Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[N:8]=[C:7]([NH:17][S:18](=[O:30])(=[O:29])[NH:19][C:20]2[CH:25]=[CH:24][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:22][CH:21]=2)[C:6]=1[O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[O:38][CH3:39].[H-].[Na+].[Br:42][C:43]1[CH:44]=[N:45][C:46](Cl)=[N:47][CH:48]=1.CN(C=O)C>C1COCC1>[Br:42][C:43]1[CH:44]=[N:45][C:46]([O:1][CH2:2][CH2:3][O:4][C:5]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)[N:8]=[C:7]([NH:17][S:18](=[O:30])(=[O:29])[NH:19][C:20]3[CH:21]=[CH:22][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:24][CH:25]=3)[C:6]=2[O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[O:38][CH3:39])=[N:47][CH:48]=1
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)Nc2ccc(C(C)C)cc2)nc(-c2ccncc2)nc1OCCO
Reactant: Clc1ncc(Br)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccccc1Oc1c(NS(=O)(=O)Nc2ccc(C(C)C)cc2)nc(-c2ccncc2)nc1OCCOc1ncc(Br)cn1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 71.9 %

Procedure:
4-i-Propyl-phenyl sulfamic acid-[6-(2-hydroxy-ethoxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-pyrimidin-4-yl]-amide (60 mg, Example 3) was dissoved in THF (8 ml). Sodium hydride (14 mg, 60% dispersion in mineral oil) was added and stirring continued for 10 min. 5-Bromo-2-chloro-pyrimidine (37 mg) was added and the mixture was heated to 60° C. for 120 min. DMF (0.5 ml) was added and the solution was stirred at r.t. for 48 h. The solvents were evaporated, water (12 ml) and a 10% solution of citric acid was added until the pH was 3. The precipitate was filtered off and washed with water and purified by chromatography through silica gel with EtOAc/Hex=1:1 to give 4-i-propyl-phenyl sulfamic acid-[6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-5-(o-methoxy-phenoxy)-2-(4-pyridyl)-pyrimidin-4-yl]-amide (55.4 mg). tR=5.30 min, (LC); [M+H]+=710.35 (ES+).
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.C(=O)=O.CC(C)=O.O[C:18]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1.ClC1C=C(C=CC=1)C(OO)=O>ClCCl>[F:7][C:18]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccccc2)CC1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C=O
Solvent: CC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(F)(c2ccccc2)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 102.1 %

Procedure:
A solution of diethylaminosulfur trifluoride (4 mL, 32.7 mmol) in dichloromethane (10 mL) was added to a cold (−78° C.; dry ice/acetone bath) solution of tert-butyl 4-hydroxy-4-phenylpiperidine-1-carboxylate (8.05 g, 29.0 mmol) in dichloromethane (100 mL) under nitrogen. The reaction was stirred at −78° C. for ˜1 hour. The reaction was removed from the bath and warmed to ambient temperature then stirred another 30 minutes. The reaction was quenched with saturated aqueous NaHCO3 (100 mL). The organic fraction was washed with brine (˜50 mL). Then 3-chloroperoxybenzoic acid (1.0995 g, 6.37 mmol) was added to the reaction and stirred at ambient temperature for 30 minutes. This step was quenched with saturated aqueous NaHCO3 (100 mL). The organic fraction was washed with saturated aqueous NaHCO3 (1×100 mL), water (1×100 mL), and brine (1×100 mL), dried (MgSO4), tested for peroxide (3-10 ppm) and concentrated to light yellow oil. The oil was dried under vacuum to afford 8.27 g (100%) of the titled compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.42 (d, J=5.7, 9H), 1.96-1.85 (m, 3.5H), 2.03 (ddd, J=5.2, 13.3, 17.8, 1.5H), 3.06 (s, 2H), 3.98 (d, J=12.0, 2H), 7.33 (d, J=7.1, 1H), 7.46-7.36 (m, 4H); MS (DCI) m/z 280 (M+H+, 60%), 297 (M+NH4+, 100%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:11][C:10](OS(C3C=CC=CC=3)(=O)=O)=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[BrH:28].C(=O)([O-])O.[Na+]>C(O)(=O)C>[Br:28][C:10]1[CH2:11][CH:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:8]([C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[N:9]=1
Reactant: CCOC(=O)C1CC(OS(=O)(=O)c2ccccc2)=NN1c1ncccc1Cl
Reactant: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)C1CC(Br)=NN1c1ncccc1Cl
Yield: 85 %

Procedure:
A solution of ethyl 1-(3-chloro-2-pyridinyl)-4,5-dihydro-3-[(phenylsulfonyl)oxy]-1H-pyrazole-5-carboxylate (i.e. the product of Step A)(1.0 g, 2.44 mmol) in acetic acid (4 mL) was added to a solution of hydrogen bromide in acetic acid (33%, 1.2 g, 4.89 mmol). After about 1 h the reaction mixture was added to saturated aqueous sodium hydrogen carbonate solution (100 mL). The mixture was then extracted with ethyl acetate (2×50 mL), and the combined extracts were dried (MgSO4) and evaporated to provide the title product as an oil (0.69 g, 85% yield), which slowly crystallized. The 1H NMR spectrum was the same as reported for the product of Example 1, Step C.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]([CH3:10])([CH3:9])[C:4](=O)[CH2:5][C:6]#[N:7].[NH2:13][NH2:14].Cl.C(Cl)Cl>CCO.O>[F:1][C:2]([F:11])([F:12])[C:3]([C:4]1[CH:5]=[C:6]([NH2:7])[NH:14][N:13]=1)([CH3:10])[CH3:9]
Reactant: CC(C)(C(=O)CC#N)C(F)(F)F
Reactant: NN
Agent: Cl
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: CC(C)(c1cc(N)[nH]n1)C(F)(F)F
Temperature: 100 °C
Reaction time: 18 h
Yield: 22 %

Procedure:
To a mixture of 5,5,5-trifluoro-4,4-dimethyl-3-oxopentanenitrile (2 g, 11.16 mmol) in EtOH (10 mL) was added hydrazine (1.263 g, 33.5 mmol) and concentrated HCl (0.5 mL). Then the mixture was stirred at 100° C. for 18 h. Then the mixture was concentrated to give the residue which was distributed between DCM (20 mL) and H2O (10 mL), and extracted with DCM (20 mL×2). The combined organic extracts were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated. The crude product was purified by silica column chromatography (100% EA, 12 g silica column). All fractions found to contain product by TLC (EA, Rf=0.3) were combined and concentrated to yield an off-white oil of 3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-pyrazol-5-amine (500 mg, 2.459 mmol, 22.03% yield): 1H NMR (400 MHz, CD3OD) δ 5.58 (s, 1H), 1.47 (s, 6H). ES-LCMS m/z 194 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH:10](Br)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:16]([NH2:22])([NH2:21])=[N:17][C:18]([NH2:20])=[S:19]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[N:20]=[C:18]([NH:17][C:16]([NH2:22])=[NH:21])[S:19][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NC(=S)N=C(N)N
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(Br)C1
Product: CC(C)(C)OC(=O)N1CCc2nc(NC(=N)N)sc2C1

Procedure:
Analogously to the preparation of Example C-01, 3-bromo-4-oxo-piperidine-1-carboxylic acid tert-butyl ester is reacted with 2-imino-4-thiobiuret to form the title compound. tR 2.55 min (LC-1); ESI-MS (+): m/z 298.25 [M+H]+.
Reaction SMILES: [OH-].[Na+].[C:3]([C:8]1[O:9][C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[C:14]([O:19][CH2:20][CH:21]([OH:31])[CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)[CH:13]=[CH:12][CH:11]=2)([O:5]CC)=[O:4]>C(O)C>[C:3]([C:8]1[O:9][C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[C:14]([O:19][CH2:20][CH:21]([OH:31])[CH2:22][O:23][C:24]1[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=1)[CH:13]=[CH:12][CH:11]=2)([OH:5])=[O:4]
Reactant: CCOC(=O)c1cc(=O)c2c(OCC(O)COc3ccc(Cl)cc3)cccc2o1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cc(=O)c2c(OCC(O)COc3ccc(Cl)cc3)cccc2o1
Yield: 102.4 %

Procedure:
A solution of sodium hydroxide (0.6 g) in ethanol was added to 1-(2-carbethoxychromon-5-yloxy)-2-hydroxy-3-p-chlorophenoxypropane (6.28 g) and the mixture was heated under reflux for 1 hour. The resulting sodium salt was filtered, dissolved in the minimum volume of hot water and poured into a solution of acetic acid (100 ml, 2N). The solution was cooled, the precipitated acid was filtered, washed with cold water and dried. Recrystallization from dilute acetic acid gave 1-(2-carboxychromon-5-yloxy)-2-hydroxy-3-p-chlorophenoxypropane (6.0 g) as white needles, m.p. 193°-195° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[CH:4]=[N:3]1.[CH3:10][NH:11][CH2:12][CH3:13]>>[CH2:12]([N:11]([CH3:10])[C:7]([C:5]1[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=1)=[O:9])[CH3:13]
Reactant: CCNC
Reactant: Cn1cc(C(=O)O)cn1
Product: CCN(C)C(=O)c1cnn(C)c1

Procedure:
This compound was prepared in the same manner as described in example 97, step a from 1-methyl-1H-pyrazole-4-carboxylic acid (1.0 g, 7.93 mmol) and N-methylethanamine (715 μl, 8.33 mmol). Yield: 995 mg (75%); off-white solid; MS: m/z=168.1 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:12])=[N:4][C:5]([NH2:11])=[C:6]([N+:8]([O-])=O)[CH:7]=1.Cl>C(O)C.O.[Fe]>[Br:1][C:2]1[C:3]([CH3:12])=[N:4][C:5]([NH2:11])=[C:6]([NH2:8])[CH:7]=1
Reactant: Cc1nc(N)c([N+](=O)[O-])cc1Br
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1nc(N)c(N)cc1Br
Reaction time: 1 h
Yield: 98.4 %

Procedure:
7.7 g (33.2 mmole) of the compound obtained in step 2 was dissolved in a mixture of 27 ml of ethanol and 7 ml of water and to the resulting solution were added 20 g (0.36 mole) of iron powder and 0.33 ml of conc. hydrochloric acid. The resultant was refluxed with stirring for 1 hour, filtered through Cellite to remove the remaining iron powder and washed with ethanol (50 ml×3). The filtrate was concentrated under reduced pressure and the residue was dissolved in ethyl acetate. The resultant was passed through silica gel and concentrated under reduced pressure to obtain 6.6 g of the title compound (yield 98%).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[C:15]3[C:10](=[N:11][CH:12]=[C:13]([C:16]4[CH:21]=[CH:20][C:19]([N:22]5[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]5)=[CH:18][CH:17]=4)[CH:14]=3)[N:9]([S:35]([C:38]3[CH:44]=[CH:43][C:41]([CH3:42])=[CH:40][CH:39]=3)(=[O:37])=[O:36])[CH:8]=2)=[C:5]([CH3:45])[N:4]([CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[C:49]([N+:53]([O-])=O)[CH:48]=2)[N:3]=1>[Pd].C(O)C>[NH2:53][C:49]1[CH:48]=[C:47]([CH:52]=[CH:51][CH:50]=1)[CH2:46][N:4]1[C:5]([CH3:45])=[C:6]([C:7]2[C:15]3[C:10](=[N:11][CH:12]=[C:13]([C:16]4[CH:17]=[CH:18][C:19]([N:22]5[CH2:23][CH2:24][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:32])[CH3:33])=[O:29])[CH2:26][CH2:27]5)=[CH:20][CH:21]=4)[CH:14]=3)[N:9]([S:35]([C:38]3[CH:44]=[CH:43][C:41]([CH3:42])=[CH:40][CH:39]=3)(=[O:36])=[O:37])[CH:8]=2)[C:2]([CH3:1])=[N:3]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc([N+](=O)[O-])c4)c3C)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4)cnc32)cc1
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(N)c4)c3C)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4)cnc32)cc1
Yield: 78.2 %

Procedure:
Using similar reaction conditions as described in example-8, tert-butyl 4-(4-(3-(3,5-dimethyl-1-(3-nitrobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazine-1-carboxylate (200 mg, 0.262 mmol) was reduced by 10% palladium on carbon (20 mg, 10% W/W), ethanol (3 mL) to yield 150 mg (yield 78.08%) of the titled compound. MS: m/z=7 32.3 (M+1).
Reaction SMILES: [Sn](Cl)Cl.Cl.[Cl:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-])=O)[CH:13]=2)[NH:8][N:7]=1>C(O)C>[Cl:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([NH2:15])[CH:13]=2)[NH:8][N:7]=1
Reactant: O=[N+]([O-])c1ccc2[nH]nc(Cl)c2c1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Product: Nc1ccc2[nH]nc(Cl)c2c1
Temperature: 60 °C
Yield: 9.4 %

Procedure:
A solution of tin dichloride (1.93 g, 10.2 mmol) in HCl solution (0.85 ml, 6 M, 5.08 mmol) was added to a suspension of the product from Step (a) (0.5 g, 2.54 mmol) in 1.5 ml ethanol. The reaction mixture was heated at 60° C. for 30 minutes and then cooled to room temperature. The solvent was evaporated to dryness and purified by silica gel chromatography eluting with 30% EtOAc in CH2Cl2 to afford the title compound, (0.04 g, 10%); MS (ES+) m/e 168 [M+H]+.
Reaction SMILES: [CH:1]1([O:4][N:5]=[C:6]([C:12](=[O:14])[CH3:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.[BrH:15].[NH+]1C=CC=CC=1>C(O)(=O)C>[Br:15][CH2:13][C:12](=[O:14])[C:6](=[N:5][O:4][CH:1]1[CH2:3][CH2:2]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)C(=NOC1CC1)C(C)=O
Reactant: Br
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Product: CCOC(=O)C(=NOC1CC1)C(=O)CBr
Temperature: 0 °C

Procedure:
A solution of ethyl 2-cyclopropyloxyimino-3-oxobutyrate (syn isomer)(358 mg) and pyridinium hydrobromide perbromide (633 mg) in acetic acid (2 ml) was heated at 50° C. for 30 minutes. The mixture was poured into ice-water and extracted with ethyl acetate. The extract was washed successively with saturated aqueous solution of sodium bicarbonate and water, dried over magnesium sulfate and concentrated in vacuo to give ethyl 4-bromo-2-cyclopropyloxyimino-3-oxobutyrate (syn isomer)(470 mg). To a solution of the compound obtained above in N,N-dimethylacetamide (2.2 ml) was added thiourea (126 mg) at ambient temperature. The mixture was stirred at the same temperature for an hour. The mixture was pouredd into ice-water and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was subjected to column chromatography on silica gel using a mixture of chloroform and ethyl acetate (4:1 V/V) as an eluent to give ethyl 2-(2-aminothiazol-4-yl)-2-(cyclopropyloxyimino)acetate (syn isomer)(l77 mg) as a crystal.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=3)[NH2:23])[CH2:14][CH2:13]2)[N:3]=1.[F:27][C:28]1[C:36]2[C:35](=[O:37])[O:34][C:33](=O)[C:32]=2[CH:31]=[CH:30][CH:29]=1>>[F:27][C:28]1[CH:29]=[CH:30][CH:31]=[C:32]2[C:36]=1[C:35](=[O:37])[N:23]([C:22]1[CH:24]=[CH:25][CH:26]=[C:20]([CH2:19][CH2:18][N:15]3[CH2:14][CH2:13][N:12]([C:8]4[CH:7]=[CH:6][CH:5]=[C:4]5[C:9]=4[CH:10]=[CH:11][C:2]([CH3:1])=[N:3]5)[CH2:17][CH2:16]3)[CH:21]=1)[C:33]2=[O:34]
Reactant: O=C1OC(=O)c2c(F)cccc21
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cccc2n1
Product: Cc1ccc2c(N3CCN(CCc4cccc(N5C(=O)c6cccc(F)c6C5=O)c4)CC3)cccc2n1

Procedure:
Prepared from 3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and 4-fluoro-2-benzofuran-1,3-dione according to Method I.
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.[S:19]1[CH2:23][CH2:22][N:21]=[C:20]1[SH:24].P([O-])([O-])([O-])=O.C([O-])(O)=O.[Na+].C.Cl>CC(C)=O>[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH2:5][S:24][C:20]3[S:19][CH2:23][CH2:22][N:21]=3)[CH2:15][S:14][C@H:9]12
Reactant: SC1=NCCS1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: Cl
Agent: O=C([O-])O
Agent: O=P([O-])([O-])[O-]
Solvent: CC(C)=O
Product: NC1C(=O)N2C(C(=O)O)=C(CSC3=NCCS3)CS[C@H]12

Procedure:
7-ACA (13.65 g) and 2-thiazoline-2-thiol (11.92 g) are suspended in 500 ml. of phosphate buffer 0.2 M (Na2HPO4 /NaH2PO4) pH 6.5. To the suspension are added with stirring 12.6 g. of NaHCO3 and 250 ml. of acetone. The reaction medium is heated for 21/4 hrs with stirring on a 80° C water bath. The solution is then treated with charcoal, cooled (5°-10° C) and acidified to pH 4 with 2 N hydrochloric acid. The obtained suspension is diluted with acetone and stirred for 15-20 minutes. The precipitate is filtered, washed with water, acetone and ethyl ether and dried under reduced pressure to yield 7-amino-3-(2-thiazolin-2-ylthiomethyl)-3-cephem-4-carboxylic acid.
Reaction SMILES: [CH:1]1([NH:7][C:8]([NH:10][C:11]2[N:12]=[C:13]3[C:19]([CH3:20])=[CH:18][N:17](COCC[Si](C)(C)C)[C:14]3=[N:15][CH:16]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N)CN>Cl.CC(O)=O.CO.O.CCN(CC)CC>[CH:1]1([NH:7][C:8]([NH:10][C:11]2[N:12]=[C:13]3[C:19]([CH3:20])=[CH:18][NH:17][C:14]3=[N:15][CH:16]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1cn(COCC[Si](C)(C)C)c2ncc(NC(=O)NC3CCCCC3)nc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: NCCN
Product: Cc1c[nH]c2ncc(NC(=O)NC3CCCCC3)nc12
Temperature: 50 °C
Reaction time: 8 h
Yield: 27.2 %

Procedure:
1-Cyclohexyl-3-[7-methyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea (38 mg, 0.094 mmol) was dissolved in a solution of HCl in AcOH (1M, 1.9 mL), and heated at 50° C. in the sealed tube overnight. The reaction mixture was concentrated to dryness, dissolved in 1 mL of MeOH:H2O:Et3N 8:1:1 and ethylenediamine (63 ul, 0.94 mmol) was added. The reaction mixture was stirred overnight, concentrated and purified by SiO2 chromatography (8 g SiO2, DCM/MeOH 0-5% MeOH) to give 7 mg of 1-cyclohexyl-3-(7-methyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)-urea as a white solid (27% yield).
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][N:15]1C(=O)C2=CC=CC=C2C1=O)=[N+:2]=[N-:3].O.NN>CO>[NH2:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][N:1]=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCCOCCOCCOCCN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CO
Product: [N-]=[N+]=NCCOCCOCCOCCN
Temperature: 25 °C
Yield: 50.5 %

Procedure:
1-Azido-11-phtalimido-3,6,9-trioxaundecane (8, Example 3, 2.0 g, 5.74 mmol), is treated with 1.0 ml 55% hydrazine hydrate in 50 ml abs. methanol and heated to reflux for 2 h. After cooling to room temperature, the mixture is concentrated in vacuo, diluted with 50 ml of water and treated with 5 ml conc. HCl. All precipitate is filtered off, the aqueous filtrate neutralized with NaOH, and the solvent removed in vacuo. The residue is dissolved in dichloromethane, and washed with 3 N NaOH and water. The organic phase is dried over MgSO4 and concentrated in vacuo yielding 0.63 g (2.9 mmol, 51%) of a colourless oil, which is used in the next step without further purification.
Reaction SMILES: C(OC([N:6]=[S:7]([CH3:36])([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][O:16][C:17]2[CH:26]=[C:25]3[C:20]([C:21]([NH:27][C:28]4[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=4)=[N:22][CH:23]=[N:24]3)=[CH:19][C:18]=2[O:34][CH3:35])=[CH:11][CH:10]=1)=[O:8])=O)C.ClCCl.CO>CO>[CH3:35][O:34][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][C:17]=1[O:16][CH2:15][C:12]1[CH:11]=[CH:10][C:9]([S:7]([CH3:36])(=[NH:6])=[O:8])=[CH:14][CH:13]=1)[N:24]=[CH:23][N:22]=[C:21]2[NH:27][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1
Reactant: CCOC(=O)N=S(C)(=O)c1ccc(COc2cc3ncnc(Nc4cccnc4)c3cc2OC)cc1
Solvent: CO
Solvent: ClCCl
Product: COc1cc2c(Nc3cccnc3)ncnc2cc1OCc1ccc(S(C)(=N)=O)cc1
Yield: 61 %

Procedure:
According to GWP 6, the conversion of (RS)-N-(ethoxycarbonyl)-S-methyl-S-[4-({[6-methoxy-4-(3-pyridylamino)quinazolin-7-yl]oxy}methyl)phenyl]sulphoximide (33 mg, 0.064 mmol) and chromatographic purification (silica gel, dichloromethane/methanol: 0→30% methanol) gives the desired product in 61% yield (17 mg).
Reaction SMILES: C([Li])CCC.CCCCCC.[CH3:12][S:13]([C:16]1[N:17]=[CH:18][N:19]2[CH:23]=[CH:22][S:21][C:20]=12)(=[O:15])=[O:14].[CH2:24]([Sn:28](Cl)([CH2:33][CH2:34][CH2:35][CH3:36])[CH2:29][CH2:30][CH2:31][CH3:32])[CH2:25][CH2:26][CH3:27].[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[CH3:12][S:13]([C:16]1[N:17]=[CH:18][N:19]2[C:23]([Sn:28]([CH2:29][CH2:30][CH2:31][CH3:32])([CH2:33][CH2:34][CH2:35][CH3:36])[CH2:24][CH2:25][CH2:26][CH3:27])=[CH:22][S:21][C:20]=12)(=[O:14])=[O:15]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: CS(=O)(=O)c1ncn2ccsc12
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCC[Sn](CCCC)(CCCC)c1csc2c(S(C)(=O)=O)ncn12
Reaction time: 0.5 h

Procedure:
A 1.6 N n-butyllithium/n-hexane solution (0.7 ml) was added to a solution of 202 mg of 7-methanesulfonylimidazo[5,1-b]thiazole in 20 ml of dry THF in an argon atmosphere at −70° C. The mixture was stirred at the same temperature for 30 min. Tri-n-butylstannyl chloride (0.3 ml) was added thereto. A saturated aqueous ammonium chloride solution was added to the reaction mixture. Ethyl acetate was then added thereto. The mixture was washed with water and saturated brine in that order. The organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by distillation. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=2:1) to give 110 mg of the title compound.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1.[CH2:9](C([Sn])=C(CCCC)CCCC)[CH2:10]CC>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:9]([C:2]1[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1)=[CH2:10]
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Reactant: O=Cc1ccc(Br)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1ccc(C=O)s1
Yield: 86.2 %

Procedure:
A solution of 5-bromo-thiophene-2-carbaldehyde (1 g, 5.23 mmol) in anhydrous toluene (20 mL), at room temperature and under an atmosphere of nitrogen, was treated with tetrakis(triphenylphosphine)palladium(0) (121 mg, 0.1 mmol) and tributylvinyltin (2.3 mL, 7.85 mmol). The reaction was heated to reflux for 1 hour, after which it was cooled and the volatiles removed in vacuo. The product was purified by silica gel chromatography using iso-hexanes/ethyl acetate 10:1 to afford the title compound (623 mg, 85%) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 5.42 (d, J=10.9 Hz, 1H), 5.84 (d, J=17.4 Hz, 1H), 6.84 (dd, J=17.4, 10.9 Hz, 1H), 7.09 (d, J=4.0 Hz, 1H), 7.66 (d, J=3.8 Hz, 1H), 9.88 (s, 1H).
Reaction SMILES: [OH:1][C@H:2]([CH2:13][NH:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][C:22]2=[O:27])=[CH:17][CH:16]=1)[CH2:3][NH:4][C:5]([C:7]1[S:8][C:9]([Cl:12])=[CH:10][CH:11]=1)=[O:6].[C:28]([Cl:31])([Cl:30])=[O:29]>>[C:28]([Cl:31])([Cl:30])=[O:29].[Cl:12][C:9]1[S:8][C:7]([C:5]([NH:4][CH2:3][C@@H:2]2[O:1][C:28](=[O:29])[N:14]([C:15]3[CH:16]=[CH:17][C:18]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][C:22]4=[O:27])=[CH:19][CH:20]=3)[CH2:13]2)=[O:6])=[CH:11][CH:10]=1
Reactant: O=C(NC[C@H](O)CNc1ccc(N2CCOCC2=O)cc1)c1ccc(Cl)s1
Agent: O=C(Cl)Cl
Product: O=C(NC[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1)c1ccc(Cl)s1

Procedure:
In this case, 5-chlorothiophene-2-carbonyl chloride (IV) is reacted with (28)-3-aminopropane-1,2-diol hydrochloride (VII) to give 5-chlorothiophene-2-carboxylic acid ((S)-2,3-dihydroxypropyl)-amide (IX). Subsequently, (IX) is converted into 5-chlorothiophene-2-carboxylic acid ((S)-3-bromo-2-hydroxypropyl)amide (X), which is then reacted with 4-(4-aminophenyl)-3-morpholinone (III) to give 5-chlorothiophene-2-carboxylic acid {(R)-2-hydroxy-3-[4-(3-oxomorpholin-4-yl)phenylamino]-propyl}amide (XI). Finally, (XI) is reacted with phosgene or a phosgene equivalent to give 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide (I).