixture. The mixture was stirred at rt for 35 min and then was stirred for a further 1 h at 65° C., and then it was cooled to rt. To the mixture was added 10% aqueous citric acid, and the resulting aqueous mixture was extracted twice with ethyl acetate. The organic extracts were combined, washed with brine, dried over magnesium sulfate, filtered, and concentrated to a brown solid. Contaminants were removed by trituration with methanol. Desired phenylmethyl 2-[(2-{[(ethyloxy)carbonyl]amino}-1,3-benzoxazol-5-yl)carbonyl]benzoate was isolated as a white solid (637 mg, 1.4 mmol, 9.4% yield). A sample was further purified by reverse phase HPLC. 1H NMR (400 MHz, CDCl3): 10.91 (br s, 1H), 8.12 (m 1H), 7.95 (br s, 1H), 7.67 (m, 1H), 7.63-7.52 (m, 3H), 7.47-7.38 (m, 2H), 7.26-7.13 (m, 5H), 5.08 (s, 2H), 4.29 (q, 2H), 1.38 (t, 3H); MS (EI) for C25H20N2O6: 445 (MH+).
Reaction SMILES: N1C=CN=C1.C(N(CC)CC)C.[CH:13](O)=[O:14].C(Cl)(=O)C(Cl)=O.[O:22]=[C:23]1[NH:28][C:27]([CH2:29][C:30]2[CH:34]=[CH:33][S:32][CH:31]=2)=[N:26][C:25]([N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)=[C:24]1[C:41]#[N:42]>ClCCl>[CH:13]([N:38]1[CH2:37][CH2:36][N:35]([C:25]2[N:26]=[C:27]([CH2:29][C:30]3[CH:34]=[CH:33][S:32][CH:31]=3)[NH:28][C:23](=[O:22])[C:24]=2[C:41]#[N:42])[CH2:40][CH2:39]1)=[O:14]
Reactant: O=CO
Reactant: N#Cc1c(N2CCNCC2)nc(Cc2ccsc2)[nH]c1=O
Agent: O=C(Cl)C(=O)Cl
Agent: c1c[nH]cn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1c(N2CCN(C=O)CC2)nc(Cc2ccsc2)[nH]c1=O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
11.3 mg (0.17 mmol) of imidazole are introduced together with 33.6 mg (0.33 mmol) of triethylamine and 7.64 mg (0.17 mmol) of formic acid into 5 ml of dichloromethane under an argon atmosphere and cooled to 0° C. Then a solution of 21.1 mg (0.17 mmol) of oxalyl chloride in dichloromethane is added dropwise, and the mixture is then stirred for 15 min. 50 mg (0.17 mmol) of 6-oxo-4-(piperazin-1-yl)-2-(3-thienylmethyl)-1,6-dihydropyrimidine-5-carbonitrile are added, and the mixture is stirred at RT overnight. It is then washed with 1 N potassium bisulphate solution, the dichloromethane phase is dried over sodium sulphate and concentrated, and the residue is flash-chromatographed on silica gel (mobile phase: dichloromethane/methanol 100:1, 80:1, 60:1). 16 mg (29% of theory) of the title compound are obtained.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:11]1(=[S:16])[O:15][CH2:14][CH2:13][CH2:12]1.O>O1CCCC1>[SH:16][CH2:11][CH2:12][CH2:13][C:14]([O:10][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:15]
Reactant: S=C1CCCO1
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(CCCS)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 102.5 %

Procedure:
Sodium hydride (60% in oil dispersion, 1.22 g, 50.9 mmol) was washed with dry tetrahydrofuran (20 ml×3) under nitrogen atomosphere. Freshly distilled tetrahydrofuran (50 ml) was added and the mixture was cooled to 0° C. with an ice bath. To this mixture was added portionwise solution of benzyl alcohol (5 g, 46.2 mmol) in dry tetrahydrofuran (10 ml) and the mixture was stirred for 1 hour at said temperature. To the resulting mixture was added γ-thiobutyrolactone (5.2 g, 50.9 mmol) slowly and the resulting mixture was warmed to room temperature. After stirring for 1 hour, H2O(30 ml) was added carefully and tetrahydrofuran was removed under reduced pressure. The residue was extracted three times with AcOEt. The organic layers were combined, washed with brine, and dried over magnesium sulfate. The solvent was evaporated to give 9.96 g of benzyl 4mercaptobutyrate as a colorless oil which was taken to the next step without further purification.
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1[N:9]=[C:8]([S:10][CH3:11])[N:7]=[C:6]([CH2:12][C:13](=[O:15])[CH3:14])[CH:5]=1>O1CCOCC1>[Br:1][CH:12]([C:6]1[CH:5]=[C:4]([CH3:3])[N:9]=[C:8]([S:10][CH3:11])[N:7]=1)[C:13](=[O:15])[CH3:14]
Reactant: BrBr
Reactant: CSc1nc(C)cc(CC(C)=O)n1
Solvent: C1COCCO1
Product: CSc1nc(C)cc(C(Br)C(C)=O)n1
Temperature: 25 °C

Procedure:
Bromine (1.46 ml, 28.5 mmol) is added to a rapidly stirred cooled (5-10° C.) solution of 1-(6-methyl-2-methylsulfanyl-pyrimidin-4-yl)-propan-2-one (7.0 g, 35 mmol) in dioxane (100 ml) over 30 minutes. The reaction is allowed to warm to room temperature and the solvent is removed in vacuo to yield the titled compound which is used immediately in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][CH2:7][C:8]3[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=3[CH:10]([C:11](O)=[O:12])[C:4]=2[CH:3]=1.[F:20][C:21]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:22]=1[NH2:23]>>[Br:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][CH2:7][C:8]3[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=3[CH:10]([C:11]([NH:23][C:22]3[CH:24]=[CH:25][C:26]([F:28])=[CH:27][C:21]=3[F:20])=[O:12])[C:4]=2[CH:3]=1
Reactant: Nc1ccc(F)cc1F
Reactant: O=C(O)C1c2ccccc2COc2ccc(Br)cc21
Product: O=C(Nc1ccc(F)cc1F)C1c2ccccc2COc2ccc(Br)cc21
Yield: 47.5 %

Procedure:
The similar procedures as in Example 1 were repeated except using 1.0 g of 2-bromo-6,11-dihydrodibenz[b,e]oxepin-11-carboxylic acid obtained in Example 46 (Compound H) in place of Compound A and 0.48 g of 2,4-difluoroaniline in place of aniline to obtain 0.64 g of Compound 40.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[C:5]=1[C:6](O)=[O:7])[CH3:3].C(Cl)(=O)C([Cl:17])=O>ClCCl.CN(C=O)C>[CH3:1][CH:2]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[C:5]=1[C:6]([Cl:17])=[O:7])[CH3:3]
Reactant: Cc1cccc(C(C)C)c1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cccc(C(C)C)c1C(=O)Cl
Reaction time: 15 h

Procedure:
A solution of 2-(1-methylethyl)-6-methylbenzoic acid (64 mg, 0.35 mmol) in dichloromethane (3 mL) containing DMF (2 drops) was treated with oxalyl chloride (0.16 mL, 1.8 mmol) and the mixture was stirred for 15 h. The mixture was concentrated, azeotroping with toluene to remove traces of oxalyl chloride and the residue was used directly in the next step.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[N:5][CH:4]=[N:3]1.C([Li])CCC.CCCCCC.Br[C:19]1[S:20][C:21]([C:28]2[N:32]3[N:33]=[C:34]([CH3:42])[CH:35]=[C:36]([CH:37]([CH2:40][CH3:41])[CH2:38][CH3:39])[C:31]3=[N:30][C:29]=2[CH3:43])=[C:22]([C:24]([F:27])([F:26])[F:25])[N:23]=1.[NH4+].[Cl-]>C1COCC1.[Cl-].[Cl-].[Zn+2]>[CH2:38]([CH:37]([C:36]1[C:31]2[N:32]([C:28]([C:21]3[S:20][C:19]([C:6]4[N:2]([CH3:1])[N:3]=[CH:4][N:5]=4)=[N:23][C:22]=3[C:24]([F:25])([F:26])[F:27])=[C:29]([CH3:43])[N:30]=2)[N:33]=[C:34]([CH3:42])[CH:35]=1)[CH2:40][CH3:41])[CH3:39]
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(Br)nc3C(F)(F)F)c(C)nc12
Reactant: Cn1cncn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCC(CC)c1cc(C)nn2c(-c3sc(-c4ncnn4C)nc3C(F)(F)F)c(C)nc12
Temperature: -78 °C
Yield: 65.8 %

Procedure:
164 mg of 1-Methyl-1,2,4-triazole (1.96 mmol) is dissolved in 2 ml of THF and cooled to −78° C. 0.8 ml of 2.5M n-butyllithium in hexane (1.96 mmol) is added slowly and stirred at −78° C., warmed up to room temperature and stirred at r.t. for 15 min and cooled to −78° C. 3.96 ml of 0.5 M ZnCl2 in THF (1.98 mmol) is added and stirred at room temperature for 15 min. 180 mg of 3-(2-bromo-4-trifluoromethyl-thiazol-5-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine and 54 mg of PdCl2(pddf) (0.06 mmol) are added. The vial is capped with a Teflon cap and heated at 80° C. overnight. NH4Cl aq. is added to quench the reaction and the mixture is extracted by CH2Cl2, dried over Na2SO4 and evaporated. The crude product is applied onto silica-gel chromatography column (Hexane:AcOEt=3:1) to give 119 mg of the title compound. Yield 58%. mass spectrum (m/e): 449 (M+1).