Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]3[CH:14]=[C:15]([F:18])[CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[C@@H:19]([NH:21][C:22]2[N:30]=[CH:29][N:28]=[C:27]3[C:23]=2[N:24]=[CH:25][N:26]3C2CCCCO2)[CH3:20])[CH:5]=[C:6]([F:8])[CH:7]=1>O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]3[CH:14]=[C:15]([F:18])[CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[C@@H:19]([NH:21][C:22]2[N:30]=[CH:29][N:28]=[C:27]3[C:23]=2[N:24]=[CH:25][NH:26]3)[CH3:20])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: C[C@H](Nc1ncnc2c1ncn2C1CCCCO1)c1nc2ccc(F)cc2n1-c1cc(F)cc(F)c1
Solvent: C1COCCO1
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccc(F)cc2n1-c1cc(F)cc(F)c1
Yield: 41.9 %

Procedure:
A solution of {(S)-1-[1-(3,5-difluorophenyl)-6-fluoro-1H-benzoimidazol-2-yl]ethyl}-[9-(tetrahydropyran-2-yl)-9H-purin-6-yl]amine (137 mg, 0.28 mmol) in 4M HCL in dioxane (10 mL) was stirred for 1 h at RT. The reaction mixture was concentrated in vacuo, diluted with MeOH and loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH, followed by 2M NH3/MeOH. The basic fractions were combined and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PPC, gradient 2.5-10% 2M NH3 in MeOH/DCM) to afford 361 as a white solid (48 mg, 42%). LCMS (Method K): RT 3.65 min [M+H]+ 410. 1H NMR (CDCl3, 400 MHz): δ 12.87 (1H, bs), 8.09-7.94 (3H, m), 7.70 (1H, dd, J=9.0, 5.0 Hz), 7.40-7.38 (2H, m), 7.27-7.23 (1H, m), 7.11 (1H, ddd, J=10.0, 10.0, 2.5 Hz), 7.05-7.02 (1H, m), 5.71-5.61 (1H, m), 1.63 (3H, d, J=7.0 Hz)
Reaction SMILES: [F:1][C:2]1[C:3]([NH2:17])=[N:4][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[N:6][CH:7]=1.[CH2:18]=[O:19]>O1CCOCC1>[F:1][C:2]1[C:3]([NH:17][CH2:18][OH:19])=[N:4][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[N:6][CH:7]=1
Reactant: Cc1ccc(COc2ncc(F)c(N)n2)cc1
Reactant: C=O
Solvent: C1COCCO1
Product: Cc1ccc(COc2ncc(F)c(NCO)n2)cc1
Temperature: 90 °C
Reaction time: 16 h
Yield: 61.8 %

Procedure:
To a solution of 5-fluoro-2-(4-methylbenzyloxy)pyrimidin-4-ylamine (0.10 g, 0.43 mmol) in dioxane (2 mL) was added paraformaldehyde (0.060 g, 2 mmol) and the mixture was agitated on an orbital shaker at 90° C. for 16 h, cooled, and evaporated to dryness. Purification by reverse phase chromatography afforded 0.070 g (63%) of the title compound as a white solid: mp 97-98° C.; 1H NMR (CDCl3) δ 7.94 (d, J=2.5 Hz, 1H), 7.36 (d, J=7.9 Hz, 2H), 7.19 (d, J=7.9 Hz, 2H), 5.97 (bs, 1H), 5.33 (s, 2H), 5.04-4.99 (m, 2H), 3.39 (t, J=8.0 Hz, 1H), 2.37 (s, 3H); MS (ESI) m/z 264 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[OH:4].[C:25]1([C:36](O)=[O:37])[CH:26]=[CH:27][CH:28]=[C:29]2[CH2:35][CH2:34][CH2:33][CH:32]=[CH:31][C:30]=12.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.C(OCC)(=O)C>[CH2:20]([O:19][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[CH2:12][CH:2]([NH:1][C:36]([C:25]1[CH:26]=[CH:27][CH:28]=[C:29]2[CH2:35][CH2:34][CH2:33][CH:32]=[CH:31][C:30]=12)=[O:37])[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[OH:4])[C:21]([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)COc1cccc(CC(N)C(O)c2cccc(Cl)c2)c1
Reactant: O=C(O)c1cccc2c1C=CCCC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)COc1cccc(CC(NC(=O)c2cccc3c2C=CCCC3)C(O)c2cccc(Cl)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.1 %

Procedure:
To a solution of (1RS,2SR)-2-amino-3-[3-(neopentyloxy)phenyl]-1-(3-chlorophenyl)-1-propanol (0.40 g, 0.86 mmol) in N,N-dimethylformamide (5 ml) were added 6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid (0.17 g, 0.90 mmol) and 1-hydroxybenzotriazole monohydrate (0.138 g, 0.90 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.173 g, 0.90 mmol) was finally added. The mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1, 0:1), and recrystallization (hexane-ethyl acetate) to give N-[(1RS,2SR)-1-[3-(neopentyloxy)benzyl]-2-(3-chlorophenyl)-2-hydroxyethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide (0.174 g, 39%) as colorless crystals.
Reaction SMILES: S([CH2:11][N+:12]#[C-])(C1C=CC(C)=CC=1)(=O)=O.[CH2:14]([CH:19]1[CH2:23][CH2:22][CH2:21][C:20]1=O)[CH2:15][CH2:16][CH2:17][CH3:18].C(O[K])(C)(C)C.O>COCCOC.C(O)C>[CH2:14]([CH:19]1[CH2:23][CH2:22][CH2:21][CH:20]1[C:11]#[N:12])[CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCC1CCCC1=O
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)O[K]
Solvent: O
Solvent: CCO
Solvent: COCCOC
Product: CCCCCC1CCCC1C#N
Temperature: 0 °C
Yield: 58.7 %

Procedure:
27.6 g of tosylmethyl isocyanide and 17 g of 2-pentylcyclopentanone were dissolved in 400 ml of 1,2-dimethoxyethane and 10 ml of ethanol. The solution was cooled to 0° C. with an ice-bath, and 29 g of tBuOK were added in 1 hour maintaining the temperature between 0 and 10° C. After completion of the reaction, the reaction mixture was poured into water and extracted with cyclohexane. The organic layer was washed 3 times with water until neutral pH. Purification by bulb-to-bulb distillation (130° C./0.06 mbar) gave 10.7 g of the pure 2-pentylcyclopentanecarbonitrile.
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1)=[O:5].[CH:20]1[C:30]2[CH2:29][CH2:28][C:27]3[CH:31]=[CH:32][CH:33]=[CH:34][C:26]=3[NH:25][C:24]=2[CH:23]=[CH:22][CH:21]=1.[H-].[Na+]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1.ClCCl.O>[CH:20]1[C:30]2[CH2:29][CH2:28][C:27]3[CH:31]=[CH:32][CH:33]=[CH:34][C:26]=3[N:25]([C:11]([C:10]3[CH:14]=[CH:15][C:7]([NH:6][C:4](=[O:5])[C:3]4[CH:16]=[CH:17][CH:18]=[CH:19][C:2]=4[CH3:1])=[CH:8][CH:9]=3)=[O:12])[C:24]=2[CH:23]=[CH:22][CH:21]=1
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)Cl)cc1
Reactant: c1ccc2c(c1)CCc1ccccc1N2
Agent: CN(C)c1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2c3ccccc3CCc3ccccc32)cc1
Temperature: 80 °C
Yield: 3.2 %

Procedure:
To a mixture of 1.37 g (5 mmol) of 4-[(2-methylbenzoyl)amino]benzoyl chloride and 0.061 g of 4-(dimethylamino)pyridine in 4 ml of pyridine is added 0.975 g (5 mmol) of 10,11-dihydro-5H-dibenz[b,f]azepine. The mixture is heated at 80° C. for 18 hours and then 0.2 g of sodium hydride (60% in oil) (5 mmol) is added. The mixture is refluxed for 2 hours, diluted with dichloromethane and water and then filtered. To the filtrate is added 1N HCl and the mixture filtered. The filtrate is dried (Na2 SO4) and the solvent removed to give a solid. The solid (1.1 g) is chromatographed on thick layer silica gel plates to give 70 mg of yellow solid, m.p. 112°-118° C. Anal. Calc'd for C29H24 N2O: C,80.5; H,5.6; N,6.5. Found: C,78.7; H,5.8; N,6.7.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[CH:21]=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])=[CH:4][C:3]=1[CH3:24].[N:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+].B(O)O>C1(C)C=CC=CC=1.C(O)C.O>[CH3:24][C:3]1[CH:4]=[C:5]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[CH:21]=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])[CH:6]=[CH:7][C:2]=1[C:28]1[CH:29]=[CH:30][N:25]=[CH:26][CH:27]=1
Reactant: OB(O)c1ccncc1
Reactant: Cc1cc(C(=O)N2Cc3cccn3Cc3ccccc32)ccc1Br
Agent: O=C([O-])[O-]
Agent: OBO
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc(C(=O)N2Cc3cccn3Cc3ccccc32)ccc1-c1ccncc1
Reaction time: 24 h
Yield: 23.1 %

Procedure:
A suspension of (4-bromo-3-methylphenyl)[10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl]methanone of Step A (1.14 g, 2.9 mmol), pyridine-4-boronic acid (0.368 mg, 2.9 mmol) and sodium carbonate (0.760 g, 7.2 mmol) in a mixture of toluene (30 mL), water (10 mL), and ethanol (5 mL) was sparged with nitrogen for 15 minutes. To this was added tetrakis(triphenylphosphine)palladium(0) (0.027 g) and the mixture was heated to reflux under a static pressure of nitrogen. After 24 hours additional boronic acid (0.128 mg, 1 mmol) and sodium carbonate (0.116 g) were added and the heating was continued for 24 hours. Additional catalyst (0.012 g) was added and heating was continued for another 24 hours. The mixture was partitioned between ethyl acetate and hexane. The water layer was washed twice with ethyl acetate and the combined organic layers were dried over anhydrous magnesium sulfate and stripped to a solid. Flash chromatography of the residue on silica gel eluting with 30% ethyl acetate in hexane provided a solid which was recrystallized from ethyl acetate/hexane to provide the title compound (0.254 g) as tan plates m.p. 208–210° C.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][OH:5].C(=O)([O-])[OH:11].[Na+]>O.[Pt]>[OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH2:6][OH:7])[C:4]([OH:11])=[O:5]
Reactant: OCC(CO)(CO)CO
Reactant: O=C([O-])O
Agent: [Pt]
Agent: [Na+]
Solvent: O
Product: O=C(O)C(CO)(CO)CO
Temperature: 35 °C
Reaction time: 8 h

Procedure:
To a solution of pentaerythritol (10.0 g) in water (600 mL) was 5% platinum/carbon (hydrous article, 13.3 g). While maintaining pH of the reaction mixture to 6˜7 by means of 8% sodium hydrogen carbonate solution, it was stirred at 35° C. for 8 hours under an atmosphere of oxygen. After catalyst was filtered, and having removed, the reaction mixture was concentrated. After having put the obtained residue through ion exchange resin Amberlyst (Amberlyst: trade name) A-21 by means of 2N hydrochloric acid, it was purified by preparative medium pressure liquid chromatography W-prep 2XY (column: main column L, inject column M; automatic condition setting: dichloromethane:methanol=4:1, Rf=0.25, preparative isolation mode GR). Furthermore, the obtained residue was purified by preparative TLC (dichloromethane:methanol=4:1) to give the title compound (123 mg) having the following physical data.
Reaction SMILES: [C:1](Cl)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[NH2:15][NH:16][C:17]([NH2:19])=[S:18]>C1COCC1>[NH2:19][C:17](=[S:18])[NH:16][NH:15][C:1](=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: NNC(N)=S
Reactant: CCCCCCCCCCCC(=O)Cl
Solvent: C1CCOC1
Product: CCCCCCCCCCCC(=O)NNC(N)=S
Temperature: 25 °C
Reaction time: 24 h
Yield: 73.1 %

Procedure:
Lauroyl chloride (12.9 g, 0.06 mol) in THF (70 mL) was added dropwise to a vigorously stirred suspension of thiosemicarbazide (10.9 g, 0.12 mol) in THF (300 mL) at 0° C. After the addition was complete, the mixture was allowed to warm to room temperature and stirred for 24 hours. The mixture was concentrated in vacuo to one-quarter of the original volume and filtered through a silica pad, eluting with ethyl acetate (500 mL). The filtrate was concentrated to 250 mL, filtered, and the residue washed with ethyl acetate and dried in vacuo to give 12.0 g of a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH:12]([CH3:17])[C:13]([O:15][CH3:16])=[O:14])[CH:6]=[CH:5]2.[CH3:18][O:19][CH2:20]Cl>CN(C)C=O>[CH3:18][O:19][CH2:20][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH:12]([CH3:17])[C:13]([O:15][CH3:16])=[O:14])[CH:6]=[CH:5]2
Reactant: COC(=O)C(C)c1ccc2cc(O)ccc2c1
Reactant: COCCl
Solvent: CN(C)C=O
Product: COCOc1ccc2cc(C(C)C(=O)OC)ccc2c1
Reaction time: 12 h

Procedure:
A mixture of 23 g. of methyl 6-hydroxy-2-naphthyl-α-methylacetate, 25 g. of chlorodimethyl ether, and 500 ml. of dimethylformamide is allowed to stand at room temperature for 12 hours. The reaction mixture is evaporated under reduced pressure to give methyl 6-methoxymethyloxy-2-naphthyl-α-methylacetate.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[S:41][C:40]([CH3:42])=[N:39][C:38]=1[CH3:43]>>[CH3:42][C:40]1[S:41][C:37]([C:16]2[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]3[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:34])[CH3:35])([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[O:9][C:8]3=[O:10])[CH3:12])=[CH:18][CH:17]=2)=[C:38]([CH3:43])[N:39]=1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: Cc1nc(C)c(Br)s1
Product: Cc1nc(C)c(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)s1

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazinan-2-one and 5-bromo-2,4-dimethyl-thiazole following a procedure analogous to that described in Example 171. Mass spectrum (ESI+): m/z=465 [M+H]+.
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][CH2:10][CH2:11][CH2:12][N:13]([C@H:29]1[CH2:34][CH2:33][C@H:32]([CH3:35])[CH2:31][CH2:30]1)[C:14](=[O:28])[NH:15][C:16]1[S:17][C:18]([S:21][C:22]([CH3:27])([CH3:26])[C:23]([OH:25])=[O:24])=[CH:19][N:20]=1.C1(S)C=CC=CC=1.C(OC(=O)C(SC1SC(N)=NC=1)(C)C)C>>[CH3:27][C:22]([S:21][C:18]1[S:17][C:16]([NH:15][C:14]([N:13]([C@H:29]2[CH2:30][CH2:31][C@H:32]([CH3:35])[CH2:33][CH2:34]2)[CH2:12][CH2:11][CH2:10][S:9][C:4]2[CH:3]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[O:28])=[N:20][CH:19]=1)([CH3:26])[C:23]([OH:25])=[O:24]
Reactant: COc1ccccc1SCCCN(C(=O)Nc1ncc(SC(C)(C)C(=O)O)s1)[C@H]1CC[C@H](C)CC1
Agent: CCOC(=O)C(C)(C)Sc1cnc(N)s1
Agent: Sc1ccccc1
Product: CC(C)(Sc1cnc(NC(=O)N(CCCSc2ccccc2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis 2-{2-[3-[3-(2-methoxy-phenylsulfanyl)-propyl]-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-2-methyl-propionic acid using thiophenol and 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester.
Reaction SMILES: [CH3:1]I.[F:3][C:4]1[C:5]([OH:14])=[C:6]([C:11](=[O:13])[CH3:12])[CH:7]=[C:8]([F:10])[CH:9]=1>>[F:3][C:4]1[C:5]([O:14][CH3:1])=[C:6]([C:11](=[O:13])[CH3:12])[CH:7]=[C:8]([F:10])[CH:9]=1
Reactant: CC(=O)c1cc(F)cc(F)c1O
Reactant: CI
Product: COc1c(F)cc(F)cc1C(C)=O

Procedure:
In an analogous manner to that described in (α) 1-(3,5-difluoro-2-hydroxy-phenyl)-ethanone was alkylated with methyliodide to yield 1-(3,5-difluoro-2-methoxy-phenyl)-ethanone as beige needles; MS: 186 (M)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1.C(O)[CH2:16][OH:17].[CH3:19][OH:20]>C([O-])(=O)C.[Mn+2].C([O-])(=O)C>[OH:17][CH2:16][CH2:11][O:10][C:8](=[O:9])[C:7]1[CH:12]=[CH:13][C:4]([C:3]([O:2][CH2:1][CH2:19][OH:20])=[O:14])=[CH:5][CH:6]=1
Reactant: OCCO
Reactant: CO
Reactant: COC(=O)c1ccc(C(=O)OC)cc1
Agent: [Mn+2]
Agent: CC(=O)[O-]
Product: O=C(OCCO)c1ccc(C(=O)OCCO)cc1

Procedure:
12 Parts by weight of dimethylterephthalate, 8 parts by weight of ethylene-glycol and 0.025 % of the brightener compound No. 201 (cf. Table shown above) were melted under a nitrogen atmosphere in a stainless stell vessel provided with a stirring device, at a temperature of from 140° to 150° C. After the melt had reached a temperature of 145° C, it was mixed with 0.02 parts of manganese acetate dissolved in one part of glycol. In a temperature range of from 160° to 220° C, the transesterification was carried out within 3 hours under atmospheric pressure, in which process methanol and, towards the end, part of the glycol were distilled off. The bis-(β-hydroxyethyl)-terephthalate obtained was brought to a temperature of 240° C in a condensation vessel made of stainless steel, after 1 part by weight of ethylene-glycol had been added, together with
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[S:14][CH:13]=[N:12][CH:11]=2)[C:5]([C:15]#[N:16])=[C:4]([S:17][CH2:18][C:19]2[N:20]=[C:21]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[S:22][CH:23]=2)[N:3]=1.[NH2:31][CH2:32][CH2:33][OH:34]>C1COCC1>[Cl:30][C:27]1[CH:26]=[CH:25][C:24]([C:21]2[S:22][CH:23]=[C:19]([CH2:18][S:17][C:4]3[C:5]([C:15]#[N:16])=[C:6]([C:10]4[S:14][CH:13]=[N:12][CH:11]=4)[C:7]([C:8]#[N:9])=[C:2]([NH:31][CH2:32][CH2:33][OH:34])[N:3]=3)[N:20]=2)=[CH:29][CH:28]=1
Reactant: N#Cc1c(Cl)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1cncs1
Reactant: NCCO
Solvent: C1CCOC1
Product: N#Cc1c(NCCO)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1cncs1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
100 mg (purity 91%, 0.186 mmol) of 2-chloro-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}sulfanyl)-4-(1,3-thiazol-5-yl)pyridine-3,5-dicarbonitrile were initially charged in 5 ml of THF, 0.023 ml (0.373 mmol) of 2-aminoethanol was added and the mixture was stirred at room temperature for 30 min. The product was then isolated by preparative HPLC. This gave 64 mg (67% of theory) of the target compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C(C1NC=CN=1)(C1NC=CN=1)=O.[Br:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][NH2:34])=[CH:28][CH:27]=1.C(N(CC)CC)C>C1COCC1>[Br:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][NH:34][C:7](=[O:9])[C:6]2[CH:10]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[O:11][CH3:12])=[CH:28][CH:27]=1
Reactant: NCCc1ccc(Br)cc1
Reactant: COc1ccc(Cl)cc1C(=O)O
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(Cl)cc1C(=O)NCCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 96.5 %

Procedure:
A solution of 8.3 g (44.4 mmol) of 5-chloro-2-methoxybenzoic acid and 7.8 g (48.1 mmol) of carbonylbisimidazole in 200 ml of absolute THF was stirred at room temperature for 2 h. 7.7 ml (50.0 mmol) of 2-(4-bromophenyl)ethylamine and 10 ml of triethylamine were added and the resulting solution was stirred at room temperature for 24 h. The reaction solution was then poured onto water, and the deposited precipitate was filtered off with suction and washed with water. Drying of the precipitate yielded 15.8 g of the title compound in the form of a slightly yellow-colored solid. M.p.: 104-109° C. Rf (silica gel, EA/heptane 2:1)=0.66. MS (ESI): m/z=368/370 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.C1C(=O)N([O:21][C:22]([O:24][CH2:25][CH:26]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:32]3[C:27]2=[CH:28][CH:29]=[CH:30][CH:31]=3)=O)C(=O)C1.C1COCC1>C([O-])(O)=O.[Na+]>[CH:37]1[C:38]2[CH:26]([CH2:25][O:24][C:22]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:6][CH:7]=3)=[O:21])[C:27]3[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:33]=2[CH:34]=[CH:35][CH:36]=1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Reactant: Nc1ccc(CCCC(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)CCCc1ccc(NC(=O)OCC2c3ccccc3-c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
To a suspension of 4-(4-aminophenyl)butyric acid (3.0 g, 16.7 mmol) in 30 mL of saturated NaHCO3 was added Fmoc-Osu and 20 mL of THF. The mixture was stirred at room temperature overnight. After dilution with 1 N HCl, the product was extracted with ethyl acetate (3×100 mL). The combined extracts were washed with dilute HCl, brine, dried (Na2SO4) and concentrated to give a white solid 6.6 g (26) (98%). 1H NMR (500 MHz, CD3OD) δ 7.80 (m, 2H), 7.70 (m, 2H), 7.39 (m, 3H), 7.32 (m, 4H), 7.90 (m, 2H), 4.46 (m, 2H), 4.27 (t, J=7.0 Hz, 1H), 2.60 (t, J=8.0 Hz, 2H), 2.28 (t, J=7.0 Hz, 2H), 1.87 (m, 2H); MS (ESI+) m/z 424.19 (M+Na+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:10])[CH3:9])=[CH:4][C:3]=1[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH2:14][CH2:13]1.Br[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30].C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[CH2:32]([O:31][C:29](=[O:30])[CH2:28][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:9])[CH3:10])=[CH:4][C:3]=1[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([S:18]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)(=[O:20])=[O:19])[CH2:14][CH2:13]1)[CH3:33]
Reactant: CCOC(=O)CBr
Reactant: CC(C)c1ccc(O)c(CN2CCN(S(=O)(=O)c3ccccc3)CC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)COc1ccc(C(C)C)cc1CN1CCN(S(=O)(=O)c2ccccc2)CC1

Procedure:
A mixture of the product from step (d) (244 mg), ethyl bromoacetate (0.1 ml) and potassium carbonate (185 mg) in acetone was heated under reflux for 2 days. Water was added and the mixture was extracted with diethyl ether. The organic extracts were dried (MgSO4), evaporated in vacuo and purified by chromatography (silica, petrol—ether as eluent) to give the sub-title compound (113 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].O[CH:12]1[CH2:17][CH2:16][CH2:15][N:14]([CH3:18])[CH2:13]1>>[CH3:18][N:14]1[CH2:15][CH2:16][CH2:17][CH:12]([O:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:13]1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CN1CCCC(O)C1
Product: CN1CCCC(Oc2ccc([N+](=O)[O-])cc2)C1

Procedure:
Using an analogous procedure to that described in Method 18, but starting from 4-nitrophenol and 3-hydroxy-1-methylpiperidine, the product was obtained. MS (MH+): 237.
Reaction SMILES: [S:1]([N:11]1[C:19]2[CH:18]=[CH:17][N:16]=[C:15]([CH2:20][NH2:21])[C:14]=2[CH:13]=[N:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].Cl[C:23]1[N:28]=[C:27]([NH:29][C:30]2[CH:34]=[C:33]([CH:35]3[CH2:37][CH2:36]3)[NH:32][N:31]=2)[CH:26]=[CH:25][N:24]=1.CCN(C(C)C)C(C)C>CC(O)C>[CH:35]1([C:33]2[NH:32][N:31]=[C:30]([NH:29][C:27]3[CH:26]=[CH:25][N:24]=[C:23]([NH:21][CH2:20][C:15]4[C:14]5[CH:13]=[N:12][N:11]([S:1]([C:4]6[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=6)(=[O:3])=[O:2])[C:19]=5[CH:18]=[CH:17][N:16]=4)[N:28]=3)[CH:34]=2)[CH2:37][CH2:36]1
Reactant: Cc1ccc(S(=O)(=O)n2ncc3c(CN)nccc32)cc1
Reactant: Clc1nccc(Nc2cc(C3CC3)[nH]n2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Cc1ccc(S(=O)(=O)n2ncc3c(CNc4nccc(Nc5cc(C6CC6)[nH]n5)n4)nccc32)cc1
Temperature: 120 °C
Yield: 76 %

Procedure:
A mixture of (1-tosyl-1H-pyrazolo[4,3-c]pyridin-4-yl)methanamine (300 mg, 1.3 mmol), 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (258 mg, 1.05 mmol), and DIPEA (0.5 mL) in IPA (2 mL) was heated at 120° C. overnight. The reaction mixture was concentrated under reduced pressure to afford 400 mg (61%) of crude N4-(5-cyclopropyl-1H-pyrazol-3-yl)-N2-((1-tosyl-1H-pyrazolo[4,3-c]pyridin-4-yl)methyl)pyrimidine-2,4-diamine as yellow oil. MS (ESI): m/z=502.3 [M+1]+.