Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([SH:5])[CH3:4].[CH2:6](Cl)/[CH:7]=[C:8](/[CH2:10][CH2:11][CH2:12][C@@H:13]([CH2:15][CH2:16][CH2:17][C@@H:18]([CH2:20][CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])[CH3:19])[CH3:14])\[CH3:9]>CN(C)C=O.C(OCC)(=O)C>[CH2:6]([S:5][CH2:3][CH3:4])/[CH:7]=[C:8](/[CH2:10][CH2:11][CH2:12][C@@H:13]([CH2:15][CH2:16][CH2:17][C@@H:18]([CH2:20][CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])[CH3:19])[CH3:14])\[CH3:9]
Reactant: C/C(=C\CCl)CCC[C@H](C)CCC[C@H](C)CCCC(C)C
Reactant: CCS
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCSC/C=C(\C)CCC[C@H](C)CCC[C@H](C)CCCC(C)C
Reaction time: 3 h
Yield: 92.5 %

Procedure:
0.84 g of sodium hydride was added to a solution of 2.40 g of ethylmercaptan dissolved in 30 ml of N,N-dimethylformamide. Thereinto was dropped 10.00 g of phytyl chloride at 40° C. The resulting mixture was stirred at the same temperature for 3 hours. After the completion of the reaction, the resulting mixture was concentrated under reduced pressure. The residue obtained was dissolved in 30 ml of ethyl acetate. The resulting solution was washed with 1N hydrochloric acid, 3% aqueous sodium hydrogencarbonate solution and water in this order and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue obtained was purified by a column chromatography (eluant: n-hexane:ethyl acetate=9:1) to obtain 10.00 g (yield: 92%) of oily ethyl phytyl thioether.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[C:16]([CH:24]1[CH2:28][N:27]([C:29]2[CH:34]=[CH:33][C:32]([OH:35])=[C:31]([F:36])[CH:30]=2)[C:26](=[O:37])[CH2:25]1)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C1C=CN=CC=1)C.O1CCOCC1.CCOC(C)=O>[C:16]([CH:24]1[CH2:28][N:27]([C:29]2[CH:34]=[CH:33][C:32]([O:35][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=4)[N:5]=[CH:4][CH:3]=3)=[C:31]([F:36])[CH:30]=2)[C:26](=[O:37])[CH2:25]1)(=[O:23])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: O=C(c1ccccc1)C1CC(=O)N(c2ccc(O)c(F)c2)C1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1cc2nccc(Oc3ccc(N4CC(C(=O)c5ccccc5)CC4=O)cc3F)c2cc1OC
Temperature: 160 °C

Procedure:
A mixture of 4-chloro-6,7-dimethoxyquinoline (0.38 g, 1.67 mmol), 4-benzoyl-1-(3-fluoro-4-hydroxyphenyl)pyrrolidin-2-one (Step 3, 0.40 g, 1.67 mmol) and DMAP (0.204 g, 1.67 mmol) in 4 mL of dioxane (in a microwave tube) was heated in a microwave (Personal Chemistry, Emrys Optimizer) at 160° C. for 1 h. The mixture was cooled to RT and diluted with 50 mL of EtOAc. The solution was washed with 20 mL of satd. NaHCO3 followed by 20 mL of brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography (50% to 100% EtOAc in hexanes then to 5% MeOH/EtOAc) to provide a white solid. MS (ESI pos. ion) m/z: 487.4 (M+H). Calc'd Exact Mass for C28H23FN2O5: 486.49.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1.Cl[C:19]([O:21][CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:20]>>[CH:22]1([O:21][C:19]([NH:1][CH:2]2[CH2:3][CH2:4][N:5]([C:8]([O:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:9])[CH2:6][CH2:7]2)=[O:20])[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=C(Cl)OC1CCCC1
Reactant: NC1CCN(C(=O)OCc2ccccc2)CC1
Product: O=C(NC1CCN(C(=O)OCc2ccccc2)CC1)OC1CCCC1

Procedure:
The title compound is prepared from benzyl 4-aminopiperidine-1-carboxylate and cyclopentyl chloroformate following a procedure analogous to that described for Intermediate 26 Step 1. LC (method 1): tR=1.06 min; Mass spectrum (ESI+): m/z=347 [M+H]+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][Si:5]([O:12][CH2:13][CH3:14])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8].NC(N)=[S:17].[I-].[Na+].N>>[SH:17][CH2:2][CH2:3][CH2:4][Si:5]([O:12][CH2:13][CH3:14])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8]
Reactant: CCO[Si](CCCCl)(OCC)OCC
Reactant: NC(N)=S
Agent: N
Agent: [I-]
Agent: [Na+]
Product: CCO[Si](CCCS)(OCC)OCC

Procedure:
A suitable method for the preparation of bis-[γ-(trialkoxysilyl)-propyl]-disulfides is disclosed in copending application Ser. No. 529,203 filed Dec. 3, 1974 entitled "Bis-[γ-(Trialkoxysilyl)-Propyl]-Disulfides of High Purity", the disclosure of which is hereby incorporated specifically herein by reference. According to the process therein disclosed such a disulfide can be prepared by reacting a γ-chloropropyl-triethoxy silane with thiourea and sodium iodide in alcohol for 24 hours at ebullition. After the reaction mixture is cooled to room temperature and over a period of 4 hours a strong current of ammonia is passed through the solution. This causes ammonium chloride to precipitate. The filtrate and precipitate are separated and the filtrate can be concentrated whereby to obtain γ-mercaptopropyl-triethoxy silane. This latter material can be reacted with sulfuryl chloride in a solvent such as anhydrous benzene at a temperature of +8 - + 12°C. The SO2Cl2 is added to the γ-mercapto-propyl-triethoxy silane dropwise over a period of about 55 minutes. Sulfur dioxide and hydrogen chloride gas which are formed are removed by a nitrogen gas purge. After a period of about 6 hours at room temperature with stirring triethylamine can be added whereby to precipitate the amine hydrochloride. The filtrate is then fractionally distilled whereby there is recovered a bis-[γ-(triethoxysilyl)-propyl]-disulfide.
Reaction SMILES: [N:1]1([C:6]2[N:11]=[CH:10][C:9]3[CH:12]([C:15]([O-:17])=[O:16])[CH2:13][CH2:14][C:8]=3[CH:7]=2)[CH:5]=[N:4][N:3]=[N:2]1.[OH-].[Li+]>O1CCCC1.O>[N:1]1([C:6]2[N:11]=[CH:10][C:9]3[CH:12]([C:15]([OH:17])=[O:16])[CH2:13][CH2:14][C:8]=3[CH:7]=2)[CH:5]=[N:4][N:3]=[N:2]1
Reactant: O=C([O-])C1CCc2cc(-n3cnnn3)ncc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C1CCc2cc(-n3cnnn3)ncc21

Procedure:
A solution of 3-(1H-tetrazol-1-yl)-6,7-dihydro-5H-cyclopenta[c]pyridine-7-carboxylate (235 mg, 0.958 mmol) in tetrahydrofuran (5 mL) and water (1.5 mL) at room temperature was treated with lithium hydroxide solution (1 M, 1.44 mL). After 30 min. the solution was concentrated to remove tetrahydrofuran and the remaining aqueous acidified with 1 N hydrochloric acid solution (to Ph ˜4) and extracted with ethyl acetate (3×). The combined organics were washed with brine, dried (Na2SO4), filtered and concentrated to provide 3-(1H-tetrazol-1-yl)-6,7-dihydro-5H-cyclopenta[c]pyridine-7-carboxylic acid. 1H NMR (500 MHz, CD3OD), δ 9.89 (s, 1H), 8.58 (s, 1H), 8.01 (s, 1H), 4.25 (dd, J=5.0, 5.0 Hz, 1H), 3.27-3.05 (m, 2H), 2.47-2.57 (m, 2H); LC/MS (M+1)+=232.2.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][CH:8]([C:12](=[O:23])[NH:13][C:14]1[CH:18]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[O:16][N:15]=1)[CH2:9]CC)([CH3:4])([CH3:3])[CH3:2].NC1C=CON=1>>[C:1]([O:5][C:6](=[O:24])[NH:7][CH:8]([C:12](=[O:23])[NH:13][C:14]1[CH:18]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[O:16][N:15]=1)[CH3:9])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCCC(NC(=O)OC(C)(C)C)C(=O)Nc1cc(C(C)(C)C)on1
Agent: Nc1ccon1
Product: CC(NC(=O)OC(C)(C)C)C(=O)Nc1cc(C(C)(C)C)on1

Procedure:
Prepared by the analogous method for the preparation of [1-(5-tert-butyl-isoxazol-3-ylcarbamoyl)butyl]-carbamic acid tert-butyl ester, starting with an appropriate amino-isoxazole (1a-b) together with an appropriate N-t-BOC-amino acid methyl or ethyl ester.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:5]=[CH:4][N:3]=1.[OH:18][C:19]1[CH:28]=[C:27]2[C:22]([CH:23]=[CH:24][C:25](=[O:29])[NH:26]2)=[CH:21][CH:20]=1.N12CCCN=C1CCCCC2>CC#N>[F:15][C:14]([F:17])([F:16])[C:11]1[CH:12]=[CH:13][C:8]([C:6]2[N:5]=[CH:4][N:3]=[C:2]([O:18][C:19]3[CH:28]=[C:27]4[C:22]([CH:23]=[CH:24][C:25](=[O:29])[NH:26]4)=[CH:21][CH:20]=3)[CH:7]=2)=[CH:9][CH:10]=1
Reactant: O=c1ccc2ccc(O)cc2[nH]1
Reactant: FC(F)(F)c1ccc(-c2cc(Cl)ncn2)cc1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=c1ccc2ccc(Oc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)cc2[nH]1

Procedure:
The title compound was prepared analogous to the methods used in Example 32(e) using 4-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidine, (Example 2(a), Method A), (0.50 g, 1.9 mmol), 7-hydroxy-1H-quinolin-2-one (0.37 g, 2.3 mmol, prepared according to Synthesis 1997, 87-90) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.35 mL, 2.3 mmol, Aldrich) in CH3CN (40 mL). Purification by flash chromatography (0→2.5% MeOH/CH2Cl2) afforded the title compound as an off-white powder. Mp 288° C. MS (ESI, pos. ion) m/z: 384 (M+1).
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]([CH2:21][CH2:22][NH:23][C:24](=[O:26])[CH3:25])[C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[C:14]([S:19][CH3:20])[CH:13]=2)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.[H-].C([SiH](CC)CC)C>>[CH2:1]([C:9]1[CH:10]=[C:11]([CH2:21][CH2:22][NH:23][C:24](=[O:26])[CH3:25])[C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[C:14]([S:19][CH3:20])[CH:13]=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CSc1ccc2cc(C(=O)c3ccccc3)cc(CCNC(C)=O)c2c1
Agent: CC[SiH](CC)CC
Agent: [H-]
Solvent: O=C(O)C(F)(F)F
Product: CSc1ccc2cc(Cc3ccccc3)cc(CCNC(C)=O)c2c1

Procedure:
A solution of the product obtained in Example 6 (2.06 mmol) in trifluoroacetic acid (20.6 mmol) is brought to 0° C. and then triethylsilane hydride (6.18 mmol) is added dropwise. Stirring is carried out at ambient temperature for one week and a fourth equivalent of triethylsilane hydride is then added. The reaction mixture is stirred for 24 hours more and is then hydrolysed and extracted with ethyl acetate. The organic phase is washed with water, dried over magnesium sulphate and evaporated. The residue is chromatographed on silica gel (eluant: acetone/toluene/cyclohexane 30/50/20) and is then recrystallised twice from toluene to yield the title product in the form of a white solid.
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:33])[C:13]1[CH:18]=[CH:17][C:16]([CH:19]=[N:20][N:21]=[C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[C:28]([F:31])[CH:29]=3)[NH:24][C:23]2=[O:32])=[CH:15][CH:14]=1.CO.[Li+].[OH-].Cl>O>[F:31][C:28]1[CH:29]=[C:30]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23](=[O:32])[C:22]2=[N:21][N:20]=[CH:19][C:16]1[CH:15]=[CH:14][C:13]([C:12]([NH:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:34])=[O:2])=[O:33])=[CH:18][CH:17]=1
Reactant: COC(=O)CCCCCCCNC(=O)c1ccc(C=NN=C2C(=O)Nc3ccc(F)cc32)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CCCCCCCNC(=O)c1ccc(C=NN=C2C(=O)Nc3ccc(F)cc32)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 32.9 %

Procedure:
8-(4-(((5-fluoro-2-oxoindolin-3-ylidene)hydrazono)methyl)benzamido)octanoic acid methyl ester (466 mg, 1 mmol) and 300ml of CH3OH were stirred at room temperature while 25 ml of 4 N solution of LiOH in H2O was added. The mixture was stirred for 24 hours at room temperature. The mixture is neutralized with concentrated hydrochloric acid to pH 7 and evaporated under vacuum to remove methanol. The residue was adjusted to pH 3 with concentrated hydrochloric acid. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (149 mg, 33% yield) as a brown solid. LC-MS (m/z) 453 (M+1).
Reaction SMILES: [C:1]1([C:7]2[S:11][C:10]([NH2:12])=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:13][CH2:14][CH2:15][CH2:16][C:17](Cl)=[O:18].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[Cl:13][CH2:14][CH2:15][CH2:16][C:17]([NH:12][C:10]1[S:11][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][N:9]=1)=[O:18]
Reactant: O=C(Cl)CCCCl
Reactant: Nc1nnc(-c2ccccc2)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C(CCCCl)Nc1nnc(-c2ccccc2)s1
Yield: 85.2 %

Procedure:
A mixture of 5-phenyl-1,3,4-thiadiazol-2-amine (7.1 g, 0.04 mol), 4-chloro-butyryl chloride (11.3 g, 9.0 ml, 0.08 mol) and potassium carbonate (5.5 g, 0.04 mole) in toluene (100 ml) was heated under reflux for 4 hr. The toluene was then evaporated under reduced pressure. The residue was then quenched with water, stirred, and filtered. The solid obtained was washed, dried and recrystallized from toluene to give the required product (9.6 g, 85% yield), mp 159-62° C., m/e 281, 87% (consistent with molecular formula C12H12ClN3OS, calcd. 281.04). 1H NMR (DMSO-d6): δ 2.07-2.10 (m, 2H, —CH2), 2.67-2.70 (m, 2H, —CH2), 3.70-3.72 (m, 2H, —CH2), 7.48-7.54 (m, 3H, ArH), 7.93-7.94 (m, 2H, ArH), 12.65 (br s, 1H, NH). 13C NMR: δ 27.9, 32.7, 45.1, 127.4, 129.8, 130.7, 131.0, 158.5, 162.4, 171.2.
Reaction SMILES: [F:1][CH:2]([F:18])[O:3][C:4]1[C:5]([CH3:17])=[C:6]([CH:10]=[CH:11][C:12]=1[S:13]([CH3:16])(=[O:15])=[O:14])[C:7]([OH:9])=O.Cl.[OH:20][C:21]1[N:25]([CH3:26])[N:24]=[CH:23][CH:22]=1.Cl.C(N=C=NCCCN(C)C)C.CN(C1C=CC=CN=1)C>C(#N)C.C(N(CC)CC)C>[F:18][CH:2]([F:1])[O:3][C:4]1[C:5]([CH3:17])=[C:6]([C:7]([C:22]2[CH:23]=[N:24][N:25]([CH3:26])[C:21]=2[OH:20])=[O:9])[CH:10]=[CH:11][C:12]=1[S:13]([CH3:16])(=[O:15])=[O:14]
Reactant: Cn1nccc1O
Reactant: Cc1c(C(=O)O)ccc(S(C)(=O)=O)c1OC(F)F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1c(C(=O)c2cnn(C)c2O)ccc(S(C)(=O)=O)c1OC(F)F
Reaction time: 12 h

Procedure:
To a stirred mixture of 3-(difluoromethoxy)-2-methyl-4-(methylsulfonyl)benzoic acid (500 mg, 1.78 mmol) and 5-hydroxy-1-methylpyrazole hydrochloride (288 mg) in anhydrous acetonitrile (10 mL) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (443 mg), triethylamine (360 mg) and dimethylaminopyridine (217 mg) at room temperature. After being stirred for 12 hours, the reaction mixture was concentrated under reduced pressure, and the residue was dissolved in 100 mL of methylene chloride. This solution was washed with 100 mL of water, and the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was dissolved in 10 mL of anhydrous acetonitrile, and triethylamine (260 mg) and acetone cyanohydrin in a catalytic amount were added, followed by stirring overnight at room temperature. 150 mL of methylene chloride was added, followed by extraction with a 1N potassium carbonate aqueous solution, and the aqueous layer was acidified by 2N hydrochloric acid. The obtained acidic aqueous solution was extracted twice with methylene chloride (100 mL), the combined organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (ethyl acetate:hexane=1:1 to 9:1) to obtain 5-hydroxy-1-methylpyrazol-4-yl 3-(difluoromethoxy)-2-methyl-4-(methylsulfonyl)phenyl ketone as an oil.
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].ClC(Cl)(Cl)S(O[CH2:18][C:19]([F:22])([F:21])[F:20])(=O)=O>C1(C)C=CC=C(C)C=1>[F:20][C:19]([F:22])([F:21])[CH2:18][NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1ccccc1N
Reactant: O=S(=O)(OCC(F)(F)F)C(Cl)(Cl)Cl
Solvent: Cc1cccc(C)c1
Product: COC(=O)c1ccccc1NCC(F)(F)F

Procedure:
A solution of methyl anthranilate (98.3 g) and trifluoroethyl trichloromethanesulphonate (91.5 g) in m-xylene (200 ml) was heated at reflux for 3 h under nitrogen. The reaction mixture was allowed to cool overnight, then filtered from a white solid, washing well with diethyl ether. The combined filtrates were evaporated in vacuo and the residual oil purified by flash chromatography (silica gel, 10% diethyl ether/hexane) to give methyl 2-[N-(2,2,2-trifluoroethyl)]aminobenzoate, contaminated with trifluoroethyl trichloromethanesulphonate. To a solution of this mixture (35.8 g) in dichloromethane (150 ml), cooled to 1° C. under nitrogen, was added dropwise bromoacetyl bromide (10.1 ml), keeping the temperature below +3° C. The reaction mixture was stirred at 0°±3° C. for 12 min, then 4N NaOH solution (33.4 ml) was added dropwise over 18 min. The cooling bath was removed and the reaction mixture was stirred at room temperature for 4 h. More bromoacetyl bromide (1.6 ml) was added dropwise and the mixture was stirred for a further 6 h. After leaving to stand overnight, the organic layer was separated, washed with 10% citric add (30 ml), brine (30 ml), saturated potassium carbonate solution (30 ml) and brine (30 ml), dried (Na2SO4) and evaporated in vacuo to leave a yellow oil. This was purified by flash chromatography (silica gel, 20-25% EtOAc/petroleum ether) to afford the title compound (27.4 g). 1H NMR (CDCl3) δ3.58 (1H, d, J=11.4 Hz), 3.64 (1H, d, J=11.3 Hz), 3.83 (1H, m), 3.90 (3H, s), 4.79 (1H, m), 7.49 (1H, d, J=7.8 Hz), 7.57 (1H, t of d, J=7.6 and 1.3 Hz), 7.68 (1H, t of d, J=7.6 and 1.7 Hz), 8.09 (1H, dd, J=7.8 and 1.6 Hz). MS (CI+, NH3) m/e 373/371 (M+NH4)+.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[N:5][CH:6]=[C:7]([CH2:13][N:14]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:8]=2)[N:3]=1.C1C2NC3C(=CC=CC=3)C=2C=CC=1.[H-].[Na+].Br.NC1N=C(N)C2C(=NC=C(CBr)N=2)N=1>>[NH2:1][C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[N:5][CH:6]=[C:7]([CH2:13][N:14]3[C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[C:26]4[C:21]3=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:8]=2)[N:3]=1
Reactant: Nc1nc(N)c2nc(CN(c3ccccc3)c3ccccc3)cnc2n1
Agent: Br
Agent: Nc1nc(N)c2nc(CBr)cnc2n1
Agent: [H-]
Product: Nc1nc(N)c2nc(Cn3c4ccccc4c4ccccc43)cnc2n1

Procedure:
N-[(2,4-Diaminopteridin-6-yl)methyl]carbazole (Formula I: Ar=2,4-diaminopteridin-6-yl; W=CH2; X=N; Z=chemical bond; m=n=0) is prepared similarly to N-(2,4-diaminopteridin-6-yl)methyl-N,N-diphenylamine as disclosed above by using carbazole (129 mg, 0.77 mmol), NaH (50 mg, 2.1 mmol), and 2,4-diamino-6-bromomethylpteridine hydrobromide (100 mg, 0.3 mmol). The product can be purified by chromatography.
Reaction SMILES: C(O[C:4]([C:6]1[CH:11]=[C:10]([C:12]2[CH:13]=[N:14][CH:15]=[C:16]([F:18])[CH:17]=2)[CH:9]=[C:8]([CH3:19])[N:7]=1)=[O:5])C.Cl.[CH:21]1([C:26]2[N:27]=[C:28]([NH2:31])[S:29][CH:30]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1>>[CH:21]1([C:26]2[N:27]=[C:28]([NH:31][C:4]([C:6]3[CH:11]=[C:10]([C:12]4[CH:13]=[N:14][CH:15]=[C:16]([F:18])[CH:17]=4)[CH:9]=[C:8]([CH3:19])[N:7]=3)=[O:5])[S:29][CH:30]=2)[CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: Nc1nc(C2CCCC2)cs1
Reactant: CCOC(=O)c1cc(-c2cncc(F)c2)cc(C)n1
Agent: Cl
Product: Cc1cc(-c2cncc(F)c2)cc(C(=O)Nc2nc(C3CCCC3)cs2)n1

Procedure:
The title compound, was prepared from 5-Fluoro-6′-methyl-[3,4′]bipyridinyl-2′-carboxylic acid ethyl ester in accordance with the general method of example 26, step 6 using 4-Cyclopentyl-thiazol-2-ylamine, hydrochloride instead of 3-chloroaniline to yield the final compound as a white solid, MS (ISP): m/e=383 [M]+.
Reaction SMILES: Br[C:2]1[CH2:3][CH2:4][CH2:5][O:6][CH:7]=1.[Cl:8][C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].C(O)C.O>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:2]2[CH2:3][CH2:4][CH2:5][O:6][CH:7]=2)=[CH:11][CH:10]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: BrC1=COCCC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: Clc1ccc(C2=COCCC2)cc1
Temperature: 100 °C
Reaction time: 12 h
Yield: 58.7 %

Procedure:
A mixture of 5-bromo-3,4-dihydro-2H-pyran (1.0 g, 6.13 mmol), (4-chlorophenyl)boronic acid (1.05 g, 6.74 mmol), potassium carbonate (2.5 g, 18.4 mmol), Pd(dppf)Cl2 (449 mg, 0.613 mmol), and ethanol/water (2/2 mL) in toluene (10 mL) was stirred at 100° C. for 12 hours. The mixture was filtered, and the filtrate was evaporated and purified by silica gel chromatography to give the title compound (700 mg, 58.8%) as orange solid. 1H NMR (400 MHz, CD3OD) δ ppm 7.25 (d, 2H), 7.20 (d, 2H) 6.90 (s, 1H), 4.03 (t, 2H), 2.37 (t, 2H), 2.02 (m, 2H)
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[C:16]([N:24]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:25][CH2:26][OH:27])[C:17]4[CH2:23][NH:22][CH2:21][CH2:20][C:18]=4[N:19]=3)=[CH:9][CH:8]=2)[CH:4]=[N:3]1.[C:34](O)(=O)C.C=O.C([BH3-])#N.[Na+]>CO>[CH3:34][N:22]1[CH2:21][CH2:20][C:18]2[N:19]=[C:14]([NH:13][C:10]3[CH:9]=[CH:8][C:7]([C:5]4[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=4)=[CH:12][CH:11]=3)[N:15]=[C:16]([N:24]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:25][CH2:26][OH:27])[C:17]=2[CH2:23]1
Reactant: CC(=O)O
Reactant: Cn1cc(-c2ccc(Nc3nc4c(c(N(CCO)c5ccccc5)n3)CNCC4)cc2)cn1
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CN1CCc2nc(Nc3ccc(-c4cnn(C)c4)cc3)nc(N(CCO)c3ccccc3)c2C1
Yield: 107.6 %

Procedure:
2-((2-(4-(1-Methyl-1H-pyrazol-4-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)(phenyl)amino)ethanol (40 mg, 0.09 mmol) was dissolved in methanol (2 mL). Acetic acid (1.037 μL, 0.02 mmol) was added followed by formaldehyde (0.014 mL, 0.18 mmol). The reaction mixture was stirred at room temperature for 30 minutes before sodium cyanoborohydride (11.39 mg, 0.18 mmol) was added. After 20 minutes the solvent was evaporated under reduced pressure, the crude dissolved in few drops of DMF and acetonitrile, filtered and purified by preparative HPLC yielding 2-((6-methyl-2-(4-(1-methyl-1H-pyrazol-4-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)(phenyl)amino)ethanol (9.8 mg, 21%) as acetic acid salt. MS (ESI) (M+H) m/z 456;
Reaction SMILES: [C:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]2[S:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][C:16]([C:19]#[C:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=O)=[CH:15][CH:14]=3)[C:5]=2[C:4]=1[OH:28])#[N:2].C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:61][CH2:62][N:63](CC)[CH2:64][CH3:65]>CN(C=O)C>[CH2:62]([N:63]([CH2:64][CH3:65])[C:25](=[O:27])[CH2:24][CH2:23][CH2:22][CH2:21][C:20]#[C:19][C:16]1[CH:15]=[CH:14][C:13]([C:12]2[C:5]3[C:4]([OH:28])=[C:3]([C:1]#[N:2])[C:8](=[O:9])[NH:7][C:6]=3[S:10][CH:11]=2)=[CH:18][CH:17]=1)[CH3:61]
Reactant: CCN(CC)CC
Reactant: N#Cc1c(O)c2c(-c3ccc(C#CCCCCC(=O)O)cc3)csc2[nH]c1=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)CCCCC#Cc1ccc(-c2csc3[nH]c(=O)c(C#N)c(O)c23)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 7-[4-(5-cyano-4-hydroxy-6-oxo-6,7-dihydro-thieno[2,3-b]pyridin-3-yl)-phenyl]-hept-6-ynoic acid (24 mg, 0.06 mmol) in 0.5 mL DMF was added HOBT (trace) followed by TBTU (23 mg, 0.07 mmol). The pH of the reaction mixture was adjusted to pH>6 using Et3N, then stirred at rt overnight. Solvent was removed in vacuo, the resulting slurry was redissolved in MeOH and purified using reverse phase HPLC to afford the titled compound. MS (ESI) m/e 448 (M+H)+; 1H NMR (400 MHz, DMSO-d6): δ 1.00 (t, J=8.1 Hz, 3H), 1.10 (t, J=8.1 Hz, 3H), 1.58–1.68 (m, 4H), 2.33 (t, J=6.90 Hz, 2H), 2.45 (t, J=6.90 Hz, 2H), 3.23–3.33 (m, 4H), 6.65 (s, 1H), 7.26 (d, J=8.59 Hz, 2H), 7.42 (d, J=8.59 Hz, 2H).