Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]([CH:22]2[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]2)[C:10](=[O:21])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18]C)=[C:14]([OH:20])[CH:13]=2)=[CH:4][CH:3]=1.B(Br)(Br)Br>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]([CH:22]2[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]2)[C:10](=[O:21])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([OH:20])[CH:13]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc(CC(=O)N(Cc2ccc(C)cc2)C2CCN(C)CC2)cc1O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1ccc(CN(C(=O)Cc2ccc(O)c(O)c2)C2CCN(C)CC2)cc1
Temperature: 78 °C
Reaction time: 2 h
Yield: 47.9 %

Procedure:
N-((4-methylphenyl)methyl)-N-(1-methylpiperidine-4-yl)-2-(3-hydroxy-4-methoxyphenyl)acetamide (57 MBT12B) (52 mg, 0.136 mmol) was dissolved in CH2Cl2 (1 mL) and cooled to−78° C. Boron tribromide (1M in CH2Cl2, 204 μl, 0.204 mmol) was added dropwise and the cooling bath was removed. After stirring for 2 h, methanol (2 mL) was added and the mixture was evaporated. The resulting oil was purified by preparative HPLC to give 24 mg (48%) of the title compound as a white solid. HPLC-MS (method A) showed MH+=369. UV/MS(%)=100/97. 1H-NMR (400 MHz, CD30D, Rotamers 33:67): δ 7.19-6.47 (m, 7H), 4.54 and 4.53 (2s, 2H), 4.23 (m, 1H), 3.83 and 3.58 (2s, 2H), 3.46 and 3.40 (2br d, J=12 Hz, 2H), 3.02 and 2.95 (2br t, J=12 Hz, 2H), 2.79 (s, 3H), 2.33 and 2.28 (2s, 3H), 2.17 and 1.84 (2dq, J=4, 12 Hz, 2H), 1.87 and 1.48 (2br d, J=12 Hz, 2H)
Reaction SMILES: [CH:1](=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[CH2:10]=[O:11].Cl>>[OH:11][CH2:10][C:7]1[CH:8]=[C:2]([CH:1]=[O:9])[C:3]([OH:4])=[CH:5][CH:6]=1
Reactant: C=O
Reactant: O=Cc1ccccc1O
Agent: Cl
Product: O=Cc1cc(CO)ccc1O
Temperature: 80 °C
Reaction time: 0.33 h

Procedure:
A mixture of 9 ml of salicylaldehyde (84.46 mmol), 17 ml of aqueous 37% formaldehyde solution (˜200 mmol) and 42 ml of concentrated HCl is heated on a water bath at 80° C. with stirring for 20 min. After cooling, the supernatant is removed by settling of the phases and the residual pink crystalline mass is taken up in 200 ml of boiling water. The suspension obtained is refluxed for 30 min. The supernatant is separated out after settling and placed at +4° C. to bring about crystallization of the final product. A further 200 ml of boiling water are added to the residual oil and the suspension is refluxed for 30 min. The supernatant is added to the first decantate. After cooling, the product is collected by filtration, washed with water and dried. It is then recrystallized from chloroform.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([CH3:14])[CH2:8][N:7]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:22]=1.[NH2:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][C:25]=1[O:33][CH3:34]>Cl.C(O)(C)C>[CH:16]1([N:7]2[CH2:8][C:9]([F:15])([CH3:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][C:25]=4[O:33][CH3:34])=[N:22][C:6]2=3)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: COc1cc(C(=O)O)ccc1N
Reactant: CN1C(=O)C(C)(F)CN(C2CCCCC2)c2nc(Cl)ncc21
Agent: Cl
Solvent: CC(C)O
Product: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(C)(F)C(=O)N2C
Temperature: 100 °C
Reaction time: 20 h
Yield: 31.9 %

Procedure:
A mixture of 2-chloro-9-cyclohexyl-7-fluoro-5,7-dimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one (330 mg, 1 mmol), 4-amino-3-methoxybenzoic acid (184 mg, 1.1 mmol), isopropanol (10 ml), and concentrated hydrochloric acid (10 drops) was stirred at 100° C. for 20 h. Solid was filtered to give 146 mg product as white solid (32%). [M+H] calc'd for C23H28FN5O4, 458; found 458.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[N:11]3[CH:12]=[CH:13][N:14]=[C:10]3[CH:9]=[C:8]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[CH:17][CH:16]=3)[N:7]=2)[CH:3]=[N:2]1.[CH:27]1([CH:32]=[CH:33][C:34]#[N:35])[CH2:31][CH2:30][CH2:29][CH2:28]1.N1CCCN2CCCCCC=12>CN(C=O)C>[CH:27]1([CH:32]([N:1]2[CH:5]=[C:4]([C:6]3[N:11]4[CH:12]=[CH:13][N:14]=[C:10]4[CH:9]=[C:8]([C:15]4[CH:20]=[CH:19][C:18]([N:21]5[CH2:26][CH2:25][O:24][CH2:23][CH2:22]5)=[CH:17][CH:16]=4)[N:7]=3)[CH:3]=[N:2]2)[CH2:33][C:34]#[N:35])[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: c1cn2c(-c3cn[nH]c3)nc(-c3ccc(N4CCOCC4)cc3)cc2n1
Reactant: N#CC=CC1CCCC1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: N#CCC(C1CCCC1)n1cc(-c2nc(-c3ccc(N4CCOCC4)cc3)cc3nccn23)cn1
Temperature: 25 °C
Yield: 46.9 %

Procedure:
4-(4-(5-(1H-Pyrazol-4-yl)imidazo[1,2-c]pyrimidin-7-yl)phenyl)morpholine (0.0300 g, 0.0866 mmol) and 3-cyclopentylaerylonitrile (Table 1, compound g; 0.0175 g, 0.144 mmol) were suspended in DMF (3 mL) and 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (0.0324 mL, 0.217 mmol) added in one portion. The reaction mixture was stirred at ambient temperature over the weekend. The reaction mixture was partitioned between saturated aqueous 1 N NaOH and EtOAc. The solids were isolated by filtration. The organics were washed with brine, dried over MgSO4 and concentrated under reduced pressure to afford the crude material, which was purified by flash column chromatography (eluant: 0.5-3% (9:1, MeOH:NH4OH)/DCM) to provide 3-cyclopentyl-3-(4-(7-(4-morpholinophenyl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)propanenitrile (0.0190 g, 0.04064 mmol, 46.9% yield). MS (apci) m/z=468.2 (M+H).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10](Br)=[CH:11][CH:12]=2)[N:7]([C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])[CH2:6][C@@H:5]1[CH3:21])(=[O:3])[CH3:2].O.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)OB([C:35]2[CH:36]=[N:37][N:38]([CH2:40][C:41]3[CH:46]=[N:45][CH:44]=[CH:43][N:42]=3)[CH:39]=2)OC1(C)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:35]3[CH:36]=[N:37][N:38]([CH2:40][C:41]4[CH:46]=[N:45][CH:44]=[CH:43][N:42]=4)[CH:39]=3)=[CH:11][CH:12]=2)[N:7]([C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])[CH2:6][C@@H:5]1[CH3:21])(=[O:3])[CH3:2]
Reactant: CC1(C)OB(c2cnn(Cc3cnccn3)c2)OC1(C)C
Reactant: CC(=O)N1c2ccc(Br)cc2N(C(=O)OC(C)C)C[C@@H]1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)N1c2ccc(-c3cnn(Cc4cnccn4)c3)cc2N(C(=O)OC(C)C)C[C@@H]1C
Temperature: 70 °C
Reaction time: 8 h
Yield: 37.5 %

Procedure:
A 100-mL round-bottom flask was charged with isopropyl (3S)-4-acetyl-7-bromo-3-methyl-1,2,3,4-tetrahydroquinoxaline-1-carboxylate (60 mg, 0.17 mmol), bis(triphenylphosphine)palladium(II) dichloride (12 mg, 0.02 mmol), water (8 mL), 1,4-dioxane (20 mL), cesium carbonate (165 mg, 0.50 mmol), and 2-[4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]methylpyrazine (60 mg, 0.21 mmol). The resulting mixture stirred overnight at 70° C. After cooling to room temperature, the reaction mixture was passed through a short pad of celite and concentrated under vacuum. The residue was purified by Prep-HPLC with the following conditions (1#waters2767): Column, Xbridge Phenyl 19×150 mm; mobile phase, Phase A: water (0.05% NH4HCO3), Phase B: CH3CN (15% CH3CN up to 60% in 8 min); Detector, UV220&254 nm to afford (S)-isopropyl 4-acetyl-3-methyl-7-(1-(pyrazin-2-ylmethyl)-1H-pyrazol-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxylate (27.7 mg, 38%) as a white solid. 1H NMR (300 MHz, CD3OD) δ ppm 1.10 (d, J=6.60 Hz, 3H), 1.27-1.37 (m, 6H), 2.22 (s, 3H), 3.35-3.50 (m, 1H), 4.05-4.17 (m, 1H), 4.95-5.10 (m, 2H), 5.58 (s, 2H), 7.39 (br s, 2H), 7.91 (s, 1H), 8.03 (s, 1H), 8.21 (s, 1H), 8.49 (s, 1H), 8.56 (d, J=2.70 Hz, 1H), 8.59-8.62 (m, 1H). MS (ESI, pos. ion) m/z 435 [M+H]+.
Reaction SMILES: C([O:3][C:4](=[O:24])[CH2:5][O:6][C:7]1[CH:22]=[CH:21][C:10]2[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])=[N:12][O:13][C:9]=2[C:8]=1[Cl:23])C.O.Cl>C(O)C.[OH-].[Na+]>[Cl:23][C:8]1[C:9]2[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[C:10]=2[CH:21]=[CH:22][C:7]=1[O:6][CH2:5][C:4]([OH:24])=[O:3]
Reactant: CCOC(=O)COc1ccc2c(-c3ccccc3Cl)noc2c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)COc1ccc2c(-c3ccccc3Cl)noc2c1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 5.86 g of the ester in 200 ml of hot ethanol, 6 ml of 50% NaOH is added. A precipitate forms and the suspension is refluxed for one hour. Two hundred milliliters of water are added to the mixture and enough concentrated HCl to make the mixture acidic. The mixture is and enough concentrated HCl to make the mixture acidic. The mixture is stirred 18 hours at room temperature. A solid product precipitates out and is filtered and recrystallized from toluene giving {[7-chloro-3-(2-chlorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetic acid, mp 165°-168° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([O:9][CH2:10][CH3:11])([O:6][CH2:7][CH3:8])[CH3:5])[CH3:2].[Cl:12]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Cl:12][CH2:5][C:4]([O:3][CH2:1][CH3:2])([O:6][CH2:7][CH3:8])[O:9][CH2:10][CH3:11]
Reactant: CCOC(C)(OCC)OCC
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(CCl)(OCC)OCC
Temperature: 40 °C
Yield: 77.1 %

Procedure:
A mixture of 1,1,1-triethoxyethane (97.3 g) and N-chlorosuccinimide (88.1 g) in carbon tetrachloride (600 ml) was warmed to 40° C. and then irradiated with an ultraviolet lamp. The reaction became exothermic and then subsided upon completion of the reaction. The precipitated succinimide byproduct was filtered off and the filtrate was concentrated to remove carbon tetrachloride. The residual liquid was distilled to obtain pure 2-chloro-1,1,1-triethoxyethane (91.0 g; b.p. 91° C./25 mm).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[CH:12]=[C:11]([C:13]3[C:18]([CH3:19])=[CH:17][N:16]=[C:15]([NH:20][CH2:21][CH2:22][CH2:23][N:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)[N:14]=3)[S:10][C:9]=2[CH:31]=1)=[O:4].C1COCC1.[OH-].[Li+].[ClH:39]>CO.O>[ClH:39].[ClH:39].[ClH:39].[CH3:19][C:18]1[C:13]([C:11]2[S:10][C:9]3[CH:31]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=[CH:7][C:8]=3[CH:12]=2)=[N:14][C:15]([NH:20][CH2:21][CH2:22][CH2:23][N:24]2[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]2)=[N:16][CH:17]=1
Reactant: COC(=O)c1ccc2cc(-c3nc(NCCCN4CCN(C)CC4)ncc3C)sc2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cnc(NCCCN2CCN(C)CC2)nc1-c1cc2ccc(C(=O)O)cc2s1
Temperature: 70 °C
Yield: 97 %

Procedure:
2-{5-Methyl-2-[3-(4-methylpiperazin-1-yl)-propylamino]-pyrimidin-4-yl}-benzo[b]thiophene-6-carboxylic acid methyl ester (1.31 g, 2.98 mmol) is dissolved in methanol (30 mL), THF (30 mL) and water (10 mL) and lithium hydroxide solution (4.6 mL of 2.0 M solution) is added. The solution is heated at 70° C. for 4.5 hours and 5 N HCl (9 mL) is added in one portion while still heating the solution. The solution is cooled to room temperature and the resulting solid is filtered and washed with methanol. The solid is dried at 60° C. in a vacuum oven for 4 hours to give the title compound (1.43 g, 97% yield). ES+(m/z) 426 [M+H].
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]2[CH:6]=[C:7]([C:9]([OH:11])=O)[O:8][C:4]=2[CH:3]=1.Cl.Cl.[NH2:16][C@@H:17]1[CH:22]2[CH2:23][CH2:24][N:19]([CH2:20][CH2:21]2)[CH2:18]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CO.CN(C=O)C>[N:19]12[CH2:24][CH2:23][CH:22]([CH2:21][CH2:20]1)[C@@H:17]([NH:16][C:9]([C:7]1[O:8][C:4]3[CH:3]=[C:2]([Br:1])[CH:13]=[CH:12][C:5]=3[CH:6]=1)=[O:11])[CH2:18]2
Reactant: O=C(O)c1cc2ccc(Br)cc2o1
Reactant: N[C@H]1CN2CCC1CC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2ccc(Br)cc2o1
Reaction time: 0.33 h

Procedure:
3.8 g (15.77 mmol) of 6-bromobenzofuran-2-carboxylic acid (Example 1A), 3.14 g (15.77 mmol) of (R)-3-aminoquinuclidine dihydrochloride, 7.19 g (18.92 mmol) of HATU, 7.34 g (56.76 mmol) of N,N-diisopropylethylamine and 50 ml of DMF are reacted by general method C. The crude product is taken up in methanol and shaken together with acidic ion exchanger (Dowex® WX2-200) for about 20 min. The loaded ion exchanger is washed successively with methanol, dichloromethane and again with methanol. The product is eluted with methanol/triethylamine 90:10. The solvent is removed in a rotary evaporator under reduced pressure. Finally; the last residues of solvent are removed under high vacuum. 5.14 g (85% of theory) of the title compound are isolated. For analysis, a small amount is converted into the hydrochloride with 4N hydrogen chloride in dioxane.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][C:3]#[CH:4].CCOCC.C([Li])CCC.[CH3:16][Si:17]([CH3:20])([CH3:19])Cl>CCCCCC.O>[CH3:16][Si:17]([CH3:20])([CH3:19])[C:4]#[C:3][CH2:2][CH2:1][OH:5]
Reactant: C#CCCO
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Solvent: O
Product: C[Si](C)(C)C#CCCO

Procedure:
A solution of 33.25 parts of 3-butyn-1-ol in 500 parts by volume ether is cooled to -60° C. under argon and treated dropwise with 400 parts by volume of a 2.5 molar solution of n-butyl lithium in hexane. One hour after the addition is complete, a solution of 130 parts by volume of trimethylchlorosilane in 130 parts by volume of ether is added dropwise. After the addition is complete, the temperature is allowed to rise to 0°. The reaction mixture is poured into water, washed with 1NHCl 3 times, additional water, dried over sodium sulfate and evaporated to a liquid which is distilled under water aspirator pressure to give 4-trimethylsilyl-3-butyn-1-ol, bp. 75-77 (13 Tor).
Reaction SMILES: C[O:2][C:3](=[O:38])[C@H:4]([CH2:28][NH:29][C:30](=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[NH:5][C:6](=[O:27])[C:7]1[CH:12]=[CH:11][C:10]([C:13]([NH:15][CH2:16][C:17]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:18]=2[CH:19]=[CH:20][NH:21]3)=[O:14])=[CH:9][C:8]=1[Cl:26].O.[OH-].[Li+]>O1CCCC1.CO.O>[C:30]([NH:29][CH2:28][C@@H:4]([C:3]([OH:38])=[O:2])[NH:5][C:6](=[O:27])[C:7]1[CH:12]=[CH:11][C:10]([C:13]([NH:15][CH2:16][C:17]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:18]=2[CH:19]=[CH:20][NH:21]3)=[O:14])=[CH:9][C:8]=1[Cl:26])(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: COC(=O)[C@H](CNC(=O)c1ccccc1)NC(=O)c1ccc(C(=O)NCc2cccc3[nH]ccc23)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(NCc1cccc2[nH]ccc12)c1ccc(C(=O)N[C@@H](CNC(=O)c2ccccc2)C(=O)O)c(Cl)c1
Yield: 74.3 %

Procedure:
3-(Benzoylamino)-L-alanine methyl ester (Example 299; 77 mg, 0.35 mmol) was mixed with 2-chloro-4-[[(1H-indol-4-yl-methyl)amino]carbonyl]benzoic acid (Example 36; 115 mg, 0.35 mmol), HOBT (57 mg, 0.42 mmol) and EDCI (80.5 mg, 0.42 mmol) in DMF (4 mL). The reaction mixture was stirred at room temperature for 16 h and then diluted with water (about 20 ml). The solution was extracted with ethyl acetate (3×10 ml) and the ethyl acetate layer was washed with dilute aqueous NaCl solution and then brine, dried (Na2SO4), concentrated, and chromatographed (40-80% ethyl acetate/hexanes) to give 3-(benzoylamino)-N-[2-chloro-4-[[(1H-indol-4-ylmethyl)amino]carbonyl]benzoyl]-L-alanine methyl ester (88 mg, 47%). A solution of the ester (51 mg, 0.096 mmol) and lithium hydroxide monohydrate (8 mg, 0.19 mmol) in tetrahydrofuran/methanol/water (3:1:1; 2 mL) was stirred at room temperature for 3 h. The solvent was removed and the product was purified by HPLC to give 3-(benzoylamino)-N-[2-chloro-4-[[(1H-indol-4-ylmethyl)amino]carbonyl]benzoyl]-L-alanine (37 mg, 75%) as a white fluffy powder.
Reaction SMILES: [CH3:1][C@H:2]1[C@H:7]([C:8]([OH:10])=[O:9])[CH2:6][CH:5]=[CH:4][CH2:3]1.C([O-])(O)=O.[Na+].[I:16]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl.O>[I:16][C@@H:4]1[C@@H:5]2[CH2:6][C@@H:7]([C:8](=[O:10])[O:9]2)[C@H:2]([CH3:1])[CH2:3]1
Reactant: II
Reactant: C[C@@H]1CC=CC[C@H]1C(=O)O
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: C[C@@H]1C[C@H](I)[C@@H]2C[C@H]1C(=O)O2
Reaction time: 24 h
Yield: 29022.6 %

Procedure:
To a solution of optically active 5 (16.8 g, 120 mmol), in methylene chloride (200 mL) and water (400 mL), was added NaHCO3 (20.1 g, 240 mmol), KI (120 g, 0.720 mmol) and iodine (91.0 g, 0.360 mmol). The resulting mixture was protected from light and stirred for 24 h. The solution was cooled (0° C.) and sodium thiosulfate was carefully added until the dark iodine color disappeared. This was extracted with diethyl ether (4×300 mL). The combined organics were dried (MgSO4) and the volatiles were removed in vacuo to give a yellowish solid (27.8 g, 87% yield). This was carried onto the next step without further purification. Rf 0.33 (ethyl acetate/hexane 1:9); m.p. 99-100° C.; 1H NMR (300 MHz, CDCl3) δ 4.86 (dd, J=3.6, 5.9, 1H), 4.35-4.38 (m, 1H), 2.90 (m, 1H), 2.63-2.73 (m, 1H), 2.49-2.52 (m, 1H), 2.20-2.36 (m, 2H), 1.95-2.00 (m, 1H). 1.38 (d, J=7.2, 3H); 13C NMR (75 MHz, CDCl3) δ 178.2, 81.6, 43.8, 34.3, 29.3, 27.8, 19.5, 19.1; MS (EI) m/z 266 (M+, 4), 139 ([M-I]+, 80), 95 (100), 79 (16), 67 (26), 55 (29); [α]D−3.60° (c=2.22, CHCl3).
Reaction SMILES: [NH:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4](=[O:11])OC1=O.[Cl:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:17][NH2:18]>C1C=CC=CC=1>[NH2:1][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:4]([NH:18][CH2:17][C:16]1[CH:19]=[CH:20][C:21]([Cl:22])=[C:14]([Cl:13])[CH:15]=1)=[O:11]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: NCc1ccc(Cl)c(Cl)c1
Solvent: c1ccccc1
Product: Nc1ccccc1C(=O)NCc1ccc(Cl)c(Cl)c1

Procedure:
A mixture of 2H-3,1-benzoxazine-2,4(1H)dione (20 g) and 3,4-dichlorobenzylamine (16.4 ml) in benzene (200 ml) was refluxed for 3 hours. After cooling, the solvent was removed under reduced pressure to give a residue, which was recrystallized from n-hexane-ethyl acetate (1:2) to afford 2-amino-N-(3,4-dichlorobenzyl)benzamide (30.5 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:24]=[CH:23][C:17]4[O:18][C:19]([F:22])([F:21])[O:20][C:16]=4[CH:15]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[CH:4][C:3]=1[CH3:25].[Cl:26][C:27]1[C:28]([O:42][CH3:43])=[N:29][CH:30]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.ClCCl.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>[Cl:26][C:27]1[CH:32]=[C:31]([C:2]2[C:3]([CH3:25])=[CH:4][CH:5]=[C:6]([NH:8][C:9]([C:11]3([C:14]4[CH:24]=[CH:23][C:17]5[O:18][C:19]([F:21])([F:22])[O:20][C:16]=5[CH:15]=4)[CH2:13][CH2:12]3)=[O:10])[N:7]=2)[CH:30]=[N:29][C:28]=1[O:42][CH3:43]
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1Cl
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1Cl
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: ClCCl
Solvent: COCCOC
Product: COc1ncc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ccc2C)cc1Cl
Temperature: 80 °C
Yield: 27.4 %

Procedure:
To N-(6-chloro-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (73 mg, 0.2 mmol) in 1,2-dimethoxyethane (2 mL) was added 3-chloro-2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (65 mg, 0.24 mmol), tetrakis(triphenylphosphine)palladium (0) (12 mg, 0.01 mmol), and 2 M sodium carbonate (0.20 mL, 0.4 mmol). The reaction mixture was heated to 80° C. in an oil bath overnight. The reaction mixture was diluted with dichloromethane (5 mL) and washed with water (5 mL). The organics were dried over sodium sulfate and evaporated to dryness. The crude reaction mixture was purified by silica gel chromatography (eluting with 0-100% ethyl acetate in hexanes) to yield the product (26 mg, 27%). ESI-MS m/z calc. 473.86. found 474.3 (M+1)+. Retention time 2.27 minutes.
Reaction SMILES: [CH2:1]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)[C:2]#[CH:3].[CH2:20]=O.[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>C(O)C>[N:22]1([CH2:20][C:3]#[C:2][CH2:1][N:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8](=[O:15])[NH:7][C:6]3[CH:16]=[CH:17][CH:18]=[N:19][C:5]2=3)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: C1CCNCC1
Reactant: C#CCN1c2ccccc2C(=O)Nc2cccnc21
Reactant: C=O
Solvent: CCO
Product: O=C1Nc2cccnc2N(CC#CCN2CCCCC2)c2ccccc21
Yield: 19 %

Procedure:
Prepared analogously to Example lb) from 5,11-dihydro-11-(prop-2-ynyl)-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one, paraformaldehyde and piperidine in a yield of 19% of theory. Colourless crystals m.p. 165°-168° C. (ethyl acetate). The hemifumarate melted at 198° C. (ethanol) with decomposition.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]([N:18]([CH2:35][CH:36]([CH3:38])[CH3:37])[C@H:19]1[CH2:24][C@@H:23]([CH:25]2[CH2:27][O:26]2)[CH2:22][N:21]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:20]1)=[O:17].[CH3:39][O-:40].[Na+].CO>CO>[OH:26][CH:25]([C@@H:23]1[CH2:24][C@H:19]([N:18]([C:16]([C:8]2[N:7]([CH2:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=2)=[O:17])[CH2:35][CH:36]([CH3:38])[CH3:37])[CH2:20][N:21]([C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[CH2:22]1)[CH2:27][O:40][CH3:39]
Reactant: C[O-]
Reactant: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C3CO3)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Agent: [Na+]
Solvent: CO
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(O)COC)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Temperature: 70 °C
Reaction time: 6 h

Procedure:
tert-Butyl (3S,5R)-3-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-oxirane-2-ylpiperidine-1-carboxylate (200 mg) was dissolved in methanol (5 ml), 28% sodium methylate-methanol solution was added, and the mixture was stirred at 70° C. for 6 hr. The solvent was evaporated under reduced pressure, and the residue was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (1:1-1:0) was concentrated under reduced pressure to give the object product (157 mg).
Reaction SMILES: COC1C=C(C=CC=1)C([Cl:17])C1C2C(=CC=CC=2)C=CC=1.O[CH:22]([C:30]1[CH:42]=[CH:41][C:33]([C:34]([N:36]([CH2:39][CH3:40])[CH2:37][CH3:38])=[O:35])=[CH:32][CH:31]=1)[C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1>>[Cl:17][CH:22]([C:30]1[CH:42]=[CH:41][C:33]([C:34]([N:36]([CH2:39][CH3:40])[CH2:37][CH3:38])=[O:35])=[CH:32][CH:31]=1)[C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1
Reactant: COc1cccc(C(Cl)c2cccc3ccccc23)c1
Reactant: CCN(CC)C(=O)c1ccc(C(O)c2ccc(Cl)cc2)cc1
Product: CCN(CC)C(=O)c1ccc(C(Cl)c2ccc(Cl)cc2)cc1

Procedure:
The compound 32 was prepared by following the synthesis procedure as described for compound 2, but substituting compound 1 for compound 31.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[NH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].F[C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1.O>CN(C=O)C>[I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)[N:3]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Nc1ncnc2[nH]nc(I)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ncnc2c1c(I)nn2-c1ccc([N+](=O)[O-])cc1
Temperature: 100 °C
Reaction time: 24 h
Yield: 89 %

Procedure:
To a solution of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1) (5.22 g, 20 mmol) in DMF (60 mL) were added K2CO3 (8.3 g, 60 mmol) and 1-fluoro-4-nitrobenzene (2.96 g, 21 mmol). After the resulting mixture was stirred at 100° C. for 24 hr under N2 atmosphere, the reaction mixture was cooled to RT before pouring into water (200 mL). The precipitate was collected, washed with water and dried to provide 3-iodo-1-(4-nitrophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (27) (6.8 g, 89%) as light yellow solid. LC-MS (ESI): m/z (M+1)383.1.