Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][CH:10]([NH:13][CH2:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[CH2:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][CH3:36])[C:30]=1[N:37]=[C:38]=[O:39])[CH3:28].Cl>ClCCl>[CH2:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][CH3:36])[C:30]=1[NH:37][C:38]([N:13]([CH2:14][CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1)[CH:10]1[CH2:9][CH2:8][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:12][CH2:11]1)=[O:39])[CH3:28]
Reactant: c1ccc(C2CCC(NCC3CCCCC3)CC2)cc1
Reactant: CCc1cccc(CC)c1N=C=O
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCc1cccc(CC)c1NC(=O)N(CC1CCCCC1)C1CCC(c2ccccc2)CC1
Temperature: 25 °C
Yield: 36.5 %

Procedure:
To the solution of 2 g of N-(4-phenylcyclohexyl)-N-cyclohexylmethylamine in dichloromethane was added 2 ml of pyridine and to the mixture was added a solution of 1.6 g of 2,6-diethylphenylisocyanate in 30 ml of dichloromethane dropwise. After the mixture was stirred at room temperature, to the solution was added diluted hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, aqueous sodium hydrogencarbonate solution and saturated brine and then dried over magnesium sulfate. The solvent was distilled away in vacuo to give 2 g of crude crystals. The crystals were recrystallized from the mixture of ethyl acetate and hexane to give 1.2 g of N-(2,6-diethylphenyl)-N'-cyclohexylmethyl-N'-(4-phenylcyclohexyl)urea, melting at 166°-168° C.
Reaction SMILES: Br[CH2:2][CH2:3][OH:4].[Cl:5][S:6]([N:9]=[C:10]=[O:11])(=[O:8])=[O:7]>ClCCl>[O:11]=[C:10]1[N:9]([S:6]([Cl:5])(=[O:8])=[O:7])[CH2:2][CH2:3][O:4]1
Reactant: OCCBr
Reactant: O=C=NS(=O)(=O)Cl
Solvent: ClCCl
Product: O=C1OCCN1S(=O)(=O)Cl
Reaction time: 0.5 h

Procedure:
A solution of 1.13 ml of 2-bromoethanol (15.9 mmol, 1.0 eq) in dichloromethane (20 ml) was slowly added to a solution of 2.25 g of chlorosulfonyl isocyanate (15.9 mmol, 1.0 eq) in dichloromethane (100 ml) under argon at 0° C. in such a way that the temperature did not exceed 10° C. After the addition was complete, stirring was continued at 0° C. for 30 min. The product obtained in this way was directly reacted further in the next step.
Reaction SMILES: [C:1](Cl)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([O:25][CH3:26])(=[O:24])[CH2:22][SH:23]>C1(C)C=CC=CC=1>[C:2]1([C:1]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[S:23][CH2:22][C:21]([O:25][CH3:26])=[O:24])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)CS
Solvent: Cc1ccccc1
Product: COC(=O)CSC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 86.6 %

Procedure:
A solution of trityl chloride (Aldrich) (5.0 g, 17.9 mmol) and methyl thioglycolate (2.1 mL, 23.3 mmol) in 50 mL of toluene is heated at reflux overnight. The reaction solution is cooled and concentrated in vacuo. The oily residue is crystallized from ethyl acetate/hexane to give 5.4 g (87%) of methyl [(triphenylmethyl)thio]acetate: melting point 111°-115° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.[C@H:10]1([NH2:17])[CH2:15][CH2:14][C@H:13]([NH2:16])[CH2:12][CH2:11]1.O>C(O)C>[Cl:9][C:4]1[N:3]=[C:2]([NH:16][C@H:13]2[CH2:14][CH2:15][C@H:10]([NH2:17])[CH2:11][CH2:12]2)[CH:7]=[C:6]([I:8])[CH:5]=1
Reactant: Clc1cc(I)cc(Cl)n1
Reactant: N[C@H]1CC[C@H](N)CC1
Solvent: CCO
Solvent: O
Product: N[C@H]1CC[C@H](Nc2cc(I)cc(Cl)n2)CC1
Temperature: 180 °C

Procedure:
A mixture of 2,6-dichloro-4-iodopyridine (1 g, 3.65 mmol) and trans-cyclohexane-1,4-diamine (2 g, 18 mmol) in ethanol (2 mL) was heated in a Biotage Initiator microwave reactor at 180° C. for 4 h. After cooling, the mixture was poured into water and the solid collected by filtration and washed with water to give the title compound. Yield: 1.02 g (79%). MS (DCI/NH3) m/z 352 (M+H)+.
Reaction SMILES: F[C:2](F)(F)[C:3]([O:5][C:6](=[O:11])[C:7]([F:10])([F:9])[F:8])=O.N1C=CC=CC=1.O[C@@H]1[CH2:40][CH2:39][C@@:38]2([CH3:41])[C@@H:23]([CH2:24][CH2:25][C@@H:26]3[C@@H:37]2[C:36](=[O:42])[CH2:35][C@@:34]2([CH3:43])[C@H:27]3[CH2:28][CH2:29][C@@H:30]2[C:31](=[O:33])[CH3:32])C1>C(Cl)Cl>[F:8][C:7]([F:10])([F:9])[C:6]([O:5][C@@H:3]1[CH2:40][CH2:39][C@@:38]2([CH3:41])[C@@H:23]([CH2:24][CH2:25][C@@H:26]3[C@@H:37]2[C:36](=[O:42])[CH2:35][C@@:34]2([CH3:43])[C@H:27]3[CH2:28][CH2:29][C@@H:30]2[C:31](=[O:33])[CH3:32])[CH2:2]1)=[O:11]
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](OC(=O)C(F)(F)F)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of trifluoroacetic anhydride (0.34 ml.) and pyridine (0.24 ml.) in methylene dichloride (10 ml.) was added to a cooled (-80°) and stirred solution of 3α-hydroxy-5α-pregnane-11,20-dione (0.50 g.) in methylene dichloride (20 ml.) and the mixture was allowed to warm up to room temperature. After 11/2 hours more trifluoroacetic anhydride (0.34 ml.) was added and the reaction was complete after 1/2 hour more. The solution was washed successively with water, sodium bicarbonate solution and water. The dried and concentrated solution afforded a crystalline residue that was triturated with petroleum to give the title compound as needles (0.44 g.) m.p. 107°-108°, [α]D + 96°.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][O-:16])[N:10]=[CH:9]2)C=CC=CC=1.[Na+].[Cl-].[CH3:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>>[CH2:31]([O:16][CH2:15][CH2:14][CH2:13][C:11]1[N:10]=[CH:9][NH:8][CH:12]=1)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: [O-]CCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CCCCCCC
Agent: [Cl-]
Agent: [Na+]
Product: CCCCCCCOCCCc1c[nH]cn1

Procedure:
5 mmol of sodium 3-(1-triphenylmethyl-1H-imidazol-4-yl)propanolate and 5 mmol of heptane chloride are treated as described in Example 5.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]3[CH:29]=[CH:28][N:27]=[C:26](Cl)[N:25]=3)[CH:19]=2)[CH2:13][CH:12]1[C:31]#[N:32])=O)C1C=CC=CC=1.[F:33][C:34]1[CH:35]=[C:36]([CH2:41][CH2:42][NH2:43])[CH:37]=[C:38]([F:40])[CH:39]=1>>[F:33][C:34]1[CH:35]=[C:36]([CH2:41][CH2:42][NH:43][C:26]2[N:25]=[C:24]([C:20]3[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=3)[CH2:17][N:14]3[CH2:15][CH2:16][NH:11][CH:12]([C:31]#[N:32])[CH2:13]3)[CH:29]=[CH:28][N:27]=2)[CH:37]=[C:38]([F:40])[CH:39]=1
Reactant: N#CC1CN(Cc2cccc(-c3ccnc(Cl)n3)c2)CCN1C(=O)OCc1ccccc1
Reactant: NCCc1cc(F)cc(F)c1
Product: N#CC1CN(Cc2cccc(-c3ccnc(NCCc4cc(F)cc(F)c4)n3)c2)CCN1

Procedure:
Intermediate 140 was coupled with 2-(3,5-difluoro-phenyl)-ethylamine following procedure F. The resulting product was deprotected following procedure G3. LC-MS showed the product had the expected M+H3O+ of 453. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.37 (d, 1H) 8.19 (s, 1H) 8.15 (d, 1H) 7.68 (d, 1H) 7.60 (t, 1H) 7.37 (d, 1H) 6.94 (d, 2H) 6.85 (m, 1H) 4.60 (s, 2H) 4.05 (dd, 1H) 3.94 (t, 2H) 3.52 (dd, 2H) 3.24 (t, 2H) 3.03 (t, 2H) 2.58 (t, 2H).
Reaction SMILES: CC([O-])(C)C.[K+].S([CH2:17][N+:18]#[C-])(C1C=CC(C)=CC=1)(=O)=O.O[CH:21]1[CH2:26][CH2:25][C:24]2([CH2:31][CH2:30][C:29](=[O:32])[CH2:28][CH2:27]2)[CH2:23][CH2:22]1>O1CCCC1.C(O)C>[OH:32][CH:29]1[CH2:30][CH2:31][C:24]2([CH2:25][CH2:26][CH:21]([C:17]#[N:18])[CH2:22][CH2:23]2)[CH2:27][CH2:28]1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: O=C1CCC2(CC1)CCC(O)CC2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCO
Solvent: C1CCOC1
Product: N#CC1CCC2(CCC(O)CC2)CC1
Reaction time: 0.5 h
Yield: 49 %

Procedure:
Potassium tert-butylate (1.44 g) was added in small portions, at 0° C. under nitrogen atmosphere, to a solution of 1.40 g of tosylmethylisocyanide and 1.00 g of 3-hydroxy-9-oxo-spiro[5.5]undecane (II-a, Prep. 1) dissolved in 7 ml of anhydrous tetrahydrofuran and 0.53 ml of absolute ethanol. After 0.5 hrs at room temperature, the mixture was filtered on an alumina cake. The cake was washed with dichloromethane and the filtrates, dried over anhydrous sodium sulfate, were evaporated under reduced pressure to give 0.52 g of crude 9-hydroxy-3-cyano-spiro[5.5]undecane as a light oil. [TLC: Rf=0.52 (SiO2 plates, diethylether). 1H-NMR (300 MHz, CDCl3, ppm from TMS): 3.63 (1H, hept), 2.57 (1H, m), 1.90-1.05 (16H, m)].
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:18]([O:22][C:23]([N:25]1[CH2:29][CH2:28][CH2:27][C@@H:26]1[CH2:30]OS(C1C=CC(C)=CC=1)(=O)=O)=[O:24])([CH3:21])([CH3:20])[CH3:19]>CN(C=O)C>[C:18]([O:22][C:23]([N:25]1[CH2:29][CH2:28][CH2:27][C@@H:26]1[CH2:30][O:17][C:14]1[CH:13]=[CH:12][C:11]([O:10][CH2:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[CH:16][CH:15]=1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCCN2C(=O)OC(C)(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.2 %

Procedure:
To a 250 mL round bottomed flask which contained a suspension of NaH (1 g, 24 mmol) in DMF (100 mL) was added p-benzyloxy phenol (4 g, 20 mmol) at 0° C., The mixture was allowed to warm to rt and stir at rt for 30 min then cooled to 0° C. To this reaction mixture was added (R)-2-(toluene-4-sulfonyloxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (7.1 g, 20 mmol) at 0° C. The resulting mixture was allowed warm to rt and stir at rt for 30 min and then was heated to 95° C. for 5 h. After cooling to rt, the mixture was poured into 500 mL ice-water solution and this solution was allowed to stir at 0° C. for 30 min. The solid formed was filtered out, dried through air to provide the crude which was further purified by recrystallization with ether-hexane to afford the title product (5 g, 65%); LCMS; 100%, ESI+, Calcd: 383.49 m/z. Found: 284.4, (M+1-boc). 1H NMR (400 MHz, CDCl3); δ 1.47 (s, 9H), 1.79-2.10 (m, 4H), 3.26-3.45 (m, 2H), 3.66-3.91 (m, 1H), 4.01-4.19 (m 2H), 5.01 (s, 2H), 6.83-6.91 (m, 4H), 7.28-7.44 (m, 5H):
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6](Br)[C:7]=1[OH:8].CN(C)C=O.Cl[C:16]([F:21])([F:20])C(O)=O.C(=O)([O-])[O-].[K+].[K+]>O>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH:16]([F:21])[F:20]
Reactant: O=C(O)C(F)(F)Cl
Reactant: Oc1c(Br)cncc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)Oc1ccncc1Br
Temperature: 120 °C

Procedure:
To a stirred solution of 3-bromopyridin-4-ol (L); 0.5 g, 0.00287 mol) in mixture of N,N-dimethylformamide (10.0 mL), water (1 mL), was added 2-chloro-2,2-difluoroacetic acid (0.74 g, 0.00574 mol) and potassium carbonate (0.47 g, 0.00344 mol). The resulting mixture was heated under microwave irradiation at 120° C. for 45 min. The reaction mixture was cooled to room temperature and poured into water (10.0 mL) and extracted with ethyl acetate (2×50.0 mL). Combined organic phase was washed with saturated sodium bicarbonate solution, water, saturated aqueous sodium chloride solution, dried over sodium sulphate, filtered and concentrated under vacuum to afford crude product. The crude was purified by silica gel (60-120) column chromatography using 0-8% methanol in dichloromethane to afford the title compound (IN-13). 1H NMR (400 MHz, DMSO-d6) δ: 8.606-8.60 (d, J=2.4 Hz, 1H), 8.08-8.05 (dd, J=5.2 Hz, 1H), 7.67-7.37 (t, J=58.8 Hz, 1H), 6.38-6.36 (dd, J=7.2 Hz, 1H). MS (M+1): 223.8.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[CH:11]=[C:10]([C:12]([OH:14])=O)[O:9][C:6]2=[N:7][CH:8]=1)#[N:2].[NH2:15][C:16]1[CH:30]=[CH:29][C:19]([O:20][CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:18][CH:17]=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.O>[C:1]([C:3]1[CH:4]=[C:5]2[CH:11]=[C:10]([C:12]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([O:20][CH2:21][C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])=[CH:29][CH:30]=3)=[O:14])[O:9][C:6]2=[N:7][CH:8]=1)#[N:2]
Reactant: N#Cc1cnc2oc(C(=O)O)cc2c1
Reactant: CC(C)(C)OC(=O)COc1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)COc1ccc(NC(=O)c2cc3cc(C#N)cnc3o2)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
5-Cyanofuro[2,3-b]pyridine-2-carboxylic acid (108 mg, 0.574 mmol) and t-butyl 4-aminophenoxyacetate (141 mg, 0.632 mmol) were dissolved in N,N-dimethylformamide (10 ml) and 1-hydroxy-1H-benzotriazole (85.3 mg, 0.632 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (121 mg, 0.632 mmol) were added. The mixture was stirred at room temperature for 14 hours. Water (100 ml) was poured into the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. Low boiling matters were distilled away under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/1) to quantitatively give 232 mg of t-butyl 4-(5-cyanofuro[2,3-b]pyridine-2-carbonylamino)phenoxyacetate as a pale-yellow solid.
Reaction SMILES: [C:1]([C:9]1[S:13][C:12]([CH:14]=O)=[CH:11][CH:10]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:16]([O:24][CH2:25][CH3:26])(=[O:23])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>>[C:1]([C:9]1[S:13][C:12]([CH:14]=[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:16]([O:24][CH2:25][CH3:26])=[O:23])=[CH:11][CH:10]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCC#Cc1ccc(C=O)s1
Reactant: CCOC(=O)CC(=O)OCC
Product: CCCCCCC#Cc1ccc(C=C(C(=O)OCC)C(=O)OCC)s1
Yield: 96.7 %

Procedure:
Reaction of 5-(1-octynyl)-2-thiophenecarboxaldehyde (2.64 g 12 mmole) with diethyl malonate as described in Example 3 yielded the title compound as a yellow oil 4.2 g (96.7%). νmax (film) 2225, 1730, 1615, 865, 805; δ(CDCl3), 0.90(3H, t, J=6 Hz), 1.5(14H, m), 2.32(2H, t, J=6 Hz), 4.30(2H, q, J=7.5), 4.4(2H, q, J=7.5), 7.03 (1H, d, J=3 Hz), 7.23(1H, d, J=3 Hz), 7.76(1H, s).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Br[CH2:10][CH2:11][CH2:12][Cl:13]>>[Cl:13][CH2:12][CH2:11][CH2:10][O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1
Reactant: Oc1cccc(F)c1
Reactant: ClCCCBr
Product: Fc1cccc(OCCCCl)c1

Procedure:
Prepared by Procedure U and Scheme AK using 3-fluorophenol and 1-bromo-3-chloropropane.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH2:20][OH:21])[CH:8]=[C:9]([O:16][CH2:17][O:18][CH3:19])[C:10]=1[CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14].C(N(CC)CC)C.[Cl-].[S:30]([O-])(=[O:33])(=[O:32])[CH3:31]>C(Cl)Cl>[CH3:19][O:18][CH2:17][O:16][C:9]1[CH:8]=[C:7]([CH:6]=[C:5]([O:4][CH2:3][O:2][CH3:1])[C:10]=1[CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])[CH2:20][O:21][S:30]([CH3:31])(=[O:33])=[O:32]
Reactant: CS(=O)(=O)[O-]
Reactant: COCOc1cc(CO)cc(OCOC)c1CC=C(C)C
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCOc1cc(COS(C)(=O)=O)cc(OCOC)c1CC=C(C)C
Temperature: 0 °C

Procedure:
[3,5-Bis-methoxymethoxy-4-(3-methyl-but-2-enyl)-phenyl]-methanol (2.0 g, 6.75 mmol) was dissolved in CH2Cl2 and placed in an ice bath. Triethylamine (1.2 ml, 8.92 mmol) was added and stirred until the reaction solution was at 0° C., followed by the dropwise addition of mesylate chloride (900 ul, 8.92 mmol). After stirring in the ice bath for 1 hour, the reaction was quenched with water, extracted with EtOAc, washed with brine, dried with MgSO4, filtered and evaporated yielding methanesulfonic acid 3,5-bis-methoxymethoxy-4-(3-methyl-but-2-enyl)-benzyl ester as a yellow oil. 1H NMR (CDCl3, 300 MHz) δ (ppm): 6.82 (s, 2H), 5.20 (t, 1H), 5.16 (s, 4H), 4.13 (s, 2H), 3.48 (s, 6H), 3.39 (d, 2H) 2.96 (s, 3H), 1.78 (s, 3H), 1.65 (s, 3H). MS (ESI) m/z: 375 (M+H)+, 397 (M+Na)+.
Reaction SMILES: [N+]([O-])(O)=O.[CH3:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:7]=1[NH:15][C:16]([NH2:18])=[NH:17].CN(C)[CH:21]=[CH:22][C:23]([C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1)=O.[OH-].[Na+]>C(O)(C)C>[CH3:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:7]=1[NH:15][C:16]1[N:18]=[C:23]([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[CH:22]=[CH:21][N:17]=1
Reactant: CN(C)C=CC(=O)c1cccnc1
Reactant: Cc1ccc([N+](=O)[O-])cc1NC(=N)N
Agent: [Na+]
Agent: [OH-]
Solvent: O=[N+]([O-])O
Solvent: CC(C)O
Product: Cc1ccc([N+](=O)[O-])cc1Nc1nccc(-c2cccnc2)n1
Temperature: 0 °C

Procedure:
248.2 g (0.96 mol) of 2-methyl-5-nitrophenylguanidine nitrate are added to a solution of 170 g (0.96 mol) of 3-dimethylamino-1-(3-pyridyl)-2-propen-1-one in 2.0 liters of isopropanol. After the addition of 42.5 g of sodium hydroxide, the reddish suspension is boiled at reflux for 12 hours. After cooling to 0° C., filtration, washing with 2.0 liters of isopropanol and 3.times.400 ml of methanol and drying, there is obtained N-(2-methyl-5-nitrophenyl)-4-(3-pyridyl)-2-pyrimidine-amine, m.p. 195° C.-198° C., Rf=0.68 (methylene chloride:methanol=9.1).
Reaction SMILES: [CH2:1]([N:4]([CH2:20][CH2:21][CH3:22])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([CH2:15][NH:16]C(=O)C)[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].[OH-].[K+]>C(O)C>[CH2:20]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([CH2:15][NH2:16])[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:21][CH3:22]
Reactant: CCCN(CCC)C1CCc2cccc(CNC(C)=O)c2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCN(CCC)C1CCc2cccc(CN)c2C1
Temperature: 90 °C

Procedure:
10.6 g (35 mmol) of 2-dipropylamino-8-acetamidomethyl-1,2,3,4-tetrahydronaphthalene in 100 ml of ethanol and 23.1 g (350 mmol) of potassium hydroxide were heated to a gentle reflux for 24 h at 90° C. under nitrogen. The batch was subsequently stirred into 1 liter of ice water and the mixture was extracted with dichloromethane. The organic phase was washed with water and dried over sodium sulphate. The solvent was removed by distillation in vacuo. The reaction product, remaining as a residue, was purified by column chromatography on silica gel using methanol/triethylamine, 95:5, as eluent.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([CH2:6][N:7]2[C:15]3[C:10](=[C:11]([NH:16][C:17]([C:19]4[N:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]5=[N:21][CH:20]=4)=[O:18])[CH:12]=[CH:13][CH:14]=3)[C:9]([CH2:28][CH3:29])=[N:8]2)=[N:2]1.Br[CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]1.O.[OH-].[Cs+]>CN(C=O)C>[CH2:28]([C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:17]([C:19]2[N:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]3=[N:21][CH:20]=2)=[O:18])[N:7]([CH2:6][C:3]2[CH:4]=[CH:5][N:1]([CH2:31][CH2:32][N:33]3[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:43])([CH3:45])[CH3:44])=[O:40])[CH2:35][CH2:34]3)[N:2]=2)[N:8]=1)[CH3:29]
Reactant: CC(C)(C)OC(=O)N1CCN(CCBr)CC1
Reactant: CCc1nn(Cc2cc[nH]n2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Agent: [Cs+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1nn(Cc2ccn(CCN3CCN(C(=O)OC(C)(C)C)CC3)n2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Reaction time: 0.5 h

Procedure:
To a solution of N-(1-((1H-pyrazol-3-yl)methyl)-3-ethyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (40.0 mg; 0.104 mmol) in dry DMF (0.5 mL) was added tert-butyl 4-(2-bromoethyl)piperazine-1-carboxylate (30.4 mg; 0.104 mmol) and cesium hydroxide hydrate (17.4 mg; 0.104 mmol). The mixture was stirred under a nitrogen atmosphere for 30 minutes. The mixture was filtered, washing with methanol and ethyl acetate, and the solvent was removed under reduced pressure. The residue (a mixture of two regioisomers) was purified by preparative thin layer chromatography on silica, eluting with 10% methanol in dichloromethane. The desired isomer tert-butyl 4-(2-(3-((3-ethyl-4-(imidazo[1,2-a]pyridine-3-carboxamido)-1H-indazol-1-yl)methyl)-1H-pyrazol-1-yl)ethyl)piperazine-1-carboxylate was isolated (21.5 mg) along with some of the alternate isomer.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.CN(C=O)C.[H-].[Na+].Cl[C:17]1[N:22]=[CH:21][N:20]=[C:19]2[N:23]([CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)[N:24]=[CH:25][C:18]=12>C(OCC)(=O)C>[O:27]1[CH2:28][CH2:29][CH2:30][CH2:31][CH:26]1[N:23]1[C:19]2=[N:20][CH:21]=[N:22][C:17]([O:8][C:5]3[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=3)=[C:18]2[CH:25]=[N:24]1
Reactant: Clc1ncnc2c1cnn2C1CCCCO1
Reactant: Nc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1ccc(Oc2ncnc3c2cnn3C2CCCCO2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 87.2 %

Procedure:
To a round bottom flask equipped with a magnetic stir bar was added 4-amino-phenol (0.251 g, 2.3 mmol, 1.1 eq) and DMF (3 ml). The mixture was cooled to 0° C. followed by the addition of NaH (0.13, 5.4 mmol, 2.7 eq). After 10 minutes 4-Chloro-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine (0.5 g, 2.1 mmol, 1.0 eq.) was added and the reaction was allowed to warm up to room temperature. After stirring at room temperature for 1 hour the reaction mixture was diluted with ethyl acetate (50 ml) and Was washed (2×) water, (1×) NaHCO3, (2×) 5% LiCl, and (1×) brine. The organic layer was dried over sodium sulfate and the solvent removed to give 4-[1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-phenylamine as a yellow solid (570 mg, 87%). 1H NMR (400 MHz, CDCl3): 8.56(s, 1H), 7.75 (s, 1H), 6.97 (d, 2H), 6.64 (d, 2H), 5.96 (dd, 1H), 5.21 (s, 2H), 3.96 (d, 1H), 3.72 (m, 1H), 2.42 (m, 1H), 2.01 (m, 1H), 1.87 (m, 1H), 1.76 (m, 1H), 1.57 (m, 2H); MS (ESI) for C16H17N5O2: 312 (MH+).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C@@H:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH3:13])[C@H:4]([N+:14]([O-])=O)[C@@H:3]1[CH3:17].C(O)(=O)C>CO.[Zn]>[CH3:1][N:2]1[CH2:6][C@@H:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH3:13])[C@H:4]([NH2:14])[C@@H:3]1[CH3:17]
Reactant: Cc1ccccc1[C@@H]1CN(C)[C@@H](C)[C@H]1[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1ccccc1[C@@H]1CN(C)[C@@H](C)[C@H]1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.7 %

Procedure:
(2R,3R,4S)+(2S,3S,4R)-1,2-dimethyl-3-nitro-4-(o-tolyl) pyrrolidine (28 mg, 0.12 mmol) was dissolved in 1 ml MeOH and Acetic Acid (2.0 ml) and charged with ZINC (39.1 mg, 0.598 mmol). The reaction was allowed to stir overnight at rt. The solution was filtered through celite and concentrated in vacuo. The residue was dissolved in 2 mL MeOH and desalted on ps-bicarb. The solvents were removed in vacuo to afford (2R,3R,4S)+(2S,3S,4R)-1,2-dimethyl-4-(o-tolyl)pyrrolidin-3-amine (17 mg, 0.08 mmol, 70% yield). LC/MS M+H 205.2
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([C:12]([NH2:14])=[O:13])[NH:9]2)=[CH:5][CH:4]=1.[Br-:15].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>N1C=CC=CC=1>[Br:15][C:7]1[C:6]2[C:10](=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[NH:9][C:8]=1[C:12]([NH2:14])=[O:13]
Reactant: COc1ccc2cc(C(N)=O)[nH]c2c1
Reactant: [Br-]
Agent: c1cc[nH+]cc1
Solvent: c1ccncc1
Product: COc1ccc2c(Br)c(C(N)=O)[nH]c2c1
Temperature: 0 °C
Reaction time: 19 h
Yield: 70.4 %

Procedure:
A solution of 540 mg (2.84 mmol) of 6-methoxy-1H-indole-2-carboxamide in 8 ml of pyridine is cooled to 0° C. and a solution of 908 mg (2.84 mmol) of pyridinium tribromide in 6 ml of pyridine is added thereto, dropwise. The reaction medium is stirred at 0° C. for 30 minutes and at ambient temperature for 19 h. 20 ml of ice-cold water is added to the reaction medium. The latter is then stirred at ambient temperature for 1 h and then filtered over sintered glass, to give 538 mg of 3-bromo-6-methoxy-1H-indole-2-carboxamide in the form of a white solid.