Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[F:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+].CCCCCCC>C1(C)C=CC=CC=1.CN(C)C=O>[CH:13]1([CH2:12][O:11][C:3]2[C:2]([C:20]3[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=3)=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][N:4]=2)[CH2:15][CH2:14]1
Reactant: OB(O)c1ccc(F)cc1
Reactant: O=C(O)c1cnc(OCC2CC2)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCCCC
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(O)c1cnc(OCC2CC2)c(-c2ccc(F)cc2)c1
Temperature: 90 °C
Reaction time: 4 h
Yield: 77 %

Procedure:
5-Bromo-6-cyclopropylmethoxy-nicotinic acid (2.28 g, 8 mmol) was dissolved in a mixture of toluene (40 mL) and dimethylformamide (4 mL). To this solution was added [4-fluoro-phenyl]-boronic acid (1.2 g, 8 mmol), [1,1′-bis(diphenylphosphino)-ferrocene]-dichloropalladium(II) dichloro-methane complex (307 mg), and 2 N sodium carbonate solution (33 mL). The whole mixture was heated with stirring at 90° C. for 4 h, cooled to room temperature and filtered. Phases were separated; the organic phase was discarded and the water phase was acidified with 1 N hydrochloric acid (pH 2) and extracted with ethylacetate. Etylacetate phases were pooled, dried with Na2SO4 and filtered over a small silica gel pad (20 g). The solvent was removed to yield a solid which was stirred with heptane (200 mL), filtered, washed with heptane and dried to yield 1.77 g of the title compound as beige solid, MS (ISP) 286.0 (M−H)−.
Reaction SMILES: [Na].[CH2:2]([NH:6][C:7]([NH2:9])=[O:8])[CH2:3][CH2:4][CH3:5].C([O:12][C:13](=O)[CH2:14][C:15](OCC)=[O:16])C>C(O)C>[CH2:2]([N:6]1[C:15](=[O:16])[CH2:14][C:13](=[O:12])[NH:9][C:7]1=[O:8])[CH2:3][CH2:4][CH3:5]
Reactant: CCCCNC(N)=O
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Na]
Solvent: CCO
Product: CCCCN1C(=O)CC(=O)NC1=O
Yield: 68.8 %

Procedure:
To a solution of 23 g (1 g-atom) sodium metal in 500 ml absolute ethanol were added at room temperature 35 g (0.3 mole) butyl-urea and 48 g (0.3 mole) malonic acid-diethylester. The alcohol was then distilled off in an oil bath held at 120°C and the residue maintained at this temperature for about 16 hours. The residue was then cooled and dissolved in about 300 ml water, stirred with activated carbon and the solution filtered. The clear filtrate was acidified by the addition of concentrated hydrochloric acid to produce 38 g 1-butyl-barbituric acid, representing a yield of 68%. The substance had, after recrystallization from benzene, a melting point of 107°-108°C.
Reaction SMILES: S(O[CH2:12][C@H:13]1[O:17][C@@H:16]([N:18]2[CH:25]=[CH:24][C:22](=[O:23])[NH:21][C:19]2=[O:20])[CH2:15][C@@H:14]1[OH:26])(C1C=CC(C)=CC=1)(=O)=O.[N-:27]=[N+:28]=[N-:29].[Na+]>CN(C=O)C>[N:27]([CH2:12][C@H:13]1[O:17][C@@H:16]([N:18]2[CH:25]=[CH:24][C:22](=[O:23])[NH:21][C:19]2=[O:20])[CH2:15][C@@H:14]1[OH:26])=[N+:28]=[N-:29]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)C[C@@H]2O)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)C[C@@H]1O
Temperature: 95 °C
Reaction time: 12 h
Yield: 59.7 %

Procedure:
To a solution of 5′-O-tosyl-2′-deoxyuridine (13.591, 0.035 mol) in dry DMF (90 mL) was added NaN3 (9.29 g, 0.141 mol) and the reaction mixture was allowed to stir at 95° C. for 12 h. The reaction mixture was cooled, the solid residue was removed by filtration and the filtrate was concentrated under vacuum to give the crude product. The crude was purified by column chromatography on silica gel (4% methanol in chloroform) which gave the title product (5.29 g, 56%) as a white solid.
Reaction SMILES: [Br-].[C:2]([CH2:4]CC[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)#[N:3].C([N-]C(C)C)(C)C.[Li+].CCCCCCC.[O:41]=[C:42]1[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:44](=[O:51])[N:43]1[CH2:52][C:53]1[CH:54]=[C:55]2[C:60](=[CH:61][CH:62]=1)[N:59]=[C:58]([CH2:63][CH2:64][C:65]#N)[CH:57]=[CH:56]2>C1COCC1>[O:51]=[C:44]1[C:45]2[C:50](=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:42](=[O:41])[N:43]1[CH2:52][C:53]1[CH:54]=[C:55]2[C:60](=[CH:61][CH:62]=1)[N:59]=[C:58]([CH:63]=[CH:64][CH2:65][CH2:4][C:2]#[N:3])[CH:57]=[CH:56]2
Reactant: N#CCCc1ccc2cc(CN3C(=O)c4ccccc4C3=O)ccc2n1
Reactant: N#CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Br-]
Agent: [Li+]
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: N#CCCC=Cc1ccc2cc(CN3C(=O)c4ccccc4C3=O)ccc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.9 %

Procedure:
The compound (675.0 mg) obtained in Example 123-1 was suspended in anhydrous THF (30 ml) and cooled with ice. Then, the suspension was added with a 2 mol/l lithium diisopropylamide/heptane solution (0.825 ml), followed by stirring at room temperature for 1 hour. Then, the solution was gradually added with a solution prepared by suspending the compound (327.9 mg) obtained in Example 119-7 in anhydrous THF (20 ml), followed by stirring at room temperature for 3 hours. After completion of the reaction, the solvent was distilled off and the residue was then purified through silica gel column chromatography (chloroform/ethyl acetate), thereby obtaining the subject compound (268.0 mg) as a yellow solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]([C:11]1[CH:15]=[CH:14][NH:13][CH:12]=1)=[O:10].Cl[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=[CH:19][CH:18]=1.O>CS(C)=O>[CH3:7][O:8][C:9]([C:11]1[CH:15]=[CH:14][N:13]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=[CH:19][CH:18]=2)[CH:12]=1)=[O:10]
Reactant: COC(=O)c1cc[nH]c1
Reactant: Clc1ccnc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1ccn(-c2ccnc3ccccc23)c1
Temperature: 100 °C
Reaction time: 23 h
Yield: 59.5 %

Procedure:
1.73 g (12.5 mmol) of potassium carbonate are added at 20° C. under an argon atmosphere to 0.625 g (5 mmol) of 3-methoxycarbonyl-1H-pyrrole and 0.82 g (5 mmol) of 4-chloroquinoline dissolved in 10 mL of dimethyl sulphoxide. After stirring at 100° C. for 23 hours, the reaction mixture is poured into 30 mL of water and then allowed to crystallise at 20° C. for 1 hour. After filtering off and air-drying the solid residue, 0.75 g of 3-methoxycarbonyl-1-(quinol-4-yl)-1H-pyrrole is obtained in the form of a beige-coloured solid melting at 156° C.
Reaction SMILES: [Mg].Br[C:3]1[CH:4]=[C:5]([O:9][CH3:10])[CH:6]=[CH:7][CH:8]=1.II.[CH3:13][N:14]([CH3:22])[CH2:15][C@H:16]([CH3:21])[C:17](=[O:20])[CH2:18][CH3:19]>O1CCCC1>[CH3:13][N:14]([CH3:22])[CH2:15][C@H:16]([CH3:21])[C@:17]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[CH:4]=1)([OH:20])[CH2:18][CH3:19]
Reactant: COc1cccc(Br)c1
Reactant: CCC(=O)[C@@H](C)CN(C)C
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: CC[C@](O)(c1cccc(OC)c1)[C@@H](C)CN(C)C
Temperature: 71.5 °C
Yield: 79.77 %

Procedure:
In a dry flask charged magnesium turning (41.0 gm 1.70 M) in tetrahydrofuran (200 ml). Under nitrogen atmosphere charged 3-Bromo anisole (20.0 gm; 0.106 M), iodine crystal (0.2 gm). Stirred and heated the reaction mass to 68-75° C. After initiation of the reaction the remaining quantity of 3-Bromo anisole (307 gm, 1.641 M) was added maintaining the reaction at reflux. Stirred and maintained the reaction mass at refluxed for 1 hrs, cooled to 25-30° C. Slowly added (2S)-1-(dimethylamino)-2-methylpentan-3-one (100.0 gm, 0.699 M) maintaining the temperature of the reaction at 25-30° C. The reaction mass was maintained for 12 hour at 25-30° C. and then quenched the reaction mass in ice cold D. M. water (1.0 Liter). Stirred and adjusted the pH of the reaction mass to 3-4 with acetic acid. Further adjusted the pH to 9-10 using ammonia solution. Stirred the reaction mass 30 minutes and extracted the reaction solution with diisopropyl ether. Combined diisopropyl ether was dried over anhydrous sodium sulphate and concentrated under reduced pressure below 40° C. to get the compound (2S,3R)-1-(dimethylamino)-3-(3-methoxyphenyl)-2-methylpentan-3-ol.
Reaction SMILES: Cl[S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13](=[O:20])[C:14](=[N+:18]=[N-:19])[C:15](=[O:17])[CH3:16])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH2:21]([OH:23])[CH3:22].O>C(N(CC)CC)C>[N+:18](=[C:14]([C:15](=[O:17])[CH3:16])[C:13](=[O:20])[CH2:12][CH2:11][C:8]1[CH:9]=[CH:10][C:5]([S:2]([O:23][CH2:21][CH3:22])(=[O:4])=[O:3])=[CH:6][CH:7]=1)=[N-:19]
Reactant: CC(=O)C(=[N+]=[N-])C(=O)CCc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCO
Solvent: CCN(CC)CC
Solvent: O
Product: CCOS(=O)(=O)c1ccc(CCC(=O)C(=[N+]=[N-])C(C)=O)cc1

Procedure:
6-(4-Chlorosulfonylphenyl)-3-diazo-2,4-hexanedione (2.0 g, 6.4 mmol) obtained in Example 3, (3) was stirred in triethylamine (1.5 ml) and ethanol (5 ml) for 16 h at room temperature, then the mixture was poured into H2O and extracted thrice with chloroform. The organic extract was washed with H2O, dried over anhydrous MgSO4 and evaporated under reduced pressure. The residue was chromatographed on silica gel (Wako Gel C-200) with chloroform as eluent to give the title compound as a pale yellow viscous oil; yield: 550 mg.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[N:6]=[C:5]([O:13][C@@H:14]2[CH2:19][CH2:18][C@H:17]([N:20]3[CH2:23][C:22]([CH2:46][C:47]#[N:48])([N:24]4[CH:28]=[C:27]([C:29]5[C:30]6[CH:37]=[CH:36][N:35]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:45])([CH3:44])[CH3:43])[C:31]=6[N:32]=[CH:33][N:34]=5)[CH:26]=[N:25]4)[CH2:21]3)[CH2:16][CH2:15]2)[CH:4]=1.C(N(CC)C(C)C)(C)C.[CH3:58][S:59](Cl)(=[O:61])=[O:60].CCOC(C)=O>C(Cl)Cl>[CH3:58][S:59]([O:1][CH2:2][C:3]1[CH:8]=[C:7]([C:9]([F:11])([F:10])[F:12])[N:6]=[C:5]([O:13][C@H:14]2[CH2:15][CH2:16][C@@H:17]([N:20]3[CH2:21][C:22]([CH2:46][C:47]#[N:48])([N:24]4[CH:28]=[C:27]([C:29]5[C:30]6[CH:37]=[CH:36][N:35]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:43])([CH3:44])[CH3:45])[C:31]=6[N:32]=[CH:33][N:34]=5)[CH:26]=[N:25]4)[CH2:23]3)[CH2:18][CH2:19]2)[CH:4]=1)(=[O:61])=[O:60]
Reactant: CS(=O)(=O)Cl
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN([C@H]5CC[C@@H](Oc6cc(CO)cc(C(F)(F)F)n6)CC5)C4)c3)ncnc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN([C@H]5CC[C@@H](Oc6cc(COS(C)(=O)=O)cc(C(F)(F)F)n6)CC5)C4)c3)ncnc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
{1-(cis-4-{[4-(Hydroxymethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy}cyclohexyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile (from Example 64, 145.0 mg, 0.2124 mmol) was dissolved in methylene chloride (2.93 mL) and was cooled to 0° C. To that N,N-diisopropylethylamine (60.5 μL, 0.347 mmol) was added followed by methanesulfonyl chloride (23 μL, 0.30 mmol). The reaction was stirred at 0° C. for 1 hour. Then the reaction mixture was worked up with EtOAc and used in the next reaction. MS (ES): 761(M+1).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].N1C=CC=CC=1.[CH2:12]([C:14]1([CH2:32][CH3:33])[N:19]=[C:18]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[C:17]2[CH:27]=[CH:28][C:29]([NH2:31])=[CH:30][C:16]=2[O:15]1)[CH3:13]>C(Cl)(Cl)Cl>[CH2:32]([C:14]1([CH2:12][CH3:13])[N:19]=[C:18]([C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)[C:17]2[CH:27]=[CH:28][C:29]([NH:31][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:30][C:16]=2[O:15]1)[CH3:33]
Reactant: CCC1(CC)N=C(c2ccc(F)cc2)c2ccc(N)cc2O1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCC1(CC)N=C(c2ccc(F)cc2)c2ccc(NS(C)(=O)=O)cc2O1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
Methanesulfonyl chloride (63 μL) and pyridine (131 μL) were added dropwise to a solution of 2,2-diethyl-4-(4-fluorophenyl)-2H-1,3-benzoxazin-7-amine (a compound of Reference Example 4, 81 mg) in chloroform (5 mL), and the mixture was stirred at 40° C. overnight. The reaction mixture was purified by column chromatography on NH-silica gel (Chromatorex NH-silica gel, Solvent: chloroform/methanol=100/0 to 90/10), and the resultant powder was suspended in diisopropyl ether. The resultant precipitates were collected by filtration and washed with hexane-diisopropyl ether to give the titled compound (69 mg) as a colorless powder.
Reaction SMILES: F[S:2]([C:5]([C:8]([C:11]([C:14]([O:17][C:18]([C:24]([O:27][CH3:28])([F:26])[F:25])([C:20]([F:23])([F:22])[F:21])[F:19])([F:16])[F:15])([F:13])[F:12])([F:10])[F:9])([F:7])[F:6])(=[O:4])=[O:3].[OH2:29].[OH-].[Li+:31]>O>[S:2]([C:5]([C:8]([C:11]([C:14]([O:17][C:18]([C:24]([O:27][CH3:28])([F:26])[F:25])([C:20]([F:23])([F:22])[F:21])[F:19])([F:16])[F:15])([F:13])[F:12])([F:10])[F:9])([F:7])[F:6])([O:29][Li:31])(=[O:4])=[O:3]
Reactant: O
Reactant: [Li+]
Reactant: COC(F)(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)C(F)(F)S(=O)(=O)F)C(F)(F)F
Agent: [OH-]
Product: [Li]OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)OC(F)(C(F)(F)F)C(F)(F)OC
Temperature: 75 °C

Procedure:
A 250 mL round bottom flask was charged with FSO2(CF2)4OCF(CF3)CF2OCH3 (23.3 g, 0.048 mole) deionized water (150 g) and lithium hydroxide monohydrate (4.08 g, 0.097 mole). The resulting mixture was heated at 75° C. for about 18 hours, filtered and the aqueous solution treated with 48% aqueous HF until slightly acidic to pH paper. Water was removed using a rotary evaporator. The solid residue was treated with ethyl alcohol (about 200 mL; contained ˜5% isopropyl alcohol) and this mixture heated to reflux for two hours. The alcohol solution was filtered and the solvent removed by using a rotary evaporator to yield LiO3S(CF2)4OCF(CF3)CF2OCH3.
Reaction SMILES: [OH-].[K+].[CH2:3]([O:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH:15]([C:18](=[O:26])[CH2:19][CH2:20][C:21]([O:23]CC)=[O:22])[CH2:14][CH2:13]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl>CCO>[CH2:3]([O:10][CH2:11][CH:12]1[CH2:13][CH2:14][CH:15]([C:18](=[O:26])[CH2:19][CH2:20][C:21]([OH:23])=[O:22])[CH2:16][CH2:17]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(=O)CCC(=O)C1CCC(COCc2ccccc2)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCC(=O)C1CCC(COCc2ccccc2)CC1
Temperature: 85 °C
Reaction time: 2 h

Procedure:
Potassium hydroxide (17.0 g, 0.30 mol) is added to EtOH (300 mL) solution of ethyl 4-[4-(benzyloxymethyl)cyclohexyl]-4-oxobutyrate (cis/trans=1/1, 33.0 g, 0.10 mol), and the mixture is stirred at 85° C. for 2 hours. After cooling to 0° C., 5N HCl is added to the mixture (to reach pH 2-3), the mixture is concentrated to remove ethanol. The crude mixture is extracted with EtOAc. The water layer is extracted with EtOAc, and the combined organic layer is washed with water and brine, dried over magnesium sulfate, and concentrated under reduced pressure to afford crude 4-[4-(benzyloxymethyl)cyclohexyl]-4-oxobutyric acid (cis/trans=ca. 1/6). The mixture of ether-hexane (ca. 1:4, 120 mL) is added to the resulting solid and sonicated. The crystal is collected by filtration, washed with small amount of ether-hexane (1:4) and dried to give trans-4-[4-(benzyloxymethyl)cyclohexyl]-4-oxobutyric acid as a pale yellow solid.
Reaction SMILES: [O:1]1[C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=[CH:2]1.Cl.[NH2:10][C@H:11]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=2[O:32][CH3:33])=[CH:21][CH:20]=1)[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(Cl)Cl>[F:31][C:29]1[CH:28]=[CH:27][C:26]([O:32][CH3:33])=[C:25]([C:22]2[CH:21]=[CH:20][C:19]([CH2:18][C@@H:11]([NH:10][C:6]([C:5]3[O:1][CH:2]=[N:3][CH:4]=3)=[O:8])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:24][CH:23]=2)[CH:30]=1
Reactant: O=C(O)c1cnco1
Reactant: CCOC(=O)C[C@H](N)Cc1ccc(-c2cc(F)ccc2OC)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)C[C@@H](Cc1ccc(-c2cc(F)ccc2OC)cc1)NC(=O)c1cnco1
Reaction time: 2 h

Procedure:
To a solution of oxazole-5-carboxylic acid (70 mg, 0.61 mmol) in DMF (1.5 mL) and DCM (1.5 mL) is added (R)-ethyl 3-amino-4-(5′-fluoro-2′-methoxybiphenyl-4-yl)butanoate hydrochloride, intermediate 10, (150 mg, 0.41 mmol), HATU (233 mg, 0.61 mmol), and TEA (284 μL, 2.04 mmol). After stirring for 2 hours, the reaction is quenched with H2O, and the crude is diluted with EtOAc, the organic layer is washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The obtained residue is purified by RP-HPLC (SunFire C18, H2O (0.1% TFA)/CH3CN), and then lyophilized to give (R)-ethyl 4-(5′-fluoro-2′-methoxybiphenyl-4-yl)-3-(oxazole-5-carboxamido)butanoate (157 mg). HPLC retention time=1.50 minutes (condition A); MS (m+1)=427.4; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.19 (t, J=7.2 Hz, 3 H) 2.46-2.62 (m, 2 H) 2.86 (dd, J=13.6, 8.1 Hz, 1 H) 3.02 (dd, J=13.6, 6.1 Hz, 1 H) 3.67 (s, 3 H) 4.05-4.15 (m, 2 H) 4.52-4.69 (m, 1 H) 6.76-6.82 (m, 1 H) 6.83-6.96 (m, 2 H) 7.11-7.21 (m, 3 H) 7.37 (d, J=8.1 Hz, 2 H) 7.61 (s, 1 H) 7.80 (s, 1 H)
Reaction SMILES: [CH3:1][NH:2][C:3](=[S:6])[NH:4][NH2:5].Cl[CH2:8][C:9](=O)[CH3:10].[CH3:12][C:13]([CH3:15])=O>>[CH3:8][C:9](=[N:5][N:4]=[C:3]1[N:2]([CH3:1])[C:13]([CH3:15])=[CH:12][S:6]1)[CH3:10]
Reactant: CC(=O)CCl
Reactant: CC(C)=O
Reactant: CNC(=S)NN
Product: CC(C)=NN=c1scc(C)n1C

Procedure:
21 g (200 mmol) of 4-methyl-3-thiosemicarbazide in 1000 mL of acetone was heated at reflux for 2 hours. To this solution was then added dropwise 20.4 g (220 mmol) of chloroacetone. The reaction mixture was allowed to reflux for 7 hours and was then concentrated. The resulting crude product was recrystallized from acetone. This gave 23 g of an orange-colored powder (63% of the theoretical).
Reaction SMILES: [CH2:1]([N:4]1[C:9](=N)[C:8]2[CH:11]=[CH:12][S:13][C:7]=2[N:6]=[C:5]1[O:14][CH2:15][CH2:16][CH3:17])[CH2:2][CH3:3].CI.C(=O)([O-])[O-].[K+].[K+].[CH3:26][N:27](C=O)C>>[CH2:1]([N:4]1[C:9](=[CH:26][NH2:27])[C:8]2[CH:11]=[CH:12][S:13][C:7]=2[N:6]=[C:5]1[O:14][CH2:15][CH2:16][CH3:17])[CH2:2][CH3:3]
Reactant: CCCOc1nc2sccc2c(=N)n1CCC
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Product: CCCOC1=Nc2sccc2C(=CN)N1CCC

Procedure:
In a sulfonation flask 4.5 g (0.018 mol) 3-propyl-2-propoxy-3H-thieno[2,3-d]pyrimidine-4-ylidene amine, 5.1 g (0.036 mol) CH3I, 5.0 g (0.036 mol) powdered potassium carbonate and 80 ml of absolute DMF are stirred for 4 hours at an internal temperature of 90-100° C. Then the solvent is distilled off in vacuum, the residue taken up in ethylacetate and the organic phase twice washed with water. After drying the organic phase over Na2SO4 the ethylacetate is distilled off in a water jet vacuum and the residue purified by column chromatography over silica gel (eluant: hexane/ethylacetate 1:6). Yield: 4.4 g of (3-propyl-2-propoxy-3H-thieno[2,3-d]pyrimidine-4-ylidene)methylamine in the form of a brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].Cl[C:26](Cl)([O:28][C:29](=[O:35])OC(Cl)(Cl)Cl)Cl.[CH2:37]([N:39]([CH2:44][CH3:45])[CH2:40][CH2:41]CO)[CH3:38].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:29](=[O:35])[O:28][CH2:26][CH2:38][CH2:37][N:39]([CH2:44][CH3:45])[CH2:40][CH3:41])=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCN(CC)CCCO
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(CC)CCCOC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)c(C)c1C
Yield: 87.6 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 3-(diethylamino)-1-propanol (30 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, and the extract was washed with water and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (65 mg, yield 78%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([OH:13])[CH2:10][CH:9]1[C:14]1[NH:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][CH:20]=2)=[CH:17][N:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:28][Si:29]([CH2:32][CH2:33][O:34][CH2:35]Cl)([CH3:31])[CH3:30]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([OH:13])[CH2:10][CH:9]1[C:14]1[N:18]([CH2:35][O:34][CH2:33][CH2:32][Si:29]([CH3:31])([CH3:30])[CH3:28])[CH:17]=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][CH:20]=2)[N:15]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(O)CC1c1ncc(-c2ccc(Br)cc2)[nH]1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(O)CC1c1nc(-c2ccc(Br)cc2)cn1COCC[Si](C)(C)C
Reaction time: 0.17 h
Yield: 98 %

Procedure:
2-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (500 mg) was dissolved in DMF (8 mL), and NaH (54 mg ) was added. The mixture was stirred over 10 min. and SEM-Cl was added slowly, and then stirred for 2 hours. The mixture was quenched with 3 mL of sat. NH4Cl and was taken up in ethyl acetate (100 mL). The organic phase was washed with saturated sodium bicarbonate (1×100 mL) and dried over sodium sulfate. After the solvent was removed, the resulting oil was subjected to silica gel chromatography using effluent of 20-50% ethyl acetate and hexanes. The fractions containing product were combined and the solvent was removed under reduced pressure to provide 2-[4-(4-Bromo-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (648 mg, 98%) as an off-white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:16]1[C:21]([CH3:22])=[CH:20][C:19]([CH2:23]Br)=[CH:18][N:17]=1)[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25][C:26]1([CH3:35])[O:31][C:30](=[O:32])[CH:29]([CH3:33])[C:28](=[O:34])[O:27]1.C(N(CC)CC)C.O>CS(C)=O>[C:1]([O:5][C:6]([N:8]([C:16]1[C:21]([CH3:22])=[CH:20][C:19]([CH2:23][C:29]2([CH3:33])[C:28](=[O:34])[O:27][C:26]([CH3:25])([CH3:35])[O:31][C:30]2=[O:32])=[CH:18][N:17]=1)[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(CBr)cnc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: CC1C(=O)OC(C)(C)OC1=O
Solvent: CCN(CC)CC
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(CC2(C)C(=O)OC(C)(C)OC2=O)cnc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 107.6 %

Procedure:
2-[N,N-bis(tert-Butoxycarbonyl)amino]-5-bromomethyl-3-methyl-pyridin (1.6 g, 4.0 mmol) was added to a solution of 2,2,5-trimethyl-1,3-dioxane-4,6-dione (630 mg, 4.0 mmol) and triethylamine (0.58 mL, 4.2 mmol) in dimethyl sulfoxide (40 mL). The reaction mixture was stirred overnight and water (100 mL) was added. The mixture was extracted with EtOAc, the combined organic phases washed with water and brine and dried. Concentration under reduced pressure gave crude 2-[N,N-bis(tert-butoxycarbonyl)amino]-3-methyl-5-(2,2,5-trimethyl-4,6-dioxo-[1,3]dioxan-5-ylmethyl)-pyridin (2.06 g)
Reaction SMILES: F[C:2]1([N+:12]([O-:14])=[O:13])[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][CH2:3]1.[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>CO.O>[CH3:15][N:16]1[CH2:21][CH2:20][N:19]([C:5]2[CH:4]=[CH:3][C:2]([N+:12]([O-:14])=[O:13])=[CH:7][C:6]=2[C:8]([F:11])([F:10])[F:9])[CH2:18][CH2:17]1
Reactant: O=[N+]([O-])C1(F)C=C(C(F)(F)F)C=CC1
Reactant: CN1CCNCC1
Solvent: O
Solvent: CO
Product: CN1CCN(c2ccc([N+](=O)[O-])cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Fluoro-5-nitrobenzotrifluoride (2 g) and 1-methylpiperazine (2 mL) were dissolved in methanol (5 mL). The yellow solution was stirred at rt overnight. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (2×100 mL). The organic solutions were evaporated to give 2-(4-methylpiperazino)-5-nitrobenzotrifluoride.