Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[O:5][C:6]2[C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=[CH:15][C:7]=2[C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([O-:3])=[O:2].Cl.[CH2:23]([N:25]([CH2:28][CH2:29]Cl)[CH2:26][CH3:27])[CH3:24].C(N(CC)CC)C>CN(C)C=O>[N+:1]([C:4]1[O:5][C:6]2[C:18]([C:19]([O:21][CH2:24][CH2:23][N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[O:20])=[CH:17][CH:16]=[CH:15][C:7]=2[C:8]=1[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)([O-:3])=[O:2]
Reactant: CCN(CC)CCCl
Reactant: O=C(O)c1cccc2c(-c3ccccc3)c([N+](=O)[O-])oc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN(CC)CCOC(=O)c1cccc2c(-c3ccccc3)c([N+](=O)[O-])oc12
Reaction time: 48 h

Procedure:
A mixture of 14.2 g (0.05 mole) of 2-nitro-3-phenyl-7-benzofurancarboxylic acid, 8.6 g (0.05 mole) of N,N-diethylamino-2-chloroethane hydrochloride, 10.1 g (0.1 mole) of triethylamine and 75 ml of N,N-dimethylformamide is heated at 90° to 100° C. for 16 hours, then left standing at 23° C. for 2 days. The mixture is cooled with an ice bath, then filtered to remove the white solid by-product. The filtrate is dissolved in diethyl ether, washed thrice with water and twice with saturated sodium chloride solution and dried. The solution is evaporated to provide an oil, N,N-diethylaminoethyl 2-nitro-3-phenyl-7-benzofurancarboxylate. This oil is dissolved in diethyl ether and treated with 25 ml of 4N-hydrochloric acid in isopropanol to provide a product which gradually solidifies. The product is recrystallized twice from ethanol to provide N,N-diethylaminoethyl 2-nitro-3-phenyl-7-benzofurancarboxylate hydrochloride, m.p. 194.5°-195° C., as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:30][CH3:31])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[O:27]CC)=[N:13][C:14]=1[CH2:15][CH3:16].Br[C:33]1N=C(C2CC2)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=NC=1CC>>[CH:30]1([C:11]2[C:12]([NH:17][C@@H:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:20][C@@H:19]3[OH:27])=[N:13][C:14]([CH2:15][CH3:16])=[C:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[N:10]=2)[CH2:33][CH2:31]1
Reactant: CCc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(C2CC2)nc1Br
Reactant: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Product: CCc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(C2CC2)nc1-c1ccc(Cl)cc1Cl

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine but substituting (1R,2S)-1-[(5-bromo-3-cyclopropyl-6-ethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol and making non-critical variations provided the title compound as a solid: 1H NMR (CDCl3) δ 0.94–1.02, 1.14–1.19, 1.26–1.30, 1.68–1.86, 2.06, 2.28–2.49, 3.08–3.32, 4.06–4.18, 4.83–4.87, 5.49, 5.62–5.66, 7.27–7.50; MS (ESI+) for C24H23Cl2N3O m/z 440 (MH)+.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][CH:12]=[C:11]3[C:7]=2[CH:8]=[C:9]([C:15]([OH:17])=O)[NH:10]3)[CH2:3][CH2:2]1.Cl.Cl.Cl.[NH2:21][CH:22]1[CH2:27][CH2:26][N:25]([CH2:28][C@@H:29]([N:31]2[CH2:36][CH2:35][CH:34]([OH:37])[CH2:33][CH2:32]2)[CH3:30])[CH2:24][CH2:23]1>>[OH:37][CH:34]1[CH2:33][CH2:32][N:31]([C@@H:29]([CH3:30])[CH2:28][N:25]2[CH2:24][CH2:23][CH:22]([NH:21][C:15]([C:9]3[NH:10][C:11]4[C:7]([CH:8]=3)=[C:6]([O:5][CH2:4][CH:1]3[CH2:2][CH2:3]3)[CH:14]=[CH:13][CH:12]=4)=[O:17])[CH2:27][CH2:26]2)[CH2:36][CH2:35]1
Reactant: O=C(O)c1cc2c(OCC3CC3)cccc2[nH]1
Reactant: C[C@@H](CN1CCC(N)CC1)N1CCC(O)CC1
Agent: Cl
Product: C[C@@H](CN1CCC(NC(=O)c2cc3c(OCC4CC4)cccc3[nH]2)CC1)N1CCC(O)CC1

Procedure:
This compound is synthesized analogously to example 1 from 4-cyclopropylmethoxy-1H-indole-2-carboxylic acid, 77 (see example 4) and amine 50.
Reaction SMILES: [Li][C:2]#[C:3][Si](C)(C)C.[O:8]=[C:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:25][C@H:24]([CH2:26][NH:27][C:28](=[O:30])[CH3:29])[O:23][C:22]3=[O:31])=[CH:17][C:16]=2[F:32])[CH2:11][CH2:10]1.[Cl-].[NH4+].[C:35](=O)([O-])[O-].[K+].[K+]>O1CCCC1>[CH2:35]([C:9]1([OH:8])[CH2:10][CH2:11][N:12]([C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:25][C@H:24]([CH2:26][NH:27][C:28](=[O:30])[CH3:29])[O:23][C:22]3=[O:31])=[CH:17][C:16]=2[F:32])[CH2:13][CH2:14]1)[C:2]#[CH:3]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(=O)CC3)c(F)c2)C(=O)O1
Reactant: [Li]C#C[Si](C)(C)C
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C#CCC1(O)CCN(c2ccc(N3C[C@H](CNC(C)=O)OC3=O)cc2F)CC1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 19 %

Procedure:
A mixture of lithio(trimethylsilyl)acetylene (1.72 mmol) and (S)-N-{3-[4-(4-oxo-piperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (1.72 mmol) in tetrahydrofuran (10 ml) was stirred at a temperature −78° C. for 15 minutes. It was allowed to come to room temperature and further stirred for 18 hours. The reaction mixture was then stirred with aqueous solution of ammonium chloride, the reaction mixture was extracted with ethyl acetate (3×40 ml). The removal of the solvent provided a residue, which was stirred in aqueous methanolic (15 ml) solution of potassium carbonate (1.72 mmol) for 3 hours. The solvent was removed and the residual mass was purified by column chromatography over silica gel to provide title compound in 19% yield. M.P. 166-167° C. and MS (M+1)=376 (MH+, 100%) M.F.=C19H22FN3O4.
Reaction SMILES: [N:1]1[C:8](Cl)=[N:7][C:5](Cl)=[N:4][C:2]=1Cl.[Cl-].[Al+3].[Cl-].[Cl-].[C:14]1([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[C:27]1([CH:34]=[CH:33][CH:32]=[C:30]([OH:31])[CH:29]=1)[OH:28]>ClC1C=CC=CC=1Cl>[OH:28][C:27]1[CH:29]=[C:30]([OH:31])[CH:32]=[CH:33][C:34]=1[C:2]1[N:4]=[C:5]([C:32]2[CH:33]=[CH:34][C:27]([OH:28])=[CH:29][C:30]=2[OH:31])[N:7]=[C:8]([C:24]2[CH:23]=[CH:22][C:21]([O:20][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:26][CH:25]=2)[N:1]=1
Reactant: c1ccc(Oc2ccccc2)cc1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: Oc1cccc(O)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1Cl
Product: Oc1ccc(-c2nc(-c3ccc(Oc4ccccc4)cc3)nc(-c3ccc(O)cc3O)n2)c(O)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 10.1 %

Procedure:
To a stirring mixture of 9 gm of cyanuric chloride, 20 gm of aluminum chloride in 50 mL of o-dichlorobenzene was added 8.5 gm of phenyl ether followed by 11 gm of resorcinol. The reaction mixture was first stirred at room temperature and then gradually heated to 110-115° C., and then held for 4 hr at this temperature. The heating was discontinued, and the reaction mixture quenched with water. O-Dichlorobenzene was removed azeotropically from the product mixture, the precipitated material filtered, and washed with water. The crude product was purified by column chromatography to give 2.3 gm of pure 2,4-bis(2,4-dihyroxyphenyl)-6-(4-phenoxyphenyl)-1,3,5-triazine, identified by HPLC, NMR, LC-UV and mass spectroscopy.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5]([CH:14]=[O:15])=[CH:4][CH:3]=1.[Si]([C:20]([F:23])([F:22])[F:21])(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].Cl>C1COCC1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:14]([OH:15])[C:20]([F:23])([F:22])[F:21])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1
Reactant: O=Cc1ccc(Br)cc1-c1ccccc1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: OC(c1ccc(Br)cc1-c1ccccc1)C(F)(F)F
Temperature: 0 °C
Reaction time: 12 h

Procedure:
To a solution of 5-bromo-[1,1′-biphenyl]-2-carbaldehyde (1.9 g, 7.3 mmol) and was added TMSCF3 (1.2 g, 8.7 mmol) in THF (20 mL) and cooled to 0° C. To this solution was added TBAF (1.46 mL, 1M in THF) and the reaction mixture was warmed to RT for 3 h. After this time, the mixture was treated with 3 N HCl (5 mL) and stirred for 12 h. Then the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated in vacuo and purified by normal phase silica gel column (EtOAc:PE=1:10) to afford 1-(5-bromo-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethanol as a colorless oil.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:15]=[CH:14][C:6]([O:7][CH2:8][C:9]([O:11]CC)=[O:10])=[C:5]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH:4]=1.[C:22]1([CH2:28][C:29](Cl)=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[Cl:2][C:3]1[CH:15]=[CH:14][C:6]([O:7][CH2:8][C:9]([OH:11])=[O:10])=[C:5]([N:16]2[CH2:17][CH2:18][N:19]([C:29](=[O:30])[CH2:28][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:20][CH2:21]2)[CH:4]=1
Reactant: CCOC(=O)COc1ccc(Cl)cc1N1CCNCC1
Reactant: O=C(Cl)Cc1ccccc1
Agent: Cl
Product: O=C(O)COc1ccc(Cl)cc1N1CCN(C(=O)Cc2ccccc2)CC1

Procedure:
Prepared from the product from example 38 step c) and benzeneacetyl chloride by the method of Example 38 step d) to give the title compound as a white solid.
Reaction SMILES: O1CCCC1.[N:6]1([C:11]2[CH:16]=[CH:15][C:14]([CH:17]([CH3:20])[C:18]#[N:19])=[CH:13][CH:12]=2)[CH:10]=[CH:9][N:8]=[CH:7]1.CC(C)([O-])C.[K+].[CH3:27][N:28]=[C:29]=[S:30]>O>[CH3:27][NH:28][C:29](=[S:30])[C:17]([C:14]1[CH:13]=[CH:12][C:11]([N:6]2[CH:10]=[CH:9][N:8]=[CH:7]2)=[CH:16][CH:15]=1)([C:18]#[N:19])[CH3:20]
Reactant: CC(C#N)c1ccc(-n2ccnc2)cc1
Reactant: CN=C=S
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CNC(=S)C(C)(C#N)c1ccc(-n2ccnc2)cc1
Reaction time: 0.5 h
Yield: 54.4 %

Procedure:
To a 10 ml tetrahydrofuran solution containing 1.00 g (5.1 mmole) of 2-[4-(1-imidazolyl)-phenyl]propionitrile was added a 10 ml tetrahydrofuran solution containing 0.69 g (6.2 mmole) of potassium tert-butoxide at 0 C. After stirring for 0.5 hour, a 5 ml tetrahydrofuran solution containing 0.45 g (6.2 mmole) of methyl isothiocyanate was added to the mixture and the mixture was stirred at room temperature for 2 hours. Water was added to the mixture and the mixture was extracted with 20 ml of ethyl acetate, dried and condensed under reduced pressure, and then purified by silica gel chromatography and condensed. The resulting condensate was suspended in 30 ml of toluene and the suspension was refluxed under heating for 0.5 hour and a solid was collected by filtration to obtain 0.75 g (yield: 54 %) of N-methyl-2-[4-(1-imidazolyl)-phenyl]-2cyanothiopropionamide as a crystalline solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([CH3:9])[N:6]=[C:5]([N:10](C2C=CC=CC=2)[C:11](=[O:13])[O-])[N:4]=1.[C:20]([CH2:22][CH:23]=[CH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([NH2:34])(=[O:33])=[O:32])#[N:21].N12CCCCC1C=NCCC2.Cl>O1CCOCC1.O>[C:20]([CH2:22][CH:23]=[CH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([NH:34][C:11]([NH:10][C:5]1[N:4]=[C:3]([O:2][CH3:1])[N:8]=[C:7]([CH3:9])[N:6]=1)=[O:13])(=[O:33])=[O:32])#[N:21]
Reactant: N#CCC=Cc1ccccc1S(N)(=O)=O
Reactant: COc1nc(C)nc(N(C(=O)[O-])c2ccccc2)n1
Agent: C1=NCCCN2CCCCC12
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: COc1nc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2C=CCC#N)n1
Reaction time: 15 h
Yield: 66.9 %

Procedure:
5.2 g of N-(4-methoxy-6-methyl-1,3,5-triazin-2-yl)phenylcarbamate are added to a solution of 4.45 g of 2-(3-cyano-1-propen-1-yl)phenylsulfonamide and 3.3 ml of 1,5-diazabicyclo[5,4,0]undec-5-ene in 80 ml of dioxan, and the mixture is stirred for 15 hours at 20°-25° C. The reaction mixture is then taken up in 350 ml of water and the aqueous solution is acidified to pH 2 with 2N HCl and extracted with ethyl acetate. The organic extracts are combined and concentrated. The oily orange-coloured residue is dissolved in a very small amount of acetone. About 20 ml of diethyl ether are added to this solution, which is diluted dropwise with hexane until the onset of crystallisation. The mixture is subsequently further cooled and the precipitated crystals are isolated by filtration. Yield: 5.2 g of the title compound with a melting point of 142°-143° C.
Reaction SMILES: C(C1[C:12]2[C:7](=[C:8]([O:13][CH3:14])[CH:9]=[CH:10][CH:11]=2)[CH2:6][CH:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:4]1)#N.[OH-:21].[K+].Cl.[CH2:24]([OH:27])[CH2:25]O>>[CH3:14][O:13][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:7]=1[CH2:6][CH:5]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:4][CH:25]2[C:24]([OH:27])=[O:21]
Reactant: OCCO
Reactant: COc1cccc2c1CC(c1ccccc1)CC2C#N
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Product: COc1cccc2c1CC(c1ccccc1)CC2C(=O)O
Temperature: -20 °C

Procedure:
A mixture of 5.03 g (19.1 mmol) of 1-cyano-5-methoxy-3-phenyl-1,2,3,4-tetrahydronaphthalene, from Step 2, 40 mL of 5% aqueous potassium hydroxide solution and 90 mL of ethylene glycol is heated at reflux temperature for 8 h. The reaction mixture is then cooled to -20° C. and made acidic by the addition of cold concentrated aqueous hydrochloric acid solution. The acidic solution is extracted with methylene chloride and the organic extracts are washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated to give the title compound which is used in the next step without purification.
Reaction SMILES: [C:1]([O-])(=O)[C:2]([CH3:4])=O.[Na+].[CH3:8][C:9]1N=[CH:13][C:12]([CH2:15]OP(O)(O)=O)=[C:11](C=O)[C:10]=1O.P([O-])([O-])([O-])=[O:25].[K+].[K+].[K+]>>[C:12]1([CH2:11][CH2:10][C:9](=[O:25])[CH3:8])[CH:13]=[CH:4][CH:2]=[CH:1][CH:15]=1
Reactant: CC(=O)C(=O)[O-]
Reactant: O=P([O-])([O-])[O-]
Reactant: Cc1ncc(COP(=O)(O)O)c(C=O)c1O
Agent: [K+]
Agent: [Na+]
Product: CC(=O)CCc1ccccc1
Reaction time: 2 h

Procedure:
Enrichment: A 140 ml. solution of 10 mM R,S-1-phenyl-3-aminobutane, 100 M of sodium pyruvate, 0.1 mM of pyridoxal phosphate, and 25 mM of potassium phosphate (pH 7) was circulated through the above matrix at ambient temperatures and a rate of 5 ml/min. After two hours, the circulating liquid was removed from the apparatus. The concentration of 1-phenylbutan-3-one formed was 5.2 mM while that of R-1-phenyl-3-aminobutane was 4.8 mM. The pH was adjusted to 12.5 and R-1-phenyl-3-aminobutane was isolated quantitatively by extraction with heptane. After removal of the heptane by evaporation, the product was analyzed as 92.8% R-1-phenyl-3-aminobutane.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C[C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[C:13]([C:20]([OH:22])=[O:21])[CH:12]=1.[F-].[Cs+].[CH3:25]OCCOC>CO.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>[CH3:9][O:8][C:5]1[N:6]=[CH:7][C:2]([C:16]2[CH:15]=[CH:14][C:13]([C:20]([O:22][CH3:25])=[O:21])=[CH:12][CH:11]=2)=[CH:3][CH:4]=1
Reactant: Cc1ccc(B(O)O)c(C(=O)O)c1
Reactant: COCCOC
Reactant: COc1ccc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CO
Product: COC(=O)c1ccc(-c2ccc(OC)nc2)cc1

Procedure:
A mixture of 5-bromo-2-methoxypyridine (2.93 g, 10 mmol), 4-methylcarboxybenzeneboronic acid (1.80 g, 10 mmol), Pd(Ph3P)4 (0.346 g, 0.3 mmol) and CsF (1.52 g, 10 mmol) in DME (60 mL) and methanol (30 mL) was heated to reflux for 18 hours and concentrated. The concentrate was dissolved in water (50 mL) and ethyl acetate (300 mL) and the organic phase was washed with water (2×50 mL) and brine (50 mL), dried (Na2SO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 3:1 hexanes/ethyl acetate to provide the desired product. MS (APCI) m/e 278, 280 (M−H)−, (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:12][CH3:13])[C:5]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][CH:6]=1.C(N(CC)CC)C.Cl[Si:22]([CH3:25])([CH3:24])[CH3:23].C(OCC)C>O1CCCC1>[CH3:23][Si:22]([CH3:25])([CH3:24])[O:1][CH2:2][CH2:3][N:4]([CH2:12][CH3:13])[C:5]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][CH:6]=1
Reactant: CCN(CCO)c1ccc(I)cc1
Reactant: C[Si](C)(C)Cl
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCN(CCO[Si](C)(C)C)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.5 %

Procedure:
A solution of 14.5 g, that is 50 mmole of 4-[(2-hydroxyethyl)ethylamino]iodobenzene and 6.0 g, that is 60 mmole triethylamine, from Aldrich Chemical Co. in 90 ml tetrahydrofuran ("THF") was stirred in an ice-water bath under nitrogen. Next, 5.5 g, 51 mmole chlorotrimethylsilane, from Aldrich Chemical Co. was added slowly while maintaining the reaction temperature below 10° C. The mixture was stirred for 30 minutes then warmed to room temperature for 1 hour. Ethyl ether was added and extracted with brine. The organic layer was separated and dried over anhydrous sodium sulfate. After removing the solvent under reduced pressure, the residue was flash column chromatographed on silica gel with 2% ethyl acetate-hexane to give 16.63 g of a clear viscous oil at a 92% yield.
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:13][C:12](=[N:14][O:15][CH3:16])[CH2:11][C@H:10]2[C:17](=[N:19][OH:20])[NH2:18])=[O:8])=[CH:3][CH:2]=1.[CH3:27][N:28]([CH3:34])[CH2:29][CH2:30][C:31](O)=O>>[CH3:16][O:15][N:14]=[C:12]1[CH2:11][C@@H:10]([C:17]2[N:18]=[C:31]([CH2:30][CH2:29][N:28]([CH3:34])[CH3:27])[O:20][N:19]=2)[N:9]([C:7]([C:4]2[CH:3]=[CH:2][C:1]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:6][CH:5]=2)=[O:8])[CH2:13]1
Reactant: CN(C)CCC(=O)O
Reactant: CON=C1C[C@@H](C(N)=NO)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Product: CON=C1C[C@@H](c2noc(CCN(C)C)n2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Yield: 25 %

Procedure:
Following the general method as outlined in Example 15, starting from (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N′-hydroxy-4-(methoxyimino)-2-pyrrolidinecarboximidamide (Intermediate 8) and N,N-dimethyl-β-alanine, the title compound was obtained in 25% yield (91.5% purity by HPLC).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5](N)=[N:4][CH:3]=1.N([O-])=O.[Na+].[CH3:17][OH:18].C(Cl)(Cl)Cl>S(=O)(=O)(O)O>[Br:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]([O:18][CH3:17])=[N:4][CH:3]=1
Reactant: COC(=O)c1nc(Br)cnc1N
Reactant: CO
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COC(=O)c1nc(Br)cnc1OC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In 100 ml of concentrated sulfuric acid is dissolved 17.00 g of methyl 6-bromo-3-amino-2-pyrazinecarboxylate obtained according to the method described in literature [J. Am. Chem. Soc., 2798-2800 (1949)]. At an ice-cooled temperature, 10.11 g of sodium nitrite is added to the suspension, which is stirred for 30 minutes. The reaction mixture is poured into 920 mL of methanol, and heated under reflux for 5 hours. The reaction mixture is cooled and then concentrated under reduced pressure. The residue thus obtained is added to a mixture of 500 mL of ice water and 600 mL of chloroform and separated into layers. The organic layer is washed successively with saturated aqueous solution of sodium hydrogen carbonate, water and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. Then, the solvent is distilled off under reduced pressure to obtain 6.30 g of methyl 6-bromo-3-methoxy-2-pyrazinecarboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](=O)[C:11]([CH3:16])([CH3:15])[CH:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1.[C:18]1(C)C=CC=CC=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([C:11]([CH3:16])([CH3:15])[CH:12]([CH3:14])[CH3:13])=[CH2:18])=[CH:4][CH:3]=1
Reactant: Cc1ccccc1
Reactant: CC(C)C(C)(C)C(=O)CCc1ccc(Cl)cc1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: C=C(CCc1ccc(Cl)cc1)C(C)(C)C(C)C
Temperature: 25 °C
Yield: 58 %

Procedure:
A suspension of 47.4 g (0.133 mol) of methyltriphenyl-phosphonium bromide and 15.3 g (0.137 mol) of potassium tert.-butylate in 250 ml of absolute toluene is heated under reflux under dry nitrogen 25.2 g (0.1 mol) of 1-(4-chlorophenyl)-4,4,5-trimethyl-hexan-3-one are introduced over the course of 5 minutes The reaction mixture is heated under reflux for a further 15 hours, then cooled to room temperature, washed twice with water and concentrated under reduced pressure The residue is taken up in ethyl acetate, cooled to 5° C. and the crop of crystals formed is filtered off with suction. The filtrate is concentrated and distilled under reduced pressure. 14.5 g (58% of theory) of 2-(4-chlorophenylethyl)-3,3,4-trimethyl-pent-1-ene are obtained in the form of a yellow oil of boiling point 88°-90° C./0.1 mbar. ##STR22##
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[CH2:25](Br)[CH:26]([CH3:28])[CH3:27].C(OC(N1CCC2C(=C(C3C=CC(Cl)=CC=3)N(CC(C)C)N=2)CC1)=O)(C)(C)C>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH2:25][CH:26]([CH3:28])[CH3:27])[N:13]=2)=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Reactant: CC(C)CBr
Agent: CC(C)Cn1nc2c(c1-c1ccc(Cl)cc1)CCN(C(=O)OC(C)(C)C)CC2
Product: CC(C)Cn1nc(-c2ccc(Cl)cc2)c2c1CCNCC2
Yield: 51 %

Procedure:
The title compound (0.031 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B; 0.2 mmol) using isobutyl bromide (0.3 mmol) in place of 2-chloromethyl-thiophene. The reaction sequence also yielded 3-(4-chloro-phenyl)-2-isobutyl-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester from the alkylation step. MS (ESI): exact mass calculated for C17H22ClN3, 303.15; found, m/z 304.1 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.64 (d, J=6.6 Hz, 2H), 7.56 (d, J=6.6 Hz, 2H), 4.20 (d, J=7.4 Hz, 2H), 3.72-3.69 (br m, 2H), 3.62-3.60 (br m, 2H), 3.44-3.42 (br m, 2H), 3.29-3.27 (br m, 2H), 2.35 (m, 1H), 1.14 (d, J=6.7 Hz, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[O:5][CH:6]1[CH2:11][CH2:10][N:9]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH2:8][CH2:7]1.[O-:22][C:23]#[N:24].[Na+].[OH-].[Na+]>C(O)(=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[O:5][CH:6]1[CH2:7][CH2:8][N:9]([CH:12]2[CH2:13][CH2:14][N:15]([C:23]([NH2:24])=[O:22])[CH2:16][CH2:17]2)[CH2:10][CH2:11]1
Reactant: Clc1ccc(OC2CCN(C3CCNCC3)CC2)cc1Cl
Reactant: N#C[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: NC(=O)N1CCC(N2CCC(Oc3ccc(Cl)c(Cl)c3)CC2)CC1
Reaction time: 0.5 h
Yield: 57.5 %

Procedure:
4-(3,4-Dichlorophenoxy)-1,4′-bipiperidine (2.0 g) was dissolved in glacial acetic acid (0.608 ml), the solution was diluted with water (6 ml) and added with stirring to a solution of sodium cyanate (0.395 g) in warm water (3 ml). The reaction was allowed to stand for 30 mins. 2M Sodium hydroxide solution was added until the solution was alkaline. The resulting precipitate was collected and washed with water followed by dichloromethane and then dried to leave the sub-title compound (1.3 g; ES+ 372/374).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:20][C:21]1[C:26]([C:27](Cl)=[O:28])=[C:25]([Cl:30])[N:24]=[CH:23][N:22]=1>O1CCCC1.ClCCl>[Cl:20][C:21]1[C:26]([C:27]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([S:8](=[O:10])(=[O:9])[NH:11][CH3:12])=[CH:4][CH:3]=2)=[O:28])=[C:25]([Cl:30])[N:24]=[CH:23][N:22]=1
Reactant: O=C(Cl)c1c(Cl)ncnc1Cl
Reactant: CNS(=O)(=O)c1ccc(N)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1ccc(NC(=O)c2c(Cl)ncnc2Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.3 %

Procedure:
4-Amino-N-methylbenzenesulfonamide (244 mg, 1.31 mmol) was dissolved in tetrahydrofuran (12 ml) and triethylamine (402 μl, 2.88 mmol) was added. Then a solution of 4,6-dichloropyrimidine-5-carbonyl chloride (300 mg, 1.42 mmol, prepared according to E. V. Tarasov et al. Synlett 2000, 5, 625-626) was dropwise added. After 2 h more triethylamine (202 μl, 1.44 mmol) and 4,6-dichloropyrimidine-5-carbonyl chloride (150 mg, 0.71 mmol) were added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was then diluted with dichloromethane, washed with 4% sodium bicarbonate solution, dried over magnesium sulphate, filtered and evaporated. The crude was purified by flash chromatography (0% to 60%, hexane-ethyl acetate) using a SP1® Purification System to give 238 mg (50% yield) of the title compound. Purity 100%.