Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OCC)(=O)[CH2:2][C:3]([O:5]CC)=[O:4].[H-].[Na+].Cl[CH2:15][C:16]1[N:17]=[C:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[O:19][C:20]=1[CH3:21].Cl>O1CCCC1.C(O)(=O)C.O>[CH3:21][C:20]1[O:19][C:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:17][C:16]=1[CH2:15][CH2:2][C:3]([OH:5])=[O:4]
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1CCC(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.2 %

Procedure:
To a mixture of diethyl malonate (115.8 g) and tetrahydrofuran (300 mL) was added sodium hydride (60%, oil, 24.12 g) under ice-cooling. After stirring the mixture at room temperature for 30 min., a solution (100 mL) of 4-chloromethyl-5-methyl-2-phenyloxazole (50.0 g) in tetrahydrofuran was added to the reaction mixture under ice-cooling, and the mixture was heated under reflux for 1 hr. Water was added to the reaction mixture, and the mixture was concentrated. Ethyl acetate was added to the residue and the mixture was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give an oil. A mixture of this oil, 6N hydrochloric acid (300 mL) and acetic acid (150 ml) was heated under reflux for 20 hrs. The reaction mixture was concentrated, and ethyl acetate was added to the residue. The mixture was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give crystals (22.4 g, 40%) of 3-(5-methyl-2-phenyl-4-oxazolyl)propionic acid from a fraction eluted with ethyl acetate-hexane (1:4, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 124-125° C.
Reaction SMILES: [O:1]=[C:2]1[N:13]([CH:14]2[CH:21]3[CH2:22][C:17]4([C:24]([NH2:26])=O)[CH2:18][CH:19]([CH2:23][CH:15]2[CH2:16]4)[CH2:20]3)[C:5]2=[C:6]3[CH:12]=[CH:11][NH:10][C:7]3=[N:8][CH:9]=[C:4]2[NH:3]1.ClC1N=C(Cl)N=C(Cl)N=1.C(=O)([O-])O.[Na+]>CN(C)C=O>[O:1]=[C:2]1[N:13]([CH:14]2[CH:21]3[CH2:22][C:17]4([C:24]#[N:26])[CH2:18][CH:19]([CH2:23][CH:15]2[CH2:16]4)[CH2:20]3)[C:5]2=[C:6]3[CH:12]=[CH:11][NH:10][C:7]3=[N:8][CH:9]=[C:4]2[NH:3]1
Reactant: NC(=O)C12CC3CC(C1)C(n1c(=O)[nH]c4cnc5[nH]ccc5c41)C(C3)C2
Agent: Clc1nc(Cl)nc(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC12CC3CC(C1)C(n1c(=O)[nH]c4cnc5[nH]ccc5c41)C(C3)C2
Temperature: 25 °C
Reaction time: 4 h
Yield: 45.2 %

Procedure:
4-(2-Oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(2H)-yl)adamantan-1-carboxamide (70 mg) was suspended in N,N-dimethylformamide (1 ml), and 2,4,6-trichloro-1,3,5-triazine (37 mg) was added under ice cooling. The mixture was stirred at ambient temperature for 4 hours. To the reaction solution was added saturated aqueous sodium hydrogencarbonate, and the obtained solid was collected by filtration, washed with water and ethyl acetate to obtain 4-(2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-1(2H)-yl)adamantan-1-carbonitrile (30 mg).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([O:26]C)=[O:25])=[CH:20][CH:19]=2)=[C:14]([O:28][CH3:29])[CH:13]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Li+].[OH-]>C1COCC1.C(OCC)(=O)C>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([OH:26])=[O:25])=[CH:20][CH:19]=2)=[C:14]([O:28][CH3:29])[CH:13]=1)([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(-c2ccc(CCCO[Si](C)(C)C(C)(C)C)cc2OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(CCCO[Si](C)(C)C(C)(C)C)ccc1-c1ccc(C(=O)O)cc1
Reaction time: 3 h

Procedure:
A mixture of Example 451A (828 mg, 2.0 mmol) and 1M LiOH (3 mL) in THF (10 mL) was heated to 50° C., stirred for 3 hours, diluted with ethyl acetate, washed with saturated sodium monobasic phosphate (10 mL), dried (MgSO4), filtered, and concentrated to provide the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[C:6]([N:8]=[C:9]=[S:10])[CH:7]=1.[NH3:17]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[C:6]([NH:8][C:9]([NH2:17])=[S:10])[CH:7]=1
Reactant: S=C=Nc1cc(Cl)ccc1N1CCOCC1
Reactant: N
Product: NC(=S)Nc1cc(Cl)ccc1N1CCOCC1

Procedure:
Reaction of 5-chloro-2-morpholinophenyl isothiocyanate (10 g) with 33% alcoholic ammonia solution (60 ml) at room temperature for 14 hours gave 1-(5-chloro-2-morpholinophenyl)thiourea as a yellow solid (m.p. 174°-175° C.).
Reaction SMILES: [F:1][C:2]([F:9])([C:5]([F:8])([F:7])[F:6])[CH2:3][NH2:4].[Br:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1([C:28](Cl)=[O:29])[C:27]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2>>[F:1][C:2]([F:9])([C:5]([F:8])([F:7])[F:6])[CH2:3][NH:4][C:28]([C:15]1([CH2:14][CH2:13][CH2:12][CH2:11][Br:10])[C:27]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:29]
Reactant: NCC(F)(F)C(F)(F)F
Reactant: O=C(Cl)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: O=C(NCC(F)(F)C(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 1 from 2,2,3,3,3-pentafluoro-propylamine and 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid chloride.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]1[C:21]([OH:23])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:24][C:25]1[CH:26]=[CH:27][C:28]([NH:31][NH2:32])=[N:29][CH:30]=1.CCN(CC)CC.C1C=CC2N(O)N=NC=2C=1.O.C(Cl)CCl>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:10][CH:9]1[C:21]([NH:32][NH:31][C:28]1[CH:27]=[CH:26][C:25]([F:24])=[CH:30][N:29]=1)=[O:23])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: NNc1ccc(F)cn1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)C(C(=O)O)C1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)C(C(=O)NNc2ccc(F)cn2)C1
Yield: 62.6 %

Procedure:
To a solution of piperazine-1,2,4-tricarboxylic acid 1,4-di-tert-butyl ester (780 mg, 2.4 mmol) and (5-fluoro-pyridin-2-yl)-hydrazine (250 mg, 2.0 mmol) and Et3N (0.83 mL, 6 mmol) in DCM (20 mL) were added HOBt.H2O (27 mg, 0.2 mmol) and EDC (542 mg, 2.4 mmol) sequentially, and then the mixture stirred at RT overnight. The mixture was partitioned between EtOAc/water and extracted with EtOAc. The combined organics were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by FCC, using 0-10% MeOH in DCM, to give the title compound as a brown solid (550 mg, 63%). LCMS (Method 4): Rt 3.28, m/z 440 [MH+].
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Br[CH:21]([CH3:26])[C:22]([O:24][CH3:25])=[O:23]>CC(=O)CC.O>[N:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[O:1][CH:21]([CH3:26])[C:22]([O:24][CH3:25])=[O:23])[CH:7]=[CH:8][CH:9]=1
Reactant: Oc1cccc2cccnc12
Reactant: COC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: COC(=O)C(C)Oc1cccc2cccnc12
Temperature: 25 °C

Procedure:
23.2 g of 8-hydroxyquinoline are dissolved in 400 ml of butan-2-one, under the influence of heat, and 30 g of potassium carbonate are added in portions. The mixture is refluxed for one hour. 2 g of potassium iodide are then added dropwise, followed by 40 g of methyl 2-bromopropionate in 100 ml of butan-2-one in the course of one hour, with stirring and boiling. The mixture is then refluxed for another 10 hours. After cooling to room temperature, the mixture is poured onto 1 liter of water and extracted with three 200 ml portions of ethyl acetate. The combined extracts are washed once with 50 ml of water, dried over sodium sulfate and filtered. The solvent is evaporated off and the oily residue is crystallised by trituration with petroleum ether. After recrystallisation from hexane, methyl 2-(8-quinolinoxy)-propionate (compound No.3) is obtained in the form of beige-coloured crystals of melting point 70° to 72° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][N:5]([CH2:7][CH:8]([CH2:12][C:13]([OH:15])=O)[C:9](O)=[O:10])[CH:6]=1.[NH2:16]C(N)=O>O>[I:1][C:2]1[CH:3]=[N:4][N:5]([CH2:7][CH:8]2[CH2:12][C:13](=[O:15])[NH:16][C:9]2=[O:10])[CH:6]=1
Reactant: O=C(O)CC(Cn1cc(I)cn1)C(=O)O
Reactant: NC(N)=O
Solvent: O
Product: O=C1CC(Cn2cc(I)cn2)C(=O)N1
Temperature: 25 °C

Procedure:
The solution of 2-((4-iodo-1H-pyrazol-1-yl)methyl)succinic acid (170 mg, 0.52 mmol) and urea (72 mg, 1.50 mmol) was stirred neat at 130° C. for 12 hours. After cooling to room temperature, the mixture was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford 3-((4-iodo-1H-pyrazol-1-yl)methyl)pyrrolidine-2,5-dione. MS ESI calc'd. for C8H9IN3O2 [M+H]+ 306. found 306. 1H NMR (400 MHz, CD3OD) δ 7.70 (s, 1H), 7.50 (s, 1H), 4.62-4.43 (m, 2H), 3.48-3.37 (m, 1H), 2.85-2.68 (m, 1H), 2.61-2.49 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:13])=[CH:4][C:5]([F:12])=[C:6]([S:8](Cl)(=[O:10])=[O:9])[CH:7]=1.N1C=CC=CC=1.[CH3:20][NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.[OH-].[Na+]>C(Cl)Cl>[Br:1][C:2]1[C:3]([Cl:13])=[CH:4][C:5]([F:12])=[C:6]([S:8]([N:21]([CH3:20])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)(=[O:10])=[O:9])[CH:7]=1
Reactant: O=S(=O)(Cl)c1cc(Br)c(Cl)cc1F
Reactant: CNc1ccccn1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN(c1ccccn1)S(=O)(=O)c1cc(Br)c(Cl)cc1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 30.7 %

Procedure:
To 5-bromo-4-chloro-2-fluorobenzenesulfonyl chloride (1.5 g, 4.89 mmol) in dry DCM (15 mL), at −20° C. was added pyridine (1.98 mL, 24.5 mmol) followed by methyl-pyridin-2-yl-amine (1.06 g, 9.78 mmol). The mixture was allowed to warm slowly to ambient temperature over 16 hrs. 1N NaOH solution (5 mL) was added and stirred for 15 mins. The mixture was extracted with DCM and the organics were washed with brine, dried over MgSO4 and the filtrate evaporated. The residue was purified by silica gel chromatography [eluent: 10% ethyl acetate in hexane] to give 5-bromo-4-chloro-2-fluoro-N-methyl-N-pyridin-2-yl-benzenesulfonamide as an oil (0.57 g, 31%). MS: 380.9 (M+H)+; tR=2.80 min (method 1).
Reaction SMILES: [CH2:1](Br)[C:2]#[CH:3].C1(C)C=CC=CC=1.[CH3:12][O:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOCC.O>[CH3:12][O:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:3][C:2]#[CH:1])[CH:16]=1
Reactant: C#CCBr
Reactant: COC(=O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: C#CCOc1cccc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of propargyl bromide in toluene (80%, 68.7 mmol, 7.40 mL) is added to a solution of 3-hydroxy-benzoic acid methyl ester (48.6 mmol) in DMF (45 mL). K2CO3 is added and the mixture is stirred at RT for 4 h. Water and ether are added, the layers are separated and the organic layer is washed with aq. NaOH solution (5%) and brine. The solvents are removed in vacuo to give the desired ester as a pale yellow solid. 1H-NMR (CDCl3): δ=2.56 (s, 1H); 3.94 (s, 3H); 4.76 (s, 2H); 7.20 (d, J=8.04 Hz, 1H); 7.39 (t, J=8.16 Hz, 1H); 7.66 (bs, 1H); 7.71 (d, J=7.78 Hz, 1H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[CH2:3][CH2:2]1.[Li+].CC([N-]C(C)C)C.C[Si](Cl)(C)C.[Br:25]N1C(=O)CCC1=O>C1COCC1>[Br:25][CH:7]([CH:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)CC1CCOCC1
Agent: CC(C)[N-]C(C)C
Agent: C[Si](C)(C)Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(Br)C1CCOCC1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
To a dry 250 mL round-bottomed flask was added 2.20 g of methyl 2-(tetrahydro-2H-pyran-4-yl)acetate (0.014 mol) and 100 mL of dry THF. This solution was cooled to −78° C. and LDA (2.0 M in THF/heptane/ethyl benzene, 10.4 mL, 0.021 mol) was added. The resulting brown solution was stirred at −78° C. for 45 min. TMSCl (3.22 g, 3.5 mL, 0.028 mol) was then added at −78° C., and the reaction mixture was then warmed to room temperature. After being re-cooled to −78° C., N-bromosuccinimide (4.94 g, 0.028 mol) was added to the reaction mixture, and the resulting suspension was allowed to slowly warm to room temperature where it continued to stir for an additional 1.5 h. The suspension was then filtered thru a pad of SiO2 using diethyl ether as the eluant. Purification of the filtrate by column chromatography (SiO2 gel, 10:1 to 4:1 hexanes/ethyl acetate) delivered the desired α-bromo ester, which was used in subsequent steps without further purification.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH2:7])=[CH:5][C:4]([CH3:8])=[N:3]1.[CH3:9][O:10][C:11](=[O:26])[C:12](=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=1)[C:13]([CH3:15])=O>C(O)C>[CH3:9][O:10][C:11]([C:12]1[CH:16]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=2)[C:5]2[C:4]([CH3:8])=[N:3][N:2]([CH3:1])[C:6]=2[NH:7][C:13]=1[CH3:15])=[O:26]
Reactant: Cc1cc(N)n(C)n1
Reactant: COC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(C)=O
Solvent: CCO
Product: COC(=O)C1=C(C)Nc2c(c(C)nn2C)C1c1cccc([N+](=O)[O-])c1

Procedure:
1,3-Dimethyl-5-pyrazolamine (3.33 g; 0.030 mol) is dissolved in ethanol (35 ml) and methyl-2-(3-nitrobenzyliden)acetoacetate (6.75 g; 0.27 mol) is added thereto. The mixture is refluxed for about 5 hours, then the solvent is evaporated under reduced pressure and the residue is taken up in methylene chloride, washed with 2% hydrochloric acid and then with saturated aqueous sodium bicarbonate, the organic phase is dried over sodium sulphate and then the solvent is evaporated. The solid compound of the title is recovered by filtration, after taking up in ethyl ether. M.p. 163°-166° C.
Reaction SMILES: C(OC(=O)C)(=O)C.[C:8]([O:12][C:13]([C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]([CH2:24][CH:25]([OH:42])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[CH:30][CH:29]=1)[CH:19]=[CH:18]2)=[O:14])([CH3:11])([CH3:10])[CH3:9].C(=O)([O-])O.[Na+].[Na+].[Cl-]>CS(C)=O>[C:8]([O:12][C:13]([C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]([CH2:24][C:25](=[O:42])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[CH:30][CH:29]=1)[CH:19]=[CH:18]2)=[O:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: CCCCCCCCc1ccc(OCC(O)Cn2ccc3cc(C(=O)OC(C)(C)C)ccc32)cc1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CS(C)=O
Product: CCCCCCCCc1ccc(OCC(=O)Cn2ccc3cc(C(=O)OC(C)(C)C)ccc32)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
5.33 g (52.2 mmol) acetic anhydride are mixed with 30 ml absolute DMSO, stirred at room temperature for 10 min and added drop-wise to a solution of 0.626 g (1.31 mmol) tert-butyl-1-[2-hydroxy-3-(4-octylphenoxy)propyl]indole-5-carboxylate in 20 ml absolute DMSO. Having stirred for 17 hours, the solution is poured into a mixture of 5% sodium hydrogen carbonate solution and saturated NaCl solution (1:1, v/v) and hydrolyzed for 10 min. Four extractions using diethyl ether, combination of the organic phases, concentration to half the volume on the rotary evaporator, three wash steps with saturated NaCl solution, drying on sodium sulfate, filtration and reconcentration on the rotary evaporator leave as a crude product a yellow oil which is purified on silica gel by means of flash column chromatography (flow agent: petroleum ether/ethyl acetate 95:5) and yields the product as a colorless oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]=[C:9]([NH:12][C:13]([NH:15][CH2:16][CH3:17])=[O:14])[CH:10]=[CH:11][C:5]2=[N:4][CH:3]=1.C(N(CC)CC)C.[C:25]1([C:31]#[CH:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.Cl>CN(C)C=O.ClCCl.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:16]([NH:15][C:13]([NH:12][C:9]1[CH:10]=[CH:11][C:5]2[C:6]([N:8]=1)=[N:7][C:2]([C:32]#[C:31][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[CH:3][N:4]=2)=[O:14])[CH3:17]
Reactant: CCNC(=O)Nc1ccc2ncc(Cl)nc2n1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCNC(=O)Nc1ccc2ncc(C#Cc3ccccc3)nc2n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
98.1 mg of 1-(3-chloropyrido[2,3-b]pyrazin-6-yl)-3-ethylurea (0.39 mmol), 10.1 mg copper(I) iodide (0.05 mmol) and 193 μl of triethylamine (1.38 mmol) were initially charged in 2 ml of anhydrous dimethylformamide under nitrogen as a protective gas. Subsequently, 29.1 mg of dichlorobis(triphenylphosphine)palladium(II) (0.04 mmol) and 54 μl of phenylacetylene (0.49 mmol) were added, and the mixture was stirred at room temperature for 16 h. For workup, the mixture was diluted with dichloromethane and added to dilute hydrochloric acid. The precipitated solid was filtered off with suction, and the organic phase was washed with dilute hydrochloric acid and distilled water. After phase separation, the organic solvent was removed under reduced pressure. The further purification was effected by column chromatography on silica gel (dichloromethane/methanol eluent). This gave a yellow solid.
Reaction SMILES: [CH:1]1([C:4]#[C:5][C:6]2[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.[H][H]>C(OCC)(=O)C.[Pd]>[CH:1]1([CH2:4][CH2:5][C:6]2[CH:7]=[CH:8][C:9]([CH:10]=[O:11])=[CH:12][CH:13]=2)[CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: O=Cc1ccc(C#CC2CC2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=Cc1ccc(CCC2CC2)cc1

Procedure:
To a solution in ethyl acetate (22.0 mL) of the compound (1.79 g) obtained in step (1) above, 10% palladium/carbon (179 mg) was added. The mixture was stirred at room temperature for 22 hours in a hydrogen atmosphere. More of 10% palladium/carbon (179 mg) was added and the mixture was stirred at room temperature for 3 hours in a hydrogen atmosphere. The insoluble matter was removed by filtration through Celite (registered trademark). After concentrating the filtrate under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=100:0-70:30) to give the titled compound as a crude product (1.23 g).
Reaction SMILES: C[O:2][C:3](=O)[N:4]([CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Br:18])[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>ClCCl.CN(C)C1C=CN=CC=1>[Br:18][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:12]=1[CH2:11][CH2:10][N:4]([CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[C:3]2=[O:2]
Reactant: CCCCCN(CCc1ccccc1Br)C(=O)OC
Agent: CN(C)c1ccncc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: CCCCCN1CCc2c(Br)cccc2C1=O
Temperature: 0 °C
Reaction time: 4 h

Procedure:
5.44 g of methyl[2-(2-bromophenyl)ethyl]pentylcarbamate are dissolved, under an inert atmosphere, in 200 cm3 of dichloromethane at a temperature close to 20° C. 6.07 g of 4-dimethylaminopyridine are added to the reaction mixture. It is cooled to a temperature in the vicinity of 0° C. 13.94 cm3 of trifluoromethanesulfonic anhydride are poured into the reaction mixture over 15 min. The suspension is kept stirring for 4 h at a temperature close to 20° C. Dichloromethane and also 50 cm3 of a water/ice mixture are added to the reaction medium. The 4-dimethylaminopyridine is filtered. The filtrate is decanted, the aqueous phase is extracted with dichloromethane. The organic phases are combined, washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated using a rotary evaporator under reduced pressure (5 kPa). The crude product obtained is purified by flash chromatography over silica (column: 200 g; particle size: 15-40 μm; eluent: 90% dichloromethane/10% ethyl acetate). After concentrating the fractions under reduced pressure, 4.14 g of 5-bromo-2-pentyl-3,4-dihydroisoquinolin-1(2H)-one are obtained in the form of a colorless oil.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])(=[O:12])=[O:11])[CH2:7][N:6]1[C:20]1[N:24]([CH2:25][CH2:26][N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[N:23]=[C:22]([CH3:33])[CH:21]=1)=[O:4].[OH-].[Li+]>>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[S:10]([C@H:8]1[CH2:7][N:6]([C:20]2[N:24]([CH2:25][CH2:26][N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[N:23]=[C:22]([CH3:33])[CH:21]=2)[C@H:5]([C:3]([OH:4])=[O:2])[CH2:9]1)(=[O:11])=[O:12]
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1c1cc(C)nn1CCN1CCOCC1
Agent: [Li+]
Agent: [OH-]
Product: Cc1cc(N2C[C@H](S(=O)(=O)c3ccccc3Cl)C[C@H]2C(=O)O)n(CCN2CCOCC2)n1

Procedure:
In analogy to the procedure described in example 253e, (2S,4R)-4-(2-chlorophenylsulfonyl)-1-(3-methyl-1-(2-morpholinoethyl)-1H-pyrazol-5-yl)pyrrolidine-2-carboxylic acid methyl ester was saponified in the presence of lithium hydroxide to give the title compound as brown oil which was used in the next step without further purification. MS (ESI): m/z=483.4 [M+H]+.
Reaction SMILES: [Cl:1][Si:2]([CH3:8])([CH3:7])[Si:3](Cl)([CH3:5])[CH3:4].[CH3:9][C-:10]1[CH:14]=[C:13]([CH3:15])[C:12]([CH3:16])=[C:11]1[CH3:17].[Na+]>COC>[Cl:1][Si:2]([CH3:8])([CH3:7])[Si:3]([CH:14]1[C:13]([CH3:15])=[C:12]([CH3:16])[C:11]([CH3:17])=[C:10]1[CH3:9])([CH3:5])[CH3:4]
Reactant: Cc1c[c-](C)c(C)c1C
Reactant: C[Si](C)(Cl)[Si](C)(C)Cl
Agent: COC
Agent: [Na+]
Product: CC1=C(C)C([Si](C)(C)[Si](C)(C)Cl)C(C)=C1C

Procedure:
To a solution of 4.802 g (25.7 mmol) 1,2-dichloro-1,1,2,2-tetramethyldisilane in 50 mL dimethylether was slowly added a solution of 2.285 g (12.8 mmol) sodium 1,2,3,4-tetramethylcyclopentadienide in 30 mL dimethylether. The reaction mixture was stirred several hours, then the solvent was removed, the residue was extracted with pentane and filtered. The pentane was removed under reduced pressure to give the product as a light-yellow oil. Mass spec: m/e 272 (8%). 1H NMR (C6D6) δ 2.70 (s, 1H), 1.83 (s, 6H), 1.69 (s, 6H), 0.28 (s, 6H), 0.23 (s, 6H); 13C NMR (C6D6) δ 135.8, 134.0, 54.4, 14.6, 11.4, 3.2, −2.4.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([NH:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:15]3[C:10]([CH:11]=[CH:12][CH:13]=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.[CH3:24][O:25][C:26](=[O:37])[C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[C:29]([Cl:36])[CH:28]=1.CCN(CC)CC>ClCCCl>[CH3:24][O:25][C:26](=[O:37])[C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34]([N:17]([C:16]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]=[C:10]3[C:15]=2[CH:14]=[CH:13][CH:12]=[CH:11]3)[CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:35])=[C:29]([Cl:36])[CH:28]=1
Reactant: COC(=O)c1ccc(N=C=O)c(Cl)c1
Reactant: Clc1ccc(-n2nc3ccccc3c2NC2CCCCC2)cc1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(NC(=O)N(c2c3ccccc3nn2-c2ccc(Cl)cc2)C2CCCCC2)c(Cl)c1

Procedure:
In analogy to the procedure described in example 1.2, [2-(4-chloro-phenyl)-2H-indazol-3-yl]-cyclohexyl-amine (example 11.1) was reacted with 3-chloro-4-isocyanato-benzoic acid methyl ester (example 9.1) in 1,2-dichloroethane in the presence of Et3N (1.4 eq.) for 2 days under reflux conditions to give the title compound as brown solid. MS: m/e=537.1 [M+H+].