Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[C:5]([C:7]2[O:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1.[Cl:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][N:20]=1>N1C=CC=CC=1>[Cl:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH:1][C:2]2[S:3][C:4]([N:12]3[CH2:13][CH2:14][O:15][CH2:16][CH2:17]3)=[C:5]([C:7]3[O:8][CH:9]=[CH:10][CH:11]=3)[N:6]=2)=[O:24])=[CH:21][N:20]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: Nc1nc(-c2ccco2)c(N2CCOCC2)s1
Solvent: c1ccncc1
Product: O=C(Nc1nc(-c2ccco2)c(N2CCOCC2)s1)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 58.5 %

Procedure:
2-Amino-4-(2-furyl)-5-morpholinothiazole (2.15 g, 8.57 mmol) obtained in Step 1 of Example 29 was dissolved in pyridine (25 mL), and 6-chloronicotinoyl chloride (1.81 g, 10.3 mmol) and N,N-dimethylaminopyridine (105 mg, 0.86 mmol) were added thereto. The mixture was stirred at room temperature for 10 hours, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (hexane:ethyl acetate=1:1 to 1:2) to afford the entitled Compound 32 (1.96 g, 59%).
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH:10]([CH:14]([NH:16][C:17]2[N:22]=[C:21]([N:23]3[C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[N:25]=[CH:24]3)[CH:20]=[CH:19][N:18]=2)[CH3:15])[CH2:9]1)=O)(C)(C)C.[CH2:32](Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C([O-])([O-])=O.[K+].[K+].Cl.CCO[C:50]([CH3:52])=O>CN(C=O)C>[CH2:32]([N:11]1[CH2:12][CH2:13][N:8]([C:6](=[O:5])[NH:8][C:9]2[C:50]3[C:52](=[CH:31][CH:26]=[CH:27][CH:28]=3)[CH:15]=[CH:14][CH:10]=2)[CH2:9][CH:10]1[CH:14]([NH:16][C:17]1[N:22]=[C:21]([N:23]2[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[N:25]=[CH:24]2)[CH:20]=[CH:19][N:18]=1)[CH3:15])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(C)=O
Reactant: CC(Nc1nccc(-n2cnc3ccccc32)n1)C1CN(C(=O)OC(C)(C)C)CCN1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(Nc1nccc(-n2cnc3ccccc32)n1)C1CN(C(=O)Nc2cccc3ccccc23)CCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-[1-(4-(tert-butyloxycarbonyl)-piperazine-2-yl)-ethylamino]-4-(benzimidazol-1-yl)-pyrimidine (2 mg) in 0.5 mL of DMF was added benzyl bromide (1.1 μL) and K2CO3 (1.3 mg). The mixture was stirred overnight at room temperature, then diluted with 5 mL of EtOAc and poured into 10 mL of 1N HCl. The phases were separated and the aqueous phase was basified (pH>11) with 5N NaOH and extracted with 4×5 mL of EtOAc. The combined organics were dried over Na2SO4 and concentrated. The residue was dissolved in 0.5 mL of CH2Cl2 and 0.25 mL of trifluoroacetic acid was added. The mixture was stirred for 2 h at room temperature, then concentrated. The residue was dissolved in 0.5 mL of pyridine and naphthyl isocyanate (1 μL) was added. The mixture was stirred overnight at room temperature, then co-concentrated with heptane. The residue was purified by preparative thin-layer chromatography, eluting with 95:5 CH2Cl2—MeOH to provide 0.9 mg of the title compound. Mass spectrum (ESI) 583.5 (M+1).
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][CH:13]3[CH2:15][CH:14]3[C:16]([OH:18])=O)[CH:10]=2)[NH:5][CH:4]=1)#[N:2].Cl.[CH3:20][N:21](C)[OH:22].Cl.[CH3:25]N(C)CCCN=C=NCC.C(N(CC)CC)C>ClCCl>[CH3:25][O:22][N:21]([CH3:20])[C:16]([CH:14]1[CH2:15][CH:13]1[CH2:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[NH:5][CH:4]=[C:3]2[C:1]#[N:2])=[O:18]
Reactant: N#Cc1c[nH]c2ccc(CC3CC3C(=O)O)cc12
Reactant: CCN=C=NCCCN(C)C
Reactant: CN(C)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)C1CC1Cc1ccc2[nH]cc(C#N)c2c1
Yield: 80.2 %

Procedure:
A solution of 2-(3-cyano-1H-indol-5-ylmethyl)-cyclopropanecarboxylic acid (0.080 g, 0.33 mmol), N, N-dimethylhydroxylamine hydrochloride (0.065 g, 0.67 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.077 g, 0.40 mmol), triethylamine (0.13 g, 1.33 mmol), and dichloromethane (5 ml) was stirred at ambient temperature for 1 h then diluted further with an additional 10 ml dichloromethane. The solution was washed with 1N hydrochloric acid (1×5 ml), 1N sodium hydroxide (1×5 ml), and brine (1×5 ml) and dried over anhydrous sodium sulfate. The filtrate was concentrated in vacuo to afford 2-(3-cyano-1H-indol-5-ylmethyl)-cyclopropanecarboxylic acid methoxy-methyl-amide (0.075 g, 79%) as a light brown film. 1H-NMR (400 MHz, CDCl3) 7.69 (1H, m), 7.57 (1H, s), 7.22 (1H, d, J=2.7 Hz), 7.11 (1H, d, J=1.52 Hz), 3.69 (3H, s), 3.20 (3H, s), 2.81 (2H, m), 2.10 (1H, m), 1.73 (1H, m), 1.28 (1H, m), 0.91 (1H, m).
Reaction SMILES: CN1C=C(CN(C)C(C2N(C3C=CC(F)=CC=3)C(S)=NC=2)=O)C(C)=N1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[C:37]([C:38]([O:40]CC)=[O:39])=[CH:36][N:35]=[C:34]2[CH2:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=2[C:51]([F:54])([F:53])[F:52])=[CH:29][CH:28]=1.[OH-].[Li+].C1COCC1>O.CO>[F:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[C:37]([C:38]([OH:40])=[O:39])=[CH:36][N:35]=[C:34]2[CH2:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=2[C:51]([F:53])([F:52])[F:54])=[CH:29][CH:28]=1
Reactant: CCOC(=O)c1cnc(CCc2ccccc2C(F)(F)F)n1-c1ccc(F)cc1
Agent: Cc1nn(C)cc1CN(C)C(=O)c1cnc(S)n1-c1ccc(F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cnc(CCc2ccccc2C(F)(F)F)n1-c1ccc(F)cc1

Procedure:
1-(4-Fluorophenyl)-2-(2-(trifluoromethyl)phenethyl)-1H-imidazole-5-carboxylic acid (48) was prepared in a similar manner as that described for the synthesis of compound 7 using ethyl 1-(4-fluorophenyl)-2-(2-(trifluoromethyl)phenethyl)-1H-imidazole-5-carboxylate (47), lithium hydroxide, THF, methanol, and water.
Reaction SMILES: O[C:2]1C=CC=C[C:3]=1N1C=CC=C1.ClC1C=CC(O)=C(N2C=CC=C2)C=1.Cl[C:27]1[CH:28]=[CH:29][C:30]2[O:35][C:34](C)([CH2:36][C:37]([OH:39])=[O:38])[C:33]3=[CH:41][CH:42]=[CH:43][N:32]3[C:31]=2[CH:44]=1>>[CH2:2]([O:39][C:37](=[O:38])[CH2:36][C:34]1[O:35][C:30]2[CH:29]=[CH:28][CH:27]=[CH:44][C:31]=2[N:32]2[CH2:43][CH:42]=[CH:41][C:33]=12)[CH3:3]
Reactant: CC1(CC(=O)O)Oc2ccc(Cl)cc2-n2cccc21
Reactant: Oc1ccccc1-n1cccc1
Agent: Oc1ccc(Cl)cc1-n1cccc1
Product: CCOC(=O)CC1=C2C=CCN2c2ccccc2O1

Procedure:
In the same manner but replacing N-(2-hydroxyphenyl)pyrrole with an equivalent amount of N-(5-chloro-2-hydroxyphenyl)pyrrole, described in Example 1, 8-chloro-4-methyl-4H-pyrrolo[2,1-c][1,4]-benzoxazine-4-acetic acid, νmaxCHCl3 2,900 - 2,500, 1,728, 1,498, 1,445 cm-1, is obtained via the intermediate ester, 8-chloro-4-methyl-4H-, pyrrolo[2,1-c][1,4]benzoxazine-4-acetic acid ethyl ester, νmaxCHCl3 1,732 cm-1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:22])[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([C:20]#[N:21])([CH3:19])[CH3:18])[CH:12]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].C(N(CC)CC)C.[CH2:30]([O:32][C:33]1[N:34]=[C:35]2[CH:41]=[C:40]([C:42](Cl)=[O:43])[S:39][C:36]2=[N:37][CH:38]=1)[CH3:31].O>C(Cl)Cl>[C:20]([C:17]([C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=1)[C:10]([NH:9][C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([NH:1][C:42]([C:40]2[S:39][C:36]3=[N:37][CH:38]=[C:33]([O:32][CH2:30][CH3:31])[N:34]=[C:35]3[CH:41]=2)=[O:43])[CH:3]=1)=[O:22])([CH3:19])[CH3:18])#[N:21]
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1N
Reactant: CCOc1cnc2sc(C(=O)Cl)cc2n1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCOc1cnc2sc(C(=O)Nc3cc(NC(=O)c4cccc(C(C)(C)C#N)c4)ccc3C)cc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 7.6 %

Procedure:
To a solution of N-(3-amino-4-methylphenyl)-3-(2-cyanopropan-2-yl)benzamide 5 (38 mg, 0.132 mmol) and triethylamine (0.092 mL, 0.66 mmol) in CH2Cl2 (1 mL) was added 2-ethoxythieno[2,3-b]pyrazine-6-carbonyl chloride (32 mg, 0.132 mmol) in CH2Cl2 (1 mL) and stirred overnight at rt. Water was added and extracted with CH2Cl2. Organic layer was washed with water, dried and evaporated. Purification by HPLC gave N-(5-(3-(2-cyanopropan-2-yl)benzamido)-2-methylphenyl)-2-ethoxythieno[2,3-b]pyrazine-6-carboxamide (5 mg, 7%). 1H-NMR (400 MHz, DMSO-d6). 1.42 (t, J=7.0 Hz, 3H), 1.76 (s, 6H), 2.26 (s, 3H), 4.46 (q, J=7.0 Hz and 14.0 Hz, 2H), 7.31 (d, 8.2 Hz, 1H), 7.58-7.66 (m, 2H), 7.76 (d, J=7.8 Hz, 1H), 7.87 (d, J=1.9 Hz, 1H), 7.95 (d, J=7.8 Hz, 1H), 8.05 (s, 1H), 8.35 (s, 1H), 8.41 (s, 1H), 10.35 (s, 1H), 10.37 (s, 1H). (m/z)=500 (M+H)+.
Reaction SMILES: O.CO[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]([CH:12]=[O:13])=[O:11].[CH3:14][CH:15]([NH2:25])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1.[CH3:26]S(C)=O>>[CH3:14][CH:15]([N:25]=[C:12]([O:13][CH3:26])[C:10]([C:5]1[CH:4]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:11])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1
Reactant: COc1ccccc1C(=O)C=O
Reactant: COc1ccc(CC(C)N)cc1
Reactant: CS(C)=O
Solvent: O
Product: COC(=NC(C)Cc1ccc(OC)cc1)C(=O)c1ccccc1

Procedure:
2.9 g of 2-methoxyphenylglyoxal hydrate (crude oil) are dissolved in 6 ml of dimethylsulfoxide, and 2 g of α-methyl-4-methoxyphenethylamine are added thereto. The mixture is treated in the same manner as described in Example 1-(2), whereby a solution of α-(α-methyl-4-methoxyphenethylimino)-2-methoxyacetophenone in dimethylsulfoxide is obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH:9]([C:15]2[N:16]=[CH:17][NH:18][CH:19]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:23][CH2:24][CH:25]1[CH2:30][CH2:29][N:28]([C:31](=[O:45])[CH:32]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:27][CH2:26]1>CN(C=O)C>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH:9]([C:15]2[N:16]=[CH:17][N:18]([CH2:23][CH2:24][CH:25]3[CH2:30][CH2:29][N:28]([C:31](=[O:45])[CH:32]([C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)[C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH2:27][CH2:26]3)[CH:19]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(Cc1ccc(N)nc1)c1c[nH]cn1
Reactant: O=C(C(c1ccccc1)c1ccccc1)N1CCC(CCBr)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1ccc(N)nc1)c1cn(CCC2CCN(C(=O)C(c3ccccc3)c3ccccc3)CC2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.6 %

Procedure:
Ethyl 3-(6-aminopyridin-3-yl)-2-(1H-imidazol-4-yl)propionate (100 mg; 0.38 mmol) was dissolved in absolute DMF (2 ml). Sodium hydride (50%; 19 mg; 0.38 mmol) was added, and the reaction mixture was stirred at RT for 1 h. Then 1-[4-(2-bromoethyl)piperidin-1-yl]-2,2-diphenylethanone (148 mg; 0.38 mmol) dissolved in absolute DMF (1 ml) was added. The reaction mixture was stirred at RT for 1 h and then concentrated under reduced pressure. The residue was taken up in 1N HCl and washed with dichlormethane (CH2Cl2; 2×). The aqueous phase was made basic with 1N NaOH and extracted with CH2Cl2 (3×). The combined organic phases were dried over Na2SO4. Removal of the solvent under reduced pressure resulted in ethyl 3-(6-aminopyridin-3-yl)-2-{1-[2-(1-diphenylacetylpiperidin-4-yl)ethyl]-1H-imidazol-4-yl}propionate (71 mg; 0.12 mmol).
Reaction SMILES: [I:1][C:2]1[C:3]([OH:12])=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].CI.[C:15]([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:15][O:12][C:3]1[C:2]([I:1])=[C:9]([O:10][CH3:11])[CH:8]=[CH:7][C:4]=1[CH:5]=[O:6]
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(C=O)c(O)c1I
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1ccc(C=O)c(OC)c1I

Procedure:
Methylation of the phenolic --OH group in (12) with MeI-K2CO3 in refluxing acetone proceed smoothly to give 2,4-dimethoxy-3-iodobenzaldehyde (13), m.p. 103.3° C. [1H-NMR: (90 MHz, CDCl3, δ): 3.90 (overlapping s, 2×3H, C2 and C4-OCH3), 6.62 and 7.78 (pair of doublets. Jab=8Hz, C5-H and C6-H), 10.12 (s, 1H, HC=O).]
Reaction SMILES: O[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.O.[OH-].[Na+].P(Cl)(Cl)([Cl:16])=O>>[Cl:16][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Oc1nc2ccccc2[nH]1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Clc1nc2ccccc2[nH]1
Reaction time: 6 h

Procedure:
A solution of 2-hydroxy benzimidazole (40.2 g) in 93 ml phosphorus oxychloride is heated to reflux under stirring for 6 hours. After achievement of the reaction the solution is let to revert to -10° C. and hydrolysed with 100 g crushed ice and 100 ml iced water. They are slowly added 249 ml sodium hydroxide 10N to get a neutral pH value. The precipitated product is filtered, washed with the minimal amount of water. The crystals are taken up in hot ethanol. After cooling, the alcoholic juice are filtered and concentrated to dryness.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[C:16]([Br:24])[CH:17]=[C:18]3[C:23]=2[N:22]=[CH:21][CH:20]=[CH:19]3)[CH2:10][CH2:9]1)C1C=CC=CC=1.ClCCOC(Cl)=O.ClC(OC=C)=O.O>ClC(Cl)C>[Br:24][C:16]1[CH:17]=[C:18]2[C:23](=[C:14]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[CH:15]=1)[N:22]=[CH:21][CH:20]=[CH:19]2
Reactant: Brc1cc(N2CCN(Cc3ccccc3)CC2)c2ncccc2c1
Agent: C=COC(=O)Cl
Agent: O=C(Cl)OCCCl
Solvent: O
Solvent: CC(Cl)Cl
Product: Brc1cc(N2CCNCC2)c2ncccc2c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 83.9 %

Procedure:
To a solution of 8-(4-benzyl-piperazin-1-yl)-6-bromo-quinoline (1.6 g, 4.2 mmol) in dichloroethane (50 mL) under a N2 atmosphere was added chloroethylchloroformate (1.26 mL, 12.6 mmol) and the reaction mixture was heated at 80° C. for 4 hours, and at ambient temperature overnight. No reaction was observed by TLC, therefore vinyl chloroformate (0.35 mL, 6.3 mmol) was added and the reaction was heated at 80° C. for another 4 hours. The cooled reaction was poured into H2O and extracted into CH2Cl2 (2×100 mL) and EtOAc (100 mL). The organic fractions were combined, dried over Na2SO4, and left in EtOAc overnight. The organic layer was concentrated and purified by column chromatography (10%MeOH/CH2Cl2+NH4OH) affording 1.03 g (84%) of a brown foam. MS (+) APCI m/z 292 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16])[C:8]([C:17]([N:19]([CH2:42][CH:43]([CH3:45])[CH3:44])[C@H:20]2[CH2:25][C@@H:24]([C:26]([N:28]3[CH2:33][CH2:32][S:31](=[O:34])[CH2:30][CH2:29]3)=[O:27])[CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21]2)=[O:18])=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)(Cl)Cl>[C:1]([C:5]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16])[C:8]([C:17]([N:19]([CH2:42][CH:43]([CH3:45])[CH3:44])[C@H:20]2[CH2:25][C@@H:24]([C:26]([N:28]3[CH2:33][CH2:32][S:31](=[O:34])[CH2:30][CH2:29]3)=[O:27])[CH2:23][NH:22][CH2:21]2)=[O:18])=[CH:7][N:6]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: COCCCNc1nc(C(C)(C)C)ncc1C(=O)N(CC(C)C)[C@H]1C[C@@H](C(=O)N2CCS(=O)CC2)CN(C(=O)OC(C)(C)C)C1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: COCCCNc1nc(C(C)(C)C)ncc1C(=O)N(CC(C)C)[C@@H]1CNC[C@H](C(=O)N2CCS(=O)CC2)C1
Reaction time: 1 h
Yield: 98.5 %

Procedure:
tert-Butyl (3S,5R)-3-[({2-tert-butyl-4-[(3-methoxypropyl)amino]pyrimidin-5-yl}carbonyl)(2-methylpropyl)amino]-5-[(1-oxidothiomorpholin-4-yl)carbonyl]piperidine-1-carboxylate (120 mg) was dissolved in chloroform (3 ml), TFA (1 ml) was added and the mixture was stirred for 1 hr. The reaction mixture was concentrated, and the residue was dissolved in ethyl acetate, washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the object compound (100 mg).
Reaction SMILES: [C:1](#[N:3])[CH3:2].CC([O-])(CC)C.[K+].C1(C)C=CC=CC=1.[CH3:18][C:19]1([C:25](OC)=O)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.Cl.[C:30]1([CH3:38])[CH:35]=[CH:34][C:33]([NH:36][NH2:37])=[CH:32][CH:31]=1.Cl>C1COCC1.CCO>[CH3:18][C:19]1([C:25]2[CH:2]=[C:1]([NH2:3])[N:36]([C:33]3[CH:34]=[CH:35][C:30]([CH3:38])=[CH:31][CH:32]=3)[N:37]=2)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1
Reactant: CC#N
Reactant: COC(=O)C1(C)CCOCC1
Reactant: Cc1ccc(NN)cc1
Agent: CCC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1ccc(-n2nc(C3(C)CCOCC3)cc2N)cc1
Temperature: 25 °C

Procedure:
To a solution of acetonitrile (300 μL, 5.7 mmol) in THF (20 mL) at RT was added a solution of potassium 2-methylbutan-2-olate in toluene (1.7 M, 10.1 mL, 17.2 mmol) followed by the dropwise addition of methyl 4-methyltetrahydro-2H-pyran-4-carboxylate (1.36 g, 8.62 mmol) and the reaction mixture maintained at RT for 16 hr. The resulting mixture was concentrated in vacuo to a volume of ˜10 mL and was then diluted with EtOH (20 mL) and p-tolylhydrazine hydrochloride (911 mg, 5.74 mmol) was added. The reaction was acidified to pH 1 by the addition of conc hydrochloric acid and the resulting heterogeneous mixture was heated to 70° C. for 5 hr, was then cooled to RT and concentrated in vacuo to a volume of ˜20 mL. The mixture was diluted with water (30 mL) and adjusted to pH 12 by the addition of 2M aq NaOH and was then extracted with ethyl acetate (2×20 mL). The combined extracts were washed with brine (30 mL) and then dried and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, EtOAc in isohexane, 0-50%, gradient elution) to afford the title compound, Intermediate 21, as a yellow solid (550 mg, 32%); Rt 1.48 min (Method 2); m/z 272 (M+H)+, (ES+).
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1)[C:6](OCC)=[O:7])C.[Li+].[BH4-].Cl>C1COCC1.C1(C)C=CC=CC=1>[C:20]([O:19][C:17]([N:14]1[CH2:15][CH2:16][CH:11]([CH:5]([CH2:4][OH:3])[CH2:6][OH:7])[CH2:12][CH2:13]1)=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: CCOC(=O)C(C(=O)OCC)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(CO)CO)CC1
Temperature: 60 °C
Reaction time: 24 h
Yield: 62 %

Procedure:
To a solution of 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)malonic acid diethyl ester (14.6 g, 0.043 mol) in anhydrous THF (100 mL) and anhydrous toluene (100 mL), LiBH4 (2.1 g. 0.96 mol) was added portion wise. The resulting mixture was heated at 60° C. for 17 h, then stirred at ambient temperature for 24 h. The reaction mixture was slowly added to aqueous HCl (0.1 M, 350 mL) and then extracted with EtOAc. The organic layer was separated and washed with brine, then dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, EtOAc:MeOH 100:0 to 98:2 to 95:5 to 90:10 to 80:20) to afford the title compound as a colourless oil (6.91 g, 63%). 1H NMR (CDCl3, 400 MHz) δ 3.90-3.75 (m, 4 H); 2.75-2.58 (m, 4 H); 1.77-1.61 (m, 4 H); 1.52 (m, 1 H); 1.45 (s, 9 H) and 1.26-1.13 (m, 1 H).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[C:18]([NH2:22])([CH3:21])([CH3:20])[CH3:19]>>[C:18]([NH:22][C:15]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])([CH3:21])([CH3:20])[CH3:19]
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Reactant: CC(C)(C)N
Product: CC(C)(C)NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42 a) and tert-butylamine (CAN 75-64-9) as starting materials. MS (EI): m/e=289.4 [M+H]+.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13]([CH:14]=O)=[C:9]3[N:8]=[C:7]([NH:16][C:17]3[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=3)[CH:6]=2)[CH2:3][CH2:2]1.[NH:25]1[CH2:31][C:29](=[O:30])[NH:28][C:26]1=[O:27].N1CCCCC1>CCO>[CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13](/[CH:14]=[C:31]4\[NH:25][C:26](=[O:27])[NH:28][C:29]\4=[O:30])=[C:9]3[N:8]=[C:7]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([C:21]#[N:22])=[CH:23][CH:24]=3)[CH:6]=2)[CH2:2][CH2:3]1
Reactant: N#Cc1ccc(Nc2cc(NC3CC3)n3ncc(C=O)c3n2)cc1
Reactant: O=C1CNC(=O)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: N#Cc1ccc(Nc2cc(NC3CC3)n3ncc(/C=C4\NC(=O)NC4=O)c3n2)cc1
Temperature: 80 °C
Reaction time: 15 h
Yield: 79.1 %

Procedure:
4-(7-(cyclopropylamino)-3-formylpyrazolo[1,5-a]pyrimidin-5-ylamino)benzonitrile (75 mg, 0.24 mmol) was suspended in EtOH (2.4 mL). Hydantoin (36 mg, 0.35 mmol) and piperidine (36 μL, 0.35 mmol) were added and the reaction was heated to 80° C. After 15 h, the solution was filtered while warm and the filter cake was washed with warm EtOH (3 mL) to give (Z)-4-(7-(cyclopropylamino)-3-((2,5-dioxoimidazolidin-4-ylidene)methyl)pyrazolo[1,5-a]pyrimidin-5-ylamino)benzonitrile (76 mg, 80%) as a bright yellow solid. LCMS (ES): >90% pure, m/z 401 [M+1]+.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][CH:15]=[CH:14]3)[CH:7]=[CH:6][N:5]=1.[C:20]1([N:26]=[C:27]=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>CN(C)C=O>[C:20]1([NH:26][C:27]([N:16]2[C:17]3[C:13](=[CH:12][C:11]([O:10][C:8]4[CH:7]=[CH:6][N:5]=[C:4]([NH2:3])[CH:9]=4)=[CH:19][CH:18]=3)[CH:14]=[CH:15]2)=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Nc1cc(Oc2ccc3[nH]ccc3c2)ccn1
Reactant: O=C=Nc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cc(Oc2ccc3c(ccn3C(=O)Nc3ccccc3)c2)ccn1
Reaction time: 0.08 h
Yield: 74.1 %

Procedure:
After adding 28 mg of sodium hydride (60% in oil) to a solution of 3.0 g of 5-[(2-amino-4-pyridyl)oxy]-1H-indole in dimethylformamide at room temperature and stirring the mixture for 5 minutes, 1.6 g of phenyl isocyanate was added and the mixture was stirred for 20 minutes. Water was added, extraction was performed with ethyl acetate and the organic layer was washed with water, and then silica gel was added and the solvent was distilled off under reduced pressure. The silica gel was charged into a dry column packed with silica gel and purified by column chromatography (ethyl acetate), to obtain 3.4 g of a colorless powder.
Reaction SMILES: [C:1]([O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14]O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:16]N1C(=O)CCC1=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])O.[Na+]>ClCCl>[C:1]([O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][I:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCCOCCO)c1ccccc1
Reactant: O=C1CCC(=O)N1I
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C(OCCOCCI)c1ccccc1
Reaction time: 14 h
Yield: 64.1 %

Procedure:
To a solution of 2,2′-oxydiethanol (2.12 g) in pyridine (20 mL) was added benzoic anhydride (4.52 g) by small portions under ice-cooling, and the reaction mixture was stirred while warming to room temperature for 18 hrs. Pyridine was evaporated under reduced pressure and the obtained residue was diluted with diethyl ether (20 mL). 5% Aqueous sodium hydrogen carbonate solution (100 mL) was added, and the mixture was extracted with diethyl ether (100 mL×3). The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel chromatography (eluent:hexane/ethyl acetate=95/5→40/60). The object fraction was concentrated under reduced pressure and dried to give 2-(2-hydroxyethoxy)ethyl benzoate (2.21 g). To a solution of the obtained 2-(2-hydroxyethoxy)ethyl benzoate (2.10 g) in dichloromethane (10 mL) were added 1-iodopyrrolidine-2,5-dione (2.70 g) and triphenylphosphine (3.14 g) by small portions under ice-cooling, and the mixture was stirred for 14 hrs. The reaction mixture was poured into 5% aqueous sodium hydrogen carbonate solution (100 mL), and extracted with ethyl acetate (120 mL×3). The organic layer washed successively with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel chromatography (eluent:hexane/ethyl acetate=100/0→60/40). The object fraction was concentrated under reduced pressure and dried to give 2-(2-iodoethoxy)ethyl benzoate (2.05 g) as a colorless transparent oil.