Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:21][C:20]([CH:22]=[N:23][N:24]3[CH2:28][C:27](=[O:29])[N:26]([CH2:30][CH2:31][CH2:32]Cl)[C:25]3=[O:34])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1.C(=O)(O)[O-].[Na+].[ClH:40]>CN(C)C=O>[ClH:10].[ClH:40].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:21][C:20]([CH:22]=[N:23][N:24]3[CH2:28][C:27](=[O:29])[N:26]([CH2:30][CH2:31][CH2:32][N:7]4[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][OH:1])[CH2:5][CH2:6]4)[C:25]3=[O:34])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1
Reactant: OCCN1CCNCC1
Reactant: O=C1CN(N=Cc2ccc(-c3ccc(Cl)cc3)o2)C(=O)N1CCCCl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CN(N=Cc2ccc(-c3ccc(Cl)cc3)o2)C(=O)N1CCCN1CCN(CCO)CC1

Procedure:
A stirred solution of 4-(2-hydroxyethyl)piperazine (3.83 g, 0.03 mole) in AR grade dimethylformamide (130 ml) is treated with 1-[[[5-(4-chlorophenyl)-2-furanyl]methylene]amino]-3-(3-chloropropyl)-2,4-imidazolidinedione (6.92 g, 0.015 mole). The reaction solution is heated at near reflux for 1.5 hours and then concentrated under reduced pressure to leave an oily residue. Said residue is treated with saturated sodium bicarbonate solution to give a yellow mixture. The mixture is filtered and washed with water to give 3.92 g crude product as the free base. The solid is dissolved in alcohol and treated with a mixture of saturated ethanolic/HCl. The solution forms a crystalline solid after 5 minutes. The solid is collected by filtration to give the crude product. 1-[[[5-(4-Chlorophenyl)-2-furanyl]methylene]amino]-3-[3-[4-(2-hydroxyethyl)-1-piperazinyl]propyl]-2,4-imidazolidinedione dihydrochloride is isolated upon one recrystallization from 95% alcohol (2.57 g).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[O:12]1[CH2:23][CH:13]1[CH2:14][O:15][C:16]1[CH:17]=[N:18][C:19]([CH3:22])=[CH:20][CH:21]=1>ClCCl>[O:12]1[CH2:23][CH:13]1[CH2:14][O:15][C:16]1[CH:17]=[N+:18]([O-:9])[C:19]([CH3:22])=[CH:20][CH:21]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(OCC2CO2)cn1
Solvent: ClCCl
Product: Cc1ccc(OCC2CO2)c[n+]1[O-]
Reaction time: 0.5 h

Procedure:
A solution of 12.2 g of m-chloroperbenzoic acid in 100 ml of dichloromethane is added dropwise over the course of approx. 10 minutes, whilst stirring, to a solution of 10 g of crude 3-(2,3-epoxy-propoxy)-6-methyl-pyridine in 100 ml of dichloromethane, the temperature of the solution rising to 32° C. The reaction mixture is stirred for a further 30 minutes and is then extracted with 40 ml of saturated potassium bicarbonate solution, dried and evaporated in vacuo. 3-(2,3-Epoxy-propoxy)-6-methylpyridine-1-oxide, thus obtained, is used further in the crude state.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([Cl:21])[CH:15]=1.O>CN(C)C=O>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=[C:16]([Cl:21])[CH:15]=1
Reactant: BrC1CCCC1
Reactant: Oc1ccc(Br)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1cc(Br)ccc1OC1CCCC1
Temperature: 25 °C
Reaction time: 96 h
Yield: 98 %

Procedure:
Potassium carbonate (2.0 g) and bromocyclopentane (0.775 mL) were added to a solution of 4-bromo-2-chlorophenol (1.0 g) in N,N-dimethylformamide (10 mL), and the mixture was stirred at room temperature for four days. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with a saturated ammonium chloride solution and water, dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to give 4-bromo-2-chloro-1-(cyclopentyloxy)benzene as a colorless oil (1.31 g, 98%).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][S:5](=[O:8])(=[O:7])[NH:4][CH2:3]1.Br[C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[O:17])=[C:12]([Cl:32])[CH:11]=1>>[Cl:32][C:12]1[CH:11]=[C:10]([N:4]2[CH2:3][C@H:2]([CH3:1])[CH2:6][S:5]2(=[O:8])=[O:7])[CH:15]=[CH:14][C:13]=1[C:16]([N:18]1[CH2:19][CH2:20][N:21]([C:24]2[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[CH:26][N:25]=2)[CH2:22][CH2:23]1)=[O:17]
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3Cl)CC2)c(C)c1
Reactant: C[C@H]1CNS(=O)(=O)C1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C[C@H](C)CS4(=O)=O)cc3Cl)CC2)c(C)c1
Yield: 21.2 %

Procedure:
Using (S)-4-methylisothiazolidine 1,1-dioxide (101 mg) described in Preparation Example 4 and (4-bromo-2-chlorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (204 mg) described in Preparation Example 119 and by the reaction and treatment in the same manner as in Example 4, the title compound (49 mg) was obtained.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([N:10]=[C:11]=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:13][NH:14][CH2:15][CH2:16][CH2:17][CH3:18]>C1C=CC=CC=1>[CH2:15]([N:14]([CH3:13])[C:11]([NH:10][C:7]1[CH:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[O:9][N:8]=1)=[O:12])[CH2:16][CH2:17][CH3:18]
Reactant: CC(C)(C)c1cc(N=C=O)no1
Reactant: CCCCNC
Solvent: c1ccccc1
Product: CCCCN(C)C(=O)Nc1cc(C(C)(C)C)on1
Yield: 90 %

Procedure:
To a suspension of 5-t-butyl-3-isoxazolyl isocyanate (1.99 g) in benzene (120 ml), N-methylbutylamine (1.15 g) is added, and the resultant mixture is refluxed for 3 hours. After cooling, the reaction mixture is evaporated to remove the solvent, and the residue is chromatographed on a plate of silica gel to give 1-butyl-1-methyl-3-(5-t-butyl-3-isoxazolyl)urea (2.73 g). This substance is recrystallized from hexane to give crystals melting at 65.5° to 66.5° C. The yield is 89.8%.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:13][C:14]1[CH:18]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[NH:16][N:15]=1>>[CH3:26][O:25][C:22]1[CH:21]=[CH:20][C:19]([C:17]2[CH:18]=[C:14]([NH:13][C:10](=[O:12])[CH2:9][CH2:8][CH2:7][N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[NH:15][N:16]=2)=[CH:24][CH:23]=1
Reactant: COc1ccc(-c2cc(N)n[nH]2)cc1
Reactant: O=C(O)CCCN1CCCCC1
Product: COc1ccc(-c2cc(NC(=O)CCCN3CCCCC3)[nH]n2)cc1
Reaction time: 10 h

Procedure:
To a suspension of 4-piperidin-1-yl-butyric acid (1.32 g, 7.93 mmol) in 12,2-dichloroethane (20 mL), N,N′-carbonyldiimidazole (1.2 g, 7.4 mmol) was added and the mixture was stirred at room temperature for 2 hours (when all the aminoacid was activated complete dissolution of the suspension was generally observed). 3-Amino-5-(4-methoxyphenyl)pyrazole (1 g, 5.29 mmol) was then added and the reaction was stirred for further 10 hours. Upon reaction completion (as monitored by LC-MS) the formation of two isomers was observed, and the mixture was heated at 50° C. until the conversion of the less stable isomer to the title compound was observed (as monitored by LC-MS). The solvent was washed with sat. Na2CO3 solution, extracted and removed under reduced pressure. The crude was crystallised from acetonitrile to give 1.2 g of the title compound (Yield: 70%).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.S[C:7]1[N:12]([CH3:13])[C:11](=[O:14])[CH:10]=[C:9]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][N:16]=2)[N:8]=1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[Cl:3][C:7]1[N:12]([CH3:13])[C:11](=[O:14])[CH:10]=[C:9]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][N:16]=2)[N:8]=1
Reactant: Cn1c(S)nc(-c2ccncn2)cc1=O
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1c(Cl)nc(-c2ccncn2)cc1=O
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 27 %

Procedure:
Phosphorous oxychloride (4.60 g, 30 mmol) was added to dimethylformamide (32 ml) and stirred 20 min at 0° C. 2-Mercapto-3-methyl-6-pyrimidin-4-yl-pyrimidin-4-one (4.40 g, 20 mmol) was added to the solution and stirred 5 min and then stirred at 70° C. for 1 hour. The reaction mixture was poured into ice water, neutralized by solid K2CO3, and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and evaporated in vacuo. Purification of the residue by silica gel column chromatography (ethyl acetate) gave the title compound (1.20 g, 27%).
Reaction SMILES: [CH:1]1([CH2:7][C:8](O)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:11]([C:15]1[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=1[NH2:17])[CH2:12][CH2:13][CH3:14].N>>[CH2:11]([C:15]1[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=1[NH:17][CH2:8][CH2:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH2:12][CH2:13][CH3:14]
Reactant: CCCCc1ccccc1N
Reactant: O=C(O)CC1CCCCC1
Agent: N
Product: CCCCc1ccccc1NCCC1CCCCC1

Procedure:
The desired anine was prepared using the method described in Example 1171A starting with cyclohexylacetic acid and 2-butylaniline. m/e (DCI/NH3) 260 (MH+)
Reaction SMILES: [CH3:1][C:2]([CH3:16])([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH2:15])[C:3]([OH:5])=[O:4]>C(O)CCCC>[CH2:1]([O:4][C:3](=[O:5])[C:2]([CH3:16])([CH3:1])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]([CH:10]([CH3:11])[CH3:9])[NH2:15])[CH2:2][CH2:6][CH2:7][CH3:8]
Reactant: CC(C)(CCCCCCCCCN)C(=O)O
Solvent: CCCCCO
Product: CCCCCOC(=O)C(C)(C)CCCCCCCCC(N)C(C)C
Yield: 184.5 %

Procedure:
The procedure described in Example (1b) is repeated, using 52.3 g (0.193 mole) of 2,2-dimethyl-11-aminoundecanoic acid and 200 ml of n-pentanol. Distillation yields 60.5 g (0.178 mole) of 2,2-dimethyl-11-isopropyl-11-aminoundecanoic acid pentyl ester, corresponding to a yield of 92.2% of theory: b.p. 138°-139°/0.01 torr; nD20 =1.4505.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[CH:6][N:5]=[C:4]2[N:11]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH:12]=[CH:13][C:3]=12.[CH2:22]([N:29]1[CH2:34][CH2:33][CH:32]([NH2:35])[CH2:31][CH2:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)C(C)C)(C)C>O>[CH2:22]([N:29]1[CH2:34][CH2:33][CH:32]([NH:35][C:2]2[C:7]([C:8]([NH2:10])=[O:9])=[CH:6][N:5]=[C:4]3[N:11]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH:12]=[CH:13][C:3]=23)[CH2:31][CH2:30]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: C[Si](C)(C)CCOCn1ccc2c(Cl)c(C(N)=O)cnc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOCn1ccc2c(NC3CCN(Cc4ccccc4)CC3)c(C(N)=O)cnc21
Temperature: 25 °C
Yield: 80.7 %

Procedure:
4-Chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (456 mg, 1.40 mmol) was stirred with 1-benzyl-4-aminopiperidine (900 mg, 4.73 mmol) and N,N-diisopropylethylamine (250 μL, 1.44 mmol) at 140° C. for 3 hours. The reaction mixture was allowed to cool to room temperature and, after addition of water, extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform→ethyl acetate/methanol=1/0→5/1 (v/v)) to give the title compound as a colorless solid (542 mg, yield 81%).
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[Br:13]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:13][CH2:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1ccccc1C
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1ccccc1CBr
Temperature: 25 °C

Procedure:
A stirred mixture of ethyl 2-methylbenzoate (30 grams, 0.183 mole) and N-bromosuccinimide (35 grams, 0.194 mole) in carbon tetrachloride (200 ml) was irradiated with an infrared lamp and heated at reflux for 20 minutes. The reaction mixture was allowed to cool to room temperature, then filtered. The filtrate was evaporated under reduced pressure to give ethyl 2-bromomethylbenzoate as a yellow oil.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)([OH:3])=[O:2].[CH3:12][Si](Cl)(C)C>CO>[CH3:12][O:2][C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)=[O:3]
Reactant: C[Si](C)(C)Cl
Reactant: O=Cc1ccc(C(=O)O)cc1
Solvent: CO
Product: COC(=O)c1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
The 4-carboxybenzaldehyde is of commercial origin. It is dissolved (3 g; 20 mmol) in a trimethylsilyl chloride solution (10 g; 92 mmol) in 100 ml of MeOH. The mixture is kept stirred for 40 h at room temperature. After evaporation, a white solid corresponding to 4-methoxycarbonylbenzaldehyde 24 is isolated, characterized by NMR and used as it is for the next reaction.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)#[CH:2].[CH3:9][O:10][C:11](=[O:26])[C:12]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[C:15](Cl)=[N:14][CH:13]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.C(N(C(C)C)C(C)C)C.[Cu]I>[CH3:9][O:10][C:11](=[O:26])[C:12]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[C:15]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=2)=[N:14][CH:13]=1
Reactant: COC(=O)c1cnc(Cl)c(-c2ccc(Cl)cc2)c1
Reactant: C#Cc1ccccn1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cnc(C#Cc2ccccn2)c(-c2ccc(Cl)cc2)c1
Temperature: 120 °C

Procedure:
A degassed solution of 2-ethynyl-pyridine (2.0 mmol, CAN 1945-84-2) in tetrahydrofuran and N-ethyldiisopropylamine (1:1, 10 ml) was added to a degassed suspension of 6-chloro-5-(4-chloro-phenyl)-nicotinic acid methyl ester (1.0 mmol), [1,1′-bis(diphenylphosphino)-ferrocene]palladium(II) dichloride dichloromethane complex (1:1) (49 mg, 0.06 mmol), polymer supported triphenylphoshine (135 mg, 1.48 mmol/g, 0.2 mmol) and copper(I)iodide (11 mg, 0.06 mmol) in tetrahydrofuran and N-ethyldiisopropylamine (1:1, 5 ml). The reaction mixture was heated at 120° C. for 20 hours under an atmosphere of nitrogen. The reaction mixture was cooled to room temperature and the solids were removed by filtration. The solids were washed with ethyl acetate (100 ml), the organic liquors were combined and washed with saturated aqueous ammonium chloride solution (3×50 ml). The organic layer was then dried over MgSO4 and concentrated in vacuo. Purification by flash column chromatography (20% ethyl acetate/heptane) gave the title compound as brown oil.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[N:3]1.[Li]CCCC.[Cl:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:23]([C:25]3[N:29]([CH3:30])[CH:28]=[N:27][CH:26]=3)=[O:24])[CH:21]=2)[N:16]=[C:15]([O:31][CH3:32])[C:14]=1[CH2:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][CH:35]=1>C1COCC1>[Cl:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:23]([C:6]3[N:2]([CH3:1])[N:3]=[N:4][CH:5]=3)([C:25]3[N:29]([CH3:30])[CH:28]=[N:27][CH:26]=3)[OH:24])[CH:21]=2)[N:16]=[C:15]([O:31][CH3:32])[C:14]=1[CH2:33][C:34]1[CH:35]=[CH:36][C:37]([C:40]([F:42])([F:41])[F:43])=[CH:38][CH:39]=1
Reactant: Cn1ccnn1
Reactant: COc1nc2ccc(C(=O)c3cncn3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)(c3cncn3C)c3cnnn3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Temperature: -43 °C
Reaction time: 0.5 h

Procedure:
To a flask containing 1-methyl-1H-1,2,3-triazole (100 mg, 1.2 mmol) was added THF (10 mL) and the colorless solution was cooled to −43° C. using a CH3CN—CO2 bath. Then, n-BuLi (2.5 M in hexanes, 490 μL, 1.23 mmol) was added dropwise which afforded an opaque mixture. The mixture was stirred at −40° C. for 30 minutes, then a homogeneous solution of (4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanone (255 mg, 0.54 mmol, Intermediate 80: step b) in 2 mL THF was introduced. After 5 minutes, the reaction mixture was then placed in an ice-water bath. The reaction was quenched after 20 minutes with aqueous NH4Cl solution and the aqueous portion was extracted with EtOAc (3×30 mL) and EtOAc:THF (1:1, 30 mL). The combined organics were washed with brine, dried over MgSO4, filtered and concentrated. The solid was triturated with MeOH and filtered to give a yellow filtrate which was concentrated and chromatographed on silica gel (3% MeOH-DCM increasing to 10% MeOH) to afford the title compound. 1H NMR (500 MHz, CDCl3) δ 8.22 (d, J=2.1 Hz, 1H), 7.76 (d, J=8.7 Hz, 2H), 7.49 (d, J=8.1 Hz, 2H), 7.41-7.35 (m, 3H), 7.10 (s, 1H), 6.99 (s, 1H), 6.22 (s, 1H), 4.29 (s, 2H), 4.07 (s, 3H), 3.89 (s, 3H), 3.41 (s, 3H). MS (ESI): mass calcd. for Chemical Formula: C26H22ClF3N6O2; Exact Mass: 542.14. m/z found 542.9 [M+H]+.
Reaction SMILES: CO[C:3]([C:5]1[S:9][C:8](/[CH:10]=[CH:11]/[C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:7][C:6]=1[CH3:24])=[O:4].[CH2:25]([CH2:27][NH2:28])[OH:26]>C1(C)C=CC=CC=1.[Cl-].[Na+].O>[OH:26][CH2:25][CH2:27][NH:28][C:3]([C:5]1[S:9][C:8](/[CH:10]=[CH:11]/[C:12]2[C:13]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:7][C:6]=1[CH3:24])=[O:4]
Reactant: NCCO
Reactant: COC(=O)c1sc(/C=C/c2c(-c3ccccc3)noc2C)nc1C
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1nc(/C=C/c2c(-c3ccccc3)noc2C)sc1C(=O)NCCO
Yield: 61.9 %

Procedure:
To a stirred solution of 4-methyl-2-[(E)-2-(5-methyl-3-phenyl-isoxazol-4-yl)-vinyl]-thiazole-5-carboxylic acid methyl ester (70 mg, 0.21 mmol) in toluene (0.5 mL) was added ethanolamine (15 mg, 0.25 mmol) and TBD (18 mg, 0.13 mmol). After 24 h the reaction mixture was diluted with brine and extracted with ethyl acetate. The combined extracts were dried, filtered and concentrated in vacuo, then purified by chromatography (silica, 0 to 10% methanol in dichloromethane) to give the title compound (48 mg, 60%) as a pale yellow oil. MS: m/e=370.1 [M+H]+.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:20]=[C:19]([NH2:21])[C:18]([O:22][CH3:23])=[C:17]3[C:13]=2[C:14]2[CH:27]=[C:26]([CH3:28])[CH:25]=[N:24][C:15]=2[NH:16]3)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2].[CH3:29][N:30]([CH3:36])[CH2:31][CH2:32][C:33](Cl)=[O:34]>N1C=CC=CC=1>[CH3:29][N:30]([CH3:36])[CH2:31][CH2:32][C:33]([NH:21][C:19]1[C:18]([O:22][CH3:23])=[C:17]2[C:13]([C:14]3[CH:27]=[C:26]([CH3:28])[CH:25]=[N:24][C:15]=3[NH:16]2)=[C:12]([C:8]2[CH:9]=[CH:10][CH:11]=[C:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH:7]=2)[CH:20]=1)=[O:34]
Reactant: CN(C)CCC(=O)Cl
Reactant: CCS(=O)(=O)c1cccc(-c2cc(N)c(OC)c3[nH]c4ncc(C)cc4c23)c1
Solvent: c1ccncc1
Product: CCS(=O)(=O)c1cccc(-c2cc(NC(=O)CCN(C)C)c(OC)c3[nH]c4ncc(C)cc4c23)c1
Temperature: 105 °C
Yield: 54.8 %

Procedure:
To a suspension of Compound 239 (150 mg, 0.38 mmol) in pyridine (2.0 mL) was added 3-(dimethylamino)propanoyl chloride (71 mg, 0.38 mmol) and the reaction mixture was heated at 105° C. for 5 h. and quenched with aqueous NH4Cl solution. Organic matter was extracted with CH2Cl2 (with 10% EtOH) and washed with brine. The organic extracts were dried (Na2SO4) and concentrated and purified by preparative HPLC to yield the title compound (103 mg, 55%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.16 (t, J=7.33 Hz, 3H) 2.24 (s, 3H) 2.33 (s, 6H) 2.56 (t, J=5.81 Hz, 2H) 2.62 (t, J=5.31 Hz, 2H) 3.41 (d, J=7.33 Hz, 2H) 3.93 (s, 3H) 7.41 (d, J=1.26 Hz, 1H) 7.87 (t, J=7.71 Hz, 1H) 7.93-7.97 (m, 1H) 8.03 (d, J=8.84 Hz, 1H) 8.06 (s, 2H) 8.22 (d, J=2.02 Hz, 1H) 10.99 (br. s., 1H) 12.07 (s, 1H); [M+H] calc'd for C26H31N4O-4S, 495.2; found, 495.4.
Reaction SMILES: [CH3:1][Si:2]([CH3:6])([CH3:5])[C:3]#[CH:4].N12CCN(CC1)CC2.Br[C:16]1[S:20][C:19]([C:21]2[N:22]=[C:23]3[N:27]([C:28]=2[NH:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH:26]=[CH:25][S:24]3)=[CH:18][CH:17]=1.C(Cl)Cl>C(#N)C>[C:30]([NH:29][C:28]1[N:27]2[C:23]([S:24][CH:25]=[CH:26]2)=[N:22][C:21]=1[C:19]1[S:20][C:16]([C:4]#[C:3][Si:2]([CH3:6])([CH3:5])[CH3:1])=[CH:17][CH:18]=1)([CH3:33])([CH3:31])[CH3:32]
Reactant: C#C[Si](C)(C)C
Reactant: CC(C)(C)Nc1c(-c2ccc(Br)s2)nc2sccn12
Agent: C1CN2CCN1CC2
Solvent: CC#N
Solvent: ClCCl
Product: CC(C)(C)Nc1c(-c2ccc(C#C[Si](C)(C)C)s2)nc2sccn12
Yield: 22.5 %

Procedure:
4.1 g (3.5 mmol) tetrakis(triphenyl)phosphine-palladium(0), 17.2 g (175.4 mmol) trimethyl-silylacetylene and 7.9 g (70.2 mmol) 1,4-diazabicyclo[2.2.2]octane were consecutively added to a suspension of 12.5 g (35.1 mmol) 6-(5-bromothiophene-2-yl)-N-tert-butylimidazo[2,1-b]thiazole-5-amine in acetonitrile (150 ml). The reaction solution was heated for 72 h under reflux and subsequently concentrated in a vacuum. 3.0 g (7.9 mmol, 23%) N-tert-butyl-6-(5-((trimethylsilyl)ethynyl)thiophene-2-yl)imidazo[2,1-b]thiazole-5-amine ([MH+] 374.1) was obtained by CC (DCM/AE 95:5).
Reaction SMILES: Br[C:2]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[OH:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.O>CS(C)=O>[C:13]1([C:2]([N:25]2[CH2:26][CH2:27][N:22]([CH2:21][CH2:20][OH:19])[CH2:23][CH2:24]2)([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OCCN1CCNCC1
Reactant: CCOC(=O)C(Br)(C(=O)OCC)c1ccccc1
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)C(C(=O)OCC)(c1ccccc1)N1CCN(CCO)CC1
Yield: 33.5 %

Procedure:
A solution of diethyl 2-bromo-2-phenylmalonate (16.8 g) in 150 ml of dimethylsulfoxide is heated to 90-100° C., then N-(2-hydroxyethyl)piperazine (27.9 g) is added and the reaction mixture is heated for additional 4 hours. The mixture is poured into water and extracted with ethyl acetate three times. The pooled organic extracts are washed with 1 N hydrochloric acid. The aqueous phase is basified with 1 N sodium hydroxide to pH=8-9 and it is extracted twice with ethyl acetate. The organic extracts are collected and are washed with a saturated aqueous solution of sodium chloride and dried over sodium sulfate. After removal of the solvent under reduced pressure, the residue is crystallized from diethylether petroleum ether 1:1 to give 6.5 g of the product, m.p. 63-64° C.
Reaction SMILES: [NH2:1][C@H:2]1[C@@H:5]([CH2:6][O:7][C:8](=[O:10])[NH2:9])[N:4]([S:11]([OH:14])(=[O:13])=[O:12])[C:3]1=[O:15].[NH2:16][C:17]1[S:18][CH:19]=[C:20](/[C:22](=[N:26]/[O:27][CH2:28][CH2:29][N:30]=[N+:31]=[N-:32])/[C:23](O)=[O:24])[N:21]=1>>[NH2:16][C:17]1[S:18][CH:19]=[C:20](/[C:22](=[N:26]/[O:27][CH2:28][CH2:29][N:30]=[N+:31]=[N-:32])/[C:23]([NH:1][C@H:2]2[C@@H:5]([CH2:6][O:7][C:8](=[O:10])[NH2:9])[N:4]([S:11]([OH:14])(=[O:12])=[O:13])[C:3]2=[O:15])=[O:24])[N:21]=1
Reactant: [N-]=[N+]=NCCO/N=C(\C(=O)O)c1csc(N)n1
Reactant: NC(=O)OC[C@@H]1[C@H](N)C(=O)N1S(=O)(=O)O
Product: [N-]=[N+]=NCCO/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1COC(N)=O)c1csc(N)n1
Yield: 59 %

Procedure:
In the same manner as described in Example 9, from 1.87 g of (3S,4S)-3-amino-4-carbamoyloxymethyl-2-oxo-1-azetidinesulphonic acid and 2 g of 2-(2-amino-4-thiazolyl)-2-[(Z)-(2-azidoethoxy)imino]-acetic acid there are obtained 2.2 g of (3S,4S)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-[(2-azidoethoxy)imino]acetamido]-4-carbamoyloxymethyl-2-oxo-1-azetidinesulphonic acid.