Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[N:8]([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=3)[C:9]3[CH:14]=[CH:13][N:12]=[CH:11][C:10]=3[N:15]=2)=[N:4][O:5][N:6]=1.[H-].[Na+].Cl.[CH3:26][N:27]([CH3:31])[CH2:28][CH2:29][Cl:30]>CN(C)C=O>[ClH:30].[CH3:26][N:27]([CH3:31])[CH2:28][CH2:29][O:22][C:19]1[CH:20]=[CH:21][C:16]([N:8]2[C:9]3[CH:14]=[CH:13][N:12]=[CH:11][C:10]=3[N:15]=[C:7]2[C:3]2[C:2]([NH2:1])=[N:6][O:5][N:4]=2)=[CH:17][CH:18]=1
Reactant: CN(C)CCCl
Reactant: Nc1nonc1-c1nc2cnccc2n1-c1ccc(O)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCOc1ccc(-n2c(-c3nonc3N)nc3cnccc32)cc1
Temperature: 60 °C

Procedure:
To a solution of the product of Example 38 (30 mg, 0.102 mmol), in N,N-dimethylformamide (2 ml), was added sodium hydride (60% dispersion in mineral oil, 4 mg, 0.10 mmol). After 5 minutes at room temperature 2-(dimethylamino)ethyl chloride hydrochloride (15 mg, 0.102 mmol) and sodium hydride (60% dispersion in mineral oil, 4 mg, 0.102 mmol) were added and the reaction heated at 60° C. for 5 hours. The solvent was evaporated in vacuo and the residue was partitioned between ethyl acetate and 2M sodium hydroxide solution. The organic phase was separated then washed with water (×3), dried over anhydrous sodium sulphate and evaporated in vacuo. Purification of the residue by silica gel chromatography eluting with 10% methanol in dichloromethane gave the free base of the title compound. The product was dissolved in methanol (1 ml) and treated with a 1M solution hydrochloric acid (36 uL, 0.036 mmol) in diethyl ether and evaporated in vacuo to yield the title compound (14 mg, 32%); MS (ES+) m/e 366 (M+H]+.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH2:13]([NH2:15])[CH3:14]>C1COCC1>[CH2:13]([NH:15][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11])[CH3:14]
Reactant: CCN
Reactant: N#Cc1ccc(F)c([N+](=O)[O-])c1
Solvent: C1CCOC1
Product: CCNc1ccc(C#N)cc1[N+](=O)[O-]
Reaction time: 16 h
Yield: 81.9 %

Procedure:
To a solution of 4-fluoro-3-nitrobenzonitrile (5.0 g, 30 mmol) in THF (15 mL, anhyd) was added a solution of ethylamine (2.0 M, 23 mL, 46 mmol) in THF. After stirring 16 h, precipitated solids were collected by filtration, triturated with a mixture of THF-hexanes (1:1, 50 mL), filtered again and dried under vacuum to give 4-ethylamino-3-nitrobenzonitrile (4.7 g, 82%) as a yellow solid. 1H-NMR (CDCl3): δ 8.51 (1H, d), 8.34 (1H, br s), 7.62 (1H, dd), 6.93 (1H, d), 3.44 (2H, m), 1.42 (3H, t).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].I[C:8]1[N:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.C(O)(C)C.[SH:19][C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1>C(OCC)(=O)C.[Cu]I.COCCOC>[OH:14][C:11]1[CH:10]=[CH:9][C:8]([S:19][C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=2)=[N:13][CH:12]=1
Reactant: Oc1ccc(I)nc1
Reactant: N#Cc1ccc(S)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(Sc2ccc(O)cn2)cc1
Temperature: 80 °C
Yield: 53 %

Procedure:
0.25 g (1.31 mM) of copper(I) iodide, 7.26 g (52.5 mM) of potassium carbonate and 5.8 g (26.25 mM) of 6-iodo-3-pyridinol are introduced into a tube under an argon atmosphere. 30 ml of isopropanol, 5 g of 1,2-dimethoxyethane and 3.55 g (26.25 mM) of 4-mercaptobenzonitrile are then added. The tube is sealed and heated at 80° C. for 24 hours. When the mixture has returned to room temperature, it is diluted with 120 ml of ethyl acetate and filtered, the solid on the filter is washed with ethyl acetate and the organic phases are concentrated under reduced pressure. The evaporation residue is purified by chromatography on a silica column (eluent: cyclohexanol/ethyl acetate 55/45; v/v) to give the expected product in the form of a beige powder with a yield of 53%.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:18])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=2)=[N:5]1.[CH3:19][C:20]1[O:24][C:23]([C:25](O)=[O:26])=[N:22][N:21]=1>>[Cl:17][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:25]([C:23]3[O:24][C:20]([CH3:19])=[N:21][N:22]=3)=[O:26])[CH3:18])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: Cc1nnc(C(=O)O)o1
Product: Cc1nnc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)o1
Yield: 3.7 %

Procedure:
(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-methyl-1,3,4-oxadiazole-2-carboxamide was prepared using the method of Example 34(d) starting from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (200 mg, 0.652 mmol) and 5-methyl-1,3,4-oxadiazole-2-carboxylic acid (100 mg, 0.782 mmol). The product was purified twice by Flash-chromatography (normal phase and reverse phase). Yield 3.7%. 1H-NMR (400 MHz; MeOD): δ 1.28 (d, 3H), 2.58 (s, 3H), 4.30-4.44 (m, 2H), 4.53-4.64 (m, 1H), 6.76-6.78 (m, 1H), 7.71 (d, 1H), 7.76-7.80 (m, 1H), 7.86-7.90 (m, 1H), 8.02-8.04 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[I-].[CH2:46]([N+:50]1[N:54]=[C:53]([CH3:55])[S:52][C:51]=1[CH3:56])[CH2:47][CH2:48][CH3:49]>>[CH2:46]([N:50]1[N:54]=[C:53]([CH3:55])[S:52]/[C:51]/1=[CH:56]\[C:5]([C:4]1[CH:8]=[CH:9][C:10]([CH3:11])=[C:2]([CH3:1])[CH:3]=1)=[O:7])[CH2:47][CH2:48][CH3:49]
Reactant: CCCC[n+]1nc(C)sc1C
Reactant: Cc1ccc(C(=O)O)cc1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN1N=C(C)S/C1=C\C(=O)c1ccc(C)c(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial 3,4-dimethylbenzoic acid (0.9 mL of 0.2 M in DMA, 1.10 equiv) was added followed by the addition of HATU (76 mg in 0.7 mL of DMA, 0.2 mmol, 1.20 equiv.), DIEA (51 mg in 0.7 mL of DMA, 0.4 mmol, 2.40 equiv.), and finally 3-butyl-2,5-dimethyl-1,3,4-thiadiazol-3-ium iodide (49 mg in 0.7 mL of DMA, 0.17 mmol, 1 equiv.). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.87-0.95 (m, 3 H) 1.30-1.41 (m, 2 H) 1.69-1.80 (m, 2 H) 2.23-2.32 (m, 6 H) 2.47 (s, 3 H) 4.21 (t, 2 H) 6.65 (s, 1 H) 7.15-7.27 (m, 1 H) 7.65-7.80 (m, 2 H); MS (ESI) m/z 303 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][N:3]1[CH2:19][C:20]([OH:22])=O.FC1C=CC(C2(C3C=CC(F)=CC=3)CCN(CC(O)=O)C2=O)=CC=1.O[NH:48]/[C:49](=[N:60]\[H])/[C:50]1[CH:55]=[CH:54][C:53]([C:56]([F:59])([F:58])[F:57])=[N:52][CH:51]=1.ON/C(=N\[H])/C1C=CC(C(F)(F)F)=CC=1>>[C:7]1([C:6]2([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:5][CH2:4][N:3]([CH2:19][C:20]3[O:22][N:60]=[C:49]([C:50]4[CH:51]=[N:52][C:53]([C:56]([F:59])([F:57])[F:58])=[CH:54][CH:55]=4)[N:48]=3)[C:2]2=[O:1])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Reactant: [H]/N=C(\NO)c1ccc(C(F)(F)F)nc1
Agent: O=C(O)CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Agent: [H]/N=C(\NO)c1ccc(C(F)(F)F)cc1
Product: O=C1N(Cc2nc(-c3ccc(C(F)(F)F)nc3)no2)CCC1(c1ccccc1)c1ccccc1

Procedure:
The title compound was prepared using the procedure described in Example 190 substituting 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid from Example 1C for 2-(3,3-bis(4-fluorophenyl)-2-oxopyrrolidin-1-yl)acetic acid and (Z)—N-hydroxy-6-(trifluoromethyl)nicotinimidamide for (Z)—N-hydroxy-4-(trifluoromethyl)benzimidamide. 1H NMR (300 MHz, CDCl3) δ ppm 9.33 (s, 1H), 8.43 (dd, J=1.5, 8.2, 1H), 7.80 (dd, J=0.5, 8.2, 1H), 7.44-7.26 (m, 10H), 4.93 (s, 2H), 3.59 (t, J=6.5, 2H), 2.90 (t, J=6.5, 2H); MS (DCI) m/z 465.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:13]C(OC(C)(C)C)=O)=[N:4][C:5](C(O)=O)=[CH:6][C:7]=1[O:8][CH3:9].[CH:21]([OH:23])=[O:22]>>[CH3:1][C:2]1[C:3]([NH2:13])([C:21]([OH:23])=[O:22])[NH:4][CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1cc(C(=O)O)nc(NC(=O)OC(C)(C)C)c1C
Reactant: O=CO
Product: COC1=C(C)C(N)(C(=O)O)NC=C1
Temperature: 40 °C

Procedure:
2.87 g of methyl 2-tert-butyloxycarbonylamino-4-methoxy-pyridin-6-carboxylic acid (compound D3) are dissolved in 72 ml of formic acid. Subsequently, the solution is warmed to 40° C. for 2.5 h. After completion of the reaction, the solution is concentrated in vacuum and coevaporated with toluene. The remaining residue is redissolved in 150 ml of dichloromethane and extracted three times each with 50 ml of sat sodium hydrogencarbonate solution. The organic layer is dried using sodium sulphate, filtered with suction and concentrated in vacuum to yield 1.85 g of the title compound as a colorless oil. ESI-MS: 183.1 [MH+]. TLC: Rf=0.28 (dichloromethane/methanol 10:1).
Reaction SMILES: Cl[CH:2]([C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7][C:6]=2[CH:5]=1)[CH3:3].[NH:17]1[CH:21]=[N:20][CH:19]=[N:18]1>O>[CH:5]1[C:6]2[CH2:7][C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14]=2[CH:15]=[CH:16][C:4]=1[CH:2]([N:17]1[CH:21]=[N:20][CH:19]=[N:18]1)[CH3:3]
Reactant: CC(Cl)c1ccc2c(c1)Cc1ccccc1-2
Reactant: c1nc[nH]n1
Solvent: O
Product: CC(c1ccc2c(c1)Cc1ccccc1-2)n1cncn1
Temperature: 120 °C

Procedure:
The thus obtained 2-(1-chloroethyl)-9H-fluorene was mixed with 1,2,4-triazole (1.31 g) and heated at 120° C. for 30 minutes without further adding solvent. After cooling, water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated and then the resulting residue was subjected to silica gel column chromatography. First, elution was carried out with a mixed solvent of chloroform and methanol (50:1), and the thus obtained crude crystals were recrystallized from a mixed solvent of ether and ethyl acetate to obtain 0.24 g of 1-[1-(9H-fluoren-2-yl) ethyl]-1H-1,2,4-triazole (Example 5). Thereafter, crude crystals obtained from the chloroform-methanol (50:1) eluate were recrystallized from a mixed solvent of ethyl acetate and ether to obtain 0.25 g of 4-[1-(9H-fluoren-2-yl) ethyl]-4H-1,2,4-triazole (Example 6).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:19][CH3:20])=[C:13]([CH:18]=1)[C:14](=[O:17])[CH2:15]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1.[H-].[Na+].O>CN(C)C=O>[N:24]1[CH:25]=[CH:26][CH:27]=[C:22]([O:21][CH2:15][C:14]([C:13]2[CH:18]=[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:10]=[CH:11][C:12]=2[O:19][CH3:20])=[O:17])[CH:23]=1
Reactant: Oc1cccnc1
Reactant: COc1ccc(OCc2ccccc2)cc1C(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(OCc2ccccc2)cc1C(=O)COc1cccnc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 25.7 %

Procedure:
To 5-benzyloxy-2-methoxyphenacyl bromide (4.0 g, 0.0119 mol) in 80 ml of dry dimethylformamide was added 3-hydroxypyridine (1.24 g, 0.013 mol, 1.1 equiv) followed by NaH (50% in oil, 0.604 g, 1.1 equiv). After stirring for 18 hours under N2, the mixture was poured into 500 ml of ice and water, and extracted 2×500 ml ethyl acetate. The organic layers were combined, washed 2×500 ml H2O and 1×300 ml brine, dried (Na2SO4), stripped to an oil, and chromatographed on silica gel using 1:1 hexane:ethyl acetate as eluant to yield 1.07 g of present title product as a solid; IR(KBr) 1670 cm-1;MS 349 (M+); 1H-NMR (300 MHz, CDCl3) delta (ppm) 3.95 (s, 3H), 5.1 (s, 2H), 5.35 (s, 2H), 2.0 (d, 1 H), 7.2-7.5 (m, 8H), 7.6 (d, 1H), 8.3 (d, 1H), 8.4 (d, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:29])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)=[N:6][N:5]2[CH:30]=1.[C:31](O)(=[O:34])[CH2:32][CH3:33].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[C:31]([NH:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:29])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)=[N:6][N:5]2[CH:30]=1)(=[O:34])[CH2:32][CH3:33]
Reactant: Nc1cn2nc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)ccc2n1
Reactant: CCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCC(=O)Nc1cn2nc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)ccc2n1
Yield: 68.1 %

Procedure:
Using N-{3-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(trifluoromethyl)benzamide (150 mg, 0.363 mmol), propionic acid (40 μL, 0.544 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (104 mg, 0.544 mmol), 1-hydroxybenzotriazole (73 mg, 0.544 mmol), triethylamine (76 μL, 0.544 mmol) and N,N-dimethylformamide (5 mL) as starting materials and in the same manner as in Example 380, the title compound (116 mg, 68%) was obtained as a white powder.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:19][CH:20]([CH3:22])[CH3:21])=[C:4]([C:14]([O:16]CC)=[O:15])[N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:6]=1[Br:7].[OH-].[Na+].C(O)(=O)C(O)=O>CO>[Br:1][C:2]1[C:3]([O:19][CH:20]([CH3:22])[CH3:21])=[C:4]([C:14]([OH:16])=[O:15])[N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:6]=1[Br:7]
Reactant: CCOC(=O)c1c(OC(C)C)c(Br)c(Br)n1-c1ccccc1
Agent: O=C(O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)Oc1c(Br)c(Br)n(-c2ccccc2)c1C(=O)O
Yield: 92.2 %

Procedure:
Ethyl 4,5-dibromo-3-(1-methylethoxy)-1-phenyl-1H-pyrrole-2-carboxylate (3.0 g, 0.007 moles) is dissolved in methanol (40 mL), 2N NaOH (20 mL) is added and the mixture stirred and heated to reflux under nitrogen. After 2 hours the mixture is cooled, then stripped of methanol under reduced pressure. The residue is acidified with oxalic acid and the precipitate is filtered off, rinsed well with warm water, and dried to afford the pure product (2.6 g); mp 76° C. (dec).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH2:18][CH2:17][C:12]3([O:16][CH2:15][CH2:14][O:13]3)[CH2:11][CH2:10]2)=[C:6]([F:8])[CH:7]=1.Cl[C:20]([O:22][CH2:23][CH3:24])=[O:21]>N1C=CC=CC=1>[CH2:23]([O:22][C:20]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH2:18][CH2:17][C:12]3([O:16][CH2:15][CH2:14][O:13]3)[CH2:11][CH2:10]2)=[C:6]([F:8])[CH:7]=1)=[O:21])[CH3:24]
Reactant: Nc1ccc(N2CCC3(CC2)OCCO3)c(F)c1
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Product: CCOC(=O)Nc1ccc(N2CCC3(CC2)OCCO3)c(F)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
5-Amino-2-(1,4-dioxa-8-azaspiro[4,5]dec-8-yl)fluorobenzene (19.26 g, 0.076 M), was dissolved in dry pyridine (75 ml) and cooled under nitrogen with stirring to 0°. Ethyl chloroformate (9.08, 0.084 M) was added dropwise, and the mixture stirred 30 minutes at the same temperature. Ice-water (300 ml) was added, and stirring continued for 1 hour. The resulting precipitate was collected, washed thoroughly with water, and dried, to give the desired product of sufficient quality for use without purification (20.5 g).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]([C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=1)[N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1.C(Cl)Cl.[CH3:21][S:22](Cl)(=[O:24])=[O:23].C(N(C(C)C)CC)(C)C>C1COCC1>[C:14]([C:13]1[CH:16]=[CH:17][C:10]([CH:4]([N:5]2[CH:9]=[CH:8][N:7]=[CH:6]2)[CH2:3][CH2:2][O:1][S:22]([CH3:21])(=[O:24])=[O:23])=[CH:11][CH:12]=1)#[N:15]
Reactant: N#Cc1ccc(C(CCO)n2ccnc2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)OCCC(c1ccc(C#N)cc1)n1ccnc1
Reaction time: 4 h

Procedure:
The 4-(3-hydroxy-1-imidazol-1-yl-propyl)-benzonitrile (1.4 gm, 6.16 mmol) was suspended in 2:1 methylene chloride: THF (100 mL) under argon and cooled to 0° C. in an ice bath. Methanesulfonylchloride (1 mL, 12.4 mmol) was added followed by diisopropylethylamine (3.22 mL, 18.5 mmol). The reaction was stirred for 4 hours and the solvent was removed in vacuo. The residue was suspended in ethyl acetate (200 mL) and extracted 2 times with saturated aqueous sodium bicarbonate (100 mL), then water (100 mL), then saturated sodium chloride solution (100 mL). The organic solvent was removed in vacuo and the residue was chromatographed on silica gel using using 1:3 ethyl acatate: hexanes. The desired fractions were concentrated in vacuo to give the desired product.
Reaction SMILES: Br[C:2]1[CH:6]=[C:5]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH3:15])=[CH:10][CH:9]=2)[S:4][C:3]=1[CH2:16][CH2:17][O:18][C:19]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C([Li])CCC.[CH2:43]([O:50][CH:51]1[CH:56]([O:57][CH2:58][C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)[CH:55]([O:65][CH2:66][C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=2)[CH:54]([CH2:73][O:74][CH2:75][C:76]2[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=2)[O:53][C:52]1=[O:82])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.[Cl-].[NH4+]>C1COCC1.CCCCCC>[CH2:43]([O:50][CH:51]1[CH:56]([O:57][CH2:58][C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)[CH:55]([O:65][CH2:66][C:67]2[CH:68]=[CH:69][CH:70]=[CH:71][CH:72]=2)[CH:54]([CH2:73][O:74][CH2:75][C:76]2[CH:77]=[CH:78][CH:79]=[CH:80][CH:81]=2)[O:53][C:52]1([C:2]1[CH:6]=[C:5]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH3:15])=[CH:10][CH:9]=2)[S:4][C:3]=1[CH2:16][CH2:17][O:18][C:19]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[OH:82])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: O=C1OC(COCc2ccccc2)C(OCc2ccccc2)C(OCc2ccccc2)C1OCc1ccccc1
Reactant: CCc1ccc(Cc2cc(Br)c(CCOC(c3ccccc3)(c3ccccc3)c3ccccc3)s2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCc1ccc(Cc2cc(C3(O)OC(COCc4ccccc4)C(OCc4ccccc4)C(OCc4ccccc4)C3OCc3ccccc3)c(CCOC(c3ccccc3)(c3ccccc3)c3ccccc3)s2)cc1
Reaction time: 0.25 h
Yield: 64.9 %

Procedure:
Under a nitrogen stream, to a solution of 3-bromo-5-((4-ethylphenyl)methyl)-2-(2-trityloxyethyl)thiophene (1.45 g, 2.55 mmol) in anhydrous THF (40 ml), a hexane solution of n-butyllithium (1.6 M, 1.76 ml, 2.81 mmol) was added dropwise at −78° C. and the mixture was stirred for 15 minutes. To this solution was added a solution of 3,4,5-trisbenzyloxy-6-(benzyloxymethyl)tetrahydropyran-2-one (1.50 g, 2.81 mmol) in anhydrous THF (10 ml) dropwise at −78° C. and the resulting solution was stirred at the same temperature for 10 minutes. After addition of saturated aqueous ammonium chloride, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and then evaporated under reduced pressure to remove the solvent. The resulting residue was purified by silica gel column chromatography (developing solution=ethyl acetate:n-hexane (1:20)) to give the titled compound (1.70 g, 65%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:14]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[N:16]=4)=[N:13][N:12]4[CH2:22][CH2:23][CH2:24][C:11]=34)=[CH:9][C:4]=2[CH2:3][CH2:2]1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1(C)C=CC=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:14]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[N:16]=4)=[N:13][N:12]4[CH2:22][CH2:23][CH2:24][C:11]=34)=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: Cc1cccc(-c2nn3c(c2-c2ccc4c(c2)CCO4)CCC3)n1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Product: Cc1cccc(-c2nn3c(c2-c2ccc4occc4c2)CCC3)n1
Temperature: 110 °C
Yield: 95.1 %

Procedure:
Dissolve 3-(2,3-dihydro-benzofuran-5-yl)-2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (Example 26; 10 mg, 0.03 mmol) and 2,3-dichloro-5,6-dicyanobenzoquinone (14 mg, 0.06 mmol) in anhydrous toluene (4 mL). Heat the mixture for 6 hr at 110° C. Evaporate the solvent and purify the crude product by flash chromatography to give target compound as a pale yellow solid (9 mg, 91%). MS m/e (315.2, M+1).
Reaction SMILES: [C:1]([NH:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][C:10](Cl)=[N:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[CH:15]1([NH:18][C:19]([C:21]2[CH:22]=[C:23]([F:31])[C:24]([CH3:30])=[C:25](B(O)O)[CH:26]=2)=[O:20])[CH2:17][CH2:16]1.C(=O)([O-])O.[Na+]>CC(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:15]1([NH:18][C:19]([C:21]2[CH:22]=[C:23]([F:31])[C:24]([CH3:30])=[C:25]([C:10]3[N:9]=[CH:8][C:7]([C:6]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:14])=[CH:12][CH:11]=3)[CH:26]=2)=[O:20])[CH2:17][CH2:16]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1B(O)O
Reactant: CC(C)(C)NC(=O)c1ccc(Cl)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc(C(=O)NC(C)(C)C)cn1
Temperature: 90 °C

Procedure:
N-tertbutyl-6-Chloronicotinamide (100 mg), {5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}boronic acid (Intermediate 6, 100 mg), tetrakis(triphenylphosphine)palladium (10 mg) and aqueous sodium hydrogen carbonate (4 ml) were mixed in propan-2-ol (8 ml) and heated at 90° C. under nitrogen for 18 hrs. The solvents were evaporated from the cooled reaction under vacuum and the residue dissolved as far as possible in ethylacetate. The solution was applied to an SPE (SCX, 10 g) and washed with ethyl acetate. The product was eluted from the column with methanol/0.880 ammonia, and the solvents evaporated in vacuo. The residue was redissolved in ethyl acetate and filtered through an SPE (silica, 0.5 g). The filtrate was reduced to dryness under vacuum and triturated with ether to give 6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-(1,1-dimethylethyl)-3-pyridinecarboxamide.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6](Cl)=[O:7])(=[O:3])[CH3:2].N1C=CN=C1.[NH2:14][C:15]1[C:20]([NH2:21])=[CH:19][CH:18]=[CH:17][N:16]=1.C(=O)(O)[O-].[Na+]>O1CCCC1>[C:1]([O:4][CH2:5][C:6]([NH:21][C:20]1[C:15]([NH2:14])=[N:16][CH:17]=[CH:18][CH:19]=1)=[O:7])(=[O:3])[CH3:2]
Reactant: Nc1cccnc1N
Reactant: CC(=O)OCC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: CC(=O)OCC(=O)Nc1cccnc1N
Temperature: -78 °C
Yield: 19 %

Procedure:
Acetoxyacetyl chloride (2.73 g, 20 mmol) was added dropwise to a stirred solution of imidazole (2.72 g, 40 mmol) in dry tetrahydrofuran (20 ml) under nitrogen at 0° C. After the addition was complete, the thick white suspension was cooled to --78° C. and a solution of 2,3-diaminopyridine (2.18 g, 20 mmol) in dry tetrahydrofuran (60 ml) was added over 10 minutes. The mixture was allowed to warm to room temperature overnight and then saturated aqueous sodium bicarbonate (100 ml) was added. The mixture was extracted with dichloromethane (3×80 ml), the extracts were dried (MgSO4) and concentrated under reduced pressure to give a brown solid. Recrystallisation from ethyl acetate gave 3-(acetoxyacetyl)amino-2-aminopyridine (795 mg, 38%) as white flakes.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:17](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[N:8]1([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][CH2:12][CH:11]([C:14]([O:16][CH3:17])=[O:15])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 105.9 %

Procedure:
To a solution of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (10.50 g, 45.8 mmol) in DMF (200 mL) was added potassium carbonate (6.33 g, 45.8 mmol) followed by iodomethane (3.42 mL, 55.0 mmol). The reaction was stirred under N2 at RT 3 h. The reaction was poured into 10% aqueous K2CO3 (500 mL) and extracted with EtOAc (3×150 mL). The combined organic layers were washed with saturated NaCl (2×150 mL), dried (MgSO4) and concentrated to give 1-tert-butyl 4-methyl piperidine-1,4-dicarboxylate (11.8 g, 48.5 mmol, 106% yield) as a light yellow oil.