Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[Cl-].[NH2:3][C:4]([NH2:6])=[NH2+:5].[F:7][C:8]([F:30])([F:29])[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[CH:14]([CH2:18][C:19](OCC)=[O:20])[N:13]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:12]2=[O:28]>C(O)C.C(OCC)C>[F:30][C:8]([F:7])([F:29])[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[CH:14]([CH2:18][C:19]([NH:5][C:4]([NH2:6])=[NH:3])=[O:20])[N:13]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:12]2=[O:28]
Reactant: NC(N)=[NH2+]
Reactant: CCOC(=O)CC1c2ccc(C(F)(F)F)cc2C(=O)N1CC(C)C
Agent: [Cl-]
Agent: [Na]
Solvent: CCO
Solvent: CCOCC
Product: CC(C)CN1C(=O)c2cc(C(F)(F)F)ccc2C1CC(=O)NC(=N)N
Temperature: 20 °C
Reaction time: 16 h
Yield: 17.6 %

Procedure:
N-[2-(2-Isobutyl-3-oxo-5-trifluoromethyl-2,3-dihydro-1H-isoindol-1-yl)-acetyl]-guanidine is prepared as described in Example 9, starting with 10 cm3 of absolute ethanol, 0.19 g of sodium, 0.78 g of guanidinium chloride and 1.86 g of ethyl (5-trifluoromethyl-2-isobutyl-3-oxo-2,3-dihyrdo-1H-isoindol-1-yl)acetate in 10 cm3 of absolute ethanol. The reaction mixture is stirred at a temperature in the region of 20° C. for 16 hours and is then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue is then taken up in a mixture of 5 cm3 of water and 15 cm3 of diethyl ether and then concentrated to dryness again under the same conditions. The residue is taken up in 100 cm3 of ethyl acetate and the organic phase is washed with twice 60 cm3 of aqueous 1N sodium hydroxide solution and then with twice 60 cm3 of 4N hydrochloric acid solution. The acidic aqueous extracts are combined, treated with aqueous 30% sodium hydroxide solution to pH 14, and then extracted with 3 times 50 cm3 of ethyl acetate. The organic extracts are combined, washed with 100 cm3 of saturated sodium chloride solution, dried over magnesium sulfate and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The yellow solid thus obtained is taken up in 20 cm3 of diethyl ether, stirred at a temperature in the region of 20° C. for 1 hour and then filtered off. The solid is washed with twice 20 cm3 of diethyl ether and then dried in a desiccator under reduced pressure (2 Pa) at a temperature in the region of 35° C. 0.34 g of N-[(5-trifluoromethyl-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetyl]guanidine is thus obtained in the form of a yellow powder melting at 224° C. (Analysis: C16 H19 F3 N4 O2% calculated C, 53.93; H, 5.37; F, 15.99; N, 15.72; O, 8.98%. found C, 53.95; H, 5.15; F, 15.00; N, 15.59).
Reaction SMILES: CC(C)N=C=NC(C)C.C1C=CC2N(O)N=NC=2C=1.[O:20]1[C:24]2[CH:25]=[CH:26][C:27]([CH2:29][CH2:30][C:31]([OH:33])=O)=[CH:28][C:23]=2[O:22][CH2:21]1.Cl.Cl.[CH2:36]([N:43]1[C:52]2[C:47](=[CH:48][C:49]([Cl:53])=[CH:50][CH:51]=2)[CH2:46][CH:45]([NH2:54])[CH2:44]1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>ClCCCl>[O:20]1[C:24]2[CH:25]=[CH:26][C:27]([CH2:29][CH2:30][C:31]([NH:54][CH:45]3[CH2:46][C:47]4[C:52](=[CH:51][CH:50]=[C:49]([Cl:53])[CH:48]=4)[N:43]([CH2:36][C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)[CH2:44]3)=[O:33])=[CH:28][C:23]=2[O:22][CH2:21]1
Reactant: NC1Cc2cc(Cl)ccc2N(Cc2ccccc2)C1
Reactant: O=C(O)CCc1ccc2c(c1)OCO2
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Product: O=C(CCc1ccc2c(c1)OCO2)NC1Cc2cc(Cl)ccc2N(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 9.8 %

Procedure:
Typical procedure: To a suspension of PS-DIC 110 mg/well (Argonaut, 1.38 mmol/g loading) in DCE (0.5 mL) at room temperature was added HOBt (5 mg in 100 μL DMF), followed by 3-(benzo[d][1,3]dioxol-5-yl)propanoic acid (75 μmol). To this was added 1-benzyl-6-chloro-1,2,3,4-tetrahydroquinolin-3-amine, dihydrochloride (14 mg, 50 μmol), prepared as described in Example 19C, in 1,2-dichloroethane (0.5 mL). The reaction mixture was shaken at RT for 24 h, contents were filtered into a synthesis tube rack (STR) and the solvent was dried in a speed vac. The resulting residue was chromatographed using preparative HPLC (conditions: Xterra MS-C18 (30×50 mm); eluted with 10% to 100% B, 6 min gradient. (A=100% water with 0.1% TFA and B=acetonitrile with 0.1% TFA); flow rate at 30 mL/min; UV detection at 220 nm) to give the title compound, 3-(benzo[d][1,3]dioxol-5-yl)-N-(1-benzyl-6-chloro-1,2,3,4-tetrahydroquinolin-3-yl)propanamide, (2.2 mg, 8%). HPLC (method C): retention time=1.6 min, MS (ES): m/z 449 [M+H]+.
Reaction SMILES: [CH:1]([Si:4]([O:11][CH2:12][C@@H:13]([OH:23])[CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])([CH:8]([CH3:10])[CH3:9])[CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[H-].[Na+].[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:31]Br>C1COCC1>[CH:8]([Si:4]([O:11][CH2:12][C@@H:13]([O:23][CH2:31][C:30]1[CH:33]=[CH:34][C:35]([O:36][CH3:37])=[C:28]([O:27][CH3:26])[CH:29]=1)[CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])([CH:5]([CH3:7])[CH3:6])[CH:1]([CH3:3])[CH3:2])([CH3:9])[CH3:10]
Reactant: CC(C)[Si](OC[C@@H](O)CNC(=O)OC(C)(C)C)(C(C)C)C(C)C
Reactant: COc1ccc(CBr)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(CO[C@@H](CNC(=O)OC(C)(C)C)CO[Si](C(C)C)(C(C)C)C(C)C)cc1OC
Reaction time: 1 h
Yield: 12.8 %

Procedure:
To a 0° C. mixture of (2S)-3-(t-butoxycarbonylamino)-2-hydroxypropyl triisopropylsilyl ether (6 g, 17.2 mmol) and THF (35 mL) was added NaH (60% dispersion in oil, hexane washed). The reaction was stirred for 1 h, 3,4-dimethoxy-benzyl bromide (4.3 g, 18.9 mmol) in THF (20 mL) was added, and then stirred at ambient temperature for 18 h. The mixture was concentrated and chromatographed on SiO2 (gradient CH2Cl2 to EtOAc) to give the title compound (1.1 g, 12.8%).
Reaction SMILES: [C:1]([C:4]1[CH:27]=[CH:26][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24]C)=[O:23])=[CH:17][N:16]=2)(=[O:14])=[O:13])=[C:6]([CH2:28][CH2:29][CH3:30])[C:5]=1[OH:31])(=[O:3])[CH3:2].[OH-].[Na+].O>C1COCC1>[C:1]([C:4]1[CH:27]=[CH:26][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]([OH:24])=[O:23])=[CH:17][N:16]=2)(=[O:14])=[O:13])=[C:6]([CH2:28][CH2:29][CH3:30])[C:5]=1[OH:31])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCCS(=O)(=O)c2ccc(CC(=O)OC)cn2)ccc(C(C)=O)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCc1c(OCCCS(=O)(=O)c2ccc(CC(=O)O)cn2)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The compound of Example 8, (700 mg, 1.56 mmoles) was taken up in a mixture of THF (14 ml), 2 eq. 1N NaOH (3.3 ml) and H2O (10 ml). The reaction mixture was stirred at room temperature under N2 for 2 hours. The THF was removed in vacuo. The aqueous phase was extracted with ether, then acidified with HCl and extracted into CHCl3. The combined organic extracts were dried and concentrated. The residue was triturated with ether to afford the title compound, m.p. 154°-156°. Analysis, calculated: C, 57.92; H, 5.79; S, 7.36. Found: C, 57.93; H, 5.83; S, 7.59.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([F:10])[C:5]([Br:11])=[CH:4][CH:3]=1.F[B-](F)(F)F.[O:17]=[N+:18]=[O:19]>C(#N)C.[Cl-].[Na+].O>[NH2:1][C:2]1[C:3]([N+:18]([O-:19])=[O:17])=[CH:4][C:5]([Br:11])=[C:6]([F:10])[C:7]=1[C:8]#[N:9]
Reactant: N#Cc1c(N)ccc(Br)c1F
Reactant: O=[N+]=O
Agent: F[B-](F)(F)F
Agent: [Cl-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: N#Cc1c(N)c([N+](=O)[O-])cc(Br)c1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 52 %

Procedure:
To a cooled (0° C.) solution of 6-amino-3-bromo-2-fluoro-benzonitrile (8.0 g, 37 mmol) in acetonitrile (40 mL) under nitrogen was added dropwise a solution of nitronium tetrafluoroborate in acetonitrile. The reaction mixture and stirred for 16 h at RT. The reaction mixture was treated with brine and extracted with ethyl acetate. The organic fraction was washed with water followed by brine and dried over anhydrous sodium sulfate, filtered and concentrated. Purification by column chromatography (10 to 20% ethyl acetate:hexanes) afforded 5.0 g (52%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 8.6 (d, J=6.9 Hz, 1H), 6.8-7.1 (br. s, 2H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14]([CH3:16])=[CH2:15])[C:6]1=[O:17].[C:18]1([CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+].CC(C)CC(=O)C>O>[C:31]1([CH:24]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:25]2[CH2:26][CH2:27][N:28]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=4[N:7]([C:14]([CH3:16])=[CH2:15])[C:6]3=[O:17])[CH2:29][CH2:30]2)[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: C=C(C)n1c(=O)n(CCCCl)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: C=C(C)n1c(=O)n(CCCN2CCN(C(c3ccccc3)c3ccccc3)CC2)c2ccccc21

Procedure:
A mixture of 42.6 parts of 1-(3-chloropropyl)-1,3-dihydro-3-(1-methylethenyl)-2H-benzimidazol-2-one, 38 parts of 1-(diphenylmethyl)piperazine, 48 parts of sodium carbonate and 400 parts of 4-methyl-2-pentanone is stirred and refluxed overnight with water-separator. The reaction mixture is cooled, water is cooled and the layers are separated. The 4-methyl-2-pentanone-phase is washed with water, dried, filtered and evaporated. The oily residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and 5% of methanol as eluent. The pure fractions are collected and the eluent is evaporated, yielding 1-{3-[4-(diphenylmethyl)-1-piperazinyl]propyl}-1,3-dihydro-3-(1-methylethenyl)-2H-benzimidazol-2-one as a residue.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:36])=[C:9]([CH2:11][O:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][O:18][C:19]3[C:23]([CH:24]=O)=[CH:22][N:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:20]=3)=[CH:15][C:14]=2[O:34][CH3:35])[N:10]=1.[Cl-].[CH3:38][C:39]1[S:40][CH:41]=[C:42]([CH2:44][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:43]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:36])=[C:9]([CH2:11][O:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[CH:44]\[C:42]4[N:43]=[C:39]([CH3:38])[S:40][CH:41]=4)=[CH:22][N:21]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:20]=3)=[CH:15][C:14]=2[O:34][CH3:35])[N:10]=1
Reactant: Cc1nc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cs1
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(-c2ccco2)oc1C
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(COc2nn(-c3ccccc3)cc2/C=C\c2csc(C)n2)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 34.5 %

Procedure:
A mixture of 3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazole-4-carbaldehyde (0.80 g), [(2-methyl-1,3-thiazol-4-yl)methyl]triphenylphosphonium chloride (0.98 g), potassium carbonate (0.33 g) and N,N-dimethylformamide (50 mL) was stirred at room temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (2:3, v/v) to give 2-(2-furyl)-4-({2-methoxy-4-[({4-[(Z)-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]phenoxy}methyl)-5-methyl-1,3-oxazole as colorless crystals (0.33 g, yield 35%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 164-165° C.
Reaction SMILES: [OH-].[Na+].Cl[C:4]1[N:9]=[C:8](Cl)[N:7]=[C:6](Cl)[N:5]=1.[CH2:12]([NH2:15])[CH2:13][CH3:14]>CC(C)=O.O>[CH2:12]([NH:15][C:4]1[N:9]=[C:8]([NH:15][CH2:12][CH2:13][CH3:14])[N:7]=[CH:6][N:5]=1)[CH2:13][CH3:14]
Reactant: CCCN
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CCCNc1ncnc(NCCC)n1
Temperature: 50 °C
Yield: 100 %

Procedure:
A 2 M NaOH solution (82 mL, 162.68 mmol) was added in a dropwise manner to a suspension of 2,4,6-trichloro-1,3,5-triazine (XVIII) (15.00 g, 81.34 mmol) and n-propylamine (13.4 mL, 162.68 mmol) in acetone (300 mL) and water (15 mL) at 0° C. The reaction mixture was heated at 50° C. for 3 h and then cooled. Water (100 mL) was added to the reaction mixture; the resultant precipitate was filtered, washed with water, ethyl ether and dried to yield 2-chloro-N-(4,6-bis-(n-propylamino)-[1,3,5]triazine (XXXIV) (15.88 g, 85% yield).
Reaction SMILES: [F:1][CH:2]([F:17])[C:3]1[N:4]=[CH:5][N:6]([C:8]2[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][C:9]=2[O:15][CH3:16])[CH:7]=1.[C:18](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:19]>ClCCl>[F:17][CH:2]([F:1])[C:3]1[N:4]=[CH:5][N:6]([C:8]2[CH:14]=[CH:13][C:11]([N:12]=[C:18]=[S:19])=[CH:10][C:9]=2[O:15][CH3:16])[CH:7]=1
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Reactant: COc1cc(N)ccc1-n1cnc(C(F)F)c1
Solvent: ClCCl
Product: COc1cc(N=C=S)ccc1-n1cnc(C(F)F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.9 %

Procedure:
Step N (5): Dichloromethane (100 mL) was added to a flask charged with 4-(4-(difluoromethyl)-1H-imidazol-1-yl)-3-methoxyaniline (2.5 g, 10.45 mmol) and 1,1′-thiocarbonyldipyridin-2(1H)-one (2.43 g, 10.5 mmol). The resulting mixture was stirred for 18 h at rt. The reaction mixture was concentrated in vacuo. The crude products were purified using silica gel chromatography (0-2% EtOAc/chloroform, linear gradient) to afford 4-(difluoromethyl)-1-(4-isothiocyanato-2-methoxyphenyl)-1H-imidazole (2.26 g, 77% yield). LC-MS (M+H)+ 282.1.
Reaction SMILES: O=[C:2]1[C:11]2[C:10]([C:12]([O:14]C)=O)=[CH:9][CH:8]=[CH:7][C:6]=2[NH:5][CH:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH:3]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O.[NH2:29][NH2:30]>>[C:22]1([CH:3]2[C:2]3=[N:29][NH:30][C:12](=[O:14])[C:10]4[CH:9]=[CH:8][CH:7]=[C:6]([C:11]=43)[NH:5][CH:4]2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COC(=O)c1cccc2c1C(=O)C(c1ccccc1)C(c1ccccn1)N2
Reactant: NN
Solvent: O
Product: O=c1[nH]nc2c3c(cccc13)NC(c1ccccn1)C2c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 37 %

Procedure:
A mixture of methyl 4-oxo-3-phenyl-2-(pyridin-2-yl)-1,2,3,4-tetrahydroquinoline-5-carboxylate (30 mg, 0.08 mmol) and hydrazine monohydrate (1 mL) was stirred at room temperature for 3 h. The resulting mixture was evaporated under reduced pressure to 10 mL and then filtered, 10 mg of 9-phenyl-8-(pyridin-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one was obtained, yield 37%. 1H-NMR (400 MHz, CDCl3) δ (ppm): 4.60 (d, 1H), 4.86-4.88 (m, 1H), 5.21 (s, 1H), 6.96 (dd, 1H), 7.08-7.17 (m, 4H), 7.22-7.28 (m, 3H), 7.46-7.49 (m, 1H), 7.60 (t, 1H), 7.73 (dd, 1H), 8.59 (d, 1H), 9.77 (s, 1H); LC-MS (ESI) m/z: 341 (M+1)+.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][NH:21][CH2:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].[C:30](Cl)(=[O:32])[CH3:31]>>[C:30]([N:21]1[CH2:20][CH2:19][C:17]2[N:18]=[C:13]([C:10]3[CH:11]=[CH:12][C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:8][CH:9]=3)[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]=2[CH2:22]1)(=[O:32])[CH3:31]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CNCC3)cc1
Reactant: CC(=O)Cl
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CN(C(C)=O)CC3)cc1

Procedure:
Compound ey was prepared according to the procedure described in Example 5 by reacting (S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)phenyl)urea with acetyl chloride. LC-MS: m/z=+439 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.[H-].[Na+].Br[CH2:12][CH2:13][O:14][CH3:15].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:12][CH2:13][O:14][CH3:15])=[CH:4][N:3]=1
Reactant: COCCBr
Reactant: Oc1ccc(Br)nc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOc1ccc(Br)nc1
Reaction time: 72 h
Yield: 42 %

Procedure:
2-Bromo-5-hydroxypyridine (1 mmol) is dissolved in DMF (2.5 ml) and NaH (1.4 eq., 60% suspension in liquid paraffin) is added. After 30 min 1-Bromo-2-methoxy-ethane (1.1 eq.) is added and the reaction solution is stirred 3 days. The reaction solution is pored into water and extracted with methyl-tert.-butyl ether. The combined organic layers are dried over MgSO4 and the solvent is removed in vacuo. 2-Bromo-5-(2-methoxyethoxy)-pyridine is obtained after column chromatography as colorless powder in a yield of 42%; HPLC (method C): 1.48 min; LC-MS (method A): 1.11 min, 231.95 (M+H+).
Reaction SMILES: [CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[N:17]=[C:16]([NH:18][C:19]4[CH:24]=[CH:23][C:22]5[O:25][CH2:26][CH2:27][O:28][C:21]=5[CH:20]=4)[C:15](Br)=[CH:14][N:13]=3)=[CH:4][C:3]=2[O:2]1.[C:30]1(B(O)O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>COCCOC.CCOC(C)=O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[N:17]=[C:16]([NH:18][C:19]4[CH:24]=[CH:23][C:22]5[O:25][CH2:26][CH2:27][O:28][C:21]=5[CH:20]=4)[C:15]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:14][N:13]=3)=[CH:4][C:3]=2[O:2]1
Reactant: OB(O)c1ccccc1
Reactant: Brc1cnc(Nc2ccc3c(c2)OCCO3)nc1Nc1ccc2c(c1)OCCO2
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: c1ccc(-c2cnc(Nc3ccc4c(c3)OCCO4)nc2Nc2ccc3c(c2)OCCO3)cc1
Temperature: 80 °C

Procedure:
A mixture of N2,N4-bis(3,4-ethylenedioxyphenyl)-5-bromo-2,4-pyrimidinediamine (20 mg, 0.044 mmol) and phenylboronic acid (6.9 mg, 0.057 mmol) in DME (1 mL) was prepared in a sealed tube and purged with N2. Tetrakis(triphenylphosphine) palladium(0) (0.002 mmol) was added, and the reaction tube sealed and heated at 80° C. overnight. After cooling, the reaction mixture was diluted with EtOAc, washed with 1N NaOH and brine, dried (MgSO4), and concentrated. The residue was purified by preparative TLC (40% EtOAc/hexanes) to afford N2,N4-bis(3,4-ethylenedioxyphenyl)-5-phenyl-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 7.77 (s, 1H), 7.52-7.36 (m, 5H), 7.10 (d, 1H, J=2.4 Hz), 7.05 (d, 1H, J=2.4 Hz), 6.93 (dd, 1H, J=2.4 and 8.7 Hz), 6.87 (dd, 1H, J=2.4 and 8.7 Hz), 6.73 (d, 1H, J=8.7 Hz), 6.69 (d, 1H, J=8.7 Hz), 4.23-4.20 (m, 8H); LCMS: ret. time: 25.38 min.; purity: 100%; MS (m/e): 455 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19](O)(=[O:21])=[O:20])=[CH:15][CH:14]=3)[N:11]=[C:10]([C:23]([F:26])([F:25])[F:24])[CH:9]=2)=[CH:4][CH:3]=1.[Cl:27]CCl>CN(C)C=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([Cl:27])(=[O:21])=[O:20])=[CH:15][CH:14]=3)[N:11]=[C:10]([C:23]([F:26])([F:25])[F:24])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: ClCCl
Reactant: Cc1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(S(=O)(=O)O)cc2)cc1
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(S(=O)(=O)Cl)cc2)cc1
Yield: 74.4 %

Procedure:
To a stirred suspension of 4-(5-p-methylphenyl-3-trifluoromethyl-pyrazol-1-yl)-benzenesulfonic acid (43 g, 0.112 mol) in dichloromethane (250 ml) phosphorous pentachloride (34.20 g, 0.168 mol) was added portion-wise at room temperature, followed by addition of N,N-dimethylformamide (10 ml). The so obtained suspension was refluxed for 8 h, then concentrated in vacuo. The residue was partitioned between ethyl acetate (150 ml) and water (150 ml) and separated. The aqueous phase was extracted with ethyl acetate (1×50 ml), the combined organic layers were dried over MgSO4, filtered and concentrated. The obtained oil was crystallized from cyclohexane (120 ml) to yield 33.40 g (74%) of the title compound as white crystals. Mp: 97-98° C.
Reaction SMILES: [F:1][CH2:2][C:3]1[N:8]=[C:7]([C:9]#[C:10][CH2:11][CH2:12][NH:13][CH3:14])[CH:6]=[CH:5][CH:4]=1.[Cl:15][C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18](Cl)=[O:19]>>[Cl:15][C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18]([N:13]([CH2:12][CH2:11][C:10]#[C:9][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:2][F:1])[N:8]=1)[CH3:14])=[O:19]
Reactant: CNCCC#Cc1cccc(CF)n1
Reactant: O=C(Cl)c1ccccc1Cl
Product: CN(CCC#Cc1cccc(CF)n1)C(=O)c1ccccc1Cl
Yield: 31.1 %

Procedure:
The title compound was prepared in accordance with the general method of Example 199(D), from 4-(6-(fluoromethyl)pyridin-2-yl)-N-methylbut-3-yn-1-amine (70 mg, 0.36 mmol) and 2-chlorobenzoyl chloride (76 mg, 0.44 mmol). The crude residue was purified over silicagel chromatography (prepacked 10 g silicagel column, DCM/MeOH: from 100/0 to 98/2 as eluent) to afford 37 mg of 2-chloro-N-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-N-methylbenzamide as a brown oil (Yield: 31%).
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23](O)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH:49]([CH:52]1[CH2:56][CH2:55][CH2:54][NH:53]1)([CH3:51])[CH3:50].C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:1]1([N:6]2[CH2:7][CH2:8][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:53]3[CH2:54][CH2:55][CH2:56][CH:52]3[CH:49]([CH3:51])[CH3:50])=[O:24])=[CH:17]4)=[O:13])[CH2:10][CH2:11]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1cc2cc(C(=O)N3CCN(C4CCCC4)CC3)ccc2[nH]1
Reactant: CC(C)C1CCCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C1CCCN1C(=O)c1cc2cc(C(=O)N3CCN(C4CCCC4)CC3)ccc2[nH]1

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1 hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), 2-isopropylpyrrolidine (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide to give the desired product after purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile/water/formic acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:12])[CH3:11].[CH3:13][C:14]1[CH:15]=[C:16]([NH:23][C:24]([C:26]2([CH3:29])[CH2:28][O:27]2)=[O:25])[CH:17]=[CH:18][C:19]=1[N+:20]([O-:22])=[O:21]>>[C:10]([NH:9][C:3]1[CH:4]=[CH:5][C:6]([O:8][CH2:29][C:26]([OH:27])([CH3:28])[C:24]([NH:23][C:16]2[CH:17]=[CH:18][C:19]([N+:20]([O-:22])=[O:21])=[C:14]([CH3:13])[CH:15]=2)=[O:25])=[CH:7][C:2]=1[F:1])(=[O:12])[CH3:11]
Reactant: CC(=O)Nc1ccc(O)cc1F
Reactant: Cc1cc(NC(=O)C2(C)CO2)ccc1[N+](=O)[O-]
Product: CC(=O)Nc1ccc(OCC(C)(O)C(=O)Nc2ccc([N+](=O)[O-])c(C)c2)cc1F

Procedure:
The compound was synthesised according to the procedure described in Example 1c. N-(2-Fluoro-4-hydroxyphenyl)acetamide (0.5 g, 3.0 mmol) and 2-methyloxirane-2-carboxylic acid (3-methyl-4-nitrophenyl)amide (0.6 g, 2.5 mmol) was used as starting materials. The product was crystallised from the mixture of ethyl acetate and diethyl ether (1:1). The yield was 0.39 g. 1H NMR (DMSO-d6): 1.42 (3H, s), 2.02 (3H, s), 2.53 (3H, s), 3.97 (1H, d, J=9.7 Hz), 4.21 (1H, d, J=9.7 Hz), 6.23 (1H, bs), 6.72 (1H, m), 6.90 (1H, m), 7.56 (1H, m), 7.88 (1H, dd, J=9.0 Hz and 2.2 Hz), 7.93 (1H, d, J=2.2 Hz), 8.03 (1H, d, J=9.0 Hz), 9.51 (1H, s), 10.15 (1H, bs).