Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[OH:3][C@@H:4]([CH2:15][O:16][C@H:17]([CH3:30])[CH2:18][O:19][Si:20]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][N:9]=1)=[O:6].[Cl:31][C:32]1[C:33]([N:40]2[C:44]3=[N:45][CH:46]=[N:47][C:48](Cl)=[C:43]3[CH:42]=[N:41]2)=[C:34]([CH:37]=[CH:38][CH:39]=1)[C:35]#[N:36].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.O.CCOC(C)=O>[Cl:31][C:32]1[CH:39]=[CH:38][CH:37]=[C:34]([C:35]#[N:36])[C:33]=1[N:40]1[C:44]2=[N:45][CH:46]=[N:47][C:48]([O:3][C@@H:4]([CH2:15][O:16][C@H:17]([CH3:30])[CH2:18][O:19][Si:20]([CH:27]([CH3:29])[CH3:28])([CH:21]([CH3:23])[CH3:22])[CH:24]([CH3:26])[CH3:25])[C:5]([NH:7][C:8]3[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][N:9]=3)=[O:6])=[C:43]2[CH:42]=[N:41]1
Reactant: N#Cc1cccc(Cl)c1-n1ncc2c(Cl)ncnc21
Reactant: Cc1ccc(NC(=O)[C@@H](O)CO[C@H](C)CO[Si](C(C)C)(C(C)C)C(C)C)nc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(NC(=O)[C@H](CO[C@H](C)CO[Si](C(C)C)(C(C)C)C(C)C)Oc2ncnc3c2cnn3-c2c(Cl)cccc2C#N)nc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 68.9 %

Procedure:
Sodium hydride (64.3 mg, 1.61 mmol) was added to (S)-2-hydroxy-N-(5-methylpyridin-2-yl)-3-((R)-1-(triisopropylsilyloxy)propan-2-yloxy)propanamide (Intermediate AU4) (300 mg, 0.73 mmol) in anhydrous THF (10 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes and then 3-chloro-2-(4-chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)benzonitrile (Intermediate AH6) (212 mg, 0.73 mmol) added. The reaction mixture was allowed to warm to ambient temperature and stirred for 2 hours. The reaction mixture was neutralised with 1M citric acid and then diluted with water (50 mL) and EtOAc (100 mL). The organic layer was separated and the aqueous layer re-extracted with EtOAc (2×100 mL). The combined organics were washed with saturated brine (50 mL), dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by flash silica chromatography, elution gradient 20 to 40% EtOAc in isohexane to afford the product (334 mg, 68.8%). 1H NMR (400 MHz, DMSO) δ 0.98-0.86 (21H, m), 1.09 (3H, d), 2.24 (3H, s), 3.58-3.47 (1H, m), 3.64 (1H, m), 3.81-3.71 (1H, m), 4.10 (2H, m), 5.92 (1H, s), 7.58 (1H, d), 7.89 (2H, t), 8.18 (3H, m), 8.59 (1H, s), 8.72 (1H, s), 10.88 (1H, s). m/z (ES+) (M+H)+=664; HPLC tR=3.99 min.
Reaction SMILES: [Li]CCCC.C([Mg]Cl)CCC.Br[C:13]1[CH:14]=[N:15][CH:16]=[C:17]([Br:19])[CH:18]=1.[O:20]=[C:21]1[CH2:25][CH2:24][CH:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:22]1>[NH4+].C1(C)C=CC=CC=1.C1COCC1>[Br:19][C:17]1[CH:18]=[C:13]([C:21]2([OH:20])[CH2:25][CH2:24][CH:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:22]2)[CH:14]=[N:15][CH:16]=1
Reactant: CCOC(=O)C1CCC(=O)C1
Reactant: Brc1cncc(Br)c1
Agent: CCCC[Mg]Cl
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)C1CCC(O)(c2cncc(Br)c2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of THF:toluene (2.11 mL:2.11 mL) and n-BuLi (0.923 ml, 1.48 mmol) was cooled to −10° C. The reaction mixture was purged/filled with argon (3×). n-Butyl magnesium chloride (0.369 ml, 0.739 mmol) was added to the reaction mixture and stirred for 30 minutes. 3,5-Dibromopyridine (0.5 g, 2.111 mmol) was added to the reaction mixture over the course of 30 minutes, keeping bath below −10° C. and stirred for 1 hour. Ethyl 3-oxocyclopentanecarboxylate (0.330 g, 2.111 mmol) was added to the reaction mixture and stirred at −10° C. for ˜5 minutes. The reaction mixture was warmed to room temperature, diluted with saturated ammonium, extracted DCM (3×), and combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/hexanes) to afford ethyl 3-(5-bromopyridin-3-yl)-3-hydroxycyclopentanecarboxylate. MS ESI calc'd for C13H17BrNO3 [M+H]+ 314 and 316. found 314 and 316.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][NH2:9])[N:3]=1.[C:10](N1C=CN=C1)(N1C=CN=C1)=[O:11]>C1COCC1.O.CCOC(C)=O>[Br:1][C:2]1[N:3]2[C:10](=[O:11])[NH:9][N:8]=[C:4]2[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NNc1cccc(Br)n1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: O=c1[nH]nc2cccc(Br)n12
Reaction time: 1 h
Yield: 63.9 %

Procedure:
To a solution of 2-2 (1.1 g, 5.85 mmol) in THF (50 mL) was added carbonyldiimidazole (1.14 g, 7.02 mmol), and the mixture was stirred for 1 h. The reaction was diluted with water (150 mL) and EtOAc (150 mL), causing a precipitate to form. The mixture was filtered through a sintered glass filter, yielding 0.8 g (64%) of 2-3 as a tan solid. 1H NMR (300 MHz, CHCl3-d) δ 9.34 (s, 1H), 7.03 (m, 1H), 6.85 (m, 1H), 6.59 (m, 1H).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:33][CH2:34][CH3:35])[C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH:20]([C:21]3[N:22]([CH3:26])[CH:23]=[CH:24][N:25]=3)[C:19](=O)[C:18]3[C:17]([C:28]([O:30]CC)=O)=[CH:16][CH:15]=[CH:14][C:13]=3[NH:12]2)=[CH:7][CH:6]=1)[CH3:2].O.[NH2:37][NH2:38]>CO>[CH2:34]([O:33][CH:4]([O:3][CH2:1][CH3:2])[C:5]1[CH:6]=[CH:7][C:8]([CH:11]2[NH:12][C:13]3[C:18]4[C:19](=[N:37][NH:38][C:28](=[O:30])[C:17]=4[CH:16]=[CH:15][CH:14]=3)[CH:20]2[C:21]2[N:22]([CH3:26])[CH:23]=[CH:24][N:25]=2)=[CH:9][CH:10]=1)[CH3:35]
Reactant: NN
Reactant: CCOC(=O)c1cccc2c1C(=O)C(c1nccn1C)C(c1ccc(C(OCC)OCC)cc1)N2
Solvent: O
Solvent: CO
Product: CCOC(OCC)c1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2nccn2C)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 55 %

Procedure:
A mixture of ethyl 2-(4-(diethoxymethyl)phenyl)-3-(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (490 mg, 1.03 mmol), methanol (20 mL) and hydrazine monohydrate (2 mL) was stirred under 25° C. for 3 hr. The resulting mixture was evaporated under reduced pressure to 10 ml and then filtered, 250 mg of 8-(4-(diethoxymethyl)phenyl)-9-(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one as a solid was obtained, yield 55%. LC-MS (ESI) m/z: 446 (M+1)+.
Reaction SMILES: CO.[CH3:3][C:4]([CH3:41])([CH2:9][O:10][C:11]1[N:16]=[CH:15][C:14]([C:17]2[CH:18]=[N:19][C:20]([C:23]3[N:24]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[N:27]=3)=[CH:21][CH:22]=2)=[C:13]([CH3:40])[CH:12]=1)[C:5]([O:7]C)=[O:6].[OH-].[Na+].Cl>C(OCC)(=O)C.O1CCCC1>[CH3:3][C:4]([CH3:41])([CH2:9][O:10][C:11]1[N:16]=[CH:15][C:14]([C:17]2[CH:18]=[N:19][C:20]([C:23]3[N:24]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:38])([CH3:37])[CH3:39])[CH:25]=[C:26]([C:28]([F:29])([F:31])[F:30])[N:27]=3)=[CH:21][CH:22]=2)=[C:13]([CH3:40])[CH:12]=1)[C:5]([OH:7])=[O:6]
Reactant: COC(=O)C(C)(C)COc1cc(C)c(-c2ccc(-c3nc(C(F)(F)F)cn3COCC[Si](C)(C)C)nc2)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(OCC(C)(C)C(=O)O)ncc1-c1ccc(-c2nc(C(F)(F)F)cn2COCC[Si](C)(C)C)nc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 83.9 %

Procedure:
Methanol (0.7 mL) and tetrahydrofuran (0.7 mL) were added to methyl 2,2-dimethyl-3-({4-methyl-6′-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]-3,3′-bipyridin-6-yl}oxy)propanoate (99 mg), and after adding 2N aqueous sodium hydroxide solution (0.7 mL) to the mixture, the resulting mixture was stirred at 50° C. for 2 hours. To the reaction mixture was added ethyl acetate, and the mixture was neutralized by 2N hydrochloric acid. The organic layer was separated, washed with a saturated brine, and the residue obtained by concentrating the mixture under reduced pressure was purified by silica gel column chromatography (n-hexane:ethyl acetate=76:24 to 0:100) to obtain 2,2-dimethyl-3-({4-methyl-6′-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]-3,3′-bipyridin-6-yl}oxy)propanoic acid (81 mg).
Reaction SMILES: [C:1]([N:9]=[C:10]=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][CH2:13][CH2:14][C:15]1([CH3:29])[O:20][C:19]2[C:21]([CH3:28])=[C:22]([CH3:27])[C:23]([OH:26])=[C:24]([CH3:25])[C:18]=2[CH2:17][CH2:16]1>CC(C)=O>[OH:26][C:23]1[C:22]([CH3:27])=[C:21]([CH3:28])[C:19]2[O:20][C:15]([CH2:14][CH2:13][NH:12][C:10]([NH:9][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[S:11])([CH3:29])[CH2:16][CH2:17][C:18]=2[C:24]=1[CH3:25]
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(CCN)O2
Reactant: O=C(N=C=S)c1ccccc1
Solvent: CC(C)=O
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(CCNC(=S)NC(=O)c1ccccc1)O2
Temperature: 25 °C
Reaction time: 15 h
Yield: 56.4 %

Procedure:
A solution of benzoylisothiocyanate (28.0 g) in acetone (200 ml) was added dropwise to a solution of amine (prepared in reference example 3, 34.3 g) in acetone (800 ml). The solution was stirred for 15 hours at room temperature. The reaction solution was evaporated. The residue was purified by column chromatography on silica gel (hexane: ethyl acetate=10:1→4:1→2:1) to give the title compound (32.0 g) having the following physical data.
Reaction SMILES: Br.[NH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[NH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=2)[N:12]=[C:11](Cl)[N:10]=1.[OH-].[Na+]>COCCO.O>[NH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=2)[N:12]=[C:11]([N:2]2[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]2)[N:10]=1
Reactant: C1CNCCN1
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: COCCO
Solvent: O
Product: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Temperature: 75 °C

Procedure:
Piperazine hydrobromide (168.0 g., 1.006 mole) was added to a suspension of 4-amino-2-chloro-6,7-dimethoxyquinazoline (241.0 g., 1.006 mole) in 2-methoxyethanol (3.6 l.) and the mixture was stirred at reflux for 1.25 hours. The precipitate was separated by filtration, washed with hot 2-methoxyethanol and dried. The material then was added to a stirred solution of sodium hydroxide (81.0 g., 2.01 mole) in water (3 l.) and the mixture was heated to 75° C. The mixture then was cooled to 40° C., filtered, and the insoluble precipitate washed with water and dried. The material was triturated under refluxing absolute ethanol (6.0 l.) and the mixture was filtered. The filtrate was evaporated to dryness to yield the title compound, 180.0 g. (62%), m.p. 224°-228° C.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]([C:9]1[CH:29]=[CH:28][C:12]([CH2:13][N:14]2[CH2:20][CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]2)=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].FC(F)(F)C(O)=O>ClCCl>[N:14]1([CH2:13][C:12]2[CH:28]=[CH:29][C:9]([C:3]([OH:8])([C:2]([F:1])([F:30])[F:31])[C:4]([F:6])([F:7])[F:5])=[CH:10][CH:11]=2)[CH2:20][CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCCN(Cc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: OC(c1ccc(CN2CCCNCC2)cc1)(C(F)(F)F)C(F)(F)F
Reaction time: 24 h
Yield: 76.8 %

Procedure:
A mixture of tert-butyl 4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)-1,4-diazepane-1-carboxylate (15.34 mmol, 7 g), dichloromethane (15 mL) and trifluoroacetic acid (15.00 mL) was stirred for 24 hours. The reaction was purified by SCX chromatography to give the title compound (4.2 g). MS (ESI) m/z 357.1 [M+H]+
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.C(N(CC)CC)C.[C:18](Cl)(=[O:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].O>CC(C)=O>[C:18]([N:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[NH2:1])(=[O:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCC(=O)Cl
Reactant: Nc1nc2ccccc2[nH]1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CCCCCC(=O)n1c(N)nc2ccccc21
Reaction time: 1 h
Yield: 50.5 %

Procedure:
A solution of 2-amino benzimidazole (8 g, or 0.060 mole) and triethylamine (10 g, or 0,099 mole) in 150 ml of anhydrous acetone, is chilled to a temperature of -65° C. under nitrogen. To this solution is added 12.1 g (0.09 mole) hexanoyl chloride in solution in 150 ml of anhydrous acetone at a temperature of -60° C. After the mixture has been agitated at this temperature for around 1 hour, 100 ml of water is added to it, at a temperature of between -30° and -20° C., after which it is all poured into 500 ml of water. The precipitate is filtered, and dried in a dessicator. After purification, 7 g (50.5% yield) is obtained of a crystallized compound having a melting point of 200° C. and the following structure (90% purity): ##STR5##
Reaction SMILES: [OH:1][N:2]=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14]([NH2:16])=[O:15])[C:6]2[CH:17]=[CH:18][CH:19]=[CH:20][C:5]=2[CH2:4]1.N1C=CC=CC=1.Cl[C:28]([O:30][CH2:31][CH3:32])=[O:29]>CN(C)C1C=CN=CC=1.ClCCl>[CH2:31]([O:30][C:28]([O:1][N:2]=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14]([NH2:16])=[O:15])[C:6]2[CH:17]=[CH:18][CH:19]=[CH:20][C:5]=2[CH2:4]1)=[O:29])[CH3:32]
Reactant: CCOC(=O)Cl
Reactant: NC(=O)N1c2ccccc2CC(=NO)c2ccccc21
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)ON=C1Cc2ccccc2N(C(N)=O)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 0.2 g (0.74 mmol) of 10,11-dihydro-10-hydroxyimino-5H-dibenz[b,f]azepine-5-carboxamide and 0.01 g (0.08 mmol) of 4-dimethylaminopyridine in 10 mL of dichloromethane and 0.29 g (3.7 mmol) of pyridine was added 0.28 g (2.6 mmol) of ethyl chloroformate dropwise. The resulting mixture was stirred at room temperature for 2 hours whereupon it was extracted with 20 mL of 1M aqueous HCl and a saturated solution of NaHCO3, then dried by sodium sulphate and filtered. The solvent was removed by evaporation under reduced pressure and the residue was crystallised from a mixture of dichloromethane and ethyl acetate to give white crystals of m.p. 188.9°-190° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[C:11]([NH2:12])=[CH:10][CH:9]=[N:8]1.I[C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=[O:17].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(O)(=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[C:11]([NH:12][C:14]2[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=2[C:16]([OH:18])=[O:17])=[CH:10][CH:9]=[N:8]1
Reactant: Nc1ccnn1-c1ccccn1
Reactant: O=C(O)c1ccccc1I
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1ccccc1Nc1ccnn1-c1ccccn1
Temperature: 25 °C
Yield: 89.7 %

Procedure:
A solution of 1-(2-pyridinyl)-1H-pyrazol-5-ylamine (6.02 g, 37.6 mmol), 2-iodobenzoic acid (9.32 g, 37.6 mmol), copper acetate (II) (0.683 g, 3.76 mmol) and potassium carbonate (5.72 g, 41.4 mmol) in N,N-dimethylformamide (20 mL) was heated under reflux for 1 hour under an argon atmosphere. The solution was allowed to cool to room temperature, and poured into water. The solution was made weakly acidic by the addition of acetic acid, and the resulting crude crystals were collected by filtration. The crystals were washed with water and air dried to give the title compound (9.45 g, 90% yield).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH:6]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[O:22][N:21]=[C:20]([C:23]4[CH:28]=[CH:27][C:26]([CH2:29][OH:30])=[CH:25][CH:24]=4)[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C(N(CC)CC)C.O>ClCCl>[CH:6]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[O:22][N:21]=[C:20]([C:23]4[CH:28]=[CH:27][C:26]([CH2:29][O:30][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:25][CH:24]=4)[N:19]=3)=[CH:16][CH:17]=2)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: OCc1ccc(-c2noc(-c3ccc(C4CCCCC4)cc3)n2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1ccc(-c2noc(-c3ccc(C4CCCCC4)cc3)n2)cc1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
Methanesulfonyl chloride (0.157 mL, 0.0020 mol) is added to a stirred solution of {4-[5-(4-cyclohexyl phenyl)-[1,2,4]oxadiazole-3-yl]-phenyl}-methanol (0.45 g, 0.0013 mol) and triethylamine (0.376 mL, 0.0027 mol) in dichloromethane (10 mL) at 5° C. Reaction mixture is stirred at 5° C. for 30 minutes, then treated with demineralized water (10 mL). Dichloromethane layer is separated and aqueous layer is extracted with dichloromethane (2×15 mL). Combined organic layer is dried over sodium sulphate and concentrated under reduced pressure to yield methanesulfonic acid 4-[5-(4-cyclohexyl-phenyl)[1,2,4]oxadiazol-3-yl]-benzyl ester.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:11][C:12](=[O:14])[CH3:13])[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.N#N.[O:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH:19]=[C:18]1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[O:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH:19]=[C:18]1[C:2]1[CH:3]=[C:4]([NH:11][C:12](=[O:14])[CH3:13])[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: CC1(C)OB(c2cc3ccccc3o2)OC1(C)C
Reactant: CC(=O)Nc1cc(Br)cc([N+](=O)[O-])c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: N#N
Solvent: COCCOC
Product: CC(=O)Nc1cc(-c2cc3ccccc3o2)cc([N+](=O)[O-])c1

Procedure:
A solution of N-(3-bromo-5-nitrophenyl)acetamide of Example 1(c) (2 g, 7.7 mmol) in 1,2-dimethoxyethane (25 ml) was degassed by N2 bubbling for 5 min. 2-(Benzofuran-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.45 g, 10 mmol, 1.3 eq.) was added and the mixture was degassed for another 5 min. Pd(dppf)Cl2 (0.63 g, 0.77 mmol, 0.1 eq.) and aqueous sodium carbonate (2.45 g, 23.1 mmol, 3.0 eq.) were added and the procedure of Example 1(d) was followed. The crude residue of the product was directly used for the next step.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([CH2:14][C:15]#[C:16][C:17]3[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=3)[CH:5]=[CH:4][C:3]1=2.[CH2:27]([NH2:29])[CH3:28].C([NH-])C>>[CH2:27]([NH:29][C:21](=[O:22])[C:20]1[CH:24]=[CH:25][C:17]([C:16]#[C:15][CH2:14][C:6]2[CH:5]=[CH:4][C:3]3[C:2]([CH3:1])([CH3:26])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]=3[CH:7]=2)=[CH:18][CH:19]=1)[CH3:28]
Reactant: CC1(C)CCC(C)(C)c2cc(CC#Cc3ccc(C(=O)Cl)cc3)ccc21
Reactant: CCN
Agent: CC[NH-]
Product: CCNC(=O)c1ccc(C#CCc2ccc3c(c2)C(C)(C)CCC3(C)C)cc1

Procedure:
In a similar manner to Example 17(b), by reaction of 3 g (8.3 mmol) of 4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoyl chloride with 650 μl (10 mmol) of ethylamine (70%), 1.84 g (59.4%) of the expected ethyl amide are obtained, with a melting point of 128-9° C.
Reaction SMILES: Br[C:2]1[CH:18]=[CH:17][C:5]([O:6][CH2:7][CH2:8][O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])=[CH:4][CH:3]=1.C([Li])CCC.[Cl:24][C:25]1[CH:36]=[CH:35][C:28]([C:29](N(OC)C)=[O:30])=[CH:27][C:26]=1[S:37](=[O:40])(=[O:39])[NH2:38]>O1CCCC1>[C:13]([Si:10]([CH3:12])([CH3:11])[O:9][CH2:8][CH2:7][O:6][C:5]1[CH:17]=[CH:18][C:2]([C:29]([C:28]2[CH:35]=[CH:36][C:25]([Cl:24])=[C:26]([S:37]([NH2:38])(=[O:39])=[O:40])[CH:27]=2)=[O:30])=[CH:3][CH:4]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)OCCOc1ccc(Br)cc1
Reactant: CON(C)C(=O)c1ccc(Cl)c(S(N)(=O)=O)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCOc1ccc(C(=O)c2ccc(Cl)c(S(N)(=O)=O)c2)cc1
Temperature: -78 °C
Reaction time: 18 h
Yield: 53.1 %

Procedure:
[2-(4-Bromo-phenoxy)-ethoxy]-tert-butyl-dimethyl-silane (7.3 g, 22.12 mmol) is dissolved in tetrahydrofuran (120 mL) and cooled to −78° C. The solution is treated with a solution of n-butyllithium (1.6 M in hexanes, 13.8 mL, 22.12 mmol) and stirred 30 minutes after which a solution of 4-chloro-N-methoxy-N-methyl-3-sulfamoyl-benzamide (2.05 g, 7.37 mmol) in tetrahydrofuran (20 mL) is added. The reaction is allowed to stir for 18 hours while warming to ambient temperature. The reaction is quenched with a saturated solution of ammonium chloride and extracted twice with ether. The organic phase is separated and concentrated in vacuo. The residue is purified by column chromatography (gradient of ethyl acetate in hexanes 10-50%) affording 1.84 g (53% yield) of the title compound. MS (m/z): 470.2 (M+1).
Reaction SMILES: [Mg].O1C[CH2:5][CH2:4][CH2:3]1.C(Cl)C=C.[CH3:11][C:12]1[CH2:17][CH:16]([CH3:18])[CH:15]([CH:19]=[O:20])[CH2:14][CH:13]=1>C1(C)C=CC=CC=1>[CH3:11][C:12]1[CH2:17][CH:16]([CH3:18])[CH:15]([CH:19]([CH2:5][CH:4]=[CH2:3])[OH:20])[CH2:14][CH:13]=1
Reactant: CC1=CCC(C=O)C(C)C1
Reactant: C1CCOC1
Agent: [Mg]
Solvent: Cc1ccccc1
Solvent: C=CCCl
Product: C=CCC(O)C1CC=C(C)CC1C
Temperature: 67 °C

Procedure:
To a stirred slurry of 53 grams of magnesium (2.2 mole) and 500 ml of dry tetrahydrofuran, under nitrogen, is dropwise added a solution of 168 grams (2.2 moles) of allyl chloride and 276 grams (2.0 moles) of 4,6-dimethyl-3-cyclohexenecarboxaldehyde at reflux (67° C.) over a two-hour period. The reaction mixture is heated to reflux for 30 minutes, whereupon 400 ml of toluene is added. A distillation head is attached to the reaction flask and the tetrahydrofuran is distilled off at atmospheric pressure to a pot temperature of 114° C. The remaining solution is cooled to 0° C., whereupon 900 ml of 18% hydrochloric acid solution is slowly added with external cooling. Two clear layers are formed. The aqueous layer is discarded and the organic layer is quickly distilled. The distillate is fractionally redistilled through a 1"×12" Goodloe packed column to afford 250 grams of 4,6-dimethyl-alpha-allyl-3-cyclohexenemethanol (b.p. 88°, 2.0 mm Hg pressure).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[CH2:12][CH2:11][C:10](=[O:13])[NH:9][C:5]2=[N:6][C:7]=1Cl.B(O)(O)[C:15]1[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=1.C([O-])([O-])=O.[K+].[K+]>CC#N.O.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>[C:18]1([CH3:21])[CH:17]=[CH:16][C:15]([C:2]2[N:3]=[C:4]3[CH2:12][CH2:11][C:10](=[O:13])[NH:9][C:5]3=[N:6][C:7]=2[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[CH:20][CH:19]=1
Reactant: O=C1CCc2nc(Br)c(Cl)nc2N1
Reactant: Cc1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)NC(=O)CC3)cc1
Temperature: 80 °C
Reaction time: 66 h

Procedure:
To a stirrred suspension of 2-bromo-3-chloro-7,8-dihydropyrido[2,3-b]pyrazin-6(5H)-one (Intermediate J) (10 g, 38.1 mmol), p-tolylboronic acid (11.39 g, 84 mmol) in MeCN (400 ml) and water (100 ml) under N2 supply, was added solid K2CO3 (fine mesh) (7.90 g, 57.1 mmol) followed by Pd(PPh3)2Cl2 (1.337 g, 1.905 mmol). The yellow RM was heated to 80° C. and was left stirring for 66 hours. The RM was allowed to cool slowly to RT and then placed in the fridge for 3-4 hours. The fine yellow needles were filtered off under suction and were washed with small quantity of acetonitrile, followed by water. After air drying for 10 min, the solid was transferred, dried in vacuo at 40° C. for 2 hours, to afford the title compound as fine crystalline needles;
Reaction SMILES: [C:1]1([CH3:28])[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[CH:9][N:10]([C:12]3[C:13]4[N:14]([CH:25]=[CH:26][N:27]=4)[CH:15]=[C:16]([C:18]4[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=4)[N:17]=3)[CH:11]=2)=[CH:3][CH:2]=1.[N:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH3:38])=[C:30]=[O:31].CN(C=O)C>ClCCl>[C:33]1([CH3:38])[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[NH:29][C:30]([NH:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:16]2[N:17]=[C:12]([N:10]3[CH:11]=[C:7]([C:4]4[CH:3]=[CH:2][C:1]([CH3:28])=[CH:6][CH:5]=4)[N:8]=[CH:9]3)[C:13]3[N:14]([CH:25]=[CH:26][N:27]=3)[CH:15]=2)[CH:19]=1)=[O:31]
Reactant: Cc1ccccc1N=C=O
Reactant: Cc1ccc(-c2cn(-c3nc(-c4cccc(N)c4)cn4ccnc34)cn2)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cn(-c3nc(-c4cccc(NC(=O)Nc5ccccc5C)c4)cn4ccnc34)cn2)cc1
Yield: 59.2 %

Procedure:
A solution of 3-[8-(4-p-tolyl-imidazol-1-yl)-imidazo[1,2-a]pyrazin-6-yl]-phenylamine (5) (50 mg), 1-isocyanato-2-methyl-benzene (18 mg), in dichloromethane (DCM) (3 ml) and DMF (0.5 ml) is stirred at room temperature for 16 hr. The mixture is concentrated in vacuo, the residue slurried with diethyl ether/methanol (20:1), and filtered to give 1-o-tolyl-3-{3-[8-(4-p-tolyl-imidazol-1-yl)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-urea (6) (40 mg) as a cream solid.