Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][NH2:7])(=[O:3])[CH3:2].[CH3:8][CH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=O)[CH:11]([CH2:20][CH:21]=O)[CH2:10]1>C(Cl)Cl>[CH3:8][CH:9]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:12]2[N:7]([CH2:6][CH2:5][NH:4][C:1](=[O:3])[CH3:2])[CH:21]=[CH:20][C:11]=2[CH2:10]1
Reactant: CC(=O)NCCN
Reactant: CC1CC(CC=O)C(=O)c2ccccc21
Solvent: ClCCl
Product: CC(=O)NCCn1ccc2c1-c1ccccc1C(C)C2
Yield: 72.2 %

Procedure:
N-Acetylethylenediamine (8.1 g) was dissolved in 150 ml of methylene chloride under argon, treated in succession with 140 g of molecular sieve 4 Å and a solution of 14.5 g of 1,2,3,4-tetrahydro-4-methyl-1-oxo-2-naphthaleneacetaldehyde in 100 ml of methylene chloride and heated to reflux for 18 hours while stirring. The reaction mixture was cooled, filtered over a Celite® pad and the filtrate was freed from solvent. The crude product, 19.4 g of dark brown oil, was chromatographed on 300 g of silica gel with ethyl acetate as the eluent. The product, 14.2 g of yellow-brown oil, was dissolved in 200 ml of ethanol, boiled with 0.7 g of Norite® and, after fitration and removal of the solvent, yielded 13.9 g (72%) of N-[2-(4,5-dihydro-5-methyl-1H-benzo[g]indol-1-yl)ethyl]acetamide which was processed without further purification.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][O:26][CH2:27][C@@H:28]([O:30][C:31]1[CH:32]=[C:33]([CH:37]=[C:38]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:39]=1)[C:34]([OH:36])=O)[CH3:29].[CH2:48]([N:50]1[CH:54]=[CH:53][C:52]([NH2:55])=[N:51]1)[CH3:49].CCN(C(C)C)C(C)C>C(OCC)(=O)C.CN(C=O)C>[CH2:48]([N:50]1[CH:54]=[CH:53][C:52]([NH:55][C:34](=[O:36])[C:33]2[CH:37]=[C:38]([O:40][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH:39]=[C:31]([O:30][C@@H:28]([CH3:29])[CH2:27][O:26][CH3:25])[CH:32]=2)=[N:51]1)[CH3:49]
Reactant: COC[C@H](C)Oc1cc(OCc2ccccc2)cc(C(=O)O)c1
Reactant: CCn1ccc(N)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCn1ccc(NC(=O)c2cc(OCc3ccccc3)cc(O[C@@H](C)COC)c2)n1
Temperature: 0 °C
Reaction time: 3 h
Yield: 90.5 %

Procedure:
HATU (23.5 g, 61.83 mmol) was added to 3-[(1S)-2-methoxy-(1-methylethyl)oxy]-5-{[phenylmethyl]oxy}benzoic acid (16.28 g, 51.53 mmol) followed by addition of DMF (140 mL) and cooled to 0° C. 1-Ethyl-1H-pyrazol-3-amine (6.86 g, 61.8 mmol) was added followed by DIPEA (21.3 mL) and the reaction stirred under argon, at 0° C., for 3 hours. The solvent volume was reduced and the residue was dissolved in ethyl acetate (500 mL), washed with citric acid (200 mL), sodium hydrogen carbonate solution (150 mL) and saturated brine solution (2×150 mL). The organic layer was separated and dried (MgSO4), filtered and evaporated. Purification by column chromatography on silica, eluting with 10-50% ethyl acetate in hexanes, afforded the title compound as a pale yellow oil (19.1 g).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[NH2:9][C:10]1[C:11]([CH3:22])=[C:12]([CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH:13]=[CH:14][CH:15]=1>C(#N)C.C(OCC)(=O)C>[NH2:9][C:10]1[C:11]([CH3:22])=[C:12]([CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH:13]=[CH:14][C:15]=1[Cl:1]
Reactant: COC(=O)CCc1cccc(N)c1C
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)CCc1ccc(Cl)c(N)c1C
Reaction time: 0.5 h

Procedure:
At RT, 1.38 g (10.3 mmol) of N-chlorosuccinimide were added to a solution of 2.0 g (10.3 mmol) of methyl 3-(3-amino-2-methylphenyl)propanoate in 10 ml of acetonitrile. The reaction mixture was stirred for 30 min and then diluted with ethyl acetate. The mixture was washed successively with sat. sodium bicarbonate solution and sat. sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure. The crude product gave, after chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 10:1), 279 mg of the target product (11.8% of theory).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](Br)=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]([Sn](CCCC)(CCCC)C=C)[CH2:20]CC>CN(C=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>[N+:16]([C:10]1[CH:11]=[C:12]([CH:19]=[CH2:20])[CH:13]=[CH:14][C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1cc(Br)ccc1OCc1ccccc1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=Cc1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Yield: 93.5 %

Procedure:
A mixture of Example 68A (2.18 g, 7.08 mmol), Pd(PPh3)4 (1.23 g, 1.06 mmol) and tributyl-vinyl-stannane (2.48 mL, 8.49 mmol) in DMF (200 mL) was heated at 80° C. overnight. The solvent was removed by vacuum pump. The residue was dissolved in acetone (50 mL), and dried with silica gel powder (20 g). 10% ethyl acetate in hexanes (2 L) was used to run flash chromatography to give the title compound (1.69 g, 94%). MS (DCI) m/z 273.03 (M+NH4)+; 1H NMR (500 MHz, CD2Cl2) δ ppm 5.23 (s, 2 H) 5.72 (d, J=17.47 Hz, 1 H) 6.67 (dd, J=17.78, 10.92 Hz, 1 H) 7.12 (d, J=8.73 Hz, 1 H) 7.35 (m, 1 H) 7.38–7.43 (m, 2 H) 7.44–7.48 (m, 2 H) 7.56 (dd, J=8.73, 2.18 Hz, 1 H) 7.87 (d, J=2.18 Hz, 1 H).
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5](=[O:36])[C@H:6]([CH2:32][CH:33]([CH3:35])[CH3:34])[NH:7][C:8]1[C:9]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)=[N:10][O:11][CH:12]=1)#[N:2].CS(O)(=O)=O>C1COCC1>[C:1]([CH2:3][NH:4][C:5](=[O:36])[C@H:6]([CH2:32][CH:33]([CH3:34])[CH3:35])[NH:7][C:8]1[C:9]([C:13]2[CH:14]=[CH:15][C:16]([N:19]3[CH2:20][CH2:21][NH:22][CH2:23][CH2:24]3)=[CH:17][CH:18]=2)=[N:10][O:11][CH:12]=1)#[N:2]
Reactant: CC(C)C[C@H](Nc1conc1-c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1)C(=O)NCC#N
Agent: CS(=O)(=O)O
Solvent: C1CCOC1
Product: CC(C)C[C@H](Nc1conc1-c1ccc(N2CCNCC2)cc1)C(=O)NCC#N
Yield: 30.9 %

Procedure:
To a room temperature solution of N1-(cyanomethyl)-N2-[3-(4-[4-(tert-butoxycarbonyl)piperazin-1-yl]phenyl)isoxazol-4-yl]leucinamide (15.5 mg, 0.031 mmol) in THF (2 mL) was added 8 equivalents of methanesulfonic acid (10% solution in dichloromethane) over 28 h. The reaction mixture was quenched with aqueous NaHCO3 solution and extracted with dichloromethane (3×). The organic phase was filtered through cotton and evaporated. Purification by flash chromatography (2% to 15% methanol/dichloromethane+0.5% ammonium hydroxide) gave 3.8 mg of N1-(cyanomethyl)-N2-[3-(4-piperazin-1-ylphenyl)isoxazol-4-yl]leucinamide. MS (+ESI): 397.4 [M+1]+.
Reaction SMILES: C([O:4][CH:5]1[CH:10]2[S:11][CH:8]3[CH:9]2[CH2:12][CH:6]1[CH:7]3[O:13]C(=O)C)(=O)C.C(=O)([O-])O.[Na+]>CO>[OH:13][CH:7]1[CH:8]2[S:11][CH:10]3[CH:9]2[CH2:12][CH:6]1[CH:5]3[OH:4]
Reactant: CC(=O)OC1C2CC3C1SC3C2OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: OC1C2CC3C1SC3C2O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A 1-L flask equipped with a stirrer was charged with 110 g (0.56 mol) of the 2,6-bis(acetoxy)-8-thiatricyclo[2.2.1.13,5]octane prepared in REFERENCE PRODUCTION EXAMPLE 1 and 600 mL of methanol, to which 84 g (1.0 mol) of sodium hydrogen carbonate was added with stirring. The mixture was heated to a temperature at which methanol served as the reflux, at which it was held for 4 hours. It was then cooled to room temperature and filtered to remove the residue.
Reaction SMILES: O[C:2]1[C:11](O)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.[CH3:13][C:14]1[C:19]([CH3:20])=[CH:18][C:17]([NH2:21])=[C:16]([NH2:22])[CH:15]=1.CN(C)C1C=CC=CC=1.C(Cl)Cl>C1(C)C=CC=CC=1.CCCCCCC>[CH3:13][C:14]1[C:19]([CH3:20])=[CH:18][C:17]2[NH:21][C:2]3[CH:3]=[C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:9]4=[CH:10][C:11]=3[NH:22][C:16]=2[CH:15]=1
Reactant: Oc1cc2ccccc2cc1O
Reactant: Cc1cc(N)c(N)cc1C
Solvent: CCCCCCC
Solvent: ClCCl
Solvent: CN(C)c1ccccc1
Product: Cc1cc2c(cc1C)Nc1cc3ccccc3cc1N2
Temperature: 25 °C
Yield: 33 %

Procedure:
2,3-dihydroxynapthalene (10 g, 62.5 mmol), 4,5-dimethyl-1,2-phenylenediamine (8.5 g, 62.5 mmol) and N,N-dimethylaniline (54 ml) are placed into a round bottom flask under nitrogen atmosphere. Mixture is stirred at reflux. Reaction is monitored by TLC (CH2Cl2:Heptane/1:1) until all 2,3-dihydroxynaphthalene has reacted (˜3 hours). After cooling to room temperature, toluene (100 ml) is added and solid is collected by vacuum filtration. After washing with toluene (50 ml), ethanol (100 ml) and hexanes (50 ml), the product is dried under vacuum to yield 23.3 g (33% yield) of light yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([CH3:11])([CH3:10])[CH3:9])[N:3]=1.O.[CH3:13][N:14](C)C=O>[C-]#N.[Zn+2].[C-]#N.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>[C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:13]#[N:14])[N:3]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)c1cccc(Br)n1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: CC(C)(C)c1cccc(C#N)n1
Temperature: 80 °C
Yield: 89 %

Procedure:
To a solution of 2-bromo-6-tert-butylpyridine (Description 14; 9.9 g, 46 mmol) in anhydrous N,N-dimethylformamide (130 ml) was added zinc cyanide (6.48 g, 55.2 mmol) and Pd(PPh3)4 (2.65 g, 2.3 mmol). The mixture was degassed then heated at 80° C. overnight. The cooled reaction mixture was poured into water (500 ml), and extracted with ethyl acetate (3×150 ml). The combined organic layers were washed with water (2×300 ml), brine (100 ml), dried (Na2SO4) and evaporated. The residue was purified by column chromatography on silica eluting with 5% Et2O in iso-hexanes to give the title compound (6.6 g, 89%).
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.[CH2:14]([Sn:18](Cl)([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15][CH2:16][CH3:17].O>O1CCCC1.CCCCCC>[CH3:8][C:7]1[C:2]([Sn:18]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:14][CH2:15][CH2:16][CH3:17])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Cc1cccnc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: CCCC[Sn](CCCC)(CCCC)c1ncccc1C
Reaction time: 0.25 h
Yield: 78.8 %

Procedure:
A solution (10 mL) of 2-bromo-3-methylpyridine (1.0 g) in tetrahydrofuran was cooled to −70° C., and a 1.6 mol/L solution (4.0 mL) of n-butyllithium in hexane was added dropwise. After stirring at the same temperature for 15 min, tributyltin chloride (2.2 g) was added dropwise. After further stirring for 1 hr, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1) to give the title compound as a colorless oil (yield 1.75 g, 79%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([NH2:7])[CH2:3][CH2:2]1.Cl[C:9]1[CH:10]=[C:11]([N:28]([CH:38]2[CH2:40][CH2:39]2)[CH2:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)[C:12]2[N:13]([C:15]([C:18]([NH:20][C:21]3[CH:26]=[CH:25][N:24]=[C:23]([Cl:27])[CH:22]=3)=[O:19])=[CH:16][N:17]=2)[N:14]=1>CN1C(=O)CCC1.CO>[Cl:27][C:23]1[CH:22]=[C:21]([NH:20][C:18]([C:15]2[N:13]3[N:14]=[C:9]([NH:7][CH:4]4[CH2:5][CH2:6][O:1][CH2:2][CH2:3]4)[CH:10]=[C:11]([N:28]([CH:38]4[CH2:39][CH2:40]4)[CH2:29][C:30]4[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=4)[C:12]3=[N:17][CH:16]=2)=[O:19])[CH:26]=[CH:25][N:24]=1
Reactant: NC1CCOCC1
Reactant: COc1ccc(CN(c2cc(Cl)nn3c(C(=O)Nc4ccnc(Cl)c4)cnc23)C2CC2)cc1
Solvent: CN1CCCC1=O
Solvent: CO
Product: COc1ccc(CN(c2cc(NC3CCOCC3)nn3c(C(=O)Nc4ccnc(Cl)c4)cnc23)C2CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 12.4 %

Procedure:
A solution of tetrahydro-2H-pyran-4-amine (105 mg, 1.034 mmol) and 6-chloro-N-(2-chloropyridin-4-yl)-8-(cyclopropyl(4-methoxybenzyl)amino)imidazo[1,2-b]pyridazine-3-carboxamide (50 mg, 0.103 mmol) in NMP (1 mL) was heated to 140° C. The reaction was stirred for 16 hours until starting material was consumed and then cooled to room temperature. The crude reaction product was dissolved in a small amount of MeOH and purified by reversed phase HPLC (YMC ODS-A 5 um 30×250 mm, 10-90% aqueous methanol containing 0.1% TFA, 25 mL/min, 40 min gradient, monitored at 220 nm). The product (retention time=47.580 minutes) was isolated and lyophilized to dryness. to afford N-(2-chloropyridin-4-yl)-8-(cyclopropyl(4-methoxybenzyl)amino)-6-(tetrahydro-2H-pyran-4-ylamino)imidazo[1,2-b]pyridazine-3-carboxamide (7 mg, 11.57%). HPLC Rt=4.595 min (YMC S5 ODS 4.6×50 mm, 10-90% aqueous methanol containing 0.2% H3PO4, 4 min gradient, monitored at 220 nm). [M+H+]=548.0.
Reaction SMILES: [Si]([O:18][CH2:19][C:20]1[C:21]([N:35]2[CH2:40][C@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]2)=[C:22]([F:34])[C:23]2[O:27][N:26]=[C:25]([C:28]([O:30]CC)=O)[C:24]=2[CH:33]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:43][N:44]1[CH:48]=[CH:47][C:46]([CH2:49][NH2:50])=[N:45]1>>[CH3:42][C@@H:37]1[CH2:36][N:35]([C:21]2[C:20]([CH2:19][OH:18])=[CH:33][C:24]3[C:25]([C:28]([NH:50][CH2:49][C:46]4[CH:47]=[CH:48][N:44]([CH3:43])[N:45]=4)=[O:30])=[N:26][O:27][C:23]=3[C:22]=2[F:34])[CH2:40][C@H:39]([CH3:41])[O:38]1
Reactant: CCOC(=O)c1noc2c(F)c(N3C[C@@H](C)O[C@@H](C)C3)c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc12
Reactant: Cn1ccc(CN)n1
Product: C[C@@H]1CN(c2c(CO)cc3c(C(=O)NCc4ccn(C)n4)noc3c2F)C[C@H](C)O1

Procedure:
Starting materials: ethyl 5-((tert-butyldiphenylsilyloxy)methyl)-6-((2R,6S)-2,6-dimethylmorpholino)-7-fluorobenzo[d]isoxazole-3-carboxylate (Intermediate 204) and (1-methyl-1H-pyrazol-3-yl)methanamine
Reaction SMILES: [CH3:1][C@H:2]1[C@@H:11]2[CH2:12][CH2:13][C:14]3([CH3:18])[O:16][O:17][C@:10]42[C@H:5]([C@@H:6]([CH3:20])[C@@H:7]([OH:19])[O:8][C@@H:9]4[O:15]3)[CH2:4][CH2:3]1.[CH2:21](OC(OCC)OCC)[CH3:22].[Al+3].[Cl-].[Cl-].[Cl-]>C(O)C>[CH3:21][CH2:22][O:19][C@H:7]1[O:8][C@@H:9]2[O:15][C:14]3([CH3:18])[O:16][O:17][C@@:10]42[C@@H:5]([CH2:4][CH2:3][C@@H:2]([CH3:1])[C@@H:11]4[CH2:12][CH2:13]3)[C@H:6]1[CH3:20]
Reactant: CCOC(OCC)OCC
Reactant: C[C@H]1[C@@H](O)O[C@@H]2OC3(C)CC[C@H]4[C@H](C)CC[C@@H]1[C@@]24OO3
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCO
Product: CCO[C@H]1O[C@@H]2OC3(C)CC[C@H]4[C@H](C)CC[C@@H]([C@H]1C)[C@@]24OO3
Temperature: 40 °C
Reaction time: 0.75 h

Procedure:
Dihydroartemisinin (50 mg) was dissolved in dry ethanol (3 ml). Add 2 ml of triethylorthoformate and anhydrous AlCl3 (33 mg) was added in the reaction vessel. The reaction mixture was refluxed at 40° C. for 45 min over oil bath with constant stirring. After 45 mins of stirring the reaction product was worked up as mention in the example-3. The pure arteether yielded (45 mg).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:8]1[CH:12]=[N:11][CH:10]=[N:9]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:2]1([N:8]2[CH:12]=[N:11][CH:10]=[N:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Ic1ccccc1
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: c1ccc(-n2cncn2)cc1

Procedure:
Operating protocol A (82° C., 24 hours) was followed using 117 mg of Chxn-Py-Al (0.4 mmoles), 336 μl of iodobenzene (3 mmoles), 138 mg of 1,2,4-triazole (2 mmoles), 1.042 g of caesium carbonate (3.2 mmoles) and 1.2 ml of DMF.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([C@@H:13]3[CH2:18][CH2:17][N:16]([CH2:19][C:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[O:21])[CH2:15][C@H:14]3[C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[NH:10][N:9]=2)=[CH:4][CH:3]=1.[BH4-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([C@@H:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[OH:21])[CH2:15][C@H:14]3[C:28]3[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=3)[NH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(CN1CC[C@@H](c2cc(-c3ccc(Cl)cc3)n[nH]2)[C@H](c2ccc(F)cc2)C1)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OC(CN1CC[C@@H](c2cc(-c3ccc(Cl)cc3)n[nH]2)[C@H](c2ccc(F)cc2)C1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The product from step A (40 mg, 0.084 mmol) in ethanol (1.0 ml) was treated at rt with sodium borohydride (31.9 mg, 0.844 mmol). The mixture was stirred at rt for 16 h, then quenched with 2M aq NaOH (0.1 mL) and concentrated. Direct purification of the residue by RP-HPLC(C18, acetonitrile, water, 0.1% TFA) afforded the title compound. HPLC/MS: 476.3, 478.3 (M+1); Rt=1.66 min (LC-4 HPLC conditions).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=[C:4]2[N:11]([CH2:14][CH3:15])[N:12]=[CH:13][C:3]=12.[NH2:16][CH:17]1[CH2:22][CH2:21][CH:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1>C(#N)C>[C:26]([O:25][C:23]([CH:20]1[CH2:19][CH2:18][CH:17]([NH:16][C:2]2[C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=[C:4]3[N:11]([CH2:14][CH3:15])[N:12]=[CH:13][C:3]=23)[CH2:22][CH2:21]1)=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)C1CCC(N)CC1
Reactant: CCn1ncc2c(Cl)c(C(=O)O)cnc21
Solvent: CC#N
Product: CCn1ncc2c(NC3CCC(C(=O)OC(C)(C)C)CC3)c(C(=O)O)cnc21

Procedure:
A solution of 4-chloro-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid (0.0088 mol) (example 4a) in acetonitrile is treated with tert-butyl 4-aminocyclohexanecarboxylate (0.026 mol). The reaction mixture is refluxed for about 3-4 hrs. Solvent is evaporated off and water is added and extraction is done with ethyl acetate. The organic layer is washed with brine, dried and concentrated under reduced pressure to give crude compound, which is purified by column chromatography.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:10]([C:11](=O)/[CH:12]=[CH:13]/N(C)C)=[CH:9][N:8]([CH2:18][CH3:19])[C:7]=12.Cl.[NH:21]([C:25]1[CH:26]=[C:27]([S:31]([NH2:34])(=[O:33])=[O:32])[CH:28]=[CH:29][CH:30]=1)[C:22]([NH2:24])=[NH:23]>>[Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:10]([C:11]3[CH:12]=[CH:13][N:24]=[C:22]([NH:21][C:25]4[CH:26]=[C:27]([S:31]([NH2:34])(=[O:32])=[O:33])[CH:28]=[CH:29][CH:30]=4)[N:23]=3)=[CH:9][N:8]([CH2:18][CH3:19])[C:7]=12
Reactant: CCn1cc(C(=O)/C=C/N(C)C)c2ccnc(Cl)c21
Reactant: N=C(N)Nc1cccc(S(N)(=O)=O)c1
Agent: Cl
Product: CCn1cc(-c2ccnc(Nc3cccc(S(N)(=O)=O)c3)n2)c2ccnc(Cl)c21

Procedure:
Prepared by treatment of (E)-1-(7-chloro-1-ethyl-1H-pyrrolo[2,3-c]pyridin-3-yl)-3-(dimethylamino)prop-2-en-1-one and 3-guanidinobenzenesulfonamide hydrochloride. 1H-NMR (DMSO-d6) δ: 1.45 (t, 3H, J=7.2 Hz, CH3), 4.48 (t, 2H, J=7.2 Hz, CH2), 7.30 (m, 3H, Pyrimidin-H and NH2), 7.43 (m, 1H, Ar—H or Ph-H), 7.50 (t, 1H, J=7.6 Hz, Ph-H), 7.82 (d, 1H, J=5.6 Hz, Ar—H), 7.89 (m, 1H, Ar—H or Ph-H), 8.07 (m, 1H, Ar—H or Ph-H), 8.45 (d, 1H, J=5.6 Hz, Pyrimidin-H), 8.48 (s, 1H, Ar—H), 8.61 (s, 1H, NH). MS (ESI+) m/z 426.1490 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:7]=[CH:6][C:5]=1[NH2:19])([O-:3])=[O:2].Cl.Cl[C:22]1[CH:27]=[CH:26][N:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=1>>[N+:1]([C:4]1[CH:9]=[C:8]([C:22]2[CH:27]=[CH:26][N:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)[CH:7]=[CH:6][C:5]=1[NH2:19])([O-:3])=[O:2]
Reactant: CC1(C)OB(c2ccc(N)c([N+](=O)[O-])c2)OC1(C)C
Reactant: FC(F)(F)c1cc(Cl)ccn1
Agent: Cl
Product: Nc1ccc(-c2ccnc(C(F)(F)F)c2)cc1[N+](=O)[O-]

Procedure:
Following the procedure as described in Example 2, STEP A, the title compound was prepared from 2-nitro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (0.300 g, 1.14 mmol, as prepared in the previous step) and 4-chloro-2-trifluoromethyl-pyridine hydrochloride (322 mg, 1.48 mmol) and was obtained as an orange solid.
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C:12]1[CH:13]=[C:14]([CH:19]([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:15]=[CH:16][C:17]=1O>N1C=CC=CC=1>[CH2:7]([C:8]1[O:9][C:17]2[CH:16]=[CH:15][C:14]([CH:19]([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:13][C:12]=2[N:11]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CCOC(=O)C(C)c1ccc(O)c(N)c1
Solvent: c1ccncc1
Product: CCOC(=O)C(C)c1ccc2oc(Cc3ccccc3)nc2c1
Temperature: 100 °C

Procedure:
Phenyl acetyl chloride (2.2 ml.) was added to a stirred solution of ethyl 2-(3-amino-4-hydroxyphenyl)propionate (3.15g.) in anhydrous pyridine (50 ml.) and the solution was heated at 100° C for two hours. Excess pyridine was removed by distillation and the residue heated until the temperature of the distillate immediately above the reaction mixture was 200° C. The resultant dark brown gum was dissolved in ether (75 ml.) and then washed with water (3 × 50 ml.) The ether solution was extracted with 1N sodium hydroxide (50 ml.), washed with water (2 × 50 ml.) and evaporated to give ethyl 2-(2-benzyl-5-benzoxazolyl)propionate as a light brown mobile gum, which was shown to be pure by thin layer chromatography. Similarly the following esters were prepared and characterised:
Reaction SMILES: C(OC([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[CH:21]=[C:20]([CH3:22])[N:19]=[C:18]([N:23]2[CH:27]=[CH:26][N:25]=[CH:24]2)[N:17]=1)=O)C1C=CC=CC=1>[Pd].C(O)C>[N:23]1([C:18]2[N:19]=[C:20]([CH3:22])[CH:21]=[C:16]([CH:12]3[CH2:13][CH2:14][CH2:15][NH:11]3)[N:17]=2)[CH:27]=[CH:26][N:25]=[CH:24]1
Reactant: Cc1cc(C2CCCN2C(=O)OCc2ccccc2)nc(-n2ccnc2)n1
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(C2CCCN2)nc(-n2ccnc2)n1
Reaction time: 4 h
Yield: 89.2 %

Procedure:
10% Pd/C (12 mg) was added to a solution of 2-(2-imidazol-1-yl-6-methyl-pyrimidin-4-yl)-pyrrolidine-1-carboxylic acid benzyl ester (112 mg, 0.308 mmol) and ethanol (3 mL) at rt. The reaction was vacuum purged with N2 then stirred under a balloon of H2 for 4 h. The reaction mixture was filtered through celite and concentrated. Column chromatography (10 g, DCM to 20% MeOH/DCM) afforded 63 mg (89%) of 2-imidazol-1-yl-4-methyl-6-pyrrolidin-2-yl-pyrimidine. [M+H]+ 230.16; 1H-NMR (400 MHz, CD3OD) δ 8.74 (s, 1H), 8.05 (s, 1H), 7.31 (s, 1H), 7.14 (s, 1H), 4.95 (s, 2H), 4.25 (t, 1H), 3.25 (m, 1H), 3.05 (m, 1H), 2.59 (s, 3H), 2.35 (m, 1H), 1.90 (m, 2H); 13C-NMR (100 MHz, CD3OD) δ 173.4, 170.4, 153.9, 136.0, 128.9, 116.8, 116.0, 62.1, 46.5, 32.7, 25.3, 22.7.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH2:8][N:9]2[CH2:14][CH2:13][CH2:12][C:11]3([CH2:19][CH2:18][N:17]([C:20]4[CH:29]=[N:28][C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[N:21]=4)[CH2:16][CH2:15]3)[C:10]2=[O:30])[CH:5]=[CH:4][N:3]=1.[CH3:31][O-:32].[Na+]>CO>[CH3:31][O:32][C:2]1[CH:7]=[C:6]([CH2:8][N:9]2[CH2:14][CH2:13][CH2:12][C:11]3([CH2:19][CH2:18][N:17]([C:20]4[CH:29]=[N:28][C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[N:21]=4)[CH2:16][CH2:15]3)[C:10]2=[O:30])[CH:5]=[CH:4][N:3]=1
Reactant: C[O-]
Reactant: O=C1N(Cc2ccnc(Br)c2)CCCC12CCN(c1cnc3ccccc3n1)CC2
Agent: [Na+]
Solvent: CO
Product: COc1cc(CN2CCCC3(CCN(c4cnc5ccccc5n4)CC3)C2=O)ccn1
Temperature: 25 °C
Yield: 68 %

Procedure:
The title compound was synthesized from 2-((2-bromopyridin-4-yl)methyl)-9-(quinoxalin-2-yl)-2,9-diazaspiro[5.5]undecan-1-one (prepared according to method D) as follows: A stirred solution of 2-((2-bromopyridin-4-yl)methyl)-9-(quinoxalin-2-yl)-2,9-diazaspiro[5.5]undecan-1-one (synthesized according to method D) (70 mg, 0.15 mmol) and NaOMe (40.6 mg, 0.75 mmol) in MeOH (2 mL) was heated at 100° C. for 18 h. The reaction mixture was cooled to rt and the solvent was evaporated under reduced pressure. Water was added and the mixture was extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was washed with hexane to yield the title compound (55 mg, 68%). [1H NMR (300 MHz, CDCl3) ♀ ppm 8.60 (s, 1H), 8.12 (d, 1H), 7.85 (d, 1H), 7.68 (d, 1H), 7.56 (t, 1H), 7.38 (t, 1H), 6.75 (d, 1H), 6.55 (s, 1H), 4.56 (s, 2H), 4.31-4.13 (m, 2H), 3.92 (s, 3H), 3.70-3.55 (m, 2H), 3.25 (br s, 2H), 2.40-2.25 (m, 2H), 1.98-1.80 (m, 4H), 1.78-1.50 (m, 2H); LCMS RtF=1.30 min, [M+H]+=418.0].