Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH:3]1[C:9](=[O:10])[N:8]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]2[CH:17]=[CH:18][CH:19]=[CH:20][C:6]=2[S:5][CH2:4]1.[CH2:21]([CH2:28][C:29](=O)[C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+].[BH]C#N.[Na].Cl>C(O)C.CCOCC.C(O)(=O)C>[CH2:33]([O:32][C:30]([CH:29]([NH:2][CH:3]1[C:9](=[O:10])[N:8]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]2[CH:17]=[CH:18][CH:19]=[CH:20][C:6]=2[S:5][CH2:4]1)[CH2:28][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:31])[CH3:34]
Reactant: CCOC(=O)CN1C(=O)C(N)CSc2ccccc21
Reactant: CCOC(=O)C(=O)CCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [BH]C#N
Solvent: CCOCC
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)CN1C(=O)C(NC(CCc2ccccc2)C(=O)OCC)CSc2ccccc21
Reaction time: 2 h
Yield: 47.9 %

Procedure:
1.8 g of 3-amino-5-ethoxycarbonylmethyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrochloride was mixed with 2.5 g of ethyl benzylpyruvate and 30 ml of ethanol, and the resulting mixture was adjusted to pH 5-7 with a saturated aqueous solution of sodium carbonate. After the mixture was allowed to stand for 2 hours, a solution of 0.7 g of sodium boron cyanide hydride in 10 ml of ethanol was added dropwise thereto over a period of one hour. To this mixture were added 5 ml of acetic acid and then 2.5 g of ethyl benzylpyruvate. After 2 hours, 2.0 g of ethyl benzylpyruvate was added and the mixture was allowed to stand overnight. After the ethanol was distilled off, 5 ml of concentrated hydrochloric acid was added to the residue and the resulting mixture was stirred for an hour. After the addition of 80 ml of water, the mixture was extracted with ether. 5 ml of hydrogen chloride-ether was added to the ether extract and the separated oily material was isolated. Further, 10 ml of 6N hydrochloric acid was added to the ether layer, and the resulting mixture was stirred for a while and then allowed to stand. The lower layer was isolated and combined with the previously obtained oily material, followed by washing with ether. The aqueous layer was adjusted to pH 2-3 with a sodium hydroxide solution and then extracted with ether. After drying over anhydrous sodium sulfate, the product was concentrated to obtain 1.28 g of the desired compound in the form of an oily material.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[Na].[S:9]([CH2:13][CH2:14]O)([OH:12])(=[O:11])=[O:10]>>[OH:4][CH2:3][CH2:2][N:1]([CH:13]([S:9]([OH:12])(=[O:11])=[O:10])[CH3:14])[CH2:5][CH2:6][OH:7]
Reactant: O=S(=O)(O)CCO
Reactant: OCCNCCO
Agent: [Na]
Product: CC(N(CCO)CCO)S(=O)(=O)O
Temperature: 93.33333333333333 °C
Yield: 100 %

Procedure:
In a preferred embodiment, diethanol amine is charged to the reaction vessel in a substantially equal molar quantity to a 54 percent aqueous solution the sodium salt of isethionic acid. The reactants then are heated to a temperature of about 200° F. at ambient temperature for a sufficient period of time to separate about 38 percent by weight of the reactants as water in the cold finger trap. The bis-hydroxyethylaminoethane sulfonic acid which is produced in about a 100 percent yield is diluted to about a 50 percent solution by the addition of water.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH:5]([CH3:7])[CH3:6].Cl[C:17]1[CH:18]=[CH:19][C:20]2[C:30]3[C:25](=[C:26]([NH:31][C:32](=[O:34])[CH3:33])[N:27]=[CH:28][CH:29]=3)[CH:24]([CH3:35])[O:23][C:21]=2[CH:22]=1>>[C:32]([NH:31][C:26]1[N:27]=[CH:28][CH:29]=[C:30]2[C:20]3[CH:19]=[CH:18][C:17]([O:1][CH2:2][C@@H:3]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:13])([CH3:12])[CH3:14])[CH2:4][CH:5]([CH3:7])[CH3:6])=[CH:22][C:21]=3[O:23][CH:24]([CH3:35])[C:25]=12)(=[O:34])[CH3:33]
Reactant: CC(C)C[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: CC(=O)Nc1nccc2c1C(C)Oc1cc(Cl)ccc1-2
Product: CC(=O)Nc1nccc2c1C(C)Oc1cc(OC[C@H](CC(C)C)NC(=O)OC(C)(C)C)ccc1-2
Yield: 51 %

Procedure:
Prepared as described in Example 8, Part C using (S)-tert-butyl (1-hydroxy-4-methylpentan-2-yl)carbamate and N-(8-chloro-5-methyl-5H-chromeno[3,4-c]pyridin-4-yl)acetamide to afford tert-butyl ((2S)-1-((4-acetamido-5-methyl-5H-chromeno[3,4-c]pyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (0.6 g, 0.882 mmol, 51% yield) as a yellow solid. LCMS (ESI) m/e 470.2 [(M+H)+, calcd for C26H36N3O5 470.3]; LC/MS retention time (Method C): tR=1.89 min.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[Br:19][C:20]1[C:21]2[CH:22]=[C:23]3[CH:32]([CH2:33][C:34](O)=[O:35])[CH2:31][CH2:30][N:24]3[C:25]=2[CH:26]=[C:27]([F:29])[CH:28]=1.C(N1C=CN=C1)(N1C=CN=C1)=O>C1COCC1>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:34](=[O:35])[CH2:33][CH:32]1[C:23]2=[CH:22][C:21]3[C:20]([Br:19])=[CH:28][C:27]([F:29])=[CH:26][C:25]=3[N:24]2[CH2:30][CH2:31]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CC1CCn2c1cc1c(Br)cc(F)cc12
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(CC1CCn2c1cc1c(Br)cc(F)cc12)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution (S)-(−)-4-benzyl-2-oxazolidinone (7.8 g, 43.8 mmol) in THF (300 mL) at −78° C. was slowly added 1.6M n-butyllithium (27.3 mL, 43.8 mmol). The mixture was stirred for 30 minutes at −78° C. and a mixture of the compound of Step 1 (10.5 g, 33.7 mmol) and 1,1′-carbonyldiimidazole (6 g, 37 mmol) in THF (100 mL) was added. The mixture was stirred for 30 minutes at −78° C. and then warmed to −30° C. and stirred for 2 hours. The reaction was quenched with saturated NH4Cl, the phases were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography eluted with 10% EtOAc in Toluene, which permitted the separation of the two diastereomers. Both isomers were obtained as an yellow solid with diastereomeric excess >95%.
Reaction SMILES: [CH2:1]([O:3][C:4](/[CH:6]=[CH:7]/[CH2:8]P(=O)(OCC)OCC)=[O:5])[CH3:2].C([N-]C(C)C)(C)C.[Li+].[CH:25]([CH2:27][CH2:28][C:29]([N:32]1[CH:36]=[CH:35][N:34]=[CH:33]1)([CH3:31])[CH3:30])=O.C(O)(=O)C>O1CCCC1>[CH2:1]([O:3][C:4](/[CH:6]=[CH:7]/[CH:8]=[CH:25]/[CH2:27][CH2:28][C:29]([N:32]1[CH:36]=[CH:35][N:34]=[CH:33]1)([CH3:31])[CH3:30])=[O:5])[CH3:2]
Reactant: CCOC(=O)/C=C/CP(=O)(OCC)OCC
Reactant: CC(C)(CCC=O)n1ccnc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCOC(=O)/C=C/C=C/CCC(C)(C)n1ccnc1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 53.9 %

Procedure:
Under an atmosphere of nitrogen, 2.0 g of diethyl (E)-3-ethoxycarbonyl-2-propenylphosphonate was added dropwise to 25 ml of a 0.32 M solution of lithium diisopropylamide in tetrahydrofuran at -78° C. and the mixture was stirred at -70° C. for 30 minutes. To it was added a solution of 1.0 g of 1-(3-formyl-1,1-dimethylpropyl)imidazole (prepared as described hereafter) in 2 ml of tetrahydrofuran at -70° C., the mixture was stirred at room temperature for 30 minutes. To it was added 0.91 ml of acetic acid. After evaporation under reduced pressure, the residue was dissolved in chloroform, washed with a saturated aqueous solution of sodium bicarbonate, water, dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of chloroform and ethanol (99:1) as eluent to give 0.85 g of the title compound having the following physical characteristics:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]([NH2:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[H-].[Na+].[CH3:15][CH:16]([S:18](Cl)(=[O:20])=[O:19])[CH3:17]>O1CCCC1.C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([C:10]([NH:12][S:18]([CH:16]([CH3:17])[CH3:15])(=[O:20])=[O:19])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC(C)S(=O)(=O)Cl
Reactant: NC(=O)c1cccc([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)S(=O)(=O)NC(=O)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of 3-nitrophenylcarboxamide (2 g) in 150 ml of dry tetrahydrofuran was cooled to 0° C. and treated with 530 mg of sodium hydride (60% oil dispersion). The reaction mixture was stirred for 20 minutes and then 2-propylsulfonylchloride (1.5 ml) was introduced dropwise via syringe. After 5 minutes the reaction mixture became homogeneous and was warmed to room temperature and stirred for 2 hours. The reaction mixture was diluted with 300 ml of ethyl acetate and was washed with brine. The organic extracts were dried, concentrated in vacuo, and the residue was chromatographed on silica gel (chloroform-methanol, 95:5 v/v) to yield 0.6 g of the title compound in pure form.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1I.CN(C)C=O.C(N(CC)CC)C.[CH3:21][Si:22]([C:25]#[CH:26])([CH3:24])[CH3:23]>[Cu](I)I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd](Cl)Cl.O>[CH3:21][Si:22]([C:25]#[C:26][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)([CH3:24])[CH3:23]
Reactant: Brc1ccccc1I
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 105.9 %

Procedure:
A mixture of 150 g of 97% bromo iodo benzene, 500 ml of anhydrous dimethylformamide, 100 ml of triethylamine, 50 g of trimethylsilyl acetylene, 2.1 g of copper iodide and 2.22 g of bis-(triphenylphosphine-palladium (II) dichloride was stirred for 2 hours and then 500 ml of ice-cooled water were added. The mixture was extracted 3 times with 500 ml of ethyl acetate and the organic phase was washed with salt water, then dried over sodium sulfate, and evaporated under reduced pressure to obtain 136.542 g of a brown oil which was purified by distillation under reduced pressure to obtain 106.979 g of the expected product with a boiling point of 75°-82° C. under 0.2 mbar and a melting point of 62° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16].Br[CH2:19][CH2:20][O:21][CH3:22]>CN(C=O)C>[CH3:22][O:21][CH2:20][CH2:19][O:14][C:11]1[CH:12]=[CH:13][C:8]([NH2:7])=[C:9]([N+:15]([O-:17])=[O:16])[CH:10]=1
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOc1ccc(N)c([N+](=O)[O-])c1
Yield: 23.6 %

Procedure:
Powdered and dried Potassium carbonate (3.58 g, 0.025 mol) was added to a solution of 4-amino-3-nitrophenol (2 g, 0.012 mol) in DMF (20 mL) at 0° C. under nitrogen atmosphere. To this, 1-bromo-2-methoxyethane (1.34 mL, 0.014 mol) was added dropwise and the resultant reaction mixture was refluxed for overnight. Then, the reaction mixture was filtered through celite. The filterate was concentrated and diluted with ethyl acetate and water. The aqueous layer was separated and extracted with ethyl acetate (3×30 mL). The organic phase was washed with brine, dried on Na2SO4, filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography to obtain the title compound (0.6 g, yield: 24%) as a solid. MS (ESI): 213.15 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1OC2C(C=C)=CC=CC=2C=1C.[CH2:14]([O:16][C:17]([C:19]1[O:20][C:21]2[C:28](Br)=[CH:27][CH:26]=[CH:25][C:22]=2[C:23]=1[CH3:24])=[O:18])[CH3:15]>>[CH2:14]([O:16][C:17]([C:19]1[O:20][C:21]2[C:28]([CH:1]=[CH2:2])=[CH:27][CH:26]=[CH:25][C:22]=2[C:23]=1[CH3:24])=[O:18])[CH3:15]
Reactant: C=Cc1cccc2c(C)c(C)oc12
Reactant: CCOC(=O)c1oc2c(Br)cccc2c1C
Product: C=Cc1cccc2c(C)c(C(=O)OCC)oc12

Procedure:
This compound is obtained according to the process described in Example 6 for the preparation of 2,3-dimethyl-7-ethenylbenzofuran, by using 2-ethyloxycarbonyl-3-methyl-7-bromobenzofuran as starting material.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:12]=[C:11]([CH3:13])[NH:10][N:9]=1.[Cl:14][C:15]1[CH:16]=[C:17]([C:23]([F:26])([F:25])[F:24])[CH:18]=[C:19]([Cl:22])[C:20]=1F.Cl>CN(C=O)C>[Cl:14][C:15]1[CH:16]=[C:17]([C:23]([F:24])([F:25])[F:26])[CH:18]=[C:19]([Cl:22])[C:20]=1[O:7][C:8]1[CH:12]=[C:11]([CH3:13])[NH:10][N:9]=1
Reactant: Fc1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: Cc1cc(O)n[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)n[nH]1
Temperature: 60 °C
Yield: 53.6 %

Procedure:
Potassium carbonate (2.8 g, 20.0 mmol) was added to a solution of 3-hydroxy-5-methylpyrazole (1.47 g, 15.0 mmol) and 3,5-dichloro-4-fluorobenzotrifluoride (3.5 g, 15.0 mmol) in DMF (30 ml), and the mixture was stirred under heating at 60° C. for 6 hours. After completion of the reaction, the reaction mixture was poured into 2N hydrochloric acid (70 ml) and extracted with ethyl acetate (30 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/10→1/7), to give a white solid of 3-(2,6-dichloro-4-trifluoromethylphenyloxy)-5-methylpyrazole (2.5 g, yield: 54.0%). mp: 153-155° C.; 1H-NMR (CDCl3, TMS, ppm): δ 2.27 (s, 3H), 5.68 (s, 1H), 7.64 (s, 2H), 8.75-9.70 (br s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH2:12][C:13]1[N:17]2[N:18]=[C:19]([C:22]3[CH:23]=[N:24][N:25]([CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[CH:26]=3)[CH:20]=[CH:21][C:16]2=[N:15][CH:14]=1.[Si:33]([O:40][CH2:41][CH:42]=O)([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34].[BH3-]C#N.[Na+].CC(O)=O>CO.C(Cl)Cl>[C:36]([Si:33]([CH3:35])([CH3:34])[O:40][CH2:41][CH2:42][N:30]1[CH2:31][CH2:32][CH:27]([N:25]2[CH:26]=[C:22]([C:19]3[CH:20]=[CH:21][C:16]4[N:17]([C:13]([CH2:12][C:3]5[CH:4]=[C:5]6[C:10](=[CH:11][C:2]=5[F:1])[N:9]=[CH:8][CH:7]=[CH:6]6)=[CH:14][N:15]=4)[N:18]=3)[CH:23]=[N:24]2)[CH2:28][CH2:29]1)([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Reactant: Fc1cc2ncccc2cc1Cc1cnc2ccc(-c3cnn(C4CCNCC4)c3)nn12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)[Si](C)(C)OCCN1CCC(n2cc(-c3ccc4ncc(Cc5cc6cccnc6cc5F)n4n3)cn2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 7-fluoro-6-[6-(1-piperidin-4-yl-1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazin-3-ylmethyl]-quinoline (Example 180, 70 mg, 0.164 mmol), tert-butyldimethylsilyloxy-acetaldehyde (47 μL, 0.246 mmol) and NaBH3CN (52 mg, 0.246 mmol) in MeOH (2 mL) was stirred at rt for 2 h. The pH was then adjusted to 5-6 with AcOH and the RM was stirred at rt for 2 h more. The mixture was diluted with DCM and washed with NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated to afford the title compound as a foam (tR 4.27 min (conditions 3), MH+=586.1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][NH:13][C@@H:12]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(#N)C>[CH2:30]([N:13]1[CH2:14][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:10][CH2:11][C@@H:12]1[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)C[C@H]1CC[C@@H](NC(=O)OC(C)(C)C)CN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)C[C@H]1CC[C@@H](NC(=O)OC(C)(C)C)CN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 28 h
Yield: 82.5 %

Procedure:
To a stirred solution of ethyl {cis-5-[(tert-butoxycarbonyl)amino]piperidin-2-yl}acetate (2.25 g, 7.86 mmol, step 5 of Example 1), N,N-diisopropylethylamine (1.12 g, 8.64 mmol) in acetonitrile (45 mL) was added benzyl bromide (1.48 g, 8.64 mmol) at room temperature. After stirring at room temperature for 28 h, the mixture was concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate (250 mL). The organic solution was washed with water (100 mL×3), brine (50 mL), dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was chromatographed on a column of silica gel eluting with n-hexane/ethyl acetate (4:1) to give 2.44 g (82%) of the title compound as a colorless oil.
Reaction SMILES: [C:1]([C:9]1[CH:41]=[CH:40][C:12]2[N:13]([CH2:17][CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][CH:27]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:28]([O:30][CH3:31])=[O:29])=[CH:22][CH:21]=3)[C:14](=[O:16])[S:15][C:11]=2[CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:42][O:43][NH2:44]>>[C:36]([O:35][C:33]([NH:32][CH:27]([CH2:26][C:23]1[CH:22]=[CH:21][C:20]([O:19][CH2:18][CH2:17][N:13]2[C:12]3[CH:40]=[CH:41][C:9]([C:1](=[N:44][O:43][CH3:42])[C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:10][C:11]=3[S:15][C:14]2=[O:16])=[CH:25][CH:24]=1)[C:28]([O:30][CH3:31])=[O:29])=[O:34])([CH3:37])([CH3:38])[CH3:39]
Reactant: CON
Reactant: COC(=O)C(Cc1ccc(OCCn2c(=O)sc3cc(C(=O)c4ccccc4)ccc32)cc1)NC(=O)OC(C)(C)C
Product: CON=C(c1ccccc1)c1ccc2c(c1)sc(=O)n2CCOc1ccc(CC(NC(=O)OC(C)(C)C)C(=O)OC)cc1

Procedure:
Starting from the compound obtained in Step C, the procedure is as in Step B of Example 2, replacing the hydroxylamine by O-methylhydroxylamine.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH3:22])[C:9]([CH3:21])=[C:10]([C:11]3[CH:19]=[C:18]4[C:14]([CH2:15][CH2:16][N:17]4[CH3:20])=[CH:13][CH:12]=3)[C:3]=12.[CH3:23][N:24]1[CH:28]=[CH:27][C:26]([S:29]([NH2:32])(=[O:31])=[O:30])=[N:25]1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C1C=CC=CC=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:22][N:8]1[C:4]2=[N:5][CH:6]=[CH:7][C:2]([NH:32][S:29]([C:26]3[CH:27]=[CH:28][N:24]([CH3:23])[N:25]=3)(=[O:31])=[O:30])=[C:3]2[C:10]([C:11]2[CH:19]=[C:18]3[C:14]([CH2:15][CH2:16][N:17]3[CH3:20])=[CH:13][CH:12]=2)=[C:9]1[CH3:21]
Reactant: Cn1ccc(S(N)(=O)=O)n1
Reactant: Cc1c(-c2ccc3c(c2)N(C)CC3)c2c(Br)ccnc2n1C
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1c(-c2ccc3c(c2)N(C)CC3)c2c(NS(=O)(=O)c3ccn(C)n3)ccnc2n1C
Temperature: 150 °C
Yield: 24 %

Procedure:
To a solution of 4-bromo-1,2-dimethyl-3-(1-methylindolin-6-yl)-1H-pyrrolo[2,3-b]pyridine (D28) (85 mg, 0.239 mmol) in 1,4-dioxane (2 mL) was added 1-methyl-1H-pyrazole-3-sulfonamide (D94) (65.4 mg, 0.406 mmol), cesium carbonate (155 mg, 0.477 mmol), Pd2(dba)3 (16.39 mg, 0.018 mmol) and 2-(dimethylamino)-2′-(dicyclohexylphosphino)biphenyl (14.08 mg, 0.036 mmol). The reaction mixture was heated in the microwave at 150° C. for 30 mins. The reaction mixture was filtered through celite washing with ethyl acetate and the resulting solution evaporated to dryness. The residue was purified by column chromatography on silica gel, eluting with a gradient of 0-100% ethyl acetate in cyclohexane to afford a material which was further purified by MDAP (basic condition) to afford the title compound (25 mg). LCMS (A): m/z (M+H)+ 437, C22H24N6O2S requires 436 (acidic).
Reaction SMILES: CC1C=C(N2CCN(CC3C=CC(C(F)(F)F)=CC=3)C2=O)SC=1C(OCC)=O.[N:29]1[S:30][N:31]=[C:32]2[CH:37]=[C:36]([CH2:38][N:39]3[CH2:43][CH2:42][N:41]([C:44]4[S:45][C:46]([C:50]([O:52]CC)=[O:51])=[C:47]([CH3:49])[N:48]=4)[C:40]3=[O:55])[CH:35]=[CH:34][C:33]=12>>[N:29]1[S:30][N:31]=[C:32]2[CH:37]=[C:36]([CH2:38][N:39]3[CH2:43][CH2:42][N:41]([C:44]4[S:45][C:46]([C:50]([OH:52])=[O:51])=[C:47]([CH3:49])[N:48]=4)[C:40]3=[O:55])[CH:35]=[CH:34][C:33]=12
Reactant: CCOC(=O)c1sc(N2CCN(Cc3ccc4nsnc4c3)C2=O)nc1C
Agent: CCOC(=O)c1sc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)cc1C
Product: Cc1nc(N2CCN(Cc3ccc4nsnc4c3)C2=O)sc1C(=O)O
Yield: 85 %

Procedure:
Following the procedure as described in Example 14, making variations as required to replace ethyl 3-methyl-5-(2-oxo-3-(4-(trifluoromethyl)benzyl)imidazolidin-1-yl)thiophene-2-carboxylate with ethyl 2-(3-(benzo[c][1,2,5]thiadiazol-5-ylmethyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylate, the title compound was obtained as a colorless solid in 85% yield: MS (ES+) m/z 376.1 (M+1).
Reaction SMILES: [ClH:1].[NH2:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][N:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([F:21])[CH:19]=3)[C:14]([C:22]#[N:23])=[CH:13][C:12]2=[O:24])[CH2:5][CH2:4]1.[O:25]=[C:26]1[CH2:31][O:30][C:29]2[CH:32]=[CH:33][C:34]([CH:36]=O)=[N:35][C:28]=2[NH:27]1.C([O-])(=O)C.[Na+].C([BH3-])#N.Cl>ClCCl.O1CCOCC1.C(O)(=O)C.C(Cl)(Cl)Cl.CO>[ClH:1].[ClH:1].[F:21][C:18]1[CH:19]=[C:20]2[C:15]([C:14]([C:22]#[N:23])=[CH:13][C:12](=[O:24])[N:11]2[CH2:10][CH2:9][N:6]2[CH2:5][CH2:4][CH:3]([NH:2][CH2:36][C:34]3[CH:33]=[CH:32][C:29]4[O:30][CH2:31][C:26](=[O:25])[NH:27][C:28]=4[N:35]=3)[CH2:8][CH2:7]2)=[CH:16][CH:17]=1
Reactant: N#Cc1cc(=O)n(CCN2CCC(N)CC2)c2cc(F)ccc12
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Agent: CC(=O)[O-]
Agent: Cl
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: CO
Solvent: C1COCCO1
Product: N#Cc1cc(=O)n(CCN2CCC(NCc3ccc4c(n3)NC(=O)CO4)CC2)c2cc(F)ccc12
Reaction time: 1 h
Yield: 55 %

Procedure:
To a solution of 1-[2-(4-amino-1-piperidinyl)ethyl]-7-fluoro-2-oxo-1,2-dihydro-4-quinolinecarbonitrile hydrochloride (0.062 g, 0.16 mmol) and 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carboxaldehyde (for a synthesis see WO2003087098, Example 31(e))(0.028 g, 0.16 mmol) in 1:1 chloroform/methanol (6 ml) was added sodium acetate (00.10 g, 12 mmol), acetic acid (0.5 ml) and 3A sieves and the mixture stirred for 1 h. Polymer supported cyanoborohydride (0.10 g) was added and the mixture stirred for 18 h, then filtered and the solid washed with dichloromethane. The organics were washed with sodium carbonate solution, dried and concentrated. Chromatography over silica (10 g SPE gradient elution with dichloromethane/methanol 0-15%) provided the product which was dissolved in dichloromethane and treated with 4M HCl in 1,4-dioxane. The precipitate was isolated and washed with ether then dried to provide the title compound (0.048 g, 55%).
Reaction SMILES: S1C2C=CC=CC=2N(N(C)C(NC)=O)C1.C=O.[P:18](=[O:22])([OH:21])([OH:20])[OH:19].NC(N)=O.[OH-].[Ca+2:28].[OH-]>O>[P:18]([O-:22])([O-:21])([O-:20])=[O:19].[Ca+2:28].[P:18]([O-:22])([O-:21])([O-:20])=[O:19].[Ca+2:28].[Ca+2:28]
Reactant: O=P(O)(O)O
Agent: C=O
Agent: CNC(=O)N(C)N1CSc2ccccc21
Agent: NC(N)=O
Solvent: O
Product: O=P([O-])([O-])[O-]
Temperature: 45 °C

Procedure:
1000 g of a bacterial activated sludge (solids content approximately 8.5%) emanating from a fully biological purification plant for industrial and communal effluents and consisting of a variety of microorganisms with traces of the following plant protection agents (herbicides) as impurities: N-methyl isopropyl carbamate (0.5 g); 4-amino-6-t-butyl-3-methyl thio-4,5-dihydro-1,2,4-triazin-5-one (0.5 g) and N-(3-benzthiazolyl)-N,N'-dimethyl urea (0.5 g) are initially heated with intensive stirring to 80° C. with 100 g of 30% formalin (1 mol) and 25 g of 85% phosphoric acid in a ground glass flask. The cell walls of the bacteria are thus ruptured and the plant protection agents present are deactivated and hydrolyzed by reaction of the NH2 - or NH-functional groups thereof with formaldehyde through N-methylolation (N--CH2 --O--CH2 --N) or methylene linkage (N--CH2 --N). After this primary reaction, samples are taken and centrifuged. By titrating the formaldehyde in the filtrates, it is analytically determined that 0.05 mol of formaldehyde has been consumed. A solution of 60 g of urea (1 mol) in 100 g of water and 10 g of 30% formalin (0.1 mol) are then added to the reaction mixture. After condensation for 15 minutes at 70° C., the mixture is cooled over a period of 30 minutes to a temperature of 45° C. and a readily filterable, powder-form biomass mixed condensate is obtained. This biomass mixed condensate is neutralized using calcium hydroxide as a result of which substantially insoluble calcium phosphate precipitates in very finely divided form in the biomass condensate dispersion. The powder-form product is filtered off and washed with a 2% aqueous ammonia solution. The product is then dried under reduced pressure at 70° C., giving a substantially odorless powder in a yield of 176 g. The nitrogen content amounts to 13.4%.