Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].II.[CH:4](Br)=[CH2:5].[CH3:7][C:8]1[CH2:13][CH2:12][CH2:11][C:10]([CH3:15])([CH3:14])[C:9]=1/[CH:16]=[CH:17]/[C:18]([CH3:20])=[O:19]>O1CCCC1>[CH3:7][C:8]1[CH2:13][CH2:12][CH2:11][C:10]([CH3:14])([CH3:15])[C:9]=1/[CH:16]=[CH:17]/[C:18]([OH:19])([CH:4]=[CH2:5])[CH3:20]
Reactant: C=CBr
Reactant: CC(=O)/C=C/C1=C(C)CCCC1(C)C
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: C=CC(C)(O)/C=C/C1=C(C)CCCC1(C)C
Temperature: -30 °C
Yield: 87.5 %

Procedure:
1.3 mols of magnesium turnings are placed in a 3 L four-necked flask. 100 ml of tetrahydrofuran (THF) and a iodine crystal are added thereto. 50 ml of a 15% vinyl bromide solution in tetrahydrofuran are added with stirring and under nitrogen atmosphere. The solution immediately decolourizes, while the Grignard starts to form with an exothermic reaction: the mixture is cooled to −30° C. and one mol of beta-ionone dissolved in 500 ml of THF and 950 mL of the above 15% vinyl bromide solution are added at the same time through two dropping tunnels, at such a rate that temperature remains below −15 20° C. After completion of the addition, the cooling bath is removed and the reaction mixture is brought to room temperature. After 2 hours the reaction mixture is poured into 2 ml of ice-water containing 10 g of ammonium chloride under stirring, then is extracted with 700 ml of ethyl acetate. The organic phase is washed twice with 100 ml of 15% sodium chloride aqueous solution and dried over sodium sulfate. Solvent is evaporated off under reduced pressure and the resulting thick oil is distilled under vacuum, collecting 202 g of distillate, consisting of vinyl beta-ionol of purity higher than 95%, as determined by NMR analysis (yield: 87.5%).
Reaction SMILES: FC(F)(F)CCC([N:7]1[CH2:14][CH2:13][N:12]([C:15]2[C:16]3[CH:23]=[CH:22][NH:21][C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:11][C:8]21[CH2:10][CH2:9]2)=O.[CH2:26]([N:33]=[C:34]=[S:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1COCC1>[CH2:26]([NH:33][C:34]([N:7]1[CH:8]2[CH2:9][CH2:10][CH:14]1[CH2:13][N:12]([C:15]1[C:16]3[CH:23]=[CH:22][NH:21][C:17]=3[N:18]=[CH:19][N:20]=1)[CH2:11]2)=[S:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(CCC(F)(F)F)N1CCN(c2ncnc3[nH]ccc23)CC12CC2
Reactant: S=C=NCc1ccccc1
Solvent: C1CCOC1
Product: S=C(NCc1ccccc1)N1C2CCC1CN(c1ncnc3[nH]ccc13)C2
Reaction time: 16 h

Procedure:
4-(3,8-Diaza-bicyclo[3.2.1]oct-3-yl)-7H-pyrrolo[2,3-d]pyrimidine (intermediate 4) (0.05 mmol) was dissolved in THF (1 mL), and benzyl isothiocyanate (0.06 mmol) was added. The reaction mixture was left at rt for 16 hours. The pure compounds were obtained by standard preparative HPLC purification of the reaction mixture.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH2:10][CH2:11][NH:12][C:13](=[O:16])[O:14][CH3:15].[F:17][C:18]1[CH:31]=[CH:30][C:21]([O:22][C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)=[CH:20][CH:19]=1>CN(C)C=O>[F:17][C:18]1[CH:31]=[CH:30][C:21]([O:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:10][CH2:11][NH:12][C:13](=[O:16])[O:14][CH3:15])=[CH:25][CH:24]=2)=[CH:20][CH:19]=1
Reactant: Oc1ccc(Oc2ccc(F)cc2)cc1
Reactant: COC(=O)NCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)NCCOc1ccc(Oc2ccc(F)cc2)cc1
Temperature: 0 °C

Procedure:
3.6 g of powdered potassium carbonate, 1.5 g of finely powdered potassium iodide and 27 g of methyl 2-chloroethylcarbamate are added to a solution of 2.6 g of 4-(4-fluorophenoxy)phenol in 120 ml of dimethyl formamide, and the reaction mixture is heated for 15 hours to 95° C. The cooled reaction mixture is poured into ice-water and extracted repeatedly with ether. The combined ether phases are washed with water, dried over sodium sulfate, and the solvent is completely removed by distillation. After filtration over silica gel, the crude product is recrystallised from diethyl ether/hexane to give methyl 2-[4-(4-fluorophenoxy)phenoxy]-1-ethylcarbamate with a melting point of 64°-66° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH:8]=[CH2:9])[CH:5]=[CH:4][C:3]=1[F:10].[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.C(Cl)Cl>[F:10][C:3]1[CH:4]=[CH:5][C:6]([CH:8]=[CH2:9])=[CH:7][C:2]=1[N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: C=Cc1ccc(F)c(Br)c1
Reactant: C1COCCN1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: ClCCl
Product: C=Cc1ccc(F)c(N2CCOCC2)c1
Temperature: 25 °C

Procedure:
A mixture of 2-bromo-1-fluoro-4-vinyl-benzene (8 g), morpholine (20 mL), Pd2(dba)2 (1.83 g), di-t-butyl-biphenylphosphine (1.2 g), K3PO4 (17 g) in DME (60 mL) was stirred at reflux for 4 h. The reaction mixture was cooled down to room temperature, diluted with methylene chloride, and filtered. The filtrate was concentrated in vacuo. The crude product was purified by Flash Chromatography of Biotage eluting with 7% ethyl acetate in hexanes to give the title compound as an oil (5 g).
Reaction SMILES: FC(F)(F)C([N:5]([CH2:16][CH:17]=[CH2:18])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][C:13](Cl)=[O:14])=O.C(N(CC)CC)C.[C:28]([CH:33]([CH:35]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[OH:36])[OH:34])([O:30][CH2:31][CH3:32])=[O:29]>CCOCC>[CH2:16]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][C:13]([O:36][CH:35]([CH:33]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[OH:34])[C:37]([O:39][CH2:40][CH3:41])=[O:38])=[O:14])[CH:17]=[CH2:18]
Reactant: C=CCN(C(=O)C(F)(F)F)c1ccccc1CC(=O)Cl
Reactant: CCOC(=O)C(O)C(O)C(=O)OCC
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C=CCNc1ccccc1CC(=O)OC(C(=O)OCC)C(O)C(=O)OCC

Procedure:
A mixture of 2-[N-trifluoroacetyl-(allylamino)]phenylacetyl chloride and 1.2 g. triethylamine in 100 ml. warm ether is treated with 2.5 g. diethyl tartrate and refluxed for 24 hours. The hot solution is filtered, the residue is washed with hot ether, and the solution is evaporated. After treatment with aqueous methanolic potassium carbonate, the product is precipitated by acidification, filtered, and dried. Crystallization from acetone yields diethyl O-[2-(allylamino)phenylacetyl]tartrate as a white, crystalline solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[CH:14])=[CH:9][CH:8]=1.C([Li])CCC.[C:23](=[O:25])=[O:24].Cl>C1COCC1.O>[F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:23]([OH:25])=[O:24])=[CH:9][CH:8]=1
Reactant: C#Cc1ccc(OCc2cccc(F)c2)cc1
Reactant: O=C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C#Cc1ccc(OCc2cccc(F)c2)cc1
Temperature: -78 °C
Yield: 68 %

Procedure:
1.93 g (8.5 mmol) of 1-(3-fluoro-benzyloxy)-4-ethynyl-benzene is dissolved in 30 ml THF and cooled to −78° C. 5.8 ml (9.4 mmol) of a 1.6 molar solution of n-butyl lithium is slowly added under stirring. The resulting solution is stirred at −78° C. for 30 minutes. An excess of solid carbon dioxide is added and the suspension is slowly allowed to warm to RT. Water is added and the mixture is acidified by addition of aqueous 0.1 molar hydrochloric acid. Extraction with ethyl acetate yields a semi-solid residue which is triturated in diethyl ether to give 1.58 g (68%) of a colorless solid. MS (neg.ions): m/e=269.1 (M−H).
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH:12]1[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]1>CN.CO>[NH2:3][CH:12]1[CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CC(N2C(=O)c3ccccc3C2=O)C1
Agent: CN
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC(N)C1

Procedure:
A solution of tert-butyl 3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-azetidinecarboxylate (Preparation 77) in methylamine in methanol (2M) (10 ml) was stirred in a sealed tube at 55° C. for 3 hours. On cooling a precipitate formed and the reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (100 ml) and washed with water (100 ml, containing (2M) hydrochloric acid (3 ml)) and water (50 ml, containing (2M) hydrochloric acid (2 ml)). The combined aqueous was basified with (2M) sodium hydroxide solution (20 ml) and extracted with ethyl acetate (3×75 ml). The combined organic layers were dried over anhydrous magnesium sulphate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of 97.5:2.5:0.25 (dichloromethane:methanol:ammonia) gradually changing to 90:10:1 (dichloromethane:methanol:ammonia) to afford the title compound (935 mg) of approximately 90% purity, which was used in preparation without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:13]([C:19]3[N:20]([CH:29]([CH3:31])[CH3:30])[C:21]([C:24]([O:26]CC)=O)=[N:22][N:23]=3)=[N:14][CH:15]=[C:16]([Cl:18])[CH:17]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:32]([F:35])([F:34])[F:33].C1COCC1.[NH4+:41].[OH-]>CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:13]([C:19]3[N:20]([CH:29]([CH3:30])[CH3:31])[C:21]([C:24]([NH2:41])=[O:26])=[N:22][N:23]=3)=[N:14][CH:15]=[C:16]([Cl:18])[CH:17]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:32]([F:34])([F:35])[F:33]
Reactant: CCOC(=O)c1nnc(-c2ncc(Cl)cc2NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)n1C(C)C
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)n1c(C(N)=O)nnc1-c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 8 %

Procedure:
To a vial containing Ethyl 5-(3-(4-chloro-3-(trifluoromethyl)benzenesulfonamido)-5-chloropyridin-2-yl)-4-isopropyl-4H-1,2,4-triazole-3-carboxylate (59 mg, 0.1 mmol) was added THF (0.6 mL) and NH4OH (0.2 mL). The solution was stirred at room temperature for 16 h. EtOAc (30 mL) was added. The organic phase washed with water (2×10 mL) and dried over Na2SO4. The volatiles were removed in vacuo. The resulting residue was purified by preparative HPLC (20→95% gradient of MeCN—H2O with 0.1% TFA) and the pure fractions lyophilized to afford the title compound (4.0 mg, 8% yield). HPLC retention time=2.76 minutes. 1H NMR (400 MHz, CDCl3) δ 8.41 (d, J=2.0, 1H), 8.16 (d, J=2.0, 1H), 8.05 (d, J=2.4, 1H), 7.85 (dd, J=2.4, 8.4, 1H), 7.53 (d, J=8.4, 1H), 5.75 (sept, J=6.8, 1H), 1.52 (d, J=6.8, 6H). MS (ES) [M+H]+ expected 523.0, found 522.9.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][NH:13][C:14](=[O:35])[C@@H:15]3[CH2:19][CH2:18][CH2:17][N:16]3[C:20](=[O:34])[C@H:21]([NH:29][CH2:30][C:31]([OH:33])=[O:32])[CH2:22][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.S(Cl)(Cl)=O.[CH3:40][CH:41](O)[CH3:42]>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][NH:13][C:14](=[O:35])[C@@H:15]3[CH2:19][CH2:18][CH2:17][N:16]3[C:20](=[O:34])[C@H:21]([NH:29][CH2:30][C:31]([O:33][CH:41]([CH3:42])[CH3:40])=[O:32])[CH2:22][CH:23]3[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1nccc2cc(CNC(=O)[C@@H]3CCCN3C(=O)[C@@H](CC3CCCCC3)NCC(=O)O)ccc12
Reactant: CC(C)O
Solvent: O=S(Cl)Cl
Product: CC(C)OC(=O)CN[C@H](CC1CCCCC1)C(=O)N1CCC[C@H]1C(=O)NCc1ccc2c(N)nccc2c1

Procedure:
To a stirred solution of 96 mg of N-(1-amino-isoquinolin-6-ylmethyl) 1-(2-hydroxycarbonylmethylamino-2(R)-cyclohexylmethyl-acetyl)-prolinamide in 6 mL of 2-propanol was added 0.03 mL of thionyl chloride and the reaction mixture was heated at reflux temperature for two days. After this period the reaction mixture was concentrated, ethyl acetate added, washed with aqueous 5% sodium hydrogencarbonate and brine, dried over sodium sulphate and concentrated. The residue was dissolved in a t-butanol/water 1/1 (v/v) mixture lyophilisation yielded 56 mg of the title compound. MS ESI+: 524 (M+H).
Reaction SMILES: [C:1]([CH:4]1[CH2:10][CH2:9][CH2:8][CH2:7][NH:6][CH2:5]1)([OH:3])=[O:2].S(Cl)(Cl)=O.CCOCC.[CH2:20](O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([O:2][C:1]([CH:4]1[CH2:10][CH2:9][CH2:8][CH2:7][NH:6][CH2:5]1)=[O:3])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: OCc1ccccc1
Reactant: O=C(O)C1CCCCNC1
Solvent: O=S(Cl)Cl
Solvent: CCOCC
Product: O=C(OCc1ccccc1)C1CCCCNC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Suspend 1.15 g 3-carboxyperhydroazepine [P. Krogsgaard-Larsen et al., Acta Chem. Scand., B32, 327 (1978)] in 8 ml benzyl alcohol. Cool the mixture to 0° and add 1 ml thionyl chloride. Stir the mixture at room temperature for 48 hours, then add it dropwise to 300 ml ether with vigorous stirring. Decant the ether and dissolve the residue in H2O. Wash the aqueous solution with ether, then make it to pH 12 and extract with ethyl acetate. Dry the extracts and concentrate in vacuo to obtain 3-benzyloxycarbonylperhydroazepine.
Reaction SMILES: [NH2:1][C:2]1[CH:38]=[CH:37][C:5]([CH:6]=[CH:7][C:8]([NH:10][CH2:11][C:12]([N:14]([C:16]2[C:17]([Cl:36])=[C:18]([C:32]([Cl:35])=[CH:33][CH:34]=2)[CH2:19][O:20][C:21]2[C:22]3[N:23]([C:27]([Br:31])=[C:28]([CH3:30])[N:29]=3)[CH:24]=[CH:25][CH:26]=2)[CH3:15])=[O:13])=[O:9])=[CH:4][CH:3]=1.[C:39]1(=[O:45])[O:44][C:42](=[O:43])[CH2:41][CH2:40]1>O1CCOCC1>[Br:31][C:27]1[N:23]2[CH:24]=[CH:25][CH:26]=[C:21]([O:20][CH2:19][C:18]3[C:32]([Cl:35])=[CH:33][CH:34]=[C:16]([N:14]([C:12](=[O:13])[CH2:11][NH:10][C:8](=[O:9])[CH:7]=[CH:6][C:5]4[CH:4]=[CH:3][C:2]([NH:1][C:39](=[O:45])[CH2:40][CH2:41][C:42]([OH:44])=[O:43])=[CH:38][CH:37]=4)[CH3:15])[C:17]=3[Cl:36])[C:22]2=[N:29][C:28]=1[CH3:30]
Reactant: O=C1CCC(=O)O1
Reactant: Cc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)C=Cc4ccc(N)cc4)c3Cl)cccn2c1Br
Solvent: C1COCCO1
Product: Cc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)C=Cc4ccc(NC(=O)CCC(=O)O)cc4)c3Cl)cccn2c1Br
Yield: 100.4 %

Procedure:
A solution of 8-[3-[N-(4-aminocinnamoylglycyl)-N-methylamino]-2,6-dichlorobenzyloxy]-3-bromo-2-methylimidazo[1,2-a]pyridine (150 mg) and succinic anhydride (26 mg) in dioxane (3 ml) was refluxed for 2 hours. After cooling, the solution was removed in vacuo to give 3-bromo-8-[3-[N-[4-(3-carboxypropionamido)cinnamoylglycyl]-N-methylamino]-2,6-dichlorobenzyloxy]-2-methylimidazo[1,2-a]pyridine (175 mg) as amorphous.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C:10]2[CH:11]=[N:12][N:13]([CH3:31])[C:14]=2[C@H:15]2[O:21][CH2:20][C@H:19]([F:22])[C@H:18]([NH:23]C(=O)OC(C)(C)C)[CH2:17][CH2:16]2)=[O:8])[N:6]=1.[CH:32]1([C:35]2[C:39](B3OC(C)(C)C(C)(C)O3)=[CH:38][N:37]([CH3:49])[N:36]=2)[CH2:34][CH2:33]1>>[NH2:23][C@H:18]1[C@@H:19]([F:22])[CH2:20][O:21][C@H:15]([C:14]2[N:13]([CH3:31])[N:12]=[CH:11][C:10]=2[NH:9][C:7]([C:5]2[N:6]=[C:2]([C:39]3[C:35]([CH:32]4[CH2:34][CH2:33]4)=[N:36][N:37]([CH3:49])[CH:38]=3)[S:3][CH:4]=2)=[O:8])[CH2:16][CH2:17]1
Reactant: Cn1ncc(NC(=O)c2csc(Br)n2)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@@H](F)CO1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)c(C2CC2)n1
Product: Cn1cc(-c2nc(C(=O)Nc3cnn(C)c3[C@@H]3CC[C@@H](N)[C@@H](F)CO3)cs2)c(C2CC2)n1

Procedure:
Following the procedure for Example 101 starting from tert-butyl ((3R,4R,7S)-7-(4-(2-bromothiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-3-fluorooxepan-4-yl)carbamate (Intermediate 100), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with 3-cyclopropyl-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole gave 253. 1H NMR (400 MHz, DMSO-d6) δ 9.76 (s, 1H), 8.27 (s, 1H), 8.20 (s, 1H), 7.81 (s, 1H), 5.02-4.76 (m, 2H), 4.16-3.90 (m, 2H), 3.80 (s, 3H), 3.76 (s, 3H), 3.29-3.16 (m, 1H), 2.41-2.30 (m, 1H), 2.18-2.09 (m, 1H), 1.86-1.74 (m, 2H), 1.66-1.58 (m, 1H), 1.02-0.90 (m, 2H), 0.89-0.80 (m, 2H). LCMS (ES+) m/z 460 (M+1).
Reaction SMILES: Br.[NH2:2][C:3]1[S:4][C:5]([C:9](=O)[CH2:10]Br)=[C:6]([CH3:8])[N:7]=1.[NH2:13][C:14]1[N:19]=[CH:18][CH:17]=[CH:16][N:15]=1.C(N(CC)CC)C>C(O)C>[NH2:2][C:3]1[S:4][C:5]([C:9]2[N:13]=[C:14]3[N:19]=[CH:18][CH:17]=[CH:16][N:15]3[CH:10]=2)=[C:6]([CH3:8])[N:7]=1
Reactant: Nc1ncccn1
Reactant: Cc1nc(N)sc1C(=O)CBr
Agent: Br
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1nc(N)sc1-c1cn2cccnc2n1
Yield: 15.2 %

Procedure:
A solution of 2-amino-4-methyl-5-(2-bromoacetyl)thiazole hydrobromide (7.2 g), 2-aminopyrimidine (3.8 g) and triethylamine (11 ml) in ethanol (200 ml) was refluxed for 8 hours and the reaction mixture was evaporated in vacuo. To the residue was added water and the resulting mixture was acidified to pH 1.0 with 10% hydrochloric acid. The acidified solution was treated with charcoal and filtered. The filtrate was adjusted to pH 7.0 with 20% aqueous potassium carbonate. The resulting precipitate was collected by filtration, washed successively with water and ethyl acetate, and recrystallized from aqueous ethanol to give 2-(2-amino-4-methyl-5-thiazolyl)imidazo[1,2-a]pyrimidine (0.8 g). mp 285°-286° C. (dec.)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[N:5]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH:3]=1.[NH2:21][NH2:22]>C1COCC1>[N:15]1([C:4]2[N:5]=[C:6]([O:8][C:9]3[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=3)[N:7]=[C:2]([NH:21][NH2:22])[CH:3]=2)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: NN
Reactant: Clc1cc(N2CCOCC2)nc(Oc2cccnc2)n1
Solvent: C1CCOC1
Product: NNc1cc(N2CCOCC2)nc(Oc2cccnc2)n1
Temperature: 70 °C
Yield: 62.4 %

Procedure:
To a solution of 4-[6-chloro-2-(pyridin-3-yloxy)-pyrimidin-4-yl]-morpholine (295 mg, 1 mmol) in THF (10 mL) was added anhydrous hydrazine (0,320 ml, 10 mmol) under the nitrogen protection. The mixture was heated at 70° C. for 15 min. After cooling to room temperature, the reaction mixture was quenched by ice brine and extracted with EtOAc (100 mL). The organic phase was washed with brine (10 mL) and water (10 ml×2), dried (Na2SO4), filtered, evaporated, and purified by flash chromatography on a column of silica gel (CH2Cl2 and CH2Cl2-MeOH, 95:5) and to give [6-morpholin-4-yl-2-(pyridin-3-yloxy)-pyrimidin-4-yl]-hydrazine (180 mg) in 62% yield. M/Z (M+1) 289.2
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[F:12][C:13]1[CH:14]=[C:15]([CH:25]([NH:27][C:28]([C:30]2[N:31]=[C:32](Cl)[O:33][CH:34]=2)=[O:29])[CH3:26])[CH:16]=[C:17]([F:24])[C:18]=1[NH:19][S:20]([CH3:23])(=[O:22])=[O:21].C([O-])([O-])=O.[Cs+].[Cs+]>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>[F:12][C:13]1[CH:14]=[C:15]([CH:25]([NH:27][C:28]([C:30]2[N:31]=[C:32]([C:4]3[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[CH:3]=3)[O:33][CH:34]=2)=[O:29])[CH3:26])[CH:16]=[C:17]([F:24])[C:18]=1[NH:19][S:20]([CH3:23])(=[O:22])=[O:21]
Reactant: Cc1cc(C)cc(B(O)O)c1
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cc1cc(C)cc(-c2nc(C(=O)NC(C)c3cc(F)c(NS(C)(=O)=O)c(F)c3)co2)c1
Yield: 37.7 %

Procedure:
3,5-Dimethylbenzeneboronic acid (39 mg, 0.26 mmol) and 2-chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (50 mg, 0.13 mmol) was reacted using Pd(PPh3)2Cl2 (7 mg, 0.01 mmol), Cs2CO3 (127 mg, 0.39 mmol) as described above to give the title compound (22 mg, 38%) after purification by flash chromatography on silica gel (% EtOAc in hexane=30%˜100%).
Reaction SMILES: [CH3:1][C:2]1([C:8]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([N:25]5[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]5)[CH:20]=4)[N:17]=3)[NH:12][CH:11]=2)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>N1C=CC=CC=1>[CH3:31][S:32]([N:28]1[CH2:29][CH2:30][N:25]([C:21]2[CH:20]=[C:19]([C:16]3[N:17]=[C:18]4[C:10]([C:8]([C:2]5([CH3:1])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]5)=[O:9])=[CH:11][NH:12][C:13]4=[N:14][CH:15]=3)[CH:24]=[CH:23][CH:22]=2)[CH2:26][CH2:27]1)(=[O:34])=[O:33]
Reactant: CC1(C(=O)c2c[nH]c3ncc(-c4cccc(N5CCNCC5)c4)nc23)CCCCC1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CC1(C(=O)c2c[nH]c3ncc(-c4cccc(N5CCN(S(C)(=O)=O)CC5)c4)nc23)CCCCC1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 22.7 %

Procedure:
A solution of (1-methyl-cyclohexyl)-[2-(3-piperazin-1-yl-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-methanone (135 mg, 0.33 mmol) in pyridine (3 ml), at 0° C., was treated with methane sulfonyl chloride (0.03 ml, 0.367 mmol). The reaction mixture was allowed to stir at 0° C. for 1.5 hours, and then room temperature for 16 hours. The reaction mixture was poured onto ice cold 1N HCl and extracted with DCM. The organic layers were collected, dried over MgSO4, filtered and concentrated giving a yellow film. The crude product was purified by preparative thin layer chromatography using 3% [5% NH4OH:MeOH]/DCM as eluant providing 36 mg (22%) of {2-[3-(4-methanesulfonyl-piperazin-1-yl)-phenyl]-5H-pyrrolo[2,3-b]pyrazin-7-yl}-(1-methyl-cyclohexyl)-methanone as an off white solid. MP 230-231° C., M+H=482.
Reaction SMILES: [NH3:1].C([O:4][C:5]([C:7]1[CH:11]=[C:10]([CH3:12])[N:9]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([Cl:20])[CH:14]=2)[N:8]=1)=O)C>CO>[Cl:20][C:15]1[CH:14]=[C:13]([N:9]2[C:10]([CH3:12])=[CH:11][C:7]([C:5]([NH2:1])=[O:4])=[N:8]2)[CH:18]=[CH:17][C:16]=1[F:19]
Reactant: N
Reactant: CCOC(=O)c1cc(C)n(-c2ccc(F)c(Cl)c2)n1
Solvent: CO
Product: Cc1cc(C(N)=O)nn1-c1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 80 %

Procedure:
Ammonia gas was bubbled into a chilled solution of ethyl 1-(3-chloro-4-fluorophenyl)-5-methyl-1H-pyrazole-3-carboxylate (from Step 1) (1.0 g, 3 mmol) in MeOH (1.5 ml) for 5 minutes. The resulting mixture was placed in a sealed tube and stirred at room temperature for 2 days. The reaction was then concentrated in vacuo, and the residue obtained was dried under vacuum to give titled product (0.72 g, 80%) as a solid.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:14][C:13](B(O)O)=[CH:12][C:11]=3[CH:18]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=1.C(N(CC)CC)C>C(O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:14][C:13]([C:20]4[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=4)=[CH:12][C:11]=3[CH:18]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1ccc(Br)cc1
Reactant: OB(O)c1cc2cc(N3CCCCC3)ccc2o1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=Cc1ccc(-c2cc3cc(N4CCCCC4)ccc3o2)cc1
Yield: 30.8 %

Procedure:
A mixture of 5-(piperidin-1-yl)benzofuran-2-ylboronic acid (90 mg, 0.367 mmol), 4-bromobenzaldehyde (62 mg, 0.330 mmol), triethylamine (1.0 mL, 7.3 mmol) and bis(triphenylphosphine)palladium(II)chloride (12.8 mg, 0.02 mmol) in ethanol (9 mL) was irradiated in a microwave instrument at 100° C. for 20 min. The reaction mixture was cooled, and the solvent was removed. The residue was purification by silica gel chromatography on ISCO system yielding the title compound (31 mg, 28% yield). ESI-MS: 306.4 (M+H)+, 1H NMR (400 MHz, CDCl3) δ 10.02 (s, 1H), 7.95 (dd, 4H), 7.42 (d, 1H), 7.11 (m, 2H), 7.07 (dd, 1H), 3.13 (t, 4H), 1.78-1.74 (m, 4H), 1.62-1.56 (m, 2H).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].C(=O)([O-])[O-].[Na+].[Na+].[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1>O>[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17]([NH:3][CH2:2][CH2:1][NH:4][S:17]([C:14]2[CH:15]=[CH:16][C:11]([CH3:21])=[CH:12][CH:13]=2)(=[O:19])=[O:18])(=[O:19])=[O:18])=[CH:13][CH:12]=1
Reactant: NCCN
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(S(=O)(=O)NCCNS(=O)(=O)c2ccc(C)cc2)cc1
Reaction time: 15 h
Yield: 96.7 %

Procedure:
A mixture of ethylenediamine (18.0 g, 0.30 mol) and sodium carbonate (64.0 g, 0.60 mol) in 750 mL of deionized water was heated to 75 C. To the mixture was added p-toluenesulfonyl chloride (125.0 g, 0.66 mol) in 5 g portions over 45 minutes. Then the reaction was stirred at 75 C. for 15 hours. After the mixture was cooled to 25 C., the white precipitate was filtered, washed with water and dried in a vacuum desiccator at 1 mm to yield 1,4-bis(p-toluenesulfonyl)-1,4-diazabutane (100.1 g, 0.29 mol, 98%).