Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17](I)=[C:11]2[N:12]=[CH:13][NH:14][C:15](=[O:16])[N:10]2[N:9]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>C(O)C.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>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]([C:23]2[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=2)=[C:11]2[N:12]=[CH:13][NH:14][C:15](=[O:16])[N:10]2[N:9]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: O=c1[nH]cnc2c(I)c(-c3ccccc3Cl)nn12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Product: O=c1[nH]cnc2c(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nn12
Temperature: 68 °C
Yield: 144.2 %

Procedure:
A mixture of 7-(2-chlorophenyl)-8-iodo-3H-pyrazolo[1,5-a][1,3,5]-triazin-4-one (I-3A-9d; 500 mg, 1.34 mmol), 4-chlorophenylboronic acid (315 mg, 2.01 mmol), and tetrakis(triphenylphosphine)palladium (50 mg, 0.043 mmol) under an argon atmosphere in ethanol (12 ml) and 2M aqueous Na2CO3 (2.5 ml) was degassed (3×) by pulling a vacuum followed by refilling with argon gas. The mixture was heated at 68° C. for 7 hours and then cooled to room temperature. The mixture was extracted from water with ethyl acetate, the combined organic layers were washed with brine, dried (MgSO4), and concentrated, in vacuo, to afford a dark, viscous oil (690 mg). The product was crystallized from methanol and then collected by vacuum filtration to afford, after rinsing with methanol, intermediate I-3A-9e (218 mg, 45%) as a solid: +APcI MS (M+1) 357.0; 1H NMR (400 MHz, CD3OD) δ 8.02 (s, 1H), 7.54-7.41 (m, 4H), 7.34 (d, J=8.7 Hz, 2H), 7.23 (d, J=8.7 Hz, 2H).
Reaction SMILES: [C:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[O:14])[O:6][C:5]=1[NH:15][C@H:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:17][CH3:18])(=O)[CH3:2].[C:25]1([NH:31][NH2:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(#N)C>[C:19]1([C@@H:16]([NH:15][C:5]([C:4]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:14])[N:32]([NH:31][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:1]=2[CH3:2])=[O:6])[CH2:17][CH3:18])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC[C@H](Nc1oc(=O)c2ccccc2c1C(C)=O)c1ccccc1
Reactant: NNc1ccccc1
Solvent: CC#N
Product: CC[C@H](NC(=O)c1c(C)n(Nc2ccccc2)c(=O)c2ccccc12)c1ccccc1
Temperature: 160 °C
Yield: 66.4 %

Procedure:
A mixture of 4-acetyl-3-((S)-1-phenyl-propylamino)-isochromen-1-one (60 mg) and phenylhydrazine (28 mg, 0.259 mmol) in acetonitrile (0.5 mL) was heated under microwave irradiation at 160° C. for 15 min and evaporated. The title compound was separated by flash chromatography on SiO2 (20 g, gradient heptane-ethyl acetate, the product came out with 50% ethyl acetate) to give 51 mg of a white solid, yield 66%. LC-MS (m/z) 412.2 (MH+); tR=1.48. 1H NMR (250 MHz, 70° C., DMSO-d6): 0.97 (t, J=7.3 Hz, 3H, Me of Et), 1.75-1.94 (m, 3H, CH2 of Et), 2.25 (s, 3H, Me), 4.98 (q (unresolved dt), J(d)=7 Hz, J(0=8.1 Hz, 1H, CH—NH), 6.68 (d, J=7.9 Hz, 2H, PhN), 6.83 (t, J=7.3 Hz, 1H, PhN), 7.14-7.51 (m, 9H), 7.69 (unres dt, J(t)=7.7 Hz, J(d)=1 Hz, 1H), 8.75 (s, 1H, NHPh), 8.8 (br. d, J=8.3 Hz, NHCO).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[C:12]3=[N:13][C:14]([NH:17][CH:18]4[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20][CH2:19]4)=[CH:15][CH:16]=[C:11]3[N:10]=[CH:9]2)[CH:5]=[CH:4][N:3]=1.[O:25]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26]1.C([O-])([O-])=O.[Na+].[Na+].N#N>CCO.O>[O:25]1[CH:29]=[CH:28][C:27]([C:2]2[CH:7]=[C:6]([N:8]3[C:12]4=[N:13][C:14]([NH:17][CH:18]5[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20][CH2:19]5)=[CH:15][CH:16]=[C:11]4[N:10]=[CH:9]3)[CH:5]=[CH:4][N:3]=2)=[CH:26]1
Reactant: OC1CCC(Nc2ccc3ncn(-c4ccnc(Cl)c4)c3n2)CC1
Reactant: OB(O)c1ccoc1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: OC1CCC(Nc2ccc3ncn(-c4ccnc(-c5ccoc5)c4)c3n2)CC1

Procedure:
To 4-[3-(2-Chloro-pyridin-4-yl)-3H-imidazo[4,5-b]pyridine-5-ylamino]-cyclohexanol (1 eq, 100 mg, 0.29 mmol), 3-furyl boronic acid (1.05 eq, 0.3 mmol, 34 mg), Na2CO3 (2 eq, 0.58 mmol, 62 mg) in EtOH (2 ml) and H2O (0.7 ml) under inert atmosphere of N2 is added tetakis(triphenylphosphine) palladium (0.1 eq, 0.029 mmol, 21 mg). The reaction is heated in using microwave radiation at 80° C. for 2 hours. The mixture is diluted with H2O (5 ml) and extracted with EtOAc. The combined organic portions are washed with brine, dried (MgSO4) and concentrated in vacuo. The residue is purified by flash chromatography on silica eluting with 0-2.5% MeOH in EtOAc to afford the title compound; [M+H]+ 375.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]([O:38]CC3C=CC=CC=3)=[C:17]([CH:37]=2)[C:18]([NH:20][C:21]2[CH:30]=[C:29]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:28]=[CH:27][C:22]=2[C:23]([O:25][CH3:26])=[O:24])=[O:19])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(Cl)(Cl)Cl>C(OCC)(=O)C.CO.[C].[Pd]>[C:1]([N:4]1[CH2:5][CH2:6][N:7]([CH2:10][CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]([OH:38])=[C:17]([CH:37]=2)[C:18]([NH:20][C:21]2[CH:30]=[C:29]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:28]=[CH:27][C:22]=2[C:23]([O:25][CH3:26])=[O:24])=[O:19])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(OCCN2CCN(C(C)=O)CC2)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(OCCN2CCN(C(C)=O)CC2)ccc1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution mixture of the obtained methyl 2-(5-(2-(4-acetylpiperazin-1-yl)ethoxy)-2-(benzyloxy)benzamido)-4-phenylbenzoate in ethyl acetate (1.5 mL) and methanol (1.5 mL), 10% palladium-carbon (0.15 g) was added, followed by stirring under a hydrogen atmosphere at room temperature for 1 hour and 30 minutes. Chloroform and methanol were added to the reaction mixture. The insoluble substance was removed by filtration, and the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the obtained residue, and the solid substance was collected by filtration to obtain 0.083 g of methyl 2-(5-(2-(4-acetylpiperazin-1-yl)ethoxy)-2-hydroxybenzamido)-4-phenylbenzoate as a light yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]2[NH:14][N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:12](=O)[CH2:11]2)=[CH:5][CH:4]=1.P(Cl)(Cl)([Cl:24])=O>O>[Cl:24][C:11]1[C:10]([NH:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[N:14][N:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:12]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(NC2CC(=O)N(c3ccccc3)N2)cc1
Solvent: O
Product: COc1ccc(Nc2nn(-c3ccccc3)cc2Cl)cc1

Procedure:
A mixture of 5-(4-methoxyphenylamino)-2-phenylpyrazolidin-3-one (2.81 g) and excess phosphorous oxychloride (4 ml) was heated on a steam bath at 100° for 1 hour. Water was added and the aqueous phase extracted with dichloromethane. The organic phase was dried over magnesium sulphate, filtered and evaporated to dryness, and the title compound was obtained as a colourless solid (1.5 g), mp 119°-121° by recrystallisation from cyclohexane.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]2[N:9]([CH:18]([C:20]3[O:21][C:22](=[O:36])[C:23]4[C:28]([C:29]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH3:19])[N:10]=[C:11]([C:12]3[S:16][C:15]([NH2:17])=[N:14][CH:13]=3)[C:4]=12.[CH3:37][C:38](OC(C)=O)=[O:39]>>[NH2:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]2[N:9]([CH:18]([C:20]3[O:21][C:22](=[O:36])[C:23]4[C:28]([C:29]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH3:19])[N:10]=[C:11]([C:12]3[S:16][C:15]([NH:17][C:38](=[O:39])[CH3:37])=[N:14][CH:13]=3)[C:4]=12
Reactant: CC(c1oc(=O)c2ccccc2c1-c1ccccc1)n1nc(-c2cnc(N)s2)c2c(N)ncnc21
Reactant: CC(=O)OC(C)=O
Agent: Cl
Product: CC(=O)Nc1ncc(-c2nn(C(C)c3oc(=O)c4ccccc4c3-c3ccccc3)c3ncnc(N)c23)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 10 %

Procedure:
3-(1-(4-amino-3-(2-aminothiazol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-4-phenyl-1H-isochromen-1-one hydrochloride (Example 59, 23 mg, 0.044 mmol) was dissolved in TEA (124 μL, 0.888 mmol)/Ac2O (419 μL, 4.44 mmol) and stirred at rt for 1 h. The reaction mixture was quenched by the addition of 1M HCl (1 ml) and purified via reverse phase chromatography using a Biotage C18 30 g SNAP with a gradient of water and acetonitrile to give the title compound (2.3 mg, 9.9%) as yellowish solid.
Reaction SMILES: C1(O[C:8](=[O:25])[NH:9][CH:10]2[CH2:15][CH2:14][C:13]([N:22]([CH3:24])[CH3:23])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)C=CC=CC=1.[NH:26]1[CH2:31][CH2:30][CH:29]([C:32]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[NH:34][CH:33]=2)[CH2:28][CH2:27]1>O1CCOCC1>[CH3:24][N:22]([CH3:23])[C:13]1([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:12][CH2:11][CH:10]([NH:9][C:8]([N:26]2[CH2:31][CH2:30][CH:29]([C:32]3[C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[NH:34][CH:33]=3)[CH2:28][CH2:27]2)=[O:25])[CH2:15][CH2:14]1
Reactant: c1ccc2c(C3CCNCC3)c[nH]c2c1
Reactant: CN(C)C1(c2ccccc2)CCC(NC(=O)Oc2ccccc2)CC1
Solvent: C1COCCO1
Product: CN(C)C1(c2ccccc2)CCC(NC(=O)N2CCC(c3c[nH]c4ccccc34)CC2)CC1

Procedure:
The polar diastereoisomer of (4-dimethylamino-4-phenylcyclohexyl)-carbamic acid phenyl ester (316 mg, 0.93 mmole) was added to a solution of 3-piperidine-4-yl-1H-indole (187 mg, 0.93 mmole) in dioxane (10 ml). The reaction mixture was then boiled under reflux for 32 hours. The reaction mixture was worked up by distilling off dioxane and diluting with water (10 ml). The reaction mixture was adjusted to pH 11 with 5M NaOH and extracted with EE (3×15 ml). The organic phase was dried with Na2SO4 and concentrated by evaporation. The polar diastereoisomer of 4-(1H-indol-3-yl)piperidine-1-carboxylic acid-(4-dimethylamino-4-phenylcyclohexyl)-amide was recrystallised from methanol (5 ml). It was obtained as a colourless solid in a yield of 210 mg (51%).
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]1[O:8][CH2:7][CH2:6][O:5]1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C(=O)C.[F:21][C:22]1[N:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1>C(OCC)(=O)C.O>[O:5]1[CH2:6][CH2:7][O:8][CH:4]1[CH2:3][CH2:2][O:28][C:25]1[CH:24]=[CH:23][C:22]([F:21])=[N:27][CH:26]=1
Reactant: BrCCC1OCCO1
Reactant: Oc1ccc(F)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: Fc1ccc(OCCC2OCCO2)cn1
Temperature: 100 °C
Reaction time: 12 h
Yield: 85.7 %

Procedure:
2-(2-Bromoethyl)-1,3-dioxolane (2.49 ml, 19.9 mmol) and cesium carbonate (15.1 g, 46.4 mmol) were added to an N,N-dimethylacetamide solution (25 ml) of 6-fluoropyridin-3-ol (1.5 g, 13.3 mmol), and stirred under a nitrogen atmosphere at 100° C. for 12 hours. The reaction solution was cooled with ice, water and ethyl acetate were added, and the organic layer was washed with water and saturated saline water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Biotage, hexane:ethyl acetate=5:1 to 1:1) to obtain 5-[2-(1,3-dioxolan-2-yl)ethoxy]-2-fluoropyridine (2.43 g, yield: 86%) as a colorless oil.
Reaction SMILES: [CH2:1]([NH2:6])[CH2:2][CH2:3][CH2:4][CH3:5].[Br:7][C:8]1[CH:9]=[CH:10][C:11]([O:16][CH3:17])=[C:12]([CH:15]=1)[CH:13]=O.[BH4-].[Na+].Cl.[OH-].[Na+]>O.C(O)C>[CH2:1]([NH:6][CH2:13][C:12]1[CH:15]=[C:8]([Br:7])[CH:9]=[CH:10][C:11]=1[O:16][CH3:17])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: COc1ccc(Br)cc1C=O
Reactant: CCCCCN
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCCCNCc1cc(Br)ccc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.8 %

Procedure:
Ethyl alcohol (150 ml) and n-pentylamine (12.7 g, 0.146 mol) were added to 5-bromo-2-methoxybenzaldehyde (30.0 g, 0.14 mol), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was cooled to 5° C., added with sodium borohydride (7.9 g, 0.209 mol), and then stirred at room temperature for 8 hours. The reaction mixture was added with water (50 ml) and aqueous 6N hydrochloric acid to decompose excess sodium borohydride, made alkaline with 25% aqueous sodium hydroxide, and extracted with toluene. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and then, the solvent was evaporated to give N-pentyl-(5-bromo-2-methoxyphenyl) methylamine (38.0 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([OH:12])[CH2:9][C:10]#[CH:11]>[Cu]I>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:11]#[C:10][CH2:9][CH2:8][OH:12]
Reactant: C#CCCO
Reactant: Brc1ccccn1
Agent: [Cu]I
Product: OCCC#Cc1ccccn1
Temperature: 0 °C
Reaction time: 8 h
Yield: 77.4 %

Procedure:
To a suspension of CuI (301 mg, 1.58 mmol) in TEA (40 mL) were added 2-bromopyridine (5 g, 31.6 mmol), followed by Pd2Cl2(PPh3)2 (1.11 g, 1.58 mmol) to give a yellow orange suspension. After cooling down to 0° C. under N2, 3-butyn-1-ol (2.28 g, 31.6 mmol) was added. The resulting reaction mixture turned black and it was stirred overnight at 70° C. The reaction mixture was quenched at 0° C. with water, TEA was removed under low pressure, and the organic layer was extracted 3× using DCM, washed with ammonia, water, brine, dried over MgSO4, filtered and concentrated. The crude residue was purified over silicagel chromatography (prepacked 250 g silicagel column, DCM/MeOH: from 99/1 to 95/5 as eluent) to afford 3.60 g of 4-(pyridin-2-yl)but-3-yn-1-ol as a brown oil (Yield: 77%).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[C:5]2[N:10]=[C:9]([CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[S:8][C:6]=2[N:7]=1.[N+:26]([C:29]1[CH:30]=[C:31]([CH:37]=[CH:38][CH:39]=1)[O:32][CH2:33][C:34](O)=[O:35])([O-:28])=[O:27].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[NH2:1][C:2]1[N:3]=[C:4]([N:20]2[CH2:25][CH2:24][N:23]([C:34](=[O:35])[CH2:33][O:32][C:31]3[CH:37]=[CH:38][CH:39]=[C:29]([N+:26]([O-:28])=[O:27])[CH:30]=3)[CH2:22][CH2:21]2)[C:5]2[N:10]=[C:9]([CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[S:8][C:6]=2[N:7]=1
Reactant: O=C(O)COc1cccc([N+](=O)[O-])c1
Reactant: Nc1nc(N2CCNCC2)c2nc(CCc3ccc(F)cc3)sc2n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(N2CCN(C(=O)COc3cccc([N+](=O)[O-])c3)CC2)c2nc(CCc3ccc(F)cc3)sc2n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 54.5 %

Procedure:
To a solution of 5-amino-2-[2-(4-fluorophenyl)ethyl]-7-piperazin-1-yl-thiazolo[5,4-d]pyrimidine (50 mg, 0.14 mmol) and 3-nitrophenoxyacetic acid (0.23 mmol) in DMF (2 ml) was added TBTU (0.21 mmol) followed by diisopropylethylamine (0.21 mmol, 35 μL). The reaction was stirred at room temperature for 24 hours after which the solvent was removed in vacuo. The resulting residue was purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio gradually ranging from 100% CH2Cl2 to 0.5% CH3OH in CH2Cl2), yielding the pure title compound (41 mg) which was characterized by its mass spectrum: MS m/z (%): 538 ([M+H]+, 100).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([CH3:11])=[C:5]([NH2:12])[C:4]=1[NH2:13].CO[C:16]1C(OC)=C[C:19]2[NH:20][C:21](CCCNC)=N[C:18]=2[CH:17]=1>>[CH3:1][O:2][C:3]1[C:4]2[N:13]=[C:16]([CH2:17][CH2:18][CH2:19][NH:20][CH3:21])[NH:12][C:5]=2[C:6]([CH3:11])=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1cc(C)c(N)c(N)c1OC
Reactant: CNCCCc1nc2cc(OC)c(OC)cc2[nH]1
Product: CNCCCc1nc2c(OC)c(OC)cc(C)c2[nH]1

Procedure:
Prepared from 3,4-dimethoxy-6-methyl-benzene-1,2-diamine in analogy to the methods described for [3-(5,6-dimethoxy-1H-benzoimidazol-2-yl)-propyl]-methyl-amine.
Reaction SMILES: Br[CH2:2][C:3]1[C:15]([F:16])=[CH:14][C:6]([C:7]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[O:8])=[C:5]([F:17])[CH:4]=1.[C:18]([O:22][C:23]1[C:28]([Cl:29])=[CH:27][C:26](B2OC(C)(C)C(C)(C)O2)=[CH:25][N:24]=1)([CH3:21])([CH3:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+]>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.O1CCCC1>[C:18]([O:22][C:23]1[N:24]=[CH:25][C:26]([CH2:2][C:3]2[C:15]([F:16])=[CH:14][C:6]([C:7]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[O:8])=[C:5]([F:17])[CH:4]=2)=[CH:27][C:28]=1[Cl:29])([CH3:21])([CH3:19])[CH3:20]
Reactant: CS(=O)(=O)NC(=O)c1cc(F)c(CBr)cc1F
Reactant: CC(C)(C)Oc1ncc(B2OC(C)(C)C(C)(C)O2)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)Oc1ncc(Cc2cc(F)c(C(=O)NS(C)(=O)=O)cc2F)cc1Cl
Yield: 23.1 %

Procedure:
4-(Bromomethyl)-2,5-difluoro-N-(methylsulfonyl)benzamide (Preparation 245, 70 mg, 0.21 mmol), 2-tert-butoxy-3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (Preparation 118, 72.9 mg, 0.234 mmol), tetrakistriphenylphosphinepalladium (24.3 mg, 0.021 mmol), aqueous potassium carbonate solution (1.8 M, 0.35 mL, 0.639 mmol) and tetrahydrofuran (15 mL) were combined and stirred under nitrogen at reflux for 5 hours. After cooling, the mixture was filtered through Celite™ and the filtrate evaporated. The residue was dissolved in water (20 mL) and acidified with aqueous potassium hydrogen sulphate solution (0.5 M) to pH 2 and the mixture extracted with ethyl acetate (30 mL). The organic layer was separated and washed with brine (3×20 mL), dried over sodium sulphate, filtered and evaporated to give an oil. The oil was purified using silica gel column chromatography eluting with heptane to ethyl acetate:heptane 1:1 to give a solid. The solid was further purified by reverse phase HPLC to give the title compound (21 mg, 23%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6]=[C:7]([NH:9][C:10]([NH:12][CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[O:11])[S:8][C:4]=2[CH:3]=1.[OH-].[Na+].[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:27]=1[S:33](Cl)(=[O:35])=[O:34]>>[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:27]=1[S:33]([O:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6]=[C:7]([NH:9][C:10](=[O:11])[NH:12][CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[S:8][C:4]=2[CH:3]=1)(=[O:35])=[O:34]
Reactant: O=C(NCCN1CCOCC1)Nc1nc2ccc(O)cc2s1
Reactant: O=S(=O)(Cl)c1c(Cl)cccc1Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(NCCN1CCOCC1)Nc1nc2ccc(OS(=O)(=O)c3c(Cl)cccc3Cl)cc2s1
Temperature: 20 °C
Reaction time: 5 h

Procedure:
To a solution of 260 mg of 1-(6-hydroxy-1,3-benzothiazol-2-yl)-3-(2-morpholin-4-ylethyl)urea in 19.4 cm3 of aqueous 0.1N sodium hydroxide solution are added 209 mg of finely ground 2,6-dichlorobenzenesulfonyl chloride. After stirring for about 5 hours at a temperature in the region of 20° C., a further 70 mg of 2,6-dichlorobenzenesulfonyl chloride are added. After stirring for about 18 hours at the same temperature, the reaction mixture is concentrated under reduced pressure (13 kPa) to a volume of about 5 cm3. The suspension obtained is cooled for about one hour at a temperature in the region of 5° C. The solid is filtered off by suction, washed with three times 2 cm3 of water precooled to about 5° C., and dried under reduced pressure (13 kPa) over phosphorus pentoxide. 216 mg of 2-{[(2-morpholin-4-ylethyl)carbamoyl]amino}-1,3-benzothiazol-6-yl 2,6-dichlorobenzenesulfonate are thus obtained in the form of a cream-coloured powder, the characteristics of which are as follows:
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]N)=[CH:5][CH:4]=1)#[N:2].S(OOS([O-])(=O)=O)([O-])(=O)=[O:12].[Na+].[Na+].O>CO>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:12])=[CH:5][CH:4]=1)#[N:2]
Reactant: O=S(=O)([O-])OOS(=O)(=O)[O-]
Reactant: N#Cc1ccc(CN)cc1
Agent: [Na+]
Solvent: CO
Solvent: O
Product: N#Cc1ccc(C=O)cc1
Temperature: 25 °C
Yield: 58.8 %

Procedure:
13.2 g of p-cyanobenzylamine, 28.6 g of sodium persulfate, 10 ml of water, and 100 ml of methanol were mixed and allowed to react at 50° C. for 40 minutes while stirring. After cooling the reaction mixture to room temperature, methanol was distilled off to precipitate solids. To the resulting suspension was added dichloromethane for extraction. The organic layer was washed twice with saturated aqueous sodium bicarbonate solution and then twice with water, and then magnesium sulfate was added thereto. The residue after distilling off dichloromethane was subjected to silica gel column chromatography (eluant: hexane/ethyl acetate=5/1), and hexane and ethyl acetate were distilled off. The resultant crude product concentrated to dryness was recrystallized from cyclohexane, the crystals were filtered, and dried to obtain 7.7 g (yield: 58%) of p-cyanobenzaldehyde. The obtained p-cyanobenzaldehyde had a purity of 99% by the analysis of high performance liquid chromatography.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[N:16][C:17]([N+:20]([O-])=O)=[CH:18][CH:19]=2)[CH2:10][CH:9]1[CH3:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[N:16][C:17]([NH2:20])=[CH:18][CH:19]=2)[CH2:10][CH:9]1[CH3:23])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1CN(c2ccc([N+](=O)[O-])nc2)CCN1C(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Product: CC1CN(c2ccc(N)nc2)CCN1C(=O)OC(C)(C)C
Yield: 122.4 %

Procedure:
By repeating procedures described in Example B, 2-methyl-4-(6-nitro-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (600 mg, 1.52 mmol) is hydrogenated over Pd—C on an H-cube (Thales) (instead of under an atmosphere of hydrogen) to give 4-(6-amino-pyridin-3-yl)-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (544 mg, 98%). MS (ESI) m/z 293 (M+H)+
Reaction SMILES: C1(C)C=CC=CC=1.[NH2:8][C:9]1[S:22][C:12]2[CH2:13][N:14]([C:17]([CH:19]3[CH2:21][CH2:20]3)=[O:18])[CH2:15][CH2:16][C:11]=2[C:10]=1[C:23](=[O:31])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[Cl:30].C(=O)([O-])O.[Na+].[Br:37][CH:38]([CH3:42])[C:39](Br)=[O:40]>C(OCC)(=O)C.O>[Br:37][CH:38]([CH3:42])[C:39]([NH:8][C:9]1[S:22][C:12]2[CH2:13][N:14]([C:17]([CH:19]3[CH2:20][CH2:21]3)=[O:18])[CH2:15][CH2:16][C:11]=2[C:10]=1[C:23](=[O:31])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[Cl:30])=[O:40]
Reactant: CC(Br)C(=O)Br
Reactant: Nc1sc2c(c1C(=O)c1ccccc1Cl)CCN(C(=O)C1CC1)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: CC(Br)C(=O)Nc1sc2c(c1C(=O)c1ccccc1Cl)CCN(C(=O)C1CC1)C2

Procedure:
450 ml of toluene and 150 ml of water were added to 21.83 g of 2-amino-3-(2-chlorobenzoyl)-6-cyclopropanecarbonyl-4,5,6,7-tetrahydro-thieno[2,3-C]pyridine. 10.16 g of sodium hydrogencarbonate was further added, to which 9.5 ml of 2-bromopropionyl bromide was added while heating to 50° to 60° C. Moreover, a sodium hydrogencarbonate aqueous solution (10.6 g of sodium hydrogencarbonate and 150 ml of water 1) and 5 ml of 2-bromopropionyl bromide were added to complete the reaction. After the completion of the reaction, ethyl acetate was added and the reaction solution was washed once with a saturated saline solution and dried with anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 29.9 g of the intended compound (at a quantitative yield).