Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([CH3:14])[CH2:10][CH2:9]2)[C:5]([N+:15]([O-:17])=[O:16])=[CH:4][CH:3]=1.[CH2:18]([O:25][C:26]([N:28]1[CH2:33][CH2:32][NH:31][C:30](=[O:34])[CH2:29]1)=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CNCCNC>C1(C)C=CC=CC=1.[Cu]I>[CH2:18]([O:25][C:26]([N:28]1[CH2:33][CH2:32][N:31]([C:2]2[N:7]=[C:6]([N:8]3[CH2:13][CH2:12][CH:11]([CH3:14])[CH2:10][CH2:9]3)[C:5]([N+:15]([O-:17])=[O:16])=[CH:4][CH:3]=2)[C:30](=[O:34])[CH2:29]1)=[O:27])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC1CCN(c2nc(Br)ccc2[N+](=O)[O-])CC1
Reactant: O=C1CN(C(=O)OCc2ccccc2)CCN1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Product: CC1CCN(c2nc(N3CCN(C(=O)OCc4ccccc4)CC3=O)ccc2[N+](=O)[O-])CC1
Temperature: 25 °C
Yield: 57 %

Procedure:
To a solution of 6′-bromo-4-methyl-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl (as prepared in the previous step) (300 mg, 1.00 mmol) in toluene (5 mL) was added 3-oxo-piprazine-1-carboxylic acid benzyl ester (351 mg, 1.50 mmol), K3PO4 (424 mg, 2.00 mmol) and CuI (38 mg, 0.20 mmol) followed by N,N′-dimethylethylenediamine (20 μL, 0.18 mmol) under Ar. The resulting mixture was heated at reflux overnight. The reaction mixture was allowed to cool to room temperature and filtered through a thin pad of Celite. The filtrate was concentrated in vacuo and the residue obtained was purified by chromatography on silica (20% EtOAc:hexane) to obtain 4-(4-methyl-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-6′-yl)-3-oxo-piperazine-1-carboxylic acid benzyl ester (258 mg, 57%). This compound (453 mg, 1.00 mmol) was dissolved in 30% HBr/HOAc (1 mL). The resulting mixture was stirred at room temperature overnight and Et2O (20 mL) was added dropwise. The resulting mixture was stirred for another hour, the precipitated hydrobromide was collected by suction filtration, washed with Et2O (3×20 mL), dried in vacuo for 1 h and used directly in next step.
Reaction SMILES: C([O:7][CH2:8][C@H:9]([C:15]1[C:16]([Br:27])=[C:17]2[C:22](=[CH:23][C:24]=1[CH3:25])[N:21]=[C:20]([CH3:26])[CH:19]=[CH:18]2)[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=O)C(C)(C)C.[OH-].[Na+]>C1COCC1.CO.O>[Br:27][C:16]1[C:15]([C@H:9]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])[CH2:8][OH:7])=[C:24]([CH3:25])[CH:23]=[C:22]2[C:17]=1[CH:18]=[CH:19][C:20]([CH3:26])=[N:21]2
Reactant: Cc1ccc2c(Br)c([C@@H](COC(=O)C(C)(C)C)OC(C)(C)C)c(C)cc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1ccc2c(Br)c([C@@H](CO)OC(C)(C)C)c(C)cc2n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of (S)-2-(5-bromo-2,7-dimethylquinolin-6-yl)-2-tert-butoxyethyl pivalate (50.0 g, 115 mmol) in THF (600 mL) and methanol (200 mL) was added 1M NaOH solution (300 mL, excess) at 0° C. The mixture was stirred at room temperature for 16 hours, diluted with water. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated in vacuo. The obtained residue was purified by flash chromatography to provide the desired product. LCMS-ESI+: calc'd for C17H22BrNO2: 352.1 (M+H+); Found: 352.1 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([O:18][C@H:19]2[CH2:23][CH2:22][N:21]([CH3:24])[C:20]2=[O:25])[CH:17]=1)[C:5]([NH:7][C:8]1[CH:13]=[N:12][C:11]([CH3:14])=[CH:10][N:9]=1)=[O:6].[N:26]1([C:30]([C:32]2[CH:33]=[N:34][C:35](Cl)=[C:36]([Cl:38])[CH:37]=2)=[O:31])[CH2:29][CH2:28][CH2:27]1.C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[N:26]1([C:30]([C:32]2[CH:37]=[C:36]([Cl:38])[C:35]([O:1][C:2]3[CH:3]=[C:4]([CH:15]=[C:16]([O:18][C@H:19]4[CH2:23][CH2:22][N:21]([CH3:24])[C:20]4=[O:25])[CH:17]=3)[C:5]([NH:7][C:8]3[CH:13]=[N:12][C:11]([CH3:14])=[CH:10][N:9]=3)=[O:6])=[N:34][CH:33]=2)=[O:31])[CH2:29][CH2:28][CH2:27]1
Reactant: Cc1cnc(NC(=O)c2cc(O)cc(O[C@H]3CCN(C)C3=O)c2)cn1
Reactant: O=C(c1cnc(Cl)c(Cl)c1)N1CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Cc1cnc(NC(=O)c2cc(Oc3ncc(C(=O)N4CCC4)cc3Cl)cc(O[C@H]3CCN(C)C3=O)c2)cn1
Temperature: 120 °C
Reaction time: 2 h
Yield: 87.5 %

Procedure:
A mixture of 3-hydroxy-5-[(3S)-1-methyl-2-oxo-pyrrolidin-3-yl]oxy-N-(5-methylpyrazin-2-yl)benzamide (Intermediate 18) (136 mg, 0.4 mmol), azetidin-1-yl-(5,6-dichloropyridin-3-yl)methanone (Intermediate 21) (103 mg, 0.44 mmol) and potassium carbonate (111 mg, 0.8 mmol) in DMA (5 mL) was stirred at 120° C. for 2 hours. The solution was evaporated under reduced pressure, the residue dissolved in ethyl acetate (40 mL) washed with water (2×20 mL), brine (20 mL), dried (MgSO4), filtered and the solvent removed under reduced pressure. The residue was purified by flash chromatography on silica, eluting with a gradient of 0-4% methanol in DCM to afford the product (188 mg, 87%). 1H NMR δ (300 MHz, CDCl3) 2.16-2.29 (m, 1H), 2.40 (quintet, 2H), 2.50-2.72 (m, 4H), 2.95 (s, 3H), 3.36-3.58 (m, 2H), 4.18-4.42 (m, 4H), 4.95 (t, 1H), 7.15 (s, 1H), 7.37 (s, 1H), 7.55 (s, 1H), 8.15 (s, 2H), 8.25 (s, 1H), 8.55 (s, 1H), 9.54 (s, 1H); m/z 537 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[NH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[K+].[K+].C(O)CCC.[ClH:27]>C(OCC)(=O)C>[ClH:27].[N:10]1([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1
Reactant: C1CNCCN1
Reactant: N#Cc1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCO
Product: N#Cc1ccc(N2CCNCC2)cc1

Procedure:
A mixture of 27.3 g (0.15 mole) of p-bromobenzonitrile, 38.7 g (0.45 mole) of piperazine and 42.0 g (0.30 mole) of solid potassium carbonate in a total volume of 60 ml of n-butanol was heated at reflux for 16 hr under a nitrogen atmosphere. The mixture was concentrated under reduced pressure and the slurry partitioned between 10% sodium hydroxide and chloroform. The chloroform layer was separated, dried over magnesium sulfate and concentrated under reduced pressure to give an oil. The oil was eluted through a 400 g silica gel column with a 10% methanol in methylene chloride mixture. The appropriate fractions were concentrated under reduced pressure to give a golden oil. Trituration of this oil with ethyl acetate gave a white powder. The collected white powder was stirred for 15 min in ethereal hydrogen chloride and recrystallized from methanol-water to give 1.5 g (4.5%)* of white solid, m.p. 160° C. with decomposition.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12](/[N:14]=[C:15](\N(C)C)/C)=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[Cl:20][C:21]1[CH:26]=[C:25]([NH:27][NH2:28])[N:24]=[C:23]([CH3:29])[N:22]=1>C(O)(=O)C>[Cl:20][C:21]1[CH:26]=[C:25]([N:27]2[C:12]([CH2:11][C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)=[N:14][CH:15]=[N:28]2)[N:24]=[C:23]([CH3:29])[N:22]=1
Reactant: Cc1nc(Cl)cc(NN)n1
Reactant: COc1ccc(CC(=O)/N=C(/C)N(C)C)cc1OC
Solvent: CC(=O)O
Product: COc1ccc(Cc2ncnn2-c2cc(Cl)nc(C)n2)cc1OC

Procedure:
A solution of (Z)-2-(3,4-dimethoxyphenyl)-N-(1-(dimethylamino)ethylidene)acetamide (1-2, 90 mg, 0.360 mmol, 1.0 eq) and 4-chloro-6-hydrazinyl-2-methylpyrimidine (57 mg, 0.360 mmol, 1.0 eq) in acetic acid (3 ml) was heated at 90° C. for 30 min. The reaction appeared complete by LCMS. The reaction mixture was concentrated and partitioned between dichloromethane (10 mL) and saturated aqueous sodium bicarbonate solution (10 mL). The organic layer was separated, dried over sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel column chromatography (0-100% ethyl acetate in hexanes) to afford 4-chloro-6-(5-(3,4-dimethoxybenzyl)-1H-1,2,4-triazol-1-yl)-2-methylpyrimidine (1-3). 1H NMR (500 MHz, CDCl3) δ 7.99 (s, 1H), 7.79 (s, 1H), 6.80 (m, 3H), 4.74 (s, 2H), 3.84 (s, 3H), 3.83 (s, 311), 2.76 (s, 3H). LRMS m/z (M+H) 346.4 found, 346.1 required
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([F:14])=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][N:9]=[CH:8]2)=[O:4].[Br:15]N1C(=O)CCC1=O>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[C:6]([F:14])=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][N:9]=[C:8]2[Br:15])=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc2[nH]ncc2c1F
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2[nH]nc(Br)c2c1F
Reaction time: 1 h
Yield: 97 %

Procedure:
To a solution of 2.2 g of 4-fluoro-1H-5-indazolecarboxylic acid methyl ester obtained in Production Example II-13-c in 20 ml dimethylformamide was added 2.12 g of N-bromosuccinimide at room temperature, and the mixture was stirred at the same temperature for 1 hour. After removing the solvent by distillation, 120 ml of ethyl acetate was added to the residue. The mixture was sequentially washed with half-saturated aqueous sodium hydrogencarbonate solution, water and brine, dried over anhydrous magnesium sulfate and the solvent was evaporated, to give 3.0 g of the title compound as bright yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](C2C=C(C(OCC)=O)OC=2C2C=CC=C(C#N)C=2)[CH:5]=[C:6]([F:8])[CH:7]=1.Br[C:28]1[CH:29]=[C:30]([C:41]([O:43][CH2:44][CH3:45])=[O:42])[O:31][C:32]=1[C:33]1[CH:38]=[CH:37][C:36]([F:39])=[C:35]([Cl:40])[CH:34]=1>>[Cl:40][C:35]1[CH:34]=[C:33]([C:32]2[O:31][C:30]([C:41]([O:43][CH2:44][CH3:45])=[O:42])=[CH:29][C:28]=2[C:4]2[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH:38]=[CH:37][C:36]=1[F:39]
Reactant: CCOC(=O)c1cc(Br)c(-c2ccc(F)c(Cl)c2)o1
Reactant: CCOC(=O)c1cc(-c2cc(F)cc(Cl)c2)c(-c2cccc(C#N)c2)o1
Product: CCOC(=O)c1cc(-c2cc(F)cc(Cl)c2)c(-c2ccc(F)c(Cl)c2)o1

Procedure:
The preparation of the title compound takes place in analogy to the synthesis of the compound from Example 11A starting with the compound from Example 6A. Purification is carried out using the mobile phase: cyclohexane/ethyl acetate (50:1). 1.07 g (63% of theory) of the title compound with a purity of 81% are obtained.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[F:28])=[C:8]2[C:16]=1[NH:15][C:14]1[CH:13]=[C:12]([C:17]([O:19]CC)=[O:18])[CH:11]=[CH:10][C:9]2=1)(=[O:3])[NH2:2].O.[OH-].[Li+]>C1COCC1.C(O)C.O>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[F:28])=[C:8]2[C:16]=1[NH:15][C:14]1[CH:13]=[C:12]([C:17]([OH:19])=[O:18])[CH:11]=[CH:10][C:9]2=1)(=[O:3])[NH2:2]
Reactant: CCOC(=O)c1ccc2c(c1)[nH]c1c(C(N)=O)ccc(-c3ccccc3F)c12
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)c1ccc(-c2ccccc2F)c2c1[nH]c1cc(C(=O)O)ccc12
Yield: 70.2 %

Procedure:
A suspension of ethyl 8-carbamoyl-5-(2-fluorophenyl)-9H-carbazole-2-carboxylate (Example 3-12, 0.8 g, 2.126 mmol) and lithium hydroxide monohydrate (0.255 g, 6.38 mmol) in THF-ethanol-water (3:1:1) (25.0 mL) was heated at reflux for 4 h. The mixture was concentrated and the residue was suspended in water. The pH was adjusted to 1-2 by addition of 1 M hydrochloric acid. The precipitate was collected by filtration, washed with water and dried to provide 8-carbamoyl-5-(2-fluorophenyl)-9H-carbazole-2-carboxylic acid as a yellow solid (520 mg, 71%). 1H NMR (400 MHz, DMSO-d6) δ 12.77 (br. s., 1H) 11.87 (s, 1H) 8.41 (m, 1H) 8.26 (br. s., 1H) 8.08 (d, J=7.69 Hz, 1H) 7.50-7.67 (m, 4H) 7.40-7.49 (m, 2H) 7.09-7.17 (m, 2H). Mass spectrum m/z 349.1 (M+H)+.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[C:7]([C:10]([OH:12])=O)[CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.Cl.CN([C:17]([O:21][N:22]1N=NC2C=CC=C[C:23]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN(C)C>>[CH3:17][O:21][N:22]([CH3:23])[C:10]([C:7]1[CH:8]=[CH:9][C:4]2[N:3]=[N:2][NH:1][C:5]=2[CH:6]=1)=[O:12]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: O=C(O)c1ccc2nn[nH]c2c1
Agent: CN(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Product: CON(C)C(=O)c1ccc2nn[nH]c2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 1H-1,2,3-benzotriazole-6-carboxylic acid (Aldrich, 500 mg, 3.1 mmol), N,O-dimethylhydroroxylamine hydrochloride (Aldrich, 299 mg, 3.1 mmol), HBTU (1.5 g, 4.0 mmol) and trimethylamine (1.28 ml, 9.2 mmol) were added and the mixture was stirred for 18 hours at room temperature. Then, evaporation, purification through silica gel column chromatography eluting with DCM/MeOH (10:1) to give N-methoxy-N-methyl-1H-1,2,3-benzotriazole-6-carboxamide (LC-MS (MS (ESI) m/z 205 (M−H)−, 207 (M+H)+). To a THF (50 ml) solution of the product was added 0.96 M hexane solution of ethylmagnesium bromide (15 ml, 14.4 mmol) at 0° C., and the mixture was stirred for 16 hours at room temperature. Then the reaction was quenched with aqueous solution of ammonium chloride and the product was extracted with AcOEt, washed with brine, dried over magnesium sulfate. Then, evaporation in vacuo gave 1-(1H-1,2,3-benzotriazol-6-yl)propan-1-one (LC-MS (MS (ESI) m/z 174 (M−Hy, 176 (M+H)+).
Reaction SMILES: [Cl:1][CH:2]1[C:8]2=[N:9][C:10]3[N:15]([CH2:16][CH3:17])[N:14]=[CH:13][C:11]=3[CH:12]=[C:7]2[CH2:6][CH2:5][C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2.[CH2:22]([NH2:26])[CH2:23][CH2:24][CH3:25].Cl>C(OC(=O)C)C>[ClH:1].[CH2:22]([NH:26][CH:2]1[C:8]2=[N:9][C:10]3[N:15]([CH2:16][CH3:17])[N:14]=[CH:13][C:11]=3[CH:12]=[C:7]2[CH2:6][CH2:5][C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2)[CH2:23][CH2:24][CH3:25]
Reactant: CCCCN
Reactant: CCn1ncc2cc3c(nc21)C(Cl)c1ccccc1CC3
Agent: Cl
Solvent: CCOC(C)=O
Product: CCCCNC1c2ccccc2CCc2cc3cnn(CC)c3nc21

Procedure:
11.8 g. of 11-chloro-1-ethyl-1,5,6,11-tetrahydrobenzo[5,6]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridine (0.04 mol.), from part (a), and 75 ml. of butylamine are refluxed for 5.5 hours. After evaporation of excessive butylamine, the residue is shaken with 100 ml. of water and 100 ml. of ether. The separated ethereal solution is washed twice with 50 ml. of water, treated with charcoal, dried with Na2SO4 and then evaporated to yield 8.7 g. of an oil. This material is dissolved in 125 ml. of ethylacetate and 5 ml. of ethereal hydrochloric acid (195 g./l.) are added to precipitate 8.4 g. of N-butyl-1-ethyl-1,5,6,11-tetrahydrobenzo[5,6]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridin-11-amine, hydrochloride (1:1); m.p. 231°-233° (dec.).
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:14]1[C:15]2[CH:28]=[C:27]([CH2:29][CH3:30])[S:26][C:16]=2[N:17]=[C:18]([C:20]2[CH:25]=[N:24][CH:23]=[CH:22][N:21]=2)[N:19]=1>>[N:21]1[CH:22]=[CH:23][N:24]=[CH:25][C:20]=1[C:18]1[N:19]=[C:14]([NH:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][C:11]3[O:12][CH2:1][O:2][C:3]=3[CH:4]=2)[C:15]2[CH:28]=[C:27]([CH2:29][CH3:30])[S:26][C:16]=2[N:17]=1
Reactant: CCc1cc2c(Cl)nc(-c3cnccn3)nc2s1
Reactant: NCCc1ccc2c(c1)OCO2
Product: CCc1cc2c(NCCc3ccc4c(c3)OCO4)nc(-c3cnccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-methylenedioxyphenethylamine with 4-chloro-2-(pyrazin-2-yl)-6-ethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyrazin-2-yl)-4-(3,4-methylenedioxyphenethylamino)-6-ethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: C[N:2]([CH3:20])[CH:3]=[CH:4][C:5]([C:7]1[CH:8]=[C:9]([CH2:13][CH2:14][NH:15][C:16](=[O:19])[O:17][CH3:18])[CH:10]=[CH:11][CH:12]=1)=O.N[C:22]1[C:26]([C:27]#[N:28])=C[NH:24][N:23]=1>>[C:27]([C:26]1[CH:22]=[N:23][N:24]2[C:5]([C:7]3[CH:8]=[C:9]([CH2:13][CH2:14][NH:15][C:16](=[O:19])[O:17][CH3:18])[CH:10]=[CH:11][CH:12]=3)=[CH:4][CH:3]=[N:2][C:20]=12)#[N:28]
Reactant: N#Cc1c[nH]nc1N
Reactant: COC(=O)NCCc1cccc(C(=O)C=CN(C)C)c1
Product: COC(=O)NCCc1cccc(-c2ccnc3c(C#N)cnn23)c1

Procedure:
A 2.76 g portion of [3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]ethylcarbamic acid, methyl ester was reacted with 1.08 g of 3-aminopyrazole-4-carbonitrile as described in Example 13, giving 2.6 g of the desired product, mp 162°-164° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][OH:8].[H-].[Na+].Cl[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][N:13]=1.O>CN(C)C=O>[N+:18]([C:15]1[CH:16]=[CH:17][C:12]([O:8][CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[N:13][CH:14]=1)([O-:20])=[O:19]
Reactant: OCc1ccccn1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCc2ccccn2)nc1
Temperature: -20 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
2-Pyridylcarbinol (7.5 g, 0.069 mole) in dry dimethylformamide (190 ml) was cooled to −20° C. and treated with an 80% dispersion of sodium hydride in mineral oil (2.07 g, 0.069 mole) under argon. The mixture was stirred at −20° C. for two hours. 2-Chloro-5-nitropyridine (8.83 g, 0.058 mole) was added and the mixture was stirred at −20° C. for 0.5 hour then warmed to room temperature and stirred for 18 hours. Water was added dropwise and the solvent removed in vacuo. The residue was dissolved in dichloromethane, washed with 10% aqueous sodium hydroxide solution followed by water, dried (Na2SO4) and evaporated in vacuo to afford the title compound (12.2 g, 91%) as an orange solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([NH:10][C@@H:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[OH:16])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:18][C:19](OCC)=[O:20].[NH4+].[Cl-]>C1COCC1.CO>[CH2:3]([N:10]1[C:19](=[O:20])[CH2:18][O:16][C@@H:12]2[CH2:13][CH2:14][CH2:15][C@@H:11]12)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O[C@@H]1CCC[C@H]1NCc1ccccc1
Reactant: CCOC(=O)CBr
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C1CO[C@@H]2CCC[C@H]2N1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a suspension of NaH (6.0 g of 60% w/w in oil, 150 mmol) in THF (300 mL) cooled at 0° C., trans-2-(benzylamino)cyclopentanol (9.6 g, 50 mmol) was added slowly. After stirring for 15 minutes at 0° C., ethyl bromoacetate (10 g, 60 mmol) was added slowly. The reaction mixture was then warmed to room temperature and stirred for 2 hours. Methanol (5.0 mL) was added slowly to the reaction followed by addition of saturated aqueous NH4Cl (100 mL). The reaction mixture was then extracted with EtOAc (2×300 mL), and the combined organic layers were washed with water (100 mL) and dried over anhydrous Na2SO4. Evaporation of solvent in vacuo followed by purification on a silica gel column (0 to 50% EtOAc/Hexanes) afforded trans-4-benzylhexahydrocyclopenta[b][1,4]oxazin-3(2H)-one. MS APCI calc'd for C14H17NO2 [M+H]+ 232. found 232.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH3:26])=[CH:19][CH:18]=3)[CH:12]=2)[C:7]1=[O:27])[CH3:2].[O-][CH2:30][CH2:31]CC.[Na+].C(O)CCC.Cl>>[CH2:1]([O:3][C:4]([C:5]1[NH:6][C:7](=[O:27])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][C:11]([O:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH3:26])=[CH:19][CH:18]=1)=[CH:10][CH:9]=2)=[O:28])[CH2:2][CH2:30][CH3:31]
Reactant: CCCOc1ccc(Oc2ccc3c(c2)C(=O)N(CC(=O)OCC)C3=O)cc1
Reactant: CCCC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCCCO
Product: CCCCOC(=O)c1[nH]c(=O)c2ccc(Oc3ccc(OCCC)cc3)cc2c1O
Temperature: 25 °C

Procedure:
A mixture of [1,3-dioxo-5-(4-propoxy-phenoxy)-1,3-dihydro-isoindol-2-yl]-acetic acid ethyl ester (2.485 g, 6.48 mmol), sodium butoxide, and butanol (14.3 mmol, 27 mL butanol) was heated at 90° C. to 100° C. for 2 h. Then the reaction mixture was allowed to cool to ambient temperature, acidified with 2 M HCl to pH 3-4, and extracted with EtOAc. The organic phase was then washed with water and saturated NaCl solution, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography to give the title compound (722 mg). ESI MS (m/z): 412 (M+H)+.
Reaction SMILES: [CH:1]1([C:6]([OH:16])([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([OH:9])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:17]([N:24]1[CH2:28][CH2:27][C@H:26]([NH2:29])[CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CN1CCOCC1.ON1C2C=CC=CC=2N=N1>CN(C)C=O.O>[CH:1]1([C:6]([OH:16])([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([NH:29][C@H:26]2[CH2:27][CH2:28][N:24]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:25]2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: N[C@H]1CCN(Cc2ccccc2)C1
Reactant: O=C(O)C(O)(c1ccccc1)C1CCCC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(N[C@H]1CCN(Cc2ccccc2)C1)C(O)(c1ccccc1)C1CCCC1
Temperature: 2.5 °C
Reaction time: 19 h
Yield: 95 %

Procedure:
The compound 2-cyclopentyl-2-hydroxy-2-phenylacetic acid (0.52 g, 2.36 mM) and (3S)-1-benzyl-3-aminopyrrolidine (0.5 g, 2.84 mM) were dissolved in dimethylformamide (10.0 ml) and N-methylmorpholine (1.3 ml, 11.8 mM) was added into it followed by the addition of 1-hydroxybenzotriazole (0.32 g, 2.36 mM) at 0-5° C. The reaction mixture was maintained at 0-5° C. for 1 hour and then at room temperature for 19 hours. The reaction mixture was poured into water (100.0 ml) with constant stirring. The organic compound was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated sodium bicarbonate water and brine solution followed its drying and concentration over anhydrous sodium sulphate. The residue was purified by silica gel column chromatography using 10% methanol in chloroform to get the title compound. Yield=95% (0.5 g, 2.38 mM).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[CH:33]=[CH:32][C:11]([O:12][C:13]2[C:14]([C:19]3[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH:20]=3)=[N:15][CH:16]=[CH:17][N:18]=2)=[CH:10][CH:9]=1.C(Cl)[Cl:35].[ClH:37]>O1CCOCC1>[ClH:35].[ClH:37].[NH:22]1[CH2:21][CH2:20][CH:19]([C:14]2[C:13]([O:12][C:11]3[CH:32]=[CH:33][C:8]([NH:7][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)=[CH:9][CH:10]=3)=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:24][CH2:23]1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N1CC=C(c2nccnc2Oc2ccc(Nc3ccccn3)cc2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: c1ccc(Nc2ccc(Oc3nccnc3C3CCNCC3)cc2)nc1
Reaction time: 4 h

Procedure:
To a solution of tert-butyl 4-(3-(4-(pyridin-2-ylamino)phenoxy)pyrazin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (5.2 g, 11.67 mmol) and DCM (100 mL) was added 4M HCl in dioxane (12 mL, 48.0 mmol). After 4 hours, another 5 mL of 4M HCl in dioxane was added. After a further 16 hours, the precipitates had clung to the walls of the flask and the clear stirring solution was decanted away. The precipitates were washed with another 50 mL of DCM and the solution again decanted away. The flask was placed under vacuum for 30 minutes to give N-(4-(3-(piperidin-4-yl)pyrazin-2-yloxy)phenyl)pyridin-2-amine dihydrochloride as a hydroscopic yellow solid.
Reaction SMILES: C([O:4][C@H:5]1[C@H:11]([O:12]C(=O)C)[C@@H:10]([O:16]C(=O)C)[C@:9]2([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([CH2:28][C:29]4[CH:34]=[CH:33][C:32]([O:35][CH2:36][C:37](=[N:39][O:40][CH3:41])[CH3:38])=[CH:31][CH:30]=4)[CH:22]=3)[O:20][C@@:6]1([CH2:42][O:43]C(=O)C)[CH2:7][O:8]2)(=O)C.O.[OH-].[Li+]>C1COCC1.CO.O>[CH3:41][O:40][N:39]=[C:37]([CH3:38])[CH2:36][O:35][C:32]1[CH:31]=[CH:30][C:29]([CH2:28][C:23]2[CH:22]=[C:21]([C@@:9]34[O:20][C@@:6]([CH2:42][OH:43])([CH2:7][O:8]3)[C@@H:5]([OH:4])[C@H:11]([OH:12])[C@H:10]4[OH:16])[CH:26]=[CH:25][C:24]=2[Cl:27])=[CH:34][CH:33]=1
Reactant: CON=C(C)COc1ccc(Cc2cc([C@]34OC[C@](COC(C)=O)(O3)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]4OC(C)=O)ccc2Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CON=C(C)COc1ccc(Cc2cc([C@]34OC[C@](CO)(O3)[C@@H](O)[C@H](O)[C@H]4O)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.5 %

Procedure:
To a solution of (1R,2S,3S,4R,5S)-1-(acetoxymethyl)-5-(4-chloro-3-(4-(2-(methoxy imino)propoxy)benzyl)phenyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triyl triacetate (120 mg, 0.18 mmol) in THF (0.8 mL), methanol (1.2 mL) and water (0.4 mL) was added lithium hydroxide monohydrate (15.2 mg, 0.36 mmol) at 0° C. The reaction mixture was stirred at r.t. for 1 h. Volatiles were evaporated in vacuo and the residue obtained was purified by column chromatography (silica gel, 1:9 MeOH:DCM) to provide the title compound (60 mg, 67%).