Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:9])=[CH:4][CH:3]=1.Br[CH2:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1>>[CH3:30][O:29][C:27](=[O:28])[C:26]1[CH:31]=[CH:32][C:23]([CH2:22][O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]([N:10]3[CH2:14][CH2:13][CH2:12][C@H:11]3[CH2:15][N:16]3[CH2:17][CH2:18][CH2:19][CH2:20]3)=[O:9])=[CH:4][CH:3]=2)=[CH:24][CH:25]=1
Reactant: O=C(c1ccc(O)cc1)N1CCC[C@H]1CN1CCCC1
Reactant: COC(=O)c1ccc(CBr)cc1
Product: COC(=O)c1ccc(COc2ccc(C(=O)N3CCC[C@H]3CN3CCCC3)cc2)cc1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure B using (4-Hydroxy-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone and methyl 4-(bromomethyl)benzoate. MS (ES+) 423.3
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]#[N:10])=[N:7][C:6](O)=[CH:5][N:4]=1)#[N:2].S(Cl)([Cl:14])=O.N1C=CC=CC=1>>[C:1]([C:3]1[C:8]([C:9]#[N:10])=[N:7][C:6]([Cl:14])=[CH:5][N:4]=1)#[N:2]
Reactant: O=S(Cl)Cl
Reactant: N#Cc1ncc(O)nc1C#N
Solvent: c1ccncc1
Product: N#Cc1ncc(Cl)nc1C#N
Yield: 76.6 %

Procedure:
2,3-Dicyano-5-hydroxypyrazine (7.30 g; 0.05 mole) was dissolved in 70 g (0.59 mole) of thionyl chloride, and the solution was cooled to 0° to 5° C. With stirring, 4.80 g (0.06 mole) of pyridine was added dropwise over the period of 15 minutes. Then, the mixture was stirred at 70° C. for 2 hours. After the reaction, the excess of thionyl chloride was distilled off under reduced pressure, and the residue was extracted with 150 ml of chloroform. The chloroform solution was washed twice with 50 ml of water, and dried over anhydrous calcium chloride, and then the solvent was distilled off to afford a red solid. Recrystallization of the solid from benzene afforded 6.30 g (yield 77%) of 2,3-dicyano-5-chloropyrazine.
Reaction SMILES: [C:1]1([C:7]2[N:8]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]Br)[C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[P:32]([O:39]CC)([O:36][CH2:37][CH3:38])[O:33][CH2:34][CH3:35]>C1(C)C(C)=CC=CC=1>[C:1]1([C:7]2[N:8]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][P:32]([O:36][CH2:37][CH3:38])(=[O:39])[O:33][CH2:34][CH3:35])[C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrCCCCCCCn1c(-c2ccccc2)nc(-c2ccccc2)c1-c1ccccc1
Reactant: CCOP(OCC)OCC
Solvent: Cc1ccccc1C
Product: CCOP(=O)(CCCCCCCn1c(-c2ccccc2)nc(-c2ccccc2)c1-c1ccccc1)OCC
Yield: 34.7 %

Procedure:
A mixture of 2,4,5-triphenyl-1-(7-bromoheptyl)-imidazole (0.95 g) and triethyl phosphite (1.66 g) in xylene (5 ml) was heated at reflux temperature for 20 hours. The mixture was evaporated to an oil and chromatographed on silica gel (ethyl acetate/ethanol) to give diethyl 7-(2,4,5-triphenylimidazol-1-yl)heptane-phosphonate (0.37 g, 35%) as a light brown oil. NMR μ(CDCl3) 0.9-1.7 (18H, m, 6×CH2 +2×CH3), 3.9 (2H, t, CH2N), 4.1 (4H, m, 2×CH20), 7.1-7.7 (15H, m, 3×Ph) ppm. Diethyl 7-(2,4,5-triphenylimidazol-l-yl)heptane-phosphonate (0.35 g) was dissolved in dry chloroform, cooled to -40° C and to it was added trimethylsflyl iodide (0.66 g) over 2 minutes under an atmosphere of nitrogen. The cooling bath was removed and the reaction mixture was stirred for 3 hours at room temperature then evaporated to an oil and re- evaporated from methanol and water respectively. The oil was taken up in methanol, treated with excess aqueous sodinto bicarbonate, evaporated to dryness then taken up in ethanol, filtered and the flitrate evaporated to an oil. This was taken up in water, filtered and dilute hydrochloric acid added to pH4. The precipitated oil was washed with water, taken up in methanol and precipitated with ether to give 7-(2,4,5-triphenylimidazol-1-yl)heptane-phosphonic acid (0.16 g, 51%) as a light brown oil. Found: C, 68.12; H, 6.39, N, 5.60% C28H31N2O3P+4% H2O requires: C, 68.03; H 6.76; N, 5.66%.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[C:11]#[N:12])=[CH:4][C:3]=1[CH:16]=O.[NH2:18][C:19]1[CH:20]=[C:21]([S:26]([NH2:29])(=[O:28])=[O:27])[CH:22]=[CH:23][C:24]=1[NH2:25].OS([O-])=O.[Na+]>CC(N(C)C)=O>[NH2:1][C:2]1[C:3]([C:16]2[NH:18][C:19]3[CH:20]=[C:21]([S:26]([NH2:29])(=[O:27])=[O:28])[CH:22]=[CH:23][C:24]=3[N:25]=2)=[CH:4][C:5]([C:8]2[CH:15]=[CH:14][CH:13]=[C:10]([C:11]#[N:12])[CH:9]=2)=[CH:6][N:7]=1
Reactant: Nc1ccc(S(N)(=O)=O)cc1N
Reactant: N#Cc1cccc(-c2cnc(N)c(C=O)c2)c1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: N#Cc1cccc(-c2cnc(N)c(-c3nc4ccc(S(N)(=O)=O)cc4[nH]3)c2)c1
Temperature: 200 °C
Yield: 43.6 %

Procedure:
3-(6-amino-5-formylpyridin-3-yl)benzonitrile (0.06 g, 0.27 mmol), 3,4-diaminobenzene-1-sulphonamide (0.050 g, 0.27 mmol), and NaHSO3 (0.029, 0.40 mmol) were combined in 2 mL of dimethylacetamide and heated to 200° C. in the SmithSynthesizer™ microwave instrument for 10 minutes. Upon cooling, the solvent was removed and the residue was chromatographed on silica gel eluting with hexanes/ethyl acetate (0 to 100% EtOAc over 10 minutes) to afford 2-[2-amino-5-(3-cyanophenyl)pyridin-3-yl]-1H-benzimidazole-6-sulfonamide (0.046 g) as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:12](=[O:13])[CH:11]=[CH:10][CH:9]2[OH:14])=[C:4]([CH2:15][CH3:16])[CH:3]=1.S(=O)(=O)(O)O.C(O)(C)C>CC(C)=O.[O-2].[O-2].[O-2].[Cr+6]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:12](=[O:13])[CH:11]=[CH:10][C:9]2=[O:14])=[C:4]([CH2:15][CH3:16])[CH:3]=1
Reactant: CCc1cc(Br)ccc1C1C(=O)C=CC1O
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [O-2]
Solvent: CC(C)O
Solvent: CC(C)=O
Product: CCc1cc(Br)ccc1C1C(=O)C=CC1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-(4-bromo-2-ethylphenyl)-4-hydroxycyclopent-2-enone (10.14 g, 0.036 mol) in acetone (150 ml) at 5° C. is added chromium trioxide in concentrated sulfuric acid (24 ml, 0.039 mol, 1.64M solution), at such a rate as to maintain a temperature between 10° C. to 15° C. The reaction mixture is further stirred at room temperature for 30 minutes, followed by the addition of isopropanol (150 ml) and additional stirring at room temperature for 2 hours. The green suspension is partitioned between ethyl acetate (200 ml) and water (300 ml), and the organic layer is separated. After drying over anhydrous magnesium sulfate, solvents are removed in vacuo to afford 2-(4-bromo-2-ethylphenyl)cyclopent-4-ene-1,3-dione as an orange gum.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[O:9][CH2:10][C:11]#[N:12].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:24](N)[CH2:25][NH2:26].ClC1C=CC=CC=1Cl.C>C(Cl)Cl.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[O:9][CH2:10][C:11]1[NH:26][CH2:25][CH2:24][N:12]=1
Reactant: NCCN
Reactant: Cc1ccc(Cl)c(OCC#N)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Clc1ccccc1Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Cc1ccc(Cl)c(OCC2=NCCN2)c1
Yield: 32.7 %

Procedure:
A mixture of 36.3 g of 4-chloro-m-tolyloxyacetonitrile, 46.6 g of ethylenediamine p-toluenesulfonate and 150 ml of 1,2-dichlorobenzene was heated with stirring in a 500 ml round-bottomed three-necked flask at reflux under a small flow of nitrogen for 1.5 hours, essentially as described in U.S. Pat. No. 3,449,356. The reaction mixture was cooled, diluted with methylene chloride and the solids filtered off. The solids were slurried in water and then basified with 5 normal (N) sodium hydroxide and then filtered. The solids were washed well with water and dried to obtain 42.0 g of the crude product, m.p. 91°-95° C. A 19.5 g portion of the crude product was put in solution in approximately 150 ml of boiling toluene, treated with activated charcoal and filtered. The filtrate was cooled and then filtered, which gave 14.7 g of purified 2-(((4-chloro-m-tolyl)oxy)methyl)-2-imidazoline, m.p. 90°-92° C.
Reaction SMILES: S(O)(=O)(C1C=CC([NH2:9])=CC=1)=O.C([O-])([O-])=O.[Na+].[Na+].N([O-])=O.[Na+].Cl.[OH-].[Na+].[CH3:25][C:26]1[C:31]([CH3:32])=[CH:30][CH:29]=[C:28]([CH3:33])[C:27]=1[OH:34].[O-]S(S([O-])=O)=O.[Na+].[Na+]>O.C(OCC)(=O)C>[NH2:9][C:30]1[CH:29]=[C:28]([CH3:33])[C:27]([OH:34])=[C:26]([CH3:25])[C:31]=1[CH3:32]
Reactant: Cc1ccc(C)c(O)c1C
Reactant: Nc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(N)c(C)c(C)c1O
Temperature: 15 °C
Reaction time: 0.75 h

Procedure:
Into a solution of sulfanilic acid (13.0 grams, 68 mmol) in water (68 milliliters) contained in a 250 milliliter round bottom flask equipped with a magnetic stirrer, internal thermometer and ice bath at 15° C. was added solid Na2CO3 (3.69 grams, 34 mmol) followed by a solution of NaNO2 (5.1 grams, 74 mmol) in water (14 milliliters). The latter addition caused a color change from milky-white to orange. A separate 500 milliliter three-necked flask equipped with a magnetic stirrer, internal thermometer and ice bath was charged with concentrated hydrochloric acid (12 milliliters), ice (68 grams) and the solution of the diazonium salt prepared above. This mixture was stirred at 15° C. for 45 minutes. Meanwhile a third flask (1 L) equipped with an internal thermometer, nitrogen inlet, condenser, addition funnel and mechanical stirrer was charged with water (68 milliliters), NaOH (14.96 grams, 318 mmol) and 2,3,6-trimethylphenol (9.30 grams, 68 mmol). This mixture was cooled to 0° C. by means of an ice-salt mixture and the diazonium salt - hydrochloric acid mixture prepared above was added dropwise while maintaining the temperature below 5° C. Upon completion of the diazonium salt addition the reaction mixture was warmed to 52° C. and solid Na2S2O4 (3.13 grams, 18 mmol) was added. Stirring was continued and the mixture heated to 80° C. whereupon additional Na2S2O4 (28.2 grams, 162 mmol) was added in three equal portions (9.4 grams each) at 5 minute intervals. The mixture was heated at 80° C. under nitrogen for 20 minutes, cooled to room temperature and filtered to afford the crude product as a yellow solid. The solid was dissolved in ethyl acetate (300 milliliters) and washed with water. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to afford 4-amino-2,3,6-trimethylphenol in quantitative yield which was used successfully in subsequent reactions without further purification. H'-NMR (CDCl3) 6.30 (S, 1H), 2.11 (S, 9H).
Reaction SMILES: COC1C=CC(C)=CC=1C(N[C@H]1CCC[C@@H]1NC1C=NC(C(F)(F)F)=CN=1)=O.Cl.[F:30][C:31]([F:46])([F:45])[C:32]1[N:33]=[CH:34][C:35]([NH:38][C@H:39]2[CH2:43][CH2:42][CH2:41][C@@H:40]2[NH2:44])=[N:36][CH:37]=1.[F:47][C:48]1[CH:49]=[CH:50][C:51]([N:57]2[CH:61]=[CH:60][N:59]=[N:58]2)=[C:52]([CH:56]=1)[C:53](O)=[O:54]>>[F:47][C:48]1[CH:49]=[CH:50][C:51]([N:57]2[CH:61]=[CH:60][N:59]=[N:58]2)=[C:52]([CH:56]=1)[C:53]([NH:44][C@H:40]1[CH2:41][CH2:42][CH2:43][C@@H:39]1[NH:38][C:35]1[CH:34]=[N:33][C:32]([C:31]([F:30])([F:45])[F:46])=[CH:37][N:36]=1)=[O:54]
Reactant: N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1
Reactant: O=C(O)c1cc(F)ccc1-n1ccnn1
Agent: COc1ccc(C)cc1C(=O)N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1
Agent: Cl
Product: O=C(N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1)c1cc(F)ccc1-n1ccnn1

Procedure:
Prepared according to the procedure for 2-methoxy-5-methyl-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]benzamide (Example 37) from (1S,2S)-1-N-[5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 14; 75 mg, 0.27 mmol) and 5-fluoro-2-(1H-1,2,3-triazol-1-yl)benzoic acid (Intermediate 9; 66 mg, 0.32 mmol) to afford the title compound.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([Br:8])[CH:2]=1.Br[CH2:10][C:11]#[N:12].C([O-])([O-])=O.[Cs+].[Cs+]>CC#N>[Br:8][C:3]1[CH:4]=[CH:5][C:6]([O:7][CH2:10][C:11]#[N:12])=[CH:1][CH:2]=1
Reactant: N#CCBr
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: N#CCOc1ccc(Br)cc1
Temperature: 80 °C

Procedure:
A mixture of p-bromophenol (2.61 g; 15.1 mmol), bromoacetonitrile (1.11 mL; 15.9 mmol), and Cs2CO3 (7.40 g; 22.7 mmol) in anhyd MeCN (25 mL) was heated at 80° C., under N2 overnight. The mixture was cooled, filtered through a pad of Celite and concentrated in vacuo. The residue was dissolved in a minimal amount of EtOAc/hexanes and filtered through a short pad of silica gel (EtOAc/hexanes eluent), affording the title compound as a colorless, waxy solid which was used without further purification. 1H NMR (400 MHz, CDCl3) δ 4.75 (s, 2H), 6.88 (m, 2H), 7.46 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.Br[CH2:18][CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[O:28][CH3:29].[C:30]([OH:37])(=[O:36])/[CH:31]=[CH:32]\[C:33]([OH:35])=[O:34]>C(#N)C.C(O)C>[C:30]([OH:37])(=[O:36])/[CH:31]=[CH:32]\[C:33]([OH:35])=[O:34].[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[O:28][CH3:29])[CH2:20][CH2:19][CH3:18])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: COc1ccccc1CCCCBr
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C(O)/C=C\C(=O)O
Solvent: CCO
Solvent: CC#N
Product: CCCC(c1ccccc1OC)N1CCC(c2noc3cc(F)ccc23)CC1

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.36 g, 10.7 mmole), K2CO2 (2 g, 14.5 mmol) and 2-(4-bromobutyl)anisole (2.4 g, 10 mmol) in acetonitrile (100 ml) was heated at reflux for 2.5 hours. At the end of reaction, the solvent was removed. The residue was extracted into dichloromethane (200 ml) and filtered. The dichloromethane solution was concentrated. The crude oil obtained was purified on a flash chromatography column. The material thus purified was a light yellow oil (2.73 g, 53%). This oil was dissolved in ethanol and treated with maleic acid (607 mg, 1.0 eq) in ethanol. The 4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-(2'-methoxyphenyl)butylpiperidine maleate crystals formed on concentration and subsequent cooling to 0° C. These were collected and dried to yield 2.05 g, m.p.=132°-133° C.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][C:13]1[C:14]([CH2:30][S:31][C:32]2[NH:36][C:35]3[CH:37]=[CH:38][CH:39]=[CH:40][C:34]=3[N:33]=2)=[N:15][CH:16]=[CH:17][C:18]=1[O:19][CH2:20][CH2:21][O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>ClCCl>[CH3:12][C:13]1[C:14]([CH2:30][S:31]([C:32]2[NH:33][C:34]3[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=3[N:36]=2)=[O:9])=[N:15][CH:16]=[CH:17][C:18]=1[O:19][CH2:20][CH2:21][O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1
Reactant: Cc1c(OCCOCc2ccccn2)ccnc1CSc1nc2ccccc2[nH]1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c(OCCOCc2ccccn2)ccnc1CS(=O)c1nc2ccccc2[nH]1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 79.1 %

Procedure:
0.16 g of m-chloroperbenzoic acid was added to a solution of 0.38 g of 2-[{3-methyl-4-(2-pyridylmethoxyethoxy)pyridine-2-yl}methylthio]-1H-benzimidazole in 20 ml of dichloromethane at -60° C. in a nitrogen atmosphere to obtain a mixture. This mixture was stirred for 0.5 hour. After the completion of the reaction, 0.16 g of triethylamine was added to the reaction mixture. The obtained mixture was heated to -10° C., followed by the addition of 30 ml of a saturated aqueous solution of sodium hydrogencarbonate. The obtained mixture was stirred at a room temperature for 0.5 hour and extracted with 50 ml of dichloromethane thrice. The extract was dried over magnesium sulfate and filtered. The filtrate was concentrated and dried in a vacuum to obtain a crude product. This crude product was crystallized from dichloromethane/diethyl ether to obtain 0.31 g of 2-[{3-methyl-4-(2-pyridylmethoxyethoxy)pyridine-2-yl}methylsulfinyl]-1H-benzimidazole as a white crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7](Cl)=O.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([NH:19][NH2:20])=[NH:18])=[CH:13][CH:12]=1>>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[N:18]=[C:7]([C:3]3[S:4][CH:5]=[CH:6][C:2]=3[Cl:1])[NH:20][N:19]=2)=[CH:15][CH:16]=1
Reactant: N=C(NN)c1ccc(Cl)cc1
Reactant: O=C(Cl)c1sccc1Cl
Product: Clc1ccc(-c2n[nH]c(-c3sccc3Cl)n2)cc1

Procedure:
Compounds of this invention with Formula V may be prepared as illustrated by the exemplary reaction in Scheme 4. Reaction of 3-chloro-thiophene-2-carbonyl chloride with 4-chloro-benzenecarboximidic hydrazide produces the product 3-(4-chloro-phenyl)-5-(3-chloro-thiophen-2-yl)-1H-[1,2,4]-triazole.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][O:7][C:8]([NH:10][C@H:11]([C:20](OC)=[O:21])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[O:9])=[CH:4][CH:3]=1.[H-].[Al+3].[Na+].[H-].[H-].[H-].Cl>O1CCCC1>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][O:7][C:8]([NH:10][C@H:11]([CH2:20][OH:21])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCc1ccc(Cl)cc1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: O=C(N[C@H](CO)Cc1ccc(O)cc1)OCc1ccc(Cl)cc1
Yield: 66.1 %

Procedure:
In 30 ml of tetrahydrofuran was dissoled 1.0 g of methyl N-(4-chlorobenzyloxycarbonyl)tyrosinate. To the solution was slowly added 280 mg of sodium aluminium hydride with stirring and the mixture was stirred for two hours. After addition of 50 ml of 1N hydrochloric acid, the mixture was concentrated in vacuo. The residue was extracted with ethyl acetate and the extract was washed with water, dried and concentrated to dryness. The residue was crystallized from ethyl acetate-petroleum ether to give 610 mg of N-(4-chlorobenzyloxycarbonyl)-tyrosinol: yield 66%.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:8])[CH2:4][CH2:5][CH2:6][OH:7].CS(O[CH2:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])(=O)=O.O>CS(C)=O>[CH2:18]([O:17][CH2:16][CH2:15][CH2:14][O:7][CH2:6][CH2:5][CH2:4][CH2:3][OH:8])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: OCCCCO
Reactant: CCCCCCCCCCCCCCCCCCOCCCOS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCCCCCCCCCCCCCCCCCOCCCOCCCCO
Temperature: 70 °C
Reaction time: 1 h

Procedure:
Sodium hydride (1.2 g) is heated at 70° C. for 10 minutes in dimethyl sulfoxide (50 ml), to which is added 1,4-butanediol (4.5 g). The mixture is heated for one further hour. To this reaction mixture is added dropwise a solution of 3-(octadecyloxy)propyl methanesulfonate obtained in Reference Example 1 (4.06 g) in dimethyl sulfoxide (15 ml), and the mixture is stirred at 70° C. for one hour. The reaction mixture is poured into cold water, and the mixture is subjected to extraction with a mixture of hexane and ethyl acetate. The extract is washed with water and then dried, and the solvents are then distilled off under reduced pressure. The residue is subjected to purification by means of silica gel column chromatography to obtain the above-titled compound (2.2 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[NH:12][C:13]1[C:22]2[C:17](=[C:18]([NH2:23])[CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15][N:14]=1.[Cl:24][C:25]1[C:30]([C:31](O)=[O:32])=[C:29]([F:34])[C:28]([CH2:35][NH:36][C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39])=[CH:27][CH:26]=1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:24][C:25]1[C:30]([C:31]([NH:23][C:18]2[CH:19]=[CH:20][CH:21]=[C:22]3[C:17]=2[N:16]=[CH:15][N:14]=[C:13]3[NH:12][C:3]2[CH:4]=[C:5]([C:8]([F:9])([F:10])[F:11])[CH:6]=[CH:7][C:2]=2[F:1])=[O:32])=[C:29]([F:34])[C:28]([CH2:35][NH:36][C:37](=[O:42])[C:38]([CH3:40])([CH3:39])[CH3:41])=[CH:27][CH:26]=1
Reactant: Nc1cccc2c(Nc3cc(C(F)(F)F)ccc3F)ncnc12
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1F
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)Nc2cccc3c(Nc4cc(C(F)(F)F)ccc4F)ncnc23)c1F
Yield: 6.5 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using N4-(2-fluoro-5-(trifluoromethyl)phenyl)quinazoline-4,8-diamine (Intermediate-14, 100 mg, 0.31 mmol), 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoic acid (Intermediate-2, 178 mg, 0.62 mmol), oxalyl chloride (117 mg, 0.93 mmol), DMF (1 drop) and DIPEA (120 mg, 0.93 mmol) in CH2Cl2 (5 mL) to afford 12 mg of the title product. 1H NMR (300 MHz, CDCl3): δ 9.92 (s, 1H), 9.15 (d, 1H), 9.08 (d, 1H), 8.79 (s, 1H), 7.83 (s, 1H), 7.66 (m, 2H), 7.40 (m, 2H), 4.50 (d, 2H), 1.23 (s, 9H); MS (m/z): 592.20 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:22]=[C:5]2[C:6]([NH:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[S:18]([CH3:21])(=[O:20])=[O:19])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:31]=[C:32]([CH:34]=[CH:35][CH:36]=2)[NH2:33])[CH2:26][CH2:25]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:21][S:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][NH:10][C:6]1[C:5]2[N:4]([N:3]=[C:2]([NH:33][C:32]3[CH:34]=[CH:35][CH:36]=[C:30]([N:27]4[CH2:26][CH2:25][N:24]([CH3:23])[CH2:29][CH2:28]4)[CH:31]=3)[N:22]=2)[CH:9]=[CH:8][CH:7]=1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)c1ccccc1CNc1cccn2nc(Cl)nc12
Reactant: CN1CCN(c2cccc(N)c2)CC1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCN(c2cccc(Nc3nc4c(NCc5ccccc5S(C)(=O)=O)cccn4n3)c2)CC1

Procedure:
N(8)-(2-Methanesulfonyl-benzyl)-N(2)-[3-(4-methyl-piperazin-1-yl)-phenyl]-[1,2,4]triazolo[1,5-a]pyridine-2,8-diamine was prepared from (2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-(2-methanesulfonyl-benzyl)-amine (75.0 mg, 0.223 mmol) and 3-(4-methylpiperazin-1-yl)aniline (47.0 mg, 0.246 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (25.0 mg, 0.0457 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a tan foam (0.023 g, 21%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.11 (d, J=8.0 Hz, 1H), 7.85 (d, J=6.5 Hz, 1H), 7.66-7.59 (m, 2H), 7.54-7.49 (m, 1H), 7.27-7.23 (m, 1H), 7.21 (t, J=8.2 Hz, 1H), 7.02 (d, J=9.2 Hz, 1H), 6.72-6.67 (m, 2H), 6.57 (dd, J=8.2, 1.6 Hz, 1H), 6.43 (d, J=7.6 hZ, 1H), 5.33 (t, J=6.1 Hz, 1H), 4.96 (d, J=6.2 Hz, 2H), 3.29-3.24 (m, 4H), 3.16 (s, 3H), 2.61-2.56 (m, 4H), 2.36 (s, 3H). MS=492 (MH)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[N:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][N:21]2CC3C(=CC=CC=3)C2)[C:15](=[O:30])[CH2:14]1.O.NN>CCO>[NH2:21][CH2:20][CH2:19][N:16]1[CH2:17][CH2:18][N:13]([C:6]2[C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[N:4]=3)[N:9]=[CH:8][CH:7]=2)[CH2:14][C:15]1=[O:30]
Reactant: COc1ccc2nccc(N3CCN(CCN4Cc5ccccc5C4)C(=O)C3)c2n1
Agent: NN
Solvent: O
Solvent: CCO
Product: COc1ccc2nccc(N3CCN(CCN)C(=O)C3)c2n1
Reaction time: 2 h
Yield: 65.8 %

Procedure:
To a solution of 2-(2-{4-[6-(methyloxy)-1,5-naphthyridin-4-yl]-2-oxo-1-piperazinyl}ethyl)-1H-isoindole-1,3(2H-dione (100 mg, 0.232 mmol) in EtOH (2 mL) was added hydrazine hydrate (120 μL, 3.85 mmol). After 2 h at 85° C., the solution was concentrated and the residue purified by column chromatography (silica, 5-10% MeOH in DCM (1% NH4OH)) yielding the title compound (46 mg, 66%) as a yellow oil: LCMS (ES) m/e 302 (M+H)+.