Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:25])[CH2:5][O:6][C:7]1[C:22]([Cl:23])=[CH:21][C:10]2[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])=[N:12][O:13][C:9]=2[C:8]=1[Cl:24])C.[OH-].[Na+]>C(O)C.O>[Cl:23][C:22]1[C:7]([O:6][CH2:5][C:4]([OH:25])=[O:3])=[C:8]([Cl:24])[C:9]2[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:10]=2[CH:21]=1
Reactant: CCOC(=O)COc1c(Cl)cc2c(-c3ccccc3F)noc2c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)COc1c(Cl)cc2c(-c3ccccc3F)noc2c1Cl

Procedure:
14.0 g of ethyl{[5,7-dichloro-3-(2-fluorophenyl)-1,2-benzisoxazole-6-yl]oxy}acetate is heated in 75% ethanol/H2O (700 ml) with stirring until a solution results. 20 ml of a 50% solution of NaOH is added and a precipitate forms. With additional heating and stirring the precipitate goes into solution and is allowed to stir for 2.5 hours. The ethanol is then evaporated in vacuo and the residue is made acidic with 10% HCl. The precipitated solid is filtered and dried in vacuo to afford {[5,7-dichloro-3-(2-fluorophenyl)-1,2-benzisoxazole-6-yl]oxy}acetic acid, mp 160°-170° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH:11]=[CH:10]2.[CH:18]1([C:24]2[CH:29]=[CH:28][C:27]([SH:30])=[CH:26][CH:25]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>>[CH:18]1([C:24]2[CH:25]=[CH:26][C:27]([S:30][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]3[CH:8]=[C:9]4[C:14](=[CH:15][CH:16]=3)[NH:13][C:12](=[O:17])[CH:11]=[CH:10]4)=[CH:28][CH:29]=2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: Sc1ccc(C2CCCCC2)cc1
Reactant: O=c1ccc2cc(OCCCCBr)ccc2[nH]1
Product: O=c1ccc2cc(OCCCCSc3ccc(C4CCCCC4)cc3)ccc2[nH]1

Procedure:
Prepared analogous to Example 122 from 6-(4-bromobutoxy)-carbostyril (m.p. 188°-189° C.) and 4-cyclohexylthiophenol.
Reaction SMILES: C1(C2[O:12][CH2:11][CH:10]([C:13]([N:15]3[CH2:20][CH2:19][N:18]([C:21]4[CH:26]=[CH:25][C:24]([N:27]5[CH2:31][C@H:30]([CH2:32][O:33][C:34]6[CH:38]=[CH:37][O:36][N:35]=6)[O:29][C:28]5=[O:39])=[CH:23][C:22]=4[F:40])[CH2:17][CH2:16]3)=[O:14])[CH2:9][O:8]2)C=CC=CC=1>C(O)(=O)C.O>[OH:8][CH2:9][CH:10]([CH2:11][OH:12])[C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH2:31][C@H:30]([CH2:32][O:33][C:34]4[CH:38]=[CH:37][O:36][N:35]=4)[O:29][C:28]3=[O:39])=[CH:23][C:22]=2[F:40])[CH2:17][CH2:16]1)=[O:14]
Reactant: O=C(C1COC(c2ccccc2)OC1)N1CCN(c2ccc(N3C[C@H](COc4ccon4)OC3=O)cc2F)CC1
Solvent: O
Solvent: CC(=O)O
Product: O=C(C(CO)CO)N1CCN(c2ccc(N3C[C@H](COc4ccon4)OC3=O)cc2F)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.2 %

Procedure:
3-(4-(4-(2-Phenyl-1,3-dioxan-5-ylcarbonyl)piperazin-1-yl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one (450 mg, 0.82 mmol) was dissolved in a mixture of acetic acid and water (4:1, 10 ml) and stirred at ambient temperature for 18 hours. After evaporation to dryness, the residue was azeotroped with toluene (15 ml), and the residual gum purified by chromatography on a 20 g silica Mega Bond Elut® column, eluting with a gradient increasing in polarity from 5 to 10% MeOH in dichloromethane. Relevant fractions were combined and evaporated to give the desired product (237 mg).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].C(=O)([O-])[O-].[K+].[K+].[CH2:26]([NH2:30])[CH2:27][CH2:28][CH3:29].O>C(O)C>[CH2:26]([NH:30][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18])[CH2:27][CH2:28][CH3:29]
Reactant: CCCCN
Reactant: O=[N+]([O-])c1cc(-c2nc3ccccc3o2)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCCCNc1ccc(-c2nc3ccccc3o2)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 99.1 %

Procedure:
To a suspension of 2-(4-fluoro-3-nitrophenyl)benzoxazole (see Working Example 15-2) (300 mg, 1.16 mmol) in ethanol (5 mL) was added potassium carbonate (321 mg, 2.32 mmol) and butylamine (170 mg, 2.32 mmol), and this was heated to reflux for 4 hours. After the reaction was complete, this was cooled to room temperature, water was added, and after the precipitated crystals were filtered and washed with water, they were dried to yield the title compound (358 mg, 99.1% yield).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:20]([C@H:23]([C:25]1[CH:30]=[CH:29][N:28]=[C:27]([Cl:31])[CH:26]=1)[CH3:24])=[N+]=[N-]>O1CCCC1.O>[Cl:31][C:27]1[CH:26]=[C:25]([C@@H:23]([NH2:20])[CH3:24])[CH:30]=[CH:29][N:28]=1
Reactant: C[C@H](N=[N+]=[N-])c1ccnc(Cl)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](N)c1ccnc(Cl)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 58.8 %

Procedure:
Triphenylphosphine (9.56 g) was added to a solution of 4-((S)-1-azidoethyl)-2-chloropyridine (4.44 g) in tetrahydrofuran-water (4:1, 50 mL), and the reaction solution was heated and stirred at 60° C. for two hours. The reaction solution was returned to room temperature, and the solvent was evaporated under reduced pressure. Chloroform and 5 N hydrochloric acid were added to the residue, and the aqueous layer was separated. The aqueous layer was made basic with 5 N sodium hydroxide. Chloroform was added to the reaction solution, and the organic layer was separated. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain the title compound (2.24 g). The property values of the compound are as follows.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:7]=1.C([O-])([O-])=O.[Na+].[Na+].Br[C:29]1[CH:30]=[C:31]([C:35]2[CH:40]=[C:39]([NH:41][CH:42]3[CH2:44][CH2:43]3)[N:38]=[C:37]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][N:46]=3)[CH:36]=2)[CH:32]=[N:33][CH:34]=1>COCCOC.CCOC(C)=O>[CH:42]1([NH:41][C:39]2[N:38]=[C:37]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][N:46]=3)[CH:36]=[C:35]([C:31]3[CH:32]=[N:33][CH:34]=[C:29]([C:8]4[CH:9]=[CH:10][CH:11]=[C:6]([O:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:21])[CH:7]=4)[CH:30]=3)[CH:40]=2)[CH2:44][CH2:43]1
Reactant: Brc1cncc(-c2cc(NC3CC3)nc(-c3ccccn3)c2)c1
Reactant: CN(C)CCOc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CN(C)CCOc1cccc(-c2cncc(-c3cc(NC4CC4)nc(-c4ccccn4)c3)c2)c1

Procedure:
To a solution of Dimethyl-(2-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-ethyl)-amine (2 eq, 0.272 mmol, 0.079 g) in dry DME (1 ml) under an inert atmosphere of argon is added 2M Na2CO3 (3 eq, 0.408 mmol, 0.204 ml) followed by (5″-Bromo-[2,2′;4′,3″]terpyridin-6′-yl)-cyclopropyl-amine (Example 1.26) (1 eq, 0.136 mmol, 50 mg) and PdCl2dppf (0.1 eq, 0.014 mmol, 11 mg). The reaction mixture is heated using microwave radiation at 90° C. for 90 minutes. The reaction mixture is dissolved in EtOAc and washed with water. The organic solvent is reduced in vacuo and the residue is purified by reverse phase column chromatography (Isolute™ C18, 0-40% acetonitrile in water—0.1% TFA). The appropriate fractions by HPLC are combined and concentrated in vacuo. The resulting residue is dissolved in MeOH and loaded onto a SCX-2 cartridge eluting with MeOH followed by 2M NH3 in MeOH. The methanolic ammonia fractions are combined, concentrated in vacuo and dried under vacuum to afford the title compound; [M+H]+ 452.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[CH:10]=[C:9]([CH:11]=O)[S:8][C:6]=2[N:7]=1.[NH:19]1[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20]1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[CH:10]=[C:9]([CH2:11][N:19]3[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20]3)[S:8][C:6]=2[N:7]=1
Reactant: O=Cc1cc2c(N3CCOCC3)nc(Cl)nc2s1
Reactant: OC1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: OC1CCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 36.1 %

Procedure:
To a solution of 2-chloro-4-morpholinothieno[2,3-d]pyrimidine-6-carbaldehyde (1.1 g, 3.9 mmol) in 1,2-dichloroethane (20 mL) was added pyrrolidin-3-ol (5.4 mmol), and AcOH (3.9 mmol). After the reaction mixture stirred 10 min at room temperature, Na(OAc)3BH (4.6 mmol) was added then the mixture stirred 72 h at room temperature. The reaction was quenched by the addition of saturated aqueous NaHCO3. The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The combined organics were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by silica gel chromatography (0-20% MeOH in CH2Cl2) to afford 1-((2-chloro-4-morpholinothieno[2,3-d]pyrimidin-6-yl)methyl)pyrrolidin-3-ol (0.5 g). MS (Q1) 355 (M)+
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:11][CH:12]([F:27])[C:13]1[CH:17]=[CH:16][NH:15][C:14]=1[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19].C1(P(C2C=CC=CC=2)(=O)[NH2:35])C=CC=CC=1.O>CN(C=O)C>[NH2:35][N:15]1[CH:16]=[CH:17][C:13]([CH:12]([F:11])[F:27])=[C:14]1[C:18]([NH:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:19]
Reactant: O=C(Nc1ccccc1)c1[nH]ccc1C(F)F
Reactant: NP(=O)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: Nn1ccc(C(F)F)c1C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38 %

Procedure:
1.1 ml (1.1 mmol) of a 1M solution of lithium bis(trimethylsilyl)amide was added to a solution of 3-(difluoromethyl)-N-phenyl-1H-pyrrole-2-carboxamide (100 mg, 0.42 mmol) and DPPONH2 (P,P-diphenylphosphinic amide, available from Sigma Aldrich®, cat. no. 5994-87-6) (250 mg, 1,1 mmol) in DMF (4 mL) at room temperature. A thick suspension formed and additional 4 mL of DMF were added. The mixture was stirred at room temperature for 1 hour and then it was poured into 50 mL of water and extracted with ethyl acetate. The aqueous layer was further extracted with ethyl acetate (2×). The combined organic layer was washed with water and brine and was dried over sodium sulphate, filtered and concentrated. The crude product was purified by flash chromatography (0% to 33% AcOEt/Hexanes) to yield 40 mg (38% yield) of the title compound.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([N+:16]([O-])=O)=[C:9]([O:14][CH3:15])[CH:10]=2)[CH2:5]1)[CH3:3].[H][H]>C(OCC)(=O)C.[Pd].CO>[CH3:3][CH:2]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([NH2:16])=[C:9]([O:14][CH3:15])[CH:10]=2)[CH2:5]1)[CH3:1]
Reactant: [H][H]
Reactant: COc1cc2c(cc1[N+](=O)[O-])CN(C(C)C)CC2
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cc2c(cc1N)CN(C(C)C)CC2
Yield: 100 %

Procedure:
2-(1-methylethyl)-6-(methyloxy)-7-nitro-1,2,3,4-tetrahydroisoquinoline (0.24 g, 0.94 mmol) was dissolved in ethyl acetate (5 mL), treated with 10% palladium on carbon (50 mg, Aldrich), and then diluted with methanol (10 mL). The mixture was stirred under 60 psi of hydrogen pressure for 16 h in a Fischer-Porter apparatus. The pressure was released, the reaction vessel evacuated, and back-filled with nitrogen twice. The mixture was filtered through celite and the filtrate was concentrated to provide 2-(1-methylethyl)-6-(methyloxy)-1,2,3,4-tetrahydro-7-isoquinolinamine (206 mg, 0.94 mmol, 100%). 1H NMR (400 MHz, CDCl3) δ ppm 1.13 (d, J=6.6 Hz, 6 H), 2.71-2.81 (m, 4 H), 2.87 (tt, J=6.5, 6.5 Hz, 1 H), 3.59 (s, 2 H), 3.63 (bs, 2 H), 3.81 (s, 3 H), 6.40 (s, 1 H), 6.50 (s, 1 H).
Reaction SMILES: B.[CH2:2]1COCC1.C[C:8]1([C:14]([OH:16])=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>C1COCC1>[CH3:2][CH:14]([CH:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1)[OH:16]
Reactant: C1CCOC1
Reactant: CC1(C(=O)O)CCCCC1
Agent: B
Product: CC(O)C1CCCCC1
Temperature: 5 °C
Reaction time: 0.08 h

Procedure:
A three liter, three necked round bottom flask was equipped with a thermometer, magnetic stirrer, argon inlet and outlet adapters and a one liter addition funnel containing 922 ml of 1.0 molar BH3.THF. 1-Methyl cyclohexanecarboxylic acid (119.2 g; 0.84 m) was added to the reaction vessel and dissolved in 100 ml of THF. The reaction mixture was cooled with an ice bath to 5° C. and the BH3.THF was added dropwise over 25 min maintaining the temperature between 5°-15° C. After the addition was complete, the ice bath was removed. After about five min, the reaction exothermed and foamed violently. A much slower addition rate and constant cooling should help to avoid this exotherm. The reaction was allowed to stir for two hr at RT under nitrogen, then 150 ml of methanol was added cautiously. When the foaming ceased, the reaction was concertrated in vacuo using low heat and the residue was treated with 100 ml of 5% acetic acid. After stirring for thirty min, the reaction was transferred to a one liter separatory funnel, diluted with water (slurry dissolved) and extracted three times with ether. The combined ether extracts were washed twice with saturated sodium bicarbonate, twice with brine, dried over anhydrous magnesium sulfate, filtered through celite and concentrated in vacuo (low heat) to give 79.09 g of a clear water-white oil. The oil was distilled on a Kugelrohr apparatus at 75°-130° C. (25 mm of Hg). Most distilled at 90° C. to give 72.11 g of 1-methyl-1-cyclohexylmethanol.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18]([C:30](O)=[O:31])[CH2:19][C:20]3[CH:28]=[C:27]([CH3:29])[C:23]4[NH:24][CH:25]=[N:26][C:22]=4[CH:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:33]=[CH:34][CH:35]=[CH:36][C:4]=2[NH:3]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.[CH3:66][S:67]([N:70]1[CH2:75][CH2:74][CH:73]([CH:76]2[CH2:81][CH2:80][NH:79][CH2:78][CH2:77]2)[CH2:72][CH2:71]1)(=[O:69])=[O:68]>CN(C=O)C>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C@H:18]([CH2:19][C:20]3[CH:28]=[C:27]([CH3:29])[C:23]4[NH:24][CH:25]=[N:26][C:22]=4[CH:21]=3)[C:30]([N:79]3[CH2:78][CH2:77][CH:76]([CH:73]4[CH2:72][CH2:71][N:70]([S:67]([CH3:66])(=[O:69])=[O:68])[CH2:75][CH2:74]4)[CH2:81][CH2:80]3)=[O:31])=[O:16])[CH2:13][CH2:14]2)[CH2:7][CH2:6][C:5]2[CH:33]=[CH:34][CH:35]=[CH:36][C:4]=2[NH:3]1
Reactant: CS(=O)(=O)N1CCC(C2CCNCC2)CC1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc2nc[nH]c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(C3CCN(S(C)(=O)=O)CC3)CC2)cc2nc[nH]c12

Procedure:
A solution of 120 mg (0.22 mmol) (R)-1-carboxy-2-(7-methyl-1H-benzimidazol-5-yl)-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate, 80 mg (0.25 mmol) TBTU, 40 μL (0.29 mmol) triethylamine and 80 mg (0.33 mmol) 1-methanesulphonyl-[4,4′]bipiperidinyl in 1.5 mL DMF was stirred overnight at RT. The reaction mixture was purified by HPLC without working up. The fractions containing the product were combined and lyophilised.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8]([CH2:11][O:12][C:13]3[CH:21]=[CH:20][CH:19]=[C:18]4[C:14]=3[CH:15]=[C:16]([C:22]([OH:24])=O)[NH:17]4)=[CH:9][O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[ClH:25].Cl.Cl.[C@H:28]1([CH2:38][N:39]2[CH2:44][CH2:43][CH:42]([NH2:45])[CH2:41][CH2:40]2)[C@@H:37]2[N:32]([CH2:33][CH2:34][CH2:35][CH2:36]2)[CH2:31][CH2:30][CH2:29]1>>[ClH:1].[ClH:25].[C@H:28]1([CH2:38][N:39]2[CH2:44][CH2:43][CH:42]([NH:45][C:22]([C:16]3[NH:17][C:18]4[C:14]([CH:15]=3)=[C:13]([O:12][CH2:11][C:8]3[C:7]5[C:2]([Cl:1])=[CH:3][CH:4]=[CH:5][C:6]=5[O:10][CH:9]=3)[CH:21]=[CH:20][CH:19]=4)=[O:24])[CH2:41][CH2:40]2)[C@@H:37]2[N:32]([CH2:33][CH2:34][CH2:35][CH2:36]2)[CH2:31][CH2:30][CH2:29]1
Reactant: NC1CCN(C[C@@H]2CCCN3CCCC[C@H]23)CC1
Reactant: O=C(O)c1cc2c(OCc3coc4cccc(Cl)c34)cccc2[nH]1
Agent: Cl
Product: O=C(NC1CCN(C[C@@H]2CCCN3CCCC[C@H]23)CC1)c1cc2c(OCc3coc4cccc(Cl)c34)cccc2[nH]1

Procedure:
This compound is synthesized from 4-(4-chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (118) (preparation see below) and amine 61 analogously to the method described in example 1.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:7]2=[O:22].[CH:23]1([C:26](Cl)=[O:27])[CH2:25][CH2:24]1.C(N(CC)CC)C>C1COCC1>[O:21]=[C:15]1[CH:14]([N:8]2[C:7](=[O:22])[C:6]3[C:10](=[CH:11][CH:12]=[C:4]([CH2:3][NH:2][C:26]([CH:23]4[CH2:25][CH2:24]4)=[O:27])[CH:5]=3)[C:9]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: O=C(Cl)C1CC1
Reactant: NCc1ccc2c(c1)C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1CCC(N2C(=O)c3ccc(CNC(=O)C4CC4)cc3C2=O)C(=O)N1
Temperature: 40 °C
Yield: 62.6 %

Procedure:
To a stirred mixture of 5-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (1.00 g, 3.10 mmol) and cyclopropanecarbonyl chloride (0.32 g, 3.10 mmol) in THF (35 mL), was added triethylamine (0.88 mL, 6.20 mmol) at room temperature under nitrogen. The mixture was heated to 40° C. for 6 h then cooled to rt. The mixture was filtered and the filtrate diluted with EtOAc (100 mL). The organic layer was washed with dil. aq. HCl (100 mL), water (2×75 mL), dried (MgSO4) and concentrated in vacuo to give cyclopropanecarboxylic acid [2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-amide as a white solid (0.69 g, 63% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 25/75 CH3CN/0.1% H3PO4, 2.96 min (98.96%); mp: 163-165° C.; 1H NMR (DMSO-d6) δ 0.62-0.78 (m, 4H), 1.63 (m, 1H), 1.95-2.17 (m, 1H), 2.53-2.67 (m, 2H), 2.79-3.00 (m, 1H), 4.46 (d, J=6.0 Hz, 2H), 5.15 (dd, J=5.4, 12.9 Hz, 1H), 7.67-7.79 (m, 2H), 7.89 (d, J=7.6 Hz, 1H), 8.77 (t, J=5.9 Hz, 1H), 11.13 (s, 1H); 13C NMR (DMSO-d6) δ 6.44, 13.57, 21.99, 30.93, 42.05, 48.99, 121.83, 123.54, 129.74, 131.60, 133.35, 147.77, 166.99, 167.13, 169.82, 172.73, 172.94; Anal Calcd for C18H17N3O5+0.2H2O: C, 60.23; H, 4.89; N, 11.71. Found: C, 60.16; H, 4.54; N, 11.70.
Reaction SMILES: [C:1]([O:5][C:6](=[O:8])[NH2:7])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)[O:22][C:20](=O)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15]C1=2)=O>C(Cl)Cl>[C:1]([O:5][C:6](=[O:8])[NH:7][CH:16]1[CH2:15][CH:18]([CH2:19][CH:20]=[O:22])[CH2:17]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(N)=O
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CC(CC=O)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 52.5 %

Procedure:
To a solution of 3-(2-hydroxy-ethyl)-cyclobutyl]-carbamic acid tert-butyl ester (5.2 g, 24.1 mmol) in anhydrous DCM (100 mL) was added Dess-Martin periodinane (20.5 g, 48.3 mmol) and stirred at room temperature for 5 hrs. The mixture was quenched with Na2S2O3 solution, extracted with DCM. The organic phase was concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel (eluted with PE:EA=5:1) to give the title compound (2.7 g, yield 52%) as an oily liquid.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=1.CCN(C(C)C)C(C)C.[NH2:21][CH:22]1[CH2:27][CH2:26][CH:25]([OH:28])[C:24]([CH3:30])([CH3:29])[CH2:23]1>C1COCC1>[OH:28][C@@H:25]1[CH2:26][CH2:27][C@H:22]([NH:21][C:2]2[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=2)[CH2:23][C:24]1([CH3:30])[CH3:29]
Reactant: CSc1ncc(C#N)c(Cl)n1
Reactant: CC1(C)CC(N)CCC1O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CSc1ncc(C#N)c(N[C@H]2CC[C@@H](O)C(C)(C)C2)n1
Temperature: 50 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
To a mixture of 4-chloro-2-(methylthio)pyrimidine-5-carbonitrile (1.0 equiv.) and DIEA (3.0 equiv) in THF (0.05 M) was added 4-amino-2,2-dimethylcyclohexanol (peak 1, obtained above) (1.2 equiv.). The mixture was stirred at 50° C. overnight. After reaction completion, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (20% ethyl acetate in petroleum ether) to afford the title compound (82% yield) as a white solid. MS (ESI) m/z 293.1 [M+H]+. The single crystal X-ray diffraction studies were carried out on a Bruker Kappa APEX-II CCD diffractometer equipped with Mo Kα radiation (λ=0.71073 Å). Crystals of the subject compound were grown by vapor diffusion of pentane into an isopropanol solution. A 0.215×0.183×0.055 mm colorless plate was mounted on a cryoloop with paratone oil. Data were collected in a nitrogen gas stream at 90 (2) K using φ and ω scans. Crystal-to-detector distance was 60 mm and exposure time was 5 seconds per frame using a scan width of 0.5°. Data collection was 99.9% complete to 25.00° in θ. A total of 45590 reflections were collected covering the indices, −53<=h<=56, −14<=k<=13, −23<=l<=27. 21888 reflections were found to be symmetry independent, with a Rint of 0.0549. Indexing and unit cell refinement indicated a C-centered, monoclinic lattice. The space group was found to be C2. The data were integrated using the Bruker SAINT software program and scaled using the SADABS software program. Solution by direct methods (SHELXS) produced a complete phasing model consistent with the proposed structure.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:27][CH2:26][N:25]([C:28](=[O:31])[CH2:29]Cl)[CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[N:12]=[CH:11][C:10]=1[CH2:32][C:33]([NH2:35])=[O:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(NCC)C>[CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:27][CH2:26][N:25]([C:28](=[O:31])[CH2:29][N:8]([CH2:9][CH3:10])[CH2:1][CH3:2])[CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[N:12]=[CH:11][C:10]=1[CH2:32][C:33]([NH2:35])=[O:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)Cc1cnc(Nc2ccc(N3CCN(C(=O)CCl)CC3)cc2)cc1NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCNCC
Solvent: CC#N
Product: CCN(CC)CC(=O)N1CCN(c2ccc(Nc3cc(NCc4ccccc4)c(CC(N)=O)cn3)cc2)CC1
Temperature: 80 °C
Reaction time: 1 h
Yield: 119.1 %

Procedure:
25 mg of 4-(benzylamino)-6-({4-[4-(chloroacetyl)piperazin-1-yl]phenyl}amino)pyridine-3-carboxyamide (the compound of Example 269) was dissolved in 2 mL of acetonitrile, to which 0.1 mL of diethylamine and 15 mg of potassium carbonate were added, and stirred at 80° C. for 1 hour. After cooling, the insoluble substances were filtered off, the solvent was evaporated, and the residue was purified by silica gel thin layer chromatography (chloroform:ammonia methanol=10:1) to obtain 16 mg (59%) of the title compound as a light brown crystalline powder.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.Br[C:12]1[CH:13]=[CH:14][C:15]([F:21])=[C:16]([N+:18]([O-:20])=[O:19])[CH:17]=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.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>[F:21][C:15]1[CH:14]=[CH:13][C:12]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([NH2:1])[CH:3]=2)=[CH:17][C:16]=1[N+:18]([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Reactant: Nc1cccc(B(O)O)c1
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: Cc1ccccc1
Product: Nc1cccc(-c2ccc(F)c([N+](=O)[O-])c2)c1
Temperature: 0 °C
Yield: 183.8 %

Procedure:
3-Aminophenylboronic acid (3.9 g), 5 g 5-bromo-2-fluoro-nitrobenzene, 0.8 g tetrakis(triphenylphosphine)palladium and 23 mL of 2 M sodium bicarbonate solution in 50 mL of toluene were refluxed under nitrogen for 2.5 hours. The reaction mixture was poured into 200 mL of ice water and the mixture extracted three times with 50 mL of ethyl acetate. The combined organic layers were washed with 50 mL of water and 20 mL of brine, dried over anhydrous sodium sulfate and concentrated to give 9.7 g (92% yield) of 2-fluoro-5-(3-aminophenyl)nitrobenzene as a dark brown oil.