Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:10])[CH:3]=[CH:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].C(N(CC)CC)C.[Br:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[C:21]([Cl:28])[CH:20]=1>C1(C)C=CC=CC=1>[Br:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([C:4](=[CH:3][N:2]([CH3:10])[CH3:1])[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:24])=[C:21]([Cl:28])[CH:20]=1
Reactant: O=C(Cl)c1ccc(Br)cc1Cl
Reactant: CCOC(=O)C=CN(C)C
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=CN(C)C)C(=O)c1ccc(Br)cc1Cl
Temperature: 25 °C
Yield: 68 %

Procedure:
30.2 g of ethyl 3-dimethylaminoacrylate and 29.3 ml of triethylamine were dissolved in 180 ml of toluene and heated to reflux. At this temperature there was added dropwise thereto a solution of 53 g of 4-bromo-2-chloro-benzoyl chloride in 50 ml of toluene over 30 min. and the mixture was subsequently stirred at reflux for a further 1 hr. The mixture was left to cool to room temperature and was stirred in an ice bath for a further 30 min. The suspension was filtered and the triethylamine hydrochloride was washed with 40 ml of ice-cold toluene. The filtrate was concentrated to half of the volume and then, for crystallization, diluted with 100 ml of hexane and stirred in an ice bath for a further 1 hr. 51.2 g (67%) of ethyl 2-(4-bromo-2-chlorobenzoyl)-3-dimethylamino-acrylate were obtained as white crystals. M.p. 101°.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[N:4][CH:3]=1.[Br:9]N1C(=O)CCC1=O>C(Cl)Cl>[Br:9][C:3]1[N:4]=[CH:5][C:6]([NH2:8])=[N:7][C:2]=1[Cl:1]
Reactant: Nc1cncc(Cl)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: Nc1cnc(Br)c(Cl)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 49.8 %

Procedure:
6-Chloropyrazin-2-amine (2.50 g, 19.3 mmol) was stirred in CH2Cl2 (60 mL) at 0° C. N-Bromosuccinimide (2.92 g, 16.4 mmol) was added slowly and the reaction mixture was stirred at 0° C. for 60 minutes. The reaction mixture was filtered through celite and concentrated to give a brown oil. Purification by flash chromatography, eluting with 0-25% EtOAc-hexanes, gave 5-bromo-6-chloropyrazin-2-amine as a yellow solid (1.69 g, 8.16 mmol, 42% yield).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]#[N:28])=[CH:17][CH:16]=2)=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH2:29]([N:31]=[C:32]=[S:33])[CH3:30].C(O)C>C(OCC)(=O)C>[C:27]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:18]1[CH:19]=[CH:20][C:15]([CH2:14][NH:13][C:3]2[C:2]([NH:1][C:32]([NH:31][CH2:29][CH3:30])=[S:33])=[CH:12][CH:11]=[CH:10][C:4]=2[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:16][CH:17]=1)#[N:28]
Reactant: CCN=C=S
Reactant: CCOC(=O)c1cccc(N)c1NCc1ccc(-c2ccccc2C#N)cc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCNC(=S)Nc1cccc(C(=O)OCC)c1NCc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of ethyl 3-amino-2-[[(2′-cyanobiphenyl-4-yl)methyl]amino]benzoate (1.61 g), ethyl isothiocyanate (1.5 ml) and ethanol (1 ml) was stirred at room temperature for 3 days. The reaction mixture was dissolved in ethyl acetate and the solution was washed with water, dried and concentrated to dryness to give crystals. Recrystallization from ethyl acetate-hexane afforded pale yellow crystals (1.92 g, 91%), m.p. 108–110° C.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[O:5]=[C:6]1[NH:14][CH:13]=[N:12][C:11]2[N:10]([CH2:15][CH2:16][C:17]([O:19]CC)=O)[CH:9]=[N:8][C:7]1=2.C(#N)C>CCOCC>[O:5]=[C:6]1[NH:14][CH:13]=[N:12][C:11]2[N:10]([CH2:15][CH2:16][C:17]([NH:3][CH2:2][CH2:1][NH2:4])=[O:19])[CH:9]=[N:8][C:7]1=2
Reactant: CCOC(=O)CCn1cnc2c(=O)[nH]cnc21
Reactant: NCCN
Solvent: CCOCC
Solvent: CC#N
Product: NCCNC(=O)CCn1cnc2c(=O)[nH]cnc21
Yield: 92 %

Procedure:
1.500 g (25.0 mmol) of ethylenediamine was stirred at room temperature with 250 mg (1.06 mmol) of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)propionic acid, ethyl ester (AIT-0027) for one hour. The solution was treated with 4 ml acetonitrile and 20 ml of ether with stirring. Upon filtration and washing with ether, this yielded 245 mg of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)-N-(2-aminoethyl)propanamide (AIT-0058) as a slightly yellow solid. Yield: 92%.
Reaction SMILES: [C:1]([O:9][CH2:10][C:11]1[CH:12]=[N:13][C:14]([CH3:17])=[CH:15][CH:16]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:26])C=1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[C:1]([O:9][CH2:10][C:11]1[CH:12]=[N+:13]([O-:26])[C:14]([CH3:17])=[CH:15][CH:16]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(COC(=O)c2ccccc2)cn1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: Cc1ccc(COC(=O)c2ccccc2)c[n+]1[O-]
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of 1767 mg of (6-methylpyridin-3-yl)methyl benzoate in 26.5 ml of chloroform was added 2440 mg of m-chloroperbenzoic acid under ice-cooling, followed by stirring for 1 hour. An aqueous potassium carbonate solution was added thereto to carry out a liquid separation operation, and the organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The residue was concentrated under reduced pressure to obtain 1891 mg of (6-methyl-1-oxidopyridin-3-yl)methyl benzoate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:18]3[CH:17]=[N:16][CH:15]=[N:14][C:13]=3[N:12]([CH:19]([CH3:21])[CH3:20])[CH:11]=2)=[O:9])[CH:5]=[N:6][CH:7]=1.[CH:22]1([N:25]2[C:29]([C:30]([F:33])([F:32])[F:31])=[C:28]([CH2:34][C:35](O)=[O:36])[CH:27]=[N:26]2)[CH2:24][CH2:23]1.CCCP(O)(O)=O>C1COCC1>[CH:22]1([N:25]2[C:29]([C:30]([F:32])([F:31])[F:33])=[C:28]([CH2:34][C:35]([NH:1][C:2]3[CH:7]=[N:6][CH:5]=[C:4]([C:8]([C:10]4[C:18]5[CH:17]=[N:16][CH:15]=[N:14][C:13]=5[N:12]([CH:19]([CH3:21])[CH3:20])[CH:11]=4)=[O:9])[CH:3]=3)=[O:36])[CH:27]=[N:26]2)[CH2:23][CH2:24]1
Reactant: O=C(O)Cc1cnn(C2CC2)c1C(F)(F)F
Reactant: CC(C)n1cc(C(=O)c2cncc(N)c2)c2cncnc21
Agent: CCCP(=O)(O)O
Solvent: C1CCOC1
Product: CC(C)n1cc(C(=O)c2cncc(NC(=O)Cc3cnn(C4CC4)c3C(F)(F)F)c2)c2cncnc21
Temperature: 25 °C
Reaction time: 14 h
Yield: 76 %

Procedure:
To a solution of (5-Amino-pyridin-3-yl)-(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methanone (Preparation 95, 50 mg, 0.17 mmol), (1-Cyclopropyl-5-trifluoromethyl-1H-pyrazol-4-yl)-acetic acid (Preparation 141, 47.1 mg, 0.21 mmol) and TEA (0.08 mL, 0.62 mmol) in THF (1 mL), 1-propylphosphonic acid cyclic anhydride (50% solution in EtOAc, 0.26 mL, 0.44 mmol) was added and the mixture was stirred at room temperature for 14 hours. The reaction mixture was evaporated under reduced pressure and the residue partitioned between water and ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution and dried (Na2SO4) and evaporated in vacuo. Purification by column chromatography on silica gel (gradient of EtOAc:Hexane 0:100 to 80:20) gave the title compound as a white solid in 76% yield, 67 mg. 1H NMR (400 MHz, DMSO-D6) δ: 1.05-1.07 (m, 2H), 1.08-1.15 (m, 2H), 1.54 (d, 6H), 3.73-3.76 (m, 3H), 5.06-5.13 (m, 1H), 7.55 (s, 1H), 8.44 (s, 1H), 8.51 (s, 1H), 8.73 (s, 1H), 8.94 (d, 1H), 8.99 (s, 1H), 9.44 (s, 1H), 10.61 (s, 1H). LCMS (System 10): Rt=3.03 min m/z 498 [M+H]+
Reaction SMILES: I[C:2]1[C:10]([N+]([O-])=O)=[CH:9][CH:8]=[C:7]2[C:3]=1/[C:4](=[CH:15]/[C:16]1[NH:17][CH:18]=[CH:19][C:20]=1[O:21][CH3:22])/[C:5](=[O:14])[NH:6]2.[OH:23][CH2:24][CH2:25][CH:26]=[CH:27]B(O)O.C([O-])([O-])=O.[Na+].[Na+]>C(COC)OC.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>[OH:23][CH2:24][CH2:25][CH:26]=[CH:27][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[CH:15][C:16]1[NH:17][CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[C:5](=[O:14])[NH:6]2
Reactant: OCCC=CB(O)O
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc([N+](=O)[O-])c(I)c21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1cc[nH]c1C=C1C(=O)Nc2cccc(C=CCCO)c21
Temperature: 85 °C
Reaction time: 8 h

Procedure:
To a stirred solution of (Z)-1,3-dihydro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (50 mg, 0.14 mmol) (Starting Material 2) in dimethoxyethane (5 mL) was added 4-hydroxy-1-butenyl-boronic acid (48 mg, 0.418 mmol) (from Example 68 above), tetrakis(triphenylphosphine)palladium(0) (39 mg, 0.034 mmol) (Aldrich) and 2M Na2CO3 solution in H2O (0.34 mL). The reaction mixture was stirred at 85° C. overnight in a pressure tube. The solvent was removed in vacuo, and the residue was purified by silica gel chromatography (Hex:EtOAc=5:1) to provide 1,3-dihydro-4-(4-hydroxy-but-1-enyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-indol-2-one as a yellow solid. (Yield 21 mg, 50%).
Reaction SMILES: [N:1]([CH:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:14]3[N:18]=[C:17]([C:19]4[O:23][N:22]=[C:21]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[C:20]=4[C:30]([F:33])([F:32])[F:31])[O:16][N:15]=3)[CH:10]=2)[CH:5]1[OH:34])=[N+:2]=[N-:3].N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si:49]([C:52]([CH3:55])([CH3:54])[CH3:53])([CH3:51])[CH3:50])(=O)=O>C(Cl)Cl>[N:1]([CH:4]1[CH2:13][CH2:12][C:11]2[CH:10]=[C:9]([C:14]3[N:18]=[C:17]([C:19]4[O:23][N:22]=[C:21]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[C:20]=4[C:30]([F:33])([F:32])[F:31])[O:16][N:15]=3)[CH:8]=[CH:7][C:6]=2[CH:5]1[O:34][Si:49]([C:52]([CH3:55])([CH3:54])[CH3:53])([CH3:51])[CH3:50])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NC1CCc2cc(-c3noc(-c4onc(-c5ccccc5)c4C(F)(F)F)n3)ccc2C1O
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(C)(C)[Si](C)(C)OC1c2ccc(-c3noc(-c4onc(-c5ccccc5)c4C(F)(F)F)n3)cc2CCC1N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.6 %

Procedure:
Racemic 2-azido-6-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)-1,2,3,4-tetrahydronaphthalen-1-ol (130 mg, 0.28 mmol) was dissolved in CH2Cl2 (694 μL). To this solution was added 2,6-lutidine (129 μL, 1.1 mmol) and tert-butyldimethylsilyl trifluoromethanesulfonate (133 μL, 0.55 mmol). The reaction was stirred at room temperature for 1 h. After that, the solution was loaded onto a 12 g ISCO column and purified by ISCO Combiflash Companion (0% ethyl acetate-hexane for 3 min then ramp to 20% ethyl acetate-hexane over 5 min then 20% ethyl acetate-hexane for 8 more min, product came out 8-10 min) to afford racemic-3-(6-azido-5-(tert-butyldimethylsilyloxy)-5,6,7,8-tetrahydronaphthalen-2-yl)-5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazole (130 mg, 0.22 mmol, 80%) as a white solid: LCMS=605.34 [M+Na]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.[C:12]([O:16][CH3:17])(=[O:15])[CH:13]=[CH2:14].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[O:11]=[C:9]([CH3:10])[CH2:8][C:4]1[CH:3]=[C:2](/[CH:14]=[CH:13]/[C:12]([O:16][CH3:17])=[O:15])[CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)Cc1cccc(Br)c1
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)/C=C/c1cccc(CC(C)=O)c1
Temperature: 25 °C
Yield: 105.9 %

Procedure:
A solution of 3-bromophenylacetone (50.0 g, 235 mmol), methyl acrylate (40.4 g, 469 mmol), palladium(II)acetate (7.9 g, 35.2 mmol), tri-ortho-tolylphosphine (21.4 g, 70.4 mmol) and triethylamine (82 ml) in acetonitrile (900 ml) was heated at reflux under a nitrogen atmosphere for a period of 16 hours. The reaction mixture was cooled to room temperature and the solvent removed in vacuo. Purification by flash column chromatography eluting with pentane:ethyl acetate (90:10 changing to 70:30 by volume) gave the title compound as an orange oil (54.3 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][CH:7]=[C:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:5]2=O.O.[NH2:21][NH2:22]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[C:6]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:7][NH:22][N:21]=2)[C:9]([OH:8])=[CH:10][C:11]=1[OH:12]
Reactant: O=c1c(-c2ccccc2)coc2cc(O)c(Cl)cc12
Reactant: NN
Solvent: CCO
Solvent: O
Product: Oc1cc(O)c(-c2n[nH]cc2-c2ccccc2)cc1Cl

Procedure:
This compounds was synthesised in the same manner as described above. 6-Chloro-7-hydroxy-3-phenyl-chromen-4-one (0.4 g, 1.47 mmol), hydrazine hydrate (4 ml), ethanol (10 ml). 4-Chloro-6-(4-phenyl-1H-pyrazol-3-yl)-benzene-1,3-diol precipitated out on quenching as a pale yellow (0.37 g, 88%); Rf 0.3 Cf SM 0.7 ethyl acetate/hexane (75/25).
Reaction SMILES: [C:1]1(=[O:8])[NH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[O-].[Na+].CO.[CH2:14](Cl)[CH2:15][CH2:16][CH3:17]>>[CH2:14]([N:7]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]1=[O:8])[CH2:15][CH2:16][CH3:17]
Reactant: CCCCCl
Reactant: O=C1CCCCCN1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCCN1CCCCCC1=O
Temperature: 150 °C
Reaction time: 4 h
Yield: 83 %

Procedure:
113.2 g of fresh caprolactam (1.0 mol) is dissolved in 250 g of crude distillate containing 3.4% of caprolactam (8.5 g of caprolactam prepared as in a), and the resulting mixture is heated to 150° C. 202 g of a 30.16 wt. % strength sodium methoxide-methanol solution (1.13 mol) is metered in at 140° C. over a period of one hour while distilling methanol. All the methanol is distilled by briefly applying vacuum. 104.5 g of n-butyl chloride (1.13 mol) is then metered in at 140° C. over a period of one hour. After allowing the mixture to continue reacting for 4 hours, the reaction mixture is subjected to an initial cooling, and all the NBC is distilled from the sodium chloride in vacuo; boiling point of NBC: 90° C./0.5 mbar. Weight: 406 g. GC Purity: 96.3% of NBC, 2.7% of caprolactam. Yield: 83.0% of theory or 91.2% if caprolactam is recycled. NBC can be redistilled through a column to give a product having a purity of about 99%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[N:10]([C:24]([CH2:27][CH3:28])=[CH:25][CH:26]=3)[N:11]=[C:12]([CH3:23])[C:13]=2[CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:5]=[N:6][CH:7]=1.[Cu][C:30]#[N:31]>CN1CCCC1=O>[C:30]([C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[N:10]([C:24]([CH2:27][CH3:28])=[CH:25][CH:26]=3)[N:11]=[C:12]([CH3:23])[C:13]=2[CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:5]=[N:6][CH:7]=1)#[N:31]
Reactant: N#C[Cu]
Reactant: CCOC(=O)CCCCc1c(C)nn2c(CC)ccc2c1-c1cncc(Br)c1
Solvent: CN1CCCC1=O
Product: CCOC(=O)CCCCc1c(C)nn2c(CC)ccc2c1-c1cncc(C#N)c1
Temperature: 170 °C
Reaction time: 4 h
Yield: 60 %

Procedure:
A mixture of ethyl 5-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate (167 mg) and copper(I) cyanide (37 mg) in 1-methyl-2-pyrrolidinone (3 mL) was stirred at 170° C. for 4 hours. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of hexane and ethyl acetate (20:1-5:1) to give ethyl 5-[4-(5-cyano-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate as an yellow oil (88 mg).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Cl-].[CH3:12][O:13][CH2:14][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH:34]12[O:41][CH:38]([CH2:39][CH2:40]1)[CH2:37][C:36](=O)[CH2:35]2>C1COCC1>[CH3:12][O:13][CH:14]=[C:36]1[CH2:37][CH:38]2[O:41][CH:34]([CH2:40][CH2:39]2)[CH2:35]1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1CC2CCC(C1)O2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC=C1CC2CCC(C1)O2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of sodium bis(trimethylsilyl)amide 1M in THF (24.48 ml, 24.48 mmol) was added drop wise to a suspension of (methoxymethyl)triphenylphosphonium chloride (8.39 g, 24.48 mmol) in THF (98 ml) at −40° C. Stirring was continued for 0.5 h at −40° C. and then the solution of 8-oxa-bicyclo[3.2.1]octan-3-one [CAS #77745-32-5] (1.93 g, 15.3 mmol) in THF (20 ml) was added at −40° C. The suspension was allowed to warm to RT and stirring was continued for 6 h. The reaction mixture was quenched with a saturated solution of NH4Cl and extracted with EtOAc (2×). The combined organic phases were washed with brine, dried over Na2SO4, filtered and evaporated to dryness. The crude product was purified by silica gel column chromatography (eluting with a gradient of heptane-EtOAc 97:3 to 0:100) yielding the title compound as a slightly yellow oil (1.71 g, 11.09 mmol, 72%): 1H-NMR (400 MHz, CDCl3): δ 1.58-2.43 (m, 8H), 3.54 (s, 3H), 4.41 (m, 2H), 5.85 (s, 1H)
Reaction SMILES: [I:1][C:2]1[C:7]([C:8]([OH:10])=O)=[C:6]([O:11][CH3:12])[N:5]=[CH:4][CH:3]=1.Cl.[CH:14]1([NH:20][NH2:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O.C(N(CC)CC)C>[CH:14]1([NH:20][NH:21][C:8](=[O:10])[C:7]2[C:2]([I:1])=[CH:3][CH:4]=[N:5][C:6]=2[O:11][CH3:12])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COc1nccc(I)c1C(=O)O
Reactant: NNC1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1nccc(I)c1C(=O)NNC1CCCCC1
Yield: 68.6 %

Procedure:
A solution of 4-iodo-2-methoxynicotinic acid (558 mg), cyclohexyl hydrazine hydrochloride (362 mg), EDCI hydrochloride (575 mg), HOBt (405 mg) and triethylamine (304 mg) in DMF (10 mL) was stirred overnight at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (515 mg).
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:9]([C:17]([O:19][CH3:20])=[O:18])[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(N(C(C)C)CC)(C)C.[N:30]1([CH2:35][CH2:36][O:37][CH2:38][CH:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)[CH2:34][CH2:33][CH2:32][CH2:31]1>C1COCC1.O>[C:11]1([C:10]2[C:3]3[C:2]([N:42]4[CH2:43][CH2:44][CH:39]([CH2:38][O:37][CH2:36][CH2:35][N:30]5[CH2:34][CH2:33][CH2:32][CH2:31]5)[CH2:40][CH2:41]4)=[N:7][CH:6]=[N:5][C:4]=3[S:8][C:9]=2[C:17]([O:19][CH3:20])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C1CCN(CCOCC2CCNCC2)C1
Reactant: COC(=O)c1sc2ncnc(Cl)c2c1-c1ccccc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1sc2ncnc(N3CCC(COCCN4CCCC4)CC3)c2c1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.2 %

Procedure:
To a stirred solution of methyl 4-chloro-5-phenyl-thieno[2,3-d]pyrimidine-6-carboxylate (0.850 g, 2.80 mmol) in THF (50 mL), was added diisopropylethylamine (0.73 mL, 4.20 mmol) and 4-(2-pyrrolidin-1-ylethoxymethyl)piperidine (0.890 g, 4.20 mmol) in one portion, and the reaction left to stir at room temperature for 2 hours. The reaction was diluted with water (50 mL) and extracted with ethyl acetate (3×50 mL). The reaction was dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography using DCM: MeOH (0-25%) as eluent to afford the named product (1.012 g, 75%). m/z [M+H]+481; RT=3.03 min.
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[N:5][C:4](=[C:8](Cl)Cl)[N:3]=1.[Na].[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1.[O:23]1CCOCC1>O>[CH3:22][C:12]1[CH:13]=[CH:14][C:15]([S:18]([NH:21][C:8]([C:4]2[NH:5][C:6]([Cl:7])=[C:2]([Cl:1])[N:3]=2)=[O:23])(=[O:19])=[O:20])=[CH:16][CH:17]=1
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Reactant: C1COCCO1
Reactant: ClC1=NC(=C(Cl)Cl)N=C1Cl
Agent: [Na]
Solvent: O
Product: Cc1ccc(S(=O)(=O)NC(=O)c2nc(Cl)c(Cl)[nH]2)cc1
Yield: 42 %

Procedure:
A solution of 21.8 g (0.1 mol) of 4,5-dichloro-2-dichloromethylene-imidazole in 25 ml of dioxane was added to a suspension of 22 g (0.114 mol) of the sodium salt of p-toluenesulphonamide in 200 ml of water, while stirring. The mixture was then heated briefly to the boil and the product was filtered off while the mixture was still at the boiling point. The precipitate was dried and recrystallized from acetonitrile or toluene. In this way, 14 g (42% of theory) of N-(4-methylphenylsulphonyl)-4,5-dichloroimidazole-2-carboxylic acid amide with a melting point of 238° C. were obtained.
Reaction SMILES: [NH3:1].[N+:2]([C:5]1[C:6](F)=[CH:7][C:8]([Cl:24])=[C:9]([CH:23]=1)[C:10]([NH:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([C:19]([F:22])([F:21])[F:20])[CH2:15][CH2:14]1)=[O:11])([O-:4])=[O:3].C1COCC1>O>[N+:2]([C:5]1[C:6]([NH2:1])=[CH:7][C:8]([Cl:24])=[C:9]([CH:23]=1)[C:10]([NH:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([C:19]([F:22])([F:21])[F:20])[CH2:15][CH2:14]1)=[O:11])([O-:4])=[O:3]
Reactant: O=C(N[C@H]1CC[C@H](C(F)(F)F)CC1)c1cc([N+](=O)[O-])c(F)cc1Cl
Reactant: N
Solvent: C1CCOC1
Solvent: O
Product: Nc1cc(Cl)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Conc. ammonia (0.8 ml) was added portionwise at −10° C. to a mixture of 5-nitro-2-chloro-4-fluoro-N-(trans-4-trifluoromethyl-cyclohex-1-yl)-benzamide (0.20 g, 0.54 mmol) and 10 ml THF and it was stirred overnight at room temperature. Water was added and the mixture was conc. i.vac. The residue was triturated with water and filtered. The filter cake was washed with water and dried to obtain the crude subtitle compound (MS m/z: 366 [M+H]+).
Reaction SMILES: [C-:1]#[N:2].[K+].[I-].C[N+](C)(C)[CH2:7][C:8]1[C:16]2[C:11](=[N:12][CH:13]=[CH:14][N:15]=2)[NH:10][C:9]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O.CN(C)C=O>[C:17]1([C:9]2[NH:10][C:11]3=[N:12][CH:13]=[CH:14][N:15]=[C:16]3[C:8]=2[CH2:7][C:1]#[N:2])[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: C[N+](C)(C)Cc1c(-c2ccccc2)[nH]c2nccnc12
Reactant: [C-]#N
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCc1c(-c2ccccc2)[nH]c2nccnc12
Temperature: 75 °C

Procedure:
A solution of potassium cyanide (0.84 g) in water (20 mL) was added rapidly to a stirred solution of trimethyl(6-phenyl-5H-pyrrolo[2,3-b]pyrazin-7-ylmethyl)-ammonium iodide [1.1 g, Reference Example 33] in dimethylformamide (20 mL) and the mixture heated at 75° C. for 6 hours. The cooled solution was diluted with water (100 mL) and the precipitated solid filtered to give the title compound as a yellow solid, m.p. 247–248° C.