Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:13]=[C:14]=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[ClH:16].Cl.Cl.[NH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][N:26]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)[CH2:25][CH2:24]1.C(N(CC)CC)C>C(Cl)Cl>[ClH:36].[ClH:16].[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([CH2:29][N:26]2[CH2:25][CH2:24][N:23]([CH2:22][CH2:21][CH2:20][NH:19][C:14]([NH:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:15])[CH2:28][CH2:27]2)=[CH:31][CH:32]=1
Reactant: NCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Reactant: CCCCCCCCCCCCN=C=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCNC(=O)NCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Yield: 116.3 %

Procedure:
The procedure described in Example 29 was followed using n-dodecyl isocyanate (2.11 g; 10 mmole), 1-(3-aminopropyl)-4-(4-chlorobenzyl)piperazine trihydrochloride (3.77 g; 10 mmole) methylene chloride (100 ml), and triethylamine (3.03 g; 30 mmole). Recrystallization from water provided the title compound (3.21 g; 58% yield) as colorless crystals, m.p. 215°-222° C.
Reaction SMILES: [Cl:1]N1C(=O)N(Cl)C(=O)N(Cl)C1=O.[CH3:13][C:14]1[N:15]=[C:16]([CH3:21])[C:17]([CH3:20])=[N:18][CH:19]=1>ClC(Cl)C>[Cl:1][CH2:13][C:14]1[N:15]=[C:16]([CH3:21])[C:17]([CH3:20])=[N:18][CH:19]=1
Reactant: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Reactant: Cc1cnc(C)c(C)n1
Solvent: CC(Cl)Cl
Product: Cc1ncc(CCl)nc1C
Temperature: 20 °C
Reaction time: 12 h

Procedure:
7.6 g (32.74 mmol) of trichloroisocyanuric acid are added, over 1 hour, to a solution, maintained at reflux, of 10 g of trimethylpyrazine (81.85 mmol) in 820 ml of dichloroethane. The reaction mixture is refluxed for 6 hours and then cooled to 20° C., stirred for a further 12 hours and filtered. The filtrate is concentrated under reduced pressure, taken up in 200 ml of ethyl ether, filtered again and then concentrated under reduced pressure. 9.6 g of methyldimethylpyrazine chloride are recovered in the form of a mixture, which is used without further purification in the following step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH4+].[Cl-]>C1COCC1.C(OCC)(=O)C.C(=O)([O-])[O-].[Na+].[Na+].[Zn]>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[CH:10][C:11]([NH2:14])=[CH:12][N:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cnc(-c2cccc(Cl)c2)nc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1cnc(-c2cccc(Cl)c2)nc1
Reaction time: 3 h
Yield: 28.8 %

Procedure:
2-(3-Chlorophenyl)-5-nitropyrimidine (100 mg, 0.424 mmol) was diluted with THF (1 mL) followed by the addition of Zn dust (27.8 mg, 0.424 mmol) and sat NH4Cl (1 mL). After stirring for 3 hours, the reaction was diluted with ethyl acetate and 10% sodium carbonate. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated. The material was purified using a 0.5 mm preparative TLC plate eluting with 10% methanol/DCM to yield the desired compound (25 mg, 0.122 mmol, 28.6% yield).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=O)[CH3:11])[N:5]=1)(=O)[CH3:2].[CH3:13][C:14]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]([CH3:23])[CH3:22])[C:15]=1[NH2:16]>C(O)(=O)C.C(O)C>[CH3:13][C:14]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]([CH3:23])[CH3:22])[C:15]=1[N:16]=[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=[N:16][C:15]2[C:17]([CH:21]([CH3:22])[CH3:23])=[CH:18][CH:19]=[CH:20][C:14]=2[CH3:13])[CH3:11])[N:5]=1)[CH3:2]
Reactant: CC(=O)c1cccc(C(C)=O)n1
Reactant: Cc1cccc(C(C)C)c1N
Solvent: CC(=O)O
Solvent: CCO
Product: CC(=Nc1c(C)cccc1C(C)C)c1cccc(C(C)=Nc2c(C)cccc2C(C)C)n1
Yield: 35 %

Procedure:
There were supplied 325 mg of 2,6-diacetylpyridine manufactured by Aldrich Chemical Company to a 25 mL-Schlenk tube. Thereto, 5 mL of anhydrous ethanol manufactured by Kanto Chemical Co., Inc., 0.62 mL of 2-methyl-6-isopropylaniline manufactured by Tokyo Chemical Industry Co., Ltd., and a few drops of acetic acid manufactured by Kanto Chemical Co., Inc. were added. The obtained mixture was refluxed for 24 hours. Then, the solvent contained in the mixture was distilled off, and the resultant mixture was subjected to recrystallization with methanol, thereby obtaining 298 mg (yield: 35%) of 2,6-bis[1-(2-methyl-6-isopropylphenylimino)ethyl]pyridine as a yellow powder.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C=O.[C:17]([OH:24])(=[O:23])/[CH:18]=[CH:19]/[C:20]([OH:22])=[O:21]>C(O)(=O)C.C(O)C>[C:17]([OH:24])(=[O:23])/[CH:18]=[CH:19]/[C:20]([OH:22])=[O:21].[C:9]1([C:5]2[N:4]3[CH2:3][CH2:2][NH:1][CH2:17][C:8]3=[CH:7][CH:6]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NCCn1cccc1-c1ccccc1
Agent: C=O
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCO
Solvent: CC(=O)O
Product: c1ccc(-c2ccc3n2CCNC3)cc1
Temperature: 25 °C
Reaction time: 64 h
Yield: 40 %

Procedure:
Crude 1-(2-aminoethyl)-2-phenylpyrrole (0.3 g) was dissolved in 5 ml of acetic acid under argon and treated with 0.1 ml of a 36.5% aqueous formaldehyde solution. The reaction mixture was stirred at room temperature for 64 hours and subsequently concentrated in a vacuum. The residue was stirred briefly with 50 ml of methylene chloride and 20 ml of 10% ammonia solution. The phases were separated, the organic phase was dried with MgSO4 and freed from solvent. The residue, 0.4 g of yellow oil, was chromatographed on 70 g of silica gel with methylene chloride/methanol (49:1) as the eluent. The product, 0.3 g of yellow oil, was taken up in a 20-fold amount of ethanol and treated with 2 equivalents of a saturated solution of fumaric acid in ethanol. The separated crystals were recrystallized from ethanol. There was obtained 0.2 g (40%) of 1,2,3,4-tetrahydro-6-phenylpyrrolo[1,2-a]pyrazine fumarate (1:1); m.pt.: 182°- 184° C. (dec.).
Reaction SMILES: Cl.[O:2]=[C:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH2:8][C:9]([N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:10].C(N(CC)CC)C.ClC1C(O[C:32](=[O:47])[CH2:33][N:34]2[CH2:38][CH:37]([C:39]3[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=3)[CH2:36][C:35]2=[O:46])=C(Cl)C(Cl)=C(Cl)C=1Cl.C(OCC)C>C(Cl)Cl>[Cl:45][C:42]1[CH:41]=[CH:40][C:39]([CH:37]2[CH2:38][N:34]([CH2:33][C:32]([N:14]3[CH2:15][CH2:16][N:11]([C:9](=[O:10])[CH2:8][N:4]4[CH2:5][CH2:6][CH2:7][C:3]4=[O:2])[CH2:12][CH2:13]3)=[O:47])[C:35](=[O:46])[CH2:36]2)=[CH:44][CH:43]=1
Reactant: O=C(CN1CCCC1=O)N1CCNCC1
Reactant: O=C(CN1CC(c2ccc(Cl)cc2)CC1=O)Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(CN1CCCC1=O)N1CCN(C(=O)CN2CC(c3ccc(Cl)cc3)CC2=O)CC1
Reaction time: 16 h

Procedure:
To a suspension of 6.0 g (23.3 mmol) of 1-[2-(2-oxopyrrolidin-1-yl)-acetyl]-piperazine hydrochloride in 80 ml of methylene chloride there are added firstly 2.6 g (3.6 ml; 25.5 mmol) of triethylamine and then, dropwise, a solution of 13.7 g (23.3 mmol) of 2-[4-(p-chlorophenyl)-2-oxopyrrolidin-1-yl]-acetic acid pentachlorophenyl ester in 30 ml of methylene chloride. After being stirred at 20° for 16 hours, the suspension is filtered with suction. 6.16 g of a white crystalline mass are obtained. 110 ml of ethyl ether are stirred into the filtrate, whereby a further 6.51 g of precipitate can be formed and collected. The two portions are combined, triturated under 200 ml of ethyl ether and filtered with suction, and the resulting product is dissolved in 150 ml of hot glacial acetic acid, and warm water (50°) is added until the solution becomes cloudy. The whole is cooled to 20 °; after 3 hours, the resulting crystalline product is filtered off with suction and dried on a water bath. 1-[4-(p-chlorophenyl)-2-oxopyrrolidin-1-ylacetyl]-4-(2-oxopyrrolidin1-ylacetyl)-piperazine having a melting point of 224°-226° is obtained.
Reaction SMILES: [BH4-].[Na+].[C:3]([C:6]1[N:7]=[CH:8][N:9]([CH:11]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:12](OCC)=[O:13])[CH:10]=1)(=[O:5])[NH2:4].O>CO>[OH:13][CH2:12][CH:11]([N:9]1[CH:10]=[C:6]([C:3]([NH2:4])=[O:5])[N:7]=[CH:8]1)[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)C(CCc1ccccc1)n1cnc(C(N)=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: NC(=O)c1cn(C(CO)CCc2ccccc2)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 103.1 %

Procedure:
NaBH4 (491 mg) was added portionwise to an ice cooled solution of ethyl 2-(4-carbamoyl-1-imidazolyl)-4-phenylbutyrate (obtained in Preparation 2) (391 mg) in methanol (20 ml) under an nitrogen atmosphere. After the addition was completed, the reaction mixture was stirred at room temperature for 30 minutes. Water was added, and the resulting mixture was stirred for several minutes and then evaporated under reduced pressure. The residue was partitioned between chloroform and water. The organic layer was washed with brine and dried over sodium sulfate. Evaporation of the solvent under reduced pressure gave 1-(1-hydroxy-4-phenyl-2-butyl)imidazole-4-carboxamide (347 mg) as a white solid.
Reaction SMILES: N.[Na].[CH3:3][C:4]1[N:9]=[C:8]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][S:11]2=[O:16])[CH:7]=[CH:6][CH:5]=1.[CH3:17][N:18]=[C:19]=[S:20].[Cl-].[NH4+]>O1CCCC1>[CH3:17][NH:18][C:19]([C:10]1([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]([CH3:3])[N:9]=2)[CH2:15][CH2:14][CH2:13][CH2:12][S:11]1=[O:16])=[S:20]
Reactant: CN=C=S
Reactant: Cc1cccc(C2CCCCS2=O)n1
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CNC(=S)C1(c2cccc(C)n2)CCCCS1=O
Temperature: -40 °C
Reaction time: 0.42 h
Yield: 31.5 %

Procedure:
To a solution of ferric nitrate (1.2 g) in liquid ammonia (700 cc) maintained boiling, sodium (23 g) is added in the course of 1 hour 5 minutes. After 25 minutes' stirring, a solution of 2-(6-methyl-2-pyridyl)tetrahydrothiopyran 1-oxide (106 g) in anhydrous tetrahydrofuran (500 cc) is added dropwise in the course of 40 minutes. The reaction mixture is stirred for 15 minutes; a solution of methyl isothiocyanate (74.7 g) in anhydrous tetrahydrofuran (400 cc) is then added dropwise in the course of 25 minutes. The reaction mixture is stirred for 30 minutes and is then cooled to -40° C. Ammonium chloride (70 g in total) is then added in 3 portions and stirring is then maintained for 15 hours so as to evaporate the ammonia, the temperature being allowed to rise gradually to about 20° C. Distilled water (600 cc) and ethyl acetate (650 cc) are then added to the mixture. After 15 minutes' stirring, the crystals which appear are separated by filtration, washed 3 times with ethyl acetate (180 cc in total) and 6 times with isopropyl ether (900 cc in total), and then dried under reduced pressure (0.3 mm Hg; 0.04 kPa) at a temperature in the region of 20° C. A first batch (45 g) of N-methyl-2-(6-methyl-2-pyridyl)-2-tetrahydrothiopyrancarbothioamide 1-oxide, m.p. 234° C., is thereby obtained. After decantation of the filtrate, the organic phase and the ethyl acetate washing liquors are combined, washed 3 times with distilled water (1500 cc), and dried over anhydrous magnesium sulphate, decolorising charcoal is added and the mixture is filtered and concentrated to dryness under reduced pressure (25 mm Hg; 3.25 kPa). The product obtained (125 g) is dissolved in ethyl acetate (400 cc) and then kept for 15 hours at a temperature in the region of 5° C. The crystals which appear are separated by filtration, washed twice with ethyl acetate (60 cc in total) and 5 times with isopropyl ether (300 cc in total) and dried under reduced pressure (0.2 mm Hg; 0.026 kPa) at a temperature in the region of 20° C. A second batch (17.8 g) of N-methyl-2-(6-methyl-2-pyridyl)-2-tetrahydrothiopyrancarbothioamide 1-oxide, m.p. 234° C., is thereby obtained.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH2:12][C:13]1[N:17]2[N:18]=[C:19]([C:22]3[CH:23]=[N:24][N:25]([CH2:27][C:28]#[N:29])[CH:26]=3)[CH:20]=[CH:21][C:16]2=[N:15][CH:14]=1.[F:30]C1C(CC2N3N=C(C4C=NNC=4)C=CC3=NC=2)=C(F)C=C2C=1C=CC=N2>>[F:30][C:4]1[C:3]([CH2:12][C:13]2[N:17]3[N:18]=[C:19]([C:22]4[CH:23]=[N:24][N:25]([CH2:27][C:28]#[N:29])[CH:26]=4)[CH:20]=[CH:21][C:16]3=[N:15][CH:14]=2)=[C:2]([F:1])[CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2
Reactant: N#CCn1cc(-c2ccc3ncc(Cc4cc5cccnc5cc4F)n3n2)cn1
Reactant: Fc1cc2ncccc2c(F)c1Cc1cnc2ccc(-c3cn[nH]c3)nn12
Product: N#CCn1cc(-c2ccc3ncc(Cc4c(F)cc5ncccc5c4F)n3n2)cn1

Procedure:
The title compound was prepared in analogy to the compound of Example 176 using 5,7-difluoro-6-[6-(1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazin-3-ylmethyl]-quinoline (Example 263) instead of 6-(6-chloro-imidazo[1,2-b]pyridazin-3-ylmethyl)-7-fluoro-quinoline (tR 3.28 min (conditions 13), MH+=402).
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][CH:10]=2)=[O:7])[CH2:3][CH2:2]1.[F:22][C:23]([F:40])([F:39])[C:24]([C:30]1[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=1)([OH:29])[C:25]([F:28])([F:27])[F:26].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>ClCCl>[CH:1]1([CH2:4][NH:5][C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]3[CH2:21][CH2:20][N:19]([C:34](=[O:35])[C:33]4[CH:32]=[CH:31][C:30]([C:24]([OH:29])([C:23]([F:22])([F:39])[F:40])[C:25]([F:26])([F:27])[F:28])=[CH:38][CH:37]=4)[CH2:18][CH2:17]3)=[CH:11][CH:10]=2)=[O:7])[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Reactant: O=C(NCC1CC1)Nc1ccc(OC2CCNCC2)cc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCC1CC1)Nc1ccc(OC2CCN(C(=O)c3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 4.1 %

Procedure:
1-(cyclopropylmethyl)-3-(4-(piperidin-4-yloxy)phenyl)urea (1.037 mmol, 300 mg), 4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzoic acid (1.037 mmol, 299 mg) and triethylamine (3.11 mmol, 0.432 mL, 315 mg) were combined and stirred at room temperature in dichloromethane (5 mL). 1-Propanephosphonic acid cyclic anhydride (1.555 mmol, 0.926 mL, 990 mg; 50% solution in ethyl acetate) was added and the reaction stirred at room temperature for 1 hour. The reaction mixture was washed with saturated sodium bicarbonate solution and the organic layer was separated, dried and concentrated under vacuum. The residue was dissolved in dichloromethane and purified by silica column chromatography (eluent 2-8% methanol in dichloromethane) to afford the title compound (24 mg). MS (ESI) m/z 560.2 [M+H]+
Reaction SMILES: CC1(C)COB([C:8]2[CH:9]=[C:10]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[CH:11]=[CH:12][CH:13]=2)OC1.Br[C:22]1[N:26]2[N:27]=[CH:28][C:29]([C:31]([F:34])([F:33])[F:32])=[N:30][C:25]2=[N:24][CH:23]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[N:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:10]2[CH:9]=[C:8]([C:22]3[N:26]4[N:27]=[CH:28][C:29]([C:31]([F:32])([F:33])[F:34])=[N:30][C:25]4=[N:24][CH:23]=3)[CH:13]=[CH:12][CH:11]=2)[CH:15]=1
Reactant: CC1(C)COB(c2cccc(-c3cccnc3)c2)OC1
Reactant: FC(F)(F)c1cnn2c(Br)cnc2n1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: FC(F)(F)c1cnn2c(-c3cccc(-c4cccnc4)c3)cnc2n1
Yield: 43.8 %

Procedure:
This reaction was carried out as described in Example 37, step e, using 3-[3-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)phenyl]pyridine (150 mg, 0.56 mmol), 7-bromo-3-trifluoromethylimidazo[1,2-b][1,2,4]triazine (0.1 g, 0.375 mmol), 2 M Na2CO3 (0.56 ml) and tetrakis(triphenylphosphine)-palladium(0) (0.022 g) in 1,2-dimethoxyethane (2 ml). The crude residue was purified by flash chromatography (silica gel, 5% MeOH(CH2Cl2) to yield the title compound (56 mg, 44%): 1H NMR (400 MHz, CDCl3) δ 7.42-7.45 (1H, m), 7.68-7.70 (2H, m), 7.95-7.98 (1H, m), 8.09-8.12 (1H, m), 8.34-8.35 (1H, m), 8.67 (1H, dd, J 4.7, 1.8 Hz), 8.68 (1H, s), 8.84 (1H, s), 8.93 (1H, dd, J 2.5, 0.8 Hz); MS (ES+) m/z 342 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[C:9](Cl)=[CH:8][C:7]([CH3:11])=[N:6][C:5]=1[O:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([Cl:20])=[CH:15][C:14]=1[CH3:21].[NH2:23][C@H:24]([CH2:29][OH:30])[CH2:25][CH2:26][S:27][CH3:28]>>[CH3:1][O:2][C:3](=[O:22])[C:4]1[C:9]([NH:23][CH:24]([CH2:29][OH:30])[CH2:25][CH2:26][S:27][CH3:28])=[CH:8][C:7]([CH3:11])=[N:6][C:5]=1[O:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([Cl:20])=[CH:15][C:14]=1[CH3:21]
Reactant: COC(=O)c1c(Cl)cc(C)nc1Oc1c(C)cc(Cl)cc1C
Reactant: CSCC[C@H](N)CO
Product: COC(=O)c1c(NC(CO)CCSC)cc(C)nc1Oc1c(C)cc(Cl)cc1C
Temperature: 134 °C

Procedure:
A mixture of 2-(4-chloro-2,6-dimethyl-phenoxy)-4-chloro-6-methyl-nicotinic acid methyl ester and L-methioninol in N-methyl-2-pyrodone (NMP) was heated in a 134° C. oil bath for 3 hr. Standard work-up procedure and purification provided the title compound. 1H NMR(CDCl3) d 8.25(d,1H), 7.02(s,2H), 6.30(s,1H), 3.85(s,3H), 3.6-3.9(m,3H), 2.5-2.7(m,2H), 2.14(s,3H), 2.10(s,3H), 2.06(s,6H), 1.8-2.1 (m,2H)ppm.
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH2:6][O:7][Si:8]([CH:15]([CH3:17])[CH3:16])([CH:12]([CH3:14])[CH3:13])[CH:9]([CH3:11])[CH3:10])[C:3]([OH:5])=O.CCN=C=NCCCN(C)C.Cl.[CH3:31][NH:32][O:33][CH3:34].CCOC(C)=O>ClCCl.CN(C1C=CN=CC=1)C>[CH3:34][O:33][N:32]([CH3:31])[C:3](=[O:5])[C:2]([CH3:1])([CH3:18])[CH2:6][O:7][Si:8]([CH:15]([CH3:17])[CH3:16])([CH:12]([CH3:14])[CH3:13])[CH:9]([CH3:11])[CH3:10]
Reactant: CNOC
Reactant: CC(C)[Si](OCC(C)(C)C(=O)O)(C(C)C)C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CON(C)C(=O)C(C)(C)CO[Si](C(C)C)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
A solution of 2,2-dimethyl-3-triisopropylsilanyloxy-propionic acid in anhydrous dichloromethane (13 ml) was slowly treated with EDCI (1.03 g, 5.38 mmol) followed by N,O -dimethylhydroxylamine hydrochloride (525 mg, 5.4 mmol), DMAP (55 mg, 0.045 mmol), and TEA (0.75 ml, 5.38 mmol). After stirring overnight at room temperature the reaction mixture was partitioned between DCM/water. The organic layers were collected, dried over MgSO4, filtered, and concentrated giving a greenish oil. Silica gel chromatography using 10-60% EtOAc in hexanes as eluant provided 1.13 mg (79%) of N-methoxy-2,2,N-trimethyl-3-triisopropylsilanyloxy-propionamide as a colorless oil. M+H=318.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][C:5]=1[C:14]1[NH:19][C:18](=[O:20])[C:17]2=[C:21]([CH3:27])[N:22]=[C:23]([CH2:24][CH2:25][CH3:26])[N:16]2[N:15]=1)[CH3:2].[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>ClCCl.CN(C1C=CN=CC=1)C>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:32]2[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]2)(=[O:12])=[O:11])=[CH:6][C:5]=1[C:14]1[NH:19][C:18](=[O:20])[C:17]2=[C:21]([CH3:27])[N:22]=[C:23]([CH2:24][CH2:25][CH3:26])[N:16]2[N:15]=1)[CH3:2]
Reactant: CN1CCNCC1
Reactant: CCCc1nc(C)c2c(=O)[nH]c(-c3cc(S(=O)(=O)Cl)ccc3OCC)nn12
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCc1nc(C)c2c(=O)[nH]c(-c3cc(S(=O)(=O)N4CCN(C)CC4)ccc3OCC)nn12
Temperature: 0 °C
Reaction time: 8 h
Yield: 87.8 %

Procedure:
1.23 g (3 mmol) of 4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonyl chloride are dissolved in 40 ml of dichloromethane and cooled to 0° C. After addition of a spatula tip of DMAP, 0.90 g (9.00 mmol) of N-methylpiperazine are added, and the reaction mixture is stirred at room temperature overnight. The mixture is diluted with dichloromethane, the organic phase is washed twice with water and dried over sodium sulphate and the solvent is removed under reduced pressure. Crystallization from ether gives 1.25 g (88%) of a colourless solid.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)#[N:2].P([S-])(OCC)(OCC)=[S:15].C(=O)([O-])O.[Na+].[OH-].[Na+]>C(OCC)(=O)C.Cl>[NH2:2][C:1](=[S:15])[CH2:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1
Reactant: CCOP(=S)([S-])OCC
Reactant: COC(=O)c1ccc(CC#N)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(CC(N)=S)cc1
Reaction time: 8 h
Yield: 74.8 %

Procedure:
To methyl 4-(cyanomethyl)benzoate (5.0 g, 28.5 mmol) were added 4M hydrogen chloride-ethyl acetate solution (50 mL) and O,O-diethyl dithiophosphate (6.70 mL, 40.0 mmol), and the mixture was stirred overnight. The reaction mixture was alkalified with saturated aqueous sodium hydrogen carbonate solution and 8N aqueous sodium hydroxide solution, and extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over sodium sulfate, and filtered by basic silica gel. The filtrate was concentrated under reduced pressure and recrystallized from ethyl acetate-tetrahydrofuran-hexane to give the title compound (4.46 g, 75%) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[NH:12][NH2:13].C(Cl)Cl.[CH3:17][OH:18]>>[CH2:2]([C:3]1[NH:12][C:17](=[O:18])[N:12]([C:3]2[CH:4]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:10]=[CH:11][C:2]=2[Cl:1])[N:13]=1)[CH2:11][CH2:10][CH3:5]
Reactant: CO
Reactant: COC(=O)c1ccc(Cl)c(NN)c1
Solvent: ClCCl
Product: CCCCc1nn(-c2cc(C(=O)OC)ccc2Cl)c(=O)[nH]1
Yield: 37 %

Procedure:
By the procedure of Example 3, Step C, the title compound was prepared from methyl 4-chloro-3-hydrazinobenzoate (from Step B) in 37% yield as an orange gum (TLC in 95:5 CH2Cl2 --MeOH), mass spectrum (FAB) m/e 310 (M+1)+.
Reaction SMILES: CON(C)[C:4]([C:6]1[S:7][CH:8]=[CH:9][C:10]=1[CH3:11])=[O:5].[CH2:13]([C:15]1[CH:20]=[CH:19][C:18]([Mg]Br)=[CH:17][CH:16]=1)[CH3:14]>C1COCC1>[CH2:13]([C:15]1[CH:20]=[CH:19][C:18]([C:4]([C:6]2[S:7][CH:8]=[CH:9][C:10]=2[CH3:11])=[O:5])=[CH:17][CH:16]=1)[CH3:14]
Reactant: CCc1ccc([Mg]Br)cc1
Reactant: CON(C)C(=O)c1sccc1C
Solvent: C1CCOC1
Product: CCc1ccc(C(=O)c2sccc2C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.1 %

Procedure:
To a solution of N-methoxy-N,3-dimethylthiophene-2-carboxamide (52) (J. Med. Chem., 2001, 44, 863) (5.00 g, 27.0 mmole) in THF (30 mL) was added 4-ethylphenylmagnesium bromide (0.5M in THF, 108 mL, 54.0 mmole) at 0° C. The resulting solution was stirred at ambient temperature overnight. The reaction mixture was quenched by adding MeOH (20 mL) and concentrated in vacuo. The crude residue was purified on Biotage® purification apparatus to yield the compound 53 (4-ethylphenyl)(3-methylthiophen-2-yl)methanone (4.42 g, 19.2 mmole, 71%) as brown oil.
Reaction SMILES: [CH3:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=S)=[N:8][CH:9]=[CH:10][CH:11]=1.[NH3:26]>>[CH3:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[NH:26])=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: Cc1ccccc1COc1cccnc1NC(=S)Nc1ccccc1
Reactant: N
Product: Cc1ccccc1COc1cccnc1NC(=N)Nc1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of N-[3-(2-methylbenzyloxy)pyrid-2-yl]-N'-phenylthiourea (1.76 g, 0.005 mol), yellow mercuric oxide (1.31 g, 0.006 mol) and methanolic ammonia (40 ml) was stirred for 3 days at room temperature. The solvent was removed in vacuo and the black residue was boiled with chloroform and filtered hot. Evaporation of the solvent and recrystallisation from acetonitrile gave the desired product. Yield 1.2 g (72%), m.p. 157°-158 ° C.