Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([S:28]([NH2:31])(=[O:30])=[O:29])[CH:23]=2)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[NH2:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]2[CH2:44][CH2:43][N:42]([C:45](=[O:47])[CH3:46])[CH2:41][CH2:40]2)=[CH:35][CH:34]=1.C[Si](Cl)(C)C>C(O)CCC.O1CCOCC1>[C:45]([N:42]1[CH2:41][CH2:40][N:39]([C:36]2[CH:37]=[CH:38][C:33]([NH:32][C:2]3[N:3]=[C:4]([NH:21][C:22]4[CH:23]=[C:24]([S:28]([NH2:31])(=[O:29])=[O:30])[CH:25]=[CH:26][CH:27]=4)[C:5]4[CH:10]=[CH:9][N:8]([S:11]([C:14]5[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=5)(=[O:13])=[O:12])[C:6]=4[N:7]=3)=[CH:34][CH:35]=2)[CH2:44][CH2:43]1)(=[O:47])[CH3:46]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4cccc(S(N)(=O)=O)c4)nc(Cl)nc32)cc1
Reactant: CC(=O)N1CCN(c2ccc(N)cc2)CC1
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Solvent: C1COCCO1
Product: CC(=O)N1CCN(c2ccc(Nc3nc(Nc4cccc(S(N)(=O)=O)c4)c4ccn(S(=O)(=O)c5ccc(C)cc5)c4n3)cc2)CC1
Temperature: 110 °C
Reaction time: 72 h
Yield: 28.8 %

Procedure:
A mixture of 2-chloro-N-(3-aminosulfonyl-phenyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (100 mg, 0.210 mmol), 1-(4-(4-aminophenyl)piperazin-1-yl)ethanone (92 mg, 0.42 mmol) and trimethylsilyl chloride (0.200 mL, 1.58 mmol) in nBuOH (2 mL) and dioxane (2 mL) was heated at 110° C. for 72 h. More 1-(4-(4-aminophenyl)piperazin-1-yl)ethanone (92 mg, 0.42 mmol) was added. The mixture was stirred at 110° C. for another 72 h. It was then purified by HPLC to give 3-(2-(4-(4-acetylpiperazin-1-yl)phenylamino)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)benzenesulfonamide (40 mg)
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([CH3:25])[C:5]([O:6][C:7]2[N:15]=[C:14]([CH3:16])[CH:13]=[C:12]([NH:17][CH:18]([CH2:21][OH:22])[CH2:19][CH3:20])[C:8]=2[C:9]([NH2:11])=[O:10])=[C:4]([CH3:26])[CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH3:26])[C:5]([O:6][C:7]2[N:15]=[C:14]([CH3:16])[CH:13]=[C:12]([NH:17][CH:18]([CH:21]=[O:22])[CH2:19][CH3:20])[C:8]=2[C:9]([NH2:11])=[O:10])=[C:23]([CH3:25])[CH:24]=1
Reactant: CCC(CO)Nc1cc(C)nc(Oc2c(C)cc(Cl)cc2C)c1C(N)=O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CS(C)=O
Product: CCC(C=O)Nc1cc(C)nc(Oc2c(C)cc(Cl)cc2C)c1C(N)=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-hydroxymethyl-propylamino)-6-methyl-nicotinamide and Dess-Martin reagent in methylene chloride/DMSO was stirred at rt for 4 hr. The title compound was isolated after standard work-up and silica gel Biotage purification. 1H NMR(CDCl3) d 9.52(s,1H), 8.00(brs,1H), 7.06(s,22H), 5.99(s,1H), 5.8(brs,1H), 3.85(m,1H), 2.09(s,3H), 2.08(s,6H), 1.8-2.2(m,2H), 1.08(t,3H) ppm.
Reaction SMILES: [C:1]([O:4][C:5]1[C:22]2[C@@H:21]3[C@H:12]([C@H:13]4[C@@:17]([CH2:19][CH2:20]3)([CH3:18])[C@@H:16]([OH:23])[CH2:15][CH2:14]4)[CH2:11][CH2:10][C:9]=2[CH:8]=[C:7]([O:24][CH3:25])[CH:6]=1)(=[O:3])[CH3:2].C.N([CH2:29]NC(N)=O)=O.[H+].[B-](F)(F)(F)F>C(Cl)Cl>[C:1]([O:4][C:5]1[C:22]2[C@@H:21]3[C@H:12]([C@H:13]4[C@@:17]([CH2:19][CH2:20]3)([CH3:18])[C@@H:16]([O:23][CH3:29])[CH2:15][CH2:14]4)[CH2:11][CH2:10][C:9]=2[CH:8]=[C:7]([O:24][CH3:25])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: NC(=O)NCN=O
Reactant: COc1cc2c(c(OC(C)=O)c1)[C@H]1CC[C@]3(C)[C@@H](O)CC[C@H]3[C@@H]1CC2
Agent: C
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: ClCCl
Product: COc1cc2c(c(OC(C)=O)c1)[C@H]1CC[C@]3(C)[C@@H](OC)CC[C@H]3[C@@H]1CC2

Procedure:
1-Acetoxy-3-methoxyestra-1,3,5(10)-trien-17β-ol (1.0 g) is etherified with CH2H2, generated from N-nitrosomethylurea and catalyzed with a drop of 48% HBF4 in methylene chloride. The resulting polymethylene polymer is filtered and the methylene chloride filtrate is washed with 10% sodium bicarbonate solution, water and then dried over sodium sulfate. Evaporation in vacuo gives an oil which is crystallized from ethanol to give 1-acetoxy-3,17β-dimethoxy-1,3,5(10)-estratriene as a white solid, yield 0.78 g (75%); m.p. 81°-83° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[Cl:34])[CH2:5][NH:6][C:7]([C:9]1[CH:10]=[CH:11][C:12]([C:15](NC[C@@H]2C[C@H](S)CN2C(OCC=C)=O)=[O:16])=[N:13][CH:14]=1)=[O:8].[CH3:35][O:36]C(C1C=CC(C(Cl)=O)=CN=1)=O.ClC1C=C(C=CC=1Cl)CN.C(OC(C1SC(C(=O)NCC2C=CC(Cl)=C(Cl)C=2)=CC=1)=O)C>>[CH3:35][O:36][C:15]([C:12]1[CH:11]=[CH:10][C:9]([C:7](=[O:8])[NH:6][CH2:5][C:4]2[CH:31]=[CH:32][C:33]([Cl:34])=[C:2]([Cl:1])[CH:3]=2)=[CH:14][N:13]=1)=[O:16]
Reactant: C=CCOC(=O)N1C[C@@H](S)C[C@H]1CNC(=O)c1ccc(C(=O)NCc2ccc(Cl)c(Cl)c2)cn1
Reactant: COC(=O)c1ccc(C(=O)Cl)cn1
Agent: CCOC(=O)c1ccc(C(=O)NCc2ccc(Cl)c(Cl)c2)s1
Agent: NCc1ccc(Cl)c(Cl)c1
Product: COC(=O)c1ccc(C(=O)NCc2ccc(Cl)c(Cl)c2)cn1
Yield: 61 %

Procedure:
Starting material (13(e)) was prepared as follows, 5-chlorocarbonyl-pyridine-2-carboxylic acid methyl ester was reacted with 3,4-dichlorobenzylamine analogously with preparation of compound (12(a)) in Example 12 to obtain 5(3,4-dichlorobenzylcarbamoyl)-pyridine-2-carboxylic acid methyl-ester (13(a)) as a cream solid (61%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[OH2:6]>[Al+3].[Cl-].[Cl-].[Cl-]>[CH3:2][O:1][C:5](=[O:6])[CH:4]=[CH2:3].[C:2]([CH:3]1[CH2:4][CH:2]2[O:1][CH:5]1[CH:4]=[CH:3]2)([O:1][CH3:5])=[O:6]
Reactant: c1ccoc1
Reactant: O
Agent: [Al+3]
Agent: [Cl-]
Product: C=CC(=O)OC
Product: COC(=O)C1CC2C=CC1O2
Temperature: 20 °C
Reaction time: 3 h
Yield: 292.2 %

Procedure:
1290 g (15 Mol) methylacrylate is prepared and 67.5 g (0.5 Mol) AlCl3 added thereto and dissolved with stirring. At 20° to 25° C., 1050 g (15.4 Mol) furane is added drop-wise during cooling. The temperature is maintained at 20° C. until the exothermic reaction is finished, after which stirring is continued for a further hour at 20° C. and then for 3 hours at 10° C. 300 g water is then added, the organic phase separated, and the unconverted furane and the methylacrylate distilled off under a pressure of 10 Torr and at a bath temperature of 60° C. in a rotary evaporator. Finally, the vacuum is lowered to 1 Torr and further volatile components drawn off. The crude product is passed to a thin-film evaporator under a vacuum of 1 Torr and a thermostatically controlled temperature of 95° C. A distillation temperature of approximately 70° C. is used. The 2-carbomethoxy-7-oxabicyclo(2,2,1)hept-5-ene is obtained in a yield of 1060 g (45.9% theoretical).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:11]([C:23]3[N:24]=[N:25][NH:26][N:27]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:28](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:11]([C:23]3[N:24]=[N:25][N:26]([CH3:28])[N:27]=3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)N2C(c3ccc(F)cc3)CCC2c2nn[nH]n2)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: Cc1ccc(S(=O)(=O)N2C(c3ccc(F)cc3)CCC2c2nnn(C)n2)cc1
Yield: 58.9 %

Procedure:
To a stirred solution of (2RS,5SR)-5-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-2H-tetrazole (0.72 g, 1.86 mmol) in acetone (30 ml) was added at room temperature potassium carbonate (0.51 g, 3.72 mmol) and methyl iodide (0.23 ml, 3.72 mmol) and the reaction mixture was heated under reflux conditions for 3 h. Aqueous work-up, column chromatography on silica gel (ethyl acetate/hexane 2:3) and crystallization from ethyl acetate/hexane yielded the title compound (0.44 g, 59%) as a white solid, m.p. 150° C. and MS: m/e=402.4 (M+H+). As second product of this reaction (2RS,5SR)-5-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-1-methyl-1H-tetrazole (0.26 g, yield 35%) was obtained as a white solid, m.p. 186° C. and MS: m/e=402.4 (M+H+).
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH2:8][Cl:9])([CH3:7])[C:4](O)=[O:5].C(Cl)(=O)C([Cl:13])=O>CN(C=O)C.C(Cl)Cl>[Cl:1][CH2:2][C:3]([CH2:8][Cl:9])([CH3:7])[C:4]([Cl:13])=[O:5]
Reactant: CC(CCl)(CCl)C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(CCl)(CCl)C(=O)Cl
Temperature: 0 °C

Procedure:
DMF (1 drop) was added to a solution of 2,2-bis(chloromethyl)propanoic acid (1.4 g) in DCM (1.5 ml), the solution was cooled to 0° C. and oxalyl chloride (0.75 ml) added. After gas evolution had stopped the mixture was concentrated in vacuo to give the sub-title compound as a yellow oil (1.51 g) which was used directly in the next step.
Reaction SMILES: [OH-:1].[K+].O[C:4]12[CH:18]=[CH:17][CH:16]=[CH:15][CH:5]1[CH2:6][CH:7]2[CH2:8][N:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[Br:19][CH2:20][CH2:21][CH2:22]Br>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.CCOCC>[Br:19][CH2:20][CH2:21][CH2:22][O:1][C:17]1[CH:18]=[C:4]2[CH:7]([CH2:8][N:9]3[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]3)[CH2:6][C:5]2=[CH:15][CH:16]=1
Reactant: BrCCCBr
Reactant: [OH-]
Reactant: OC12C=CC=CC1CC2CN1CCCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [K+]
Solvent: CCOCC
Product: BrCCCOc1ccc2c(c1)C(CN1CCCCC1)C2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Potassium hydroxide (1.5 g, 10%) is added over a period of 1 hour 15 min to a stirred suspension of 3-hydroxy-1-(1-piperidinylmethyl)benzocyclobutene (1.0 g), and tetrabutylammonium chloride (0.13 g) in 1,3-dibromopropane (4.6 ml) and the resulting mixture stirred at RT under nitrogen for two days. The reaction mixture is partitioned between ice-water and ether and the aqueous layer separated and extracted with ether. The combined organic extract is washed with water, ice cold 5% aqueous HCl thereby forming a precipitate which is filtered and washed with ether. The acidic layer is alkalized forming an oily precipitate which is taken up in ether. The combined ether fractions are washed with water, dried over Na2SO4, filtered and concentrated in vacuo yielding the desired product as an oil which is used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][S:15]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21](F)=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C-:29]#[N:30].CO>CN(C=O)C.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][S:15]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]([C:29]#[N:30])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(NS(=O)(=O)c2ccc(F)c3ccccc23)CC1
Reactant: [C-]#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CN(C)C=O
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(NS(=O)(=O)c2ccc(C#N)c3ccccc23)CC1
Temperature: 100 °C

Procedure:
4-(4-Fluoro-naphthalene-1-sulfonylamino)-piperidine-1-carboxylic acid tert-butyl ester 28 (2.00 g, 4.9 mmol) was dissolved in DMF (20 mL). Sodiuim cyanide (1.2 g, 24.5 mmol) and tetra-n-butylammonium bromide (7.9 g, 24.5 mmol) were added and the reaction was heated to 100° C. overnight. The reaction was diluted with dichloromethane (100 mL) and charged to a separatory funnel. The organic layer was washed three times with water, brine and dried over MgSO4. Filtration and concentration in vacuo afforded a dark colored oil. Flash column chromatography (98:2 dichloromethane:methanol) afforded an oil that was rechromatographed (99:1 dichloromethane:methanol) to afford 29 as an orange solid. Wt.: 640 mg (31%). 1H NMR (300 MHz, CDCl3) δ 8.71 (m, 1H), 8.40 (m, 1H), 8.34 (d, 1H), 8.00 (d, 1H), 7.83 (m, 2H), 4.80 (d, 1H), 3.87 (m, 2H), 3.32 (m, 1H), 2.61 (m, 2H), 1.63 (m, 2H), 1.38 (s, 9H), 1.27 (m, 2H); LC/MS m/z 414 (M−H)−.
Reaction SMILES: C1([NH:5][C:6]2[C:7]3[CH:31]=[CH:30][NH:29][C:8]=3[N:9]=[C:10]([NH:12]C3C=CC(S(N4CCC(O)CC4)(=O)=O)=CC=3)[N:11]=2)CCC1.CS(CC1C=C(C=CC=1)N)(=O)=O>>[N:9]1[C:8]2[NH:29][CH:30]=[CH:31][C:7]=2[C:6]([NH2:5])=[N:11][C:10]=1[NH2:12]
Reactant: O=S(=O)(c1ccc(Nc2nc(NC3CCC3)c3cc[nH]c3n2)cc1)N1CCC(O)CC1
Agent: CS(=O)(=O)Cc1cccc(N)c1
Product: Nc1nc(N)c2cc[nH]c2n1

Procedure:
According to the general procedure for synthesis of 1-(4-(4-(cyclobutylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)phenylsulfonyl)piperidin-4-ol, 3-(methylsulfonylmethyl)aniline and 2-Chloro-N-cylclobutyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine gave N4-cyclobutyl-N2-(3-methylsulfonylmethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-2,4-diamine (MS calcd for C18H21N5O2S 371.5. found [MH] 372.1; UV 214.5, 267.6, 304.5 nm).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([C:19]([OH:21])=O)[C:13](=[CH:17][CH:18]=1)[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:22]([N:25]([CH2:31][CH2:32][CH3:33])[CH2:26][CH2:27][CH2:28][CH2:29][NH2:30])[CH2:23][CH3:24].O>C1(C)C(C)=CC=CC=1>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[CH:11]=[C:12]2[C:13](=[CH:17][CH:18]=1)[C:14](=[O:16])[N:30]([CH2:29][CH2:28][CH2:27][CH2:26][N:25]([CH2:31][CH2:32][CH3:33])[CH2:22][CH2:23][CH3:24])[C:19]2=[O:21])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCN(CCC)CCCCN
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)c(C(=O)O)c1
Solvent: Cc1ccccc1C
Solvent: O
Product: CCCN(CCC)CCCCN1C(=O)c2ccc(CNC(=O)OC(C)(C)C)cc2C1=O
Yield: 49.2 %

Procedure:
The compound (123 mg) obtained in Example 7-4 was dissolved in xylene (5.0 ml). A xylene solution (5.0 ml) containing the compound (83.4 mg) obtained in Example 1-2 was dropped to the solution and the whole was refluxed under heating for 63 hours. The solution was added with water to stop the reaction and then subjected to extraction with chloroform. The organic layer was washed with water and a saturated saline solution, followed by drying with anhydrous sodium sulfate. The residue obtained by distilling the solvent off was then purified through silica gel column chromatography (hexane/ethyl acetate), thereby obtaining the subject compound (88.4 mg) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[C:8]3([CH2:13][CH2:14][S:15][C:6]=2[C:5]([CH3:16])=[CH:4][C:3]=1[C:17]([OH:19])=[O:18])[S:12][CH2:11][CH2:10][S:9]3.C(Cl)(=O)C(Cl)=O.[C:26]1(=O)[CH2:31][CH2:30][CH2:29][C:28](=[O:32])[CH2:27]1.C(N(CC)CC)C.[Cl-].[Na+]>C(Cl)Cl.CN(C)C=O>[CH3:1][C:2]1[C:7]2[C:8]3([CH2:13][CH2:14][S:15][C:6]=2[C:5]([CH3:16])=[CH:4][C:3]=1[C:17]([O:19][C:26]1[CH2:31][CH2:30][CH2:29][C:28](=[O:32])[CH:27]=1)=[O:18])[S:12][CH2:11][CH2:10][S:9]3
Reactant: Cc1cc(C(=O)O)c(C)c2c1SCCC21SCCS1
Reactant: O=C1CCCC(=O)C1
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)OC2=CC(=O)CCC2)c(C)c2c1SCCC21SCCS1
Temperature: 0 °C
Reaction time: 8 h
Yield: 70.7 %

Procedure:
To a solution of the title compound of Step B (0.77 g, 2.4 mmol) in methylene chloride (25 mL) under a nitrogen atmosphere was added oxalyl chloride (Aldrich, 0.63 mL, 7.2 mmol) and 1 drop of N,N-dimethylformamide. The resulting mixture was refluxed for 1.5 h and was then evaporated to dryness. To the resulting residue was added methylene chloride (25 mL) and the resulting mixture was evaporated to dryness. Another 25 mL of methylene chloride was added to the residue, and the solution was cooled to about 0° C. To this mixture was added 1,3-cyclohexanedione (Aldrich, 0.30 g, 2.6 mmol) followed by addition of triethylamine (1.0 mL, 7.2 mmol). The mixture was stirred overnight while warming to room temperature. To the reaction mixture was added saturated aqueous sodium chloride and the resulting mixture was extracted three times with diethyl ether. The combined organic extracts were dried (MgSO4), filtered, and concentrated under reduced pressure to dryness. Chromatography of the crude product on silica gel with a mixture of hexanes:ethyl acetate (3:1) yielded the title compound of Step C (0.69 g) as a semi-solid. 1H NMR (CDCl3): δ2.13 (m,2H), 2.26 (s,3H), 2.45 (t,2H), 2.66 (m,2H), 2.76 (m,2H), 2.95 (s,3H), 3.18 (m,2H), 3.50-3.70 (4H), 6.00 (s,1H), 7.50 (s,1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][CH:11]=[C:10]([C:13](=[N:15][NH:16][C:17]([N:19]3[CH2:24][CH2:23][CH:22]([C:25](O)=[O:26])[CH2:21][CH2:20]3)=[S:18])[CH3:14])[C:9]=2[OH:28])=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.[N:60]1[CH:65]=[CH:64][C:63]([CH2:66][NH2:67])=[CH:62][CH:61]=1>O.CN(C)C=O>[N:60]1[CH:65]=[CH:64][C:63]([CH2:66][NH:67][C:25]([CH:22]2[CH2:21][CH2:20][N:19]([C:17]([NH:16][N:15]=[C:13]([C:10]3[C:9]([OH:28])=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=4)[S:12][CH:11]=3)[CH3:14])=[S:18])[CH2:24][CH2:23]2)=[O:26])=[CH:62][CH:61]=1
Reactant: CC(=NNC(=S)N1CCC(C(=O)O)CC1)c1csc(-c2ccc(Br)cc2)c1O
Reactant: NCc1ccncc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(=NNC(=S)N1CCC(C(=O)NCc2ccncc2)CC1)c1csc(-c2ccc(Br)cc2)c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 34 %

Procedure:
To 1-{1-[5-(4-bromophenyl)-4-hydroxythiophen-3-yl]-ethylidene-hydrazinothiocarbonyl}-piperidine-4-carboxylic acid (84 mg, 0.17 mmol) prepared in Synthetic Example 9, dimethylformamide (2 mL) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (66 mg, 0.25 mmol) and HOBt (47 mg, 0.25 mmol) were added, and then dimethylformamide (2.5 mL) and diisopropylethylamine (91 μl, 0.52 mmol) were added. The resulting solution was stirred at room temperature for 1 hour and then stirred with a dimethylformamide solution (1.5 mL) of 4-picolylamine (47 mg, 0.43 mmol) for 24 hours. After addition of water, the reaction mixture was filtered, and the filter cake was dried and washed with isopropyl alcohol repeatedly to give the desired product (yield 34%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:16]([N:18]1[CH2:25][CH2:24][CH2:23][C@H:19]1[C:20]([NH2:22])=[O:21])=[O:17])[CH2:10][C:11]1[N:12]=[CH:13][S:14][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1CCC[C@H]1C(N[CH2:31][C:32]([O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])=[O:33])=O.ON1C2C=CC=CC=2N=N1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:16]([N:18]1[CH2:25][CH2:24][CH2:23][C@H:19]1[C:20]([NH:22][CH2:31][C:32]([O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])=[O:33])=[O:21])=[O:17])[CH2:10][C:11]1[N:12]=[CH:13][S:14][CH:15]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCCCCCCCCCCCCOC(=O)CNC(=O)[C@@H]1CCCN1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cscn1)C(=O)N1CCC[C@H]1C(N)=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCOC(=O)CNC(=O)[C@@H]1CCCN1C(=O)[C@H](Cc1cscn1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
To a solution of N-(tert-butoxycarbonyl)-3-(4-thiazolyl)-L-alanine (1, 480 mg, 1.76 mmol) which was synthesized in accordance with the method described in the literature (Synthtic Commun., 20, 3507, (1990)), the compound (10) (650 mg, 1.76 mmol), and N-hydroxybenzotriazole (70 mg, 0.528 mmol) in N,N-dimethylformamide (20 ml) was added DCC (380 mg, 1.848 mmol) and the resulting mixture was stirred overnight at room temperature. After the precipitation which appeared was filtered off, the filtrate was concentrated in vacuo. The residue was dissolved in ethyl acetate and the precipitation which appeared was filtered off again. The filtrate was concentrated in vacuo. The residue was subjected to silica gel column chromatography (ethyl acetate:toluene=9:1) to give 1.02 g of the compound (13).
Reaction SMILES: [O:1]([CH2:9][CH2:10][C:11]#[CH:12])[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].C([Li])CCC.[CH3:18][Si:19](Cl)([CH3:21])[CH3:20]>C1COCC1.CCCCCC>[CH3:18][Si:19]([CH3:21])([CH3:20])[C:12]#[C:11][CH2:10][CH2:9][O:1][Si:2]([C:5]([CH3:6])([CH3:7])[CH3:8])([CH3:3])[CH3:4]
Reactant: C#CCCO[Si](C)(C)C(C)(C)C
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)[Si](C)(C)OCCC#C[Si](C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 86.6 %

Procedure:
To a solution of 1-(t-butyldimethylsiloxy)-3-butyne (49.0 g, 0.27 mol) in 250 mL of THF, at -78° C. under Ar, was added a solution of n-butyllithium (1.6 M in hexane, 170 mL, 0.27 mol) over ca. 45 min. The mixture was stirred at -78° C. for 30 min and then at 0° C. for 1.5 h. The resulting solution was recooled at -78° C. and then trimethylsilyl chloride (34.0 mL, 0.27 mol) was added dropwise. After the addition the mixture was allowed to warm to room temperature over 18 h and then it was diluted with hexane, washed (H2O, sat. aq. NaHCO3, brine), dried (Na2SO4) and evaporated to give an oil. Distillation at reduced pressure afforded the title compound (60.0 g, 88%) as a colourless oil, bp 70°-75° C./0.1 mm: IR (neat) 2180, 1253, 1112, 841 cm-1 ; 1H NMR (CDCl3, 200 MHz) δ3.72 (t, J=7.0 Hz, 2H), 2.43 (t, J=7.0 Hz, 2H), 0.90 (s, 9H), 0.14 (s, 9H), 0.07 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:12]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][S:18][C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)=[CH:11][C:5]2[CH2:6][O:7][C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1.[OH:26]O>>[Cl:1][C:2]1[C:12]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][S:18]([C:19]2[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=2)=[O:26])=[CH:11][C:5]2[CH2:6][O:7][C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1
Reactant: Cc1ccc(SCCCCOc2cc3c(cc2Cl)NC(=O)OC3)cc1
Reactant: OO
Product: Cc1ccc(S(=O)CCCCOc2cc3c(cc2Cl)NC(=O)OC3)cc1

Procedure:
Prepared analogously to Example 2 from 7-chloro-6-[4-(4-methyl-phenylmercapto)-butoxy]-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[Br:12][CH2:13][C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([F:22])[CH:21]=1)[C:17]#[N:18]>CN(C)C=O.C(OCC)(=O)C>[BrH:12].[Cl:11][C:8]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:2](=[NH:1])[N:10]([CH2:13][C:14]2[CH:21]=[C:20]([F:22])[CH:19]=[C:16]([C:17]#[N:18])[CH:15]=2)[CH:9]=1
Reactant: N#Cc1cc(F)cc(CBr)c1
Reactant: NC(=O)c1cc(Cl)cnc1N
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Br
Product: N#Cc1cc(F)cc(Cn2cc(Cl)cc(C(N)=O)c2=N)c1
Temperature: 100 °C
Reaction time: 14 h
Yield: 20.5 %

Procedure:
(Step 4) To a solution of 2-amino-5-chloronicotinamide (0.15 g) in N,N-dimethylformamide (3 ml) was added 3-(bromomethyl)-5-fluorobenzonitrile (0.29 g) obtained in Step 3, and the mixture was stirred at 100° C. for 14 hr. The reaction mixture was diluted with ethyl acetate. The precipitate was collected by filtration and washed with ethyl acetate. The obtained precipitate was recrystallized from methanol-ethyl acetate to give the title compound (69 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([CH:17]3[CH2:22][O:21][CH2:20][CH2:19][O:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].[OH:34][CH:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.CS(C)=O>CN(C=O)C>[O:18]1[CH2:19][CH2:20][O:21][CH2:22][CH:17]1[C:16]1[C:10]2[S:9][C:8]([NH:7][C:5]([C:4]3[CH:25]=[CH:26][N:27]=[C:2]([N:38]4[CH2:39][CH2:40][CH:35]([OH:34])[CH2:36][CH2:37]4)[CH:3]=3)=[O:6])=[N:12][C:11]=2[C:13]([O:23][CH3:24])=[CH:14][CH:15]=1
Reactant: OC1CCNCC1
Reactant: COc1ccc(C2COCCO2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)c3ccnc(N4CCC(O)CC4)c3)nc12

Procedure:
From (+)-2-bromo-N-(7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-yl)-isonicotinamide with cesium carbonate and 4-hydroxypiperidine in DMF. [α]D20=+16.1° (c=0.35, DMSO), ES-MS m/e (%): 471 (M+H+, 100).