Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.S(OC)(O[CH2:19][C:20]1([CH2:24][O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:23][O:22][CH2:21]1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH2:26]([O:25][CH2:24][C:20]1([CH2:19][N:12]2[CH:13]=[C:9]([B:4]3[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]3)[CH:10]=[N:11]2)[CH2:23][O:22][CH2:21]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COS(=O)(=O)OCC1(COCc2ccccc2)COC1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(C)OB(c2cnn(CC3(COCc4ccccc4)COC3)c2)OC1(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.9 %

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (0.825 g, 4.25 mmol) and {3-[(benzyloxy)methyl]oxetan-3-yl}methyl methyl sulfate (Compound 44D, 1.35 g, 4.46 mmol) in DMF (3.90 mL) was charged with potassium carbonate (588 mg, 4.25 mmol) and allowed to stir at rt for 16 hrs. The reaction mixture was diluted with EtOAc and washed with brine (2×), dried over sodium sulfate, filtered and concentrated in vacuo and purified using a Teledyne ISCO Combiflash® Rf system [0→40% Acetone/Heptanes] to afford 1.37 g of the title compound (84%). 1H NMR (400 MHz, CD3OD) δ 7.76 (s, 1H), 7.66 (s, 1H), 7.25-7.37 (m, 5H), 4.67 (d, J=6.6 Hz, 2H), 4.48-4.52 (m, 4H), 4.42 (d, J=6.6 Hz, 2H), 3.45 (s, 2H), 1.20 (s, 12H). MS (ESI): m/z=385.20 [M+H]+. HPLC: tR=1.08 min (UPLC-TOF: polar—2 min).
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].[CH2:6]([NH:10][C:11](=[O:22])[CH2:12][CH2:13][C:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:7][CH2:8][CH3:9].Cl.O>CO>[CH2:6]([NH:10][C:11](=[O:22])[CH2:12][CH2:13][C:14](=[N:1][NH:2][C:3]([NH2:5])=[S:4])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH2:7][CH2:8][CH3:9]
Reactant: CCCCNC(=O)CCC(=O)c1ccccc1
Reactant: NNC(N)=S
Agent: Cl
Solvent: O
Solvent: CO
Product: CCCCNC(=O)CCC(=NNC(N)=S)c1ccccc1
Yield: 68.5 %

Procedure:
Thiosemicarbazide (1.95 g, 21.4 mmol) was added to a solution of N-butyl-4-oxo-4-phenyl-butyramide (5.0 g, 21.4 mmol), prepared in the previous step, in 75 ml of methanol plus 5.8 ml of 1 N HCl plus 5.8 ml of water and the reaction stirred at room temperature for 22 hours. The reaction was concentrated under reduced pressure at which time a solid formed. The solid was collected by filtration and dried to give 4.49 g of an off-white solid. Recrystallization of the solid from isopropyl alcohol gave 3.16 g (48%) of the title compound as a white solid, mp 64-68° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17](I)[CH:16]=1.B(O)(O)[C:24]1[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.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:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[CH:16]=[C:17]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)[CH:18]=[CH:19][CH:20]=1)=[O:22]
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(I)c1
Reactant: Cc1ccc(B(O)O)cc1
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: O
Solvent: COCCOC
Product: Cc1ccc(-c2cccc(C(=O)NCCc3c[nH]c4ccc(Cl)cc34)c2)cc1
Yield: 81.8 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-methylbiphenyl-3-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-iodobenzamide (0.075 g; 0.176 mmol), p-tolylboronic acid (0.025 g; 0.176 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 2 to 10% ethyl acetate in dichloromethane) furnished 0.056 g (82%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-methylbiphenyl-3-carboxamide as a white solid.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([O:15]CC3C=CC=CC=3)=[O:14])=[CH:10][CH:11]=2)[CH:6]=[CH:5]1)(=[O:3])[CH3:2].[H][H]>C(O)C.[Pd]>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([OH:15])=[O:14])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)n1ccc2cc(C(=O)OCc3ccccc3)ccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(=O)N1CCc2cc(C(=O)O)ccc21
Yield: 46.8 %

Procedure:
The benzyl 1-acetyl-1H-indole-5-carboxylate (550 mg) obtained above was suspended in ethanol (9 ml). 10% Palladium on carbon was added thereto, and the mixture was stirred for 16 hours at room temperature in a hydrogen atmosphere. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. Precipitated crystals were collected by filtration, washed with ether and dried under reduced pressure to give the title compound (180 mg, Y.:48%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([CH:12]([O:15][CH3:16])[O:13][CH3:14])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:17](=[O:19])=[O:18].Cl>C1COCC1>[C:1]([C:5]1[CH:10]=[C:9]([F:11])[C:8]([C:17]([OH:19])=[O:18])=[C:7]([CH:12]([O:13][CH3:14])[O:15][CH3:16])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(OC)c1cc(F)cc(C(C)(C)C)c1
Reactant: O=C=O
Agent: Cl
Solvent: C1CCOC1
Product: COC(OC)c1cc(C(C)(C)C)cc(F)c1C(=O)O
Temperature: -70 °C
Reaction time: 1 h

Procedure:
1-tert-Butyl-3-dimethoxymethyl-5-fluoro-benzene (333 g, 1.47 moles) was dissolved in THF (10 vol, 3.3 L) and cooled to −70° C. secBuLi (1.4M in cyclohexanes, 1.0 eq, 1000 mL) was added drop-wise over 1.5 hours. The solution was stirred at −70° C. for one hour and then CO2 gas was added to the reaction via a sintered glass gas dispersion tube, while maintaining vigorous stirring. The reaction was allowed to warm with vigorous stirring with adequate venting for release of excess CO2 from the solution. Once the internal temperature had reached +10° C. the reaction was quenched with water (3 L) followed by conc. HCl (1.15 eq, 140 mL). The aqueous fraction was extracted to ethyl acetate (1 L) and the combined organic fractions were combined and washed with water (2×1 L), and then concentrated with solvent replacement with heptanes. The resulting fine crystals were filtered, washed with heptanes and then dried at room temperature under vacuum with N2 sweep to provide 220.3 g (55.3%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:40])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([NH:15][C@@H:16]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]([F:39])([F:38])[F:37])[CH2:17][N:18]2C(=O)C3C(=CC=CC=3)C2=O)=[O:14])[O:10][C:11]=1[CH3:12].NN>O1CCCC1.CO>[NH2:18][CH2:17][C@@H:16]([NH:15][C:13]([C:9]1[O:10][C:11]([CH3:12])=[C:7]([C:6]2[N:5]([CH3:40])[N:4]=[CH:3][C:2]=2[Cl:1])[CH:8]=1)=[O:14])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:36]([F:39])([F:38])[F:37]
Reactant: Cc1oc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)cc1-c1c(Cl)cnn1C
Agent: NN
Solvent: CO
Solvent: C1CCOC1
Product: Cc1oc(C(=O)N[C@H](CN)Cc2ccccc2C(F)(F)F)cc1-c1c(Cl)cnn1C
Yield: 55.8 %

Procedure:
To a solution of 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-2-furancarboxamide (246 mg, 0.43 mmol) in tetrahydrofuran (2.1 ml) and methanol (2.1 ml) at 25° C. was added hydrazine (135 μl, 4.31 mmol) dropwise. After 12 h the solution was concentrated, dry loaded onto silica and purified by column chromatography (5% MeOH in DCM (1% NH4OH)). The free base was converted to the HCl salt by addition of excess 4M HCl in dioxane (1 ml) to the residue in MeOH (2 ml) affording the HCl salt of N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxamide (125 mg, 0.24 mmol, 56% yield) as a yellow solid: LCMS (ES) m/z=441, 443 (M, M+2)+, 1H NMR (400 MHz, DMSO-d6) δ ppm 8.63 (d, J=9.09 Hz, 1H) 8.04 (br. s., 3H) 7.65-7.72 (m, 2H) 7.59 (d, J=7.33 Hz, 1H) 7.57 (br. s., 1H) 7.39-7.47 (m, 1H) 7.29-7.37 (m, 1H) 4.54 (br. s., 1H) 3.73 (s, 3H) 2.98-3.09 (m, 4H) 2.33 (s, 3H).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([N:17]2[C:25]3[C:20](=[C:21]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18]2)([C:15]#[N:16])[CH2:13][CH3:14])=[CH:8][CH:7]=1.[Cl-].[NH4+]>CN(C=O)C>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([N:17]2[C:25]3[C:20](=[C:21]([NH:26][S:27]([CH3:30])(=[O:28])=[O:29])[CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18]2)([C:15]2[N:1]=[N:2][NH:3][N:16]=2)[CH2:13][CH3:14])=[CH:8][CH:7]=1
Reactant: CCC(C#N)(c1ccc(Cl)cc1)n1ccc2c(NS(C)(=O)=O)cccc21
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(c1ccc(Cl)cc1)(c1nn[nH]n1)n1ccc2c(NS(C)(=O)=O)cccc21
Temperature: 130 °C

Procedure:
Sodium azide (117.6m g, 1.809 mmol) was added to a stirred solution of N-(1-(1-(4-chlorophenyl)-1-cyanopropyl)-1H-indol-4-yl)methanesulfonamide (100 mg, 0.258 mmol) and ammonium chloride (110.6 g, 2.067 mmol) in DMF (2 mL) was heated at 130° C. for 3 h in microwave reactor. The reaction was quenched with water, and extracted with ethyl acetate (100 mL). The organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography eluting with PE/EA (5/1 to 1/1, v/v) to afford the title compound as a yellow solid. LC/MS m/z=431.0 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=1[F:23].C(O)C.[CH3:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([N:36]=[C:37]=[S:38])=[O:35])=[CH:30][CH:29]=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:37]([NH:36][C:34](=[O:35])[C:31]2[CH:32]=[CH:33][C:28]([CH3:27])=[CH:29][CH:30]=2)=[S:38])=[CH:18][C:17]=1[F:23]
Reactant: Cc1ccc(C(=O)N=C=S)cc1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc(C)cc4)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. Commercially available 4-methyl-1-benzenecarbonyl isothiocyanate (50 μl) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (77 mg, yield 98%).
Reaction SMILES: [S:1]([NH2:5])([NH2:4])(=[O:3])=[O:2].[Na].[C:7]1([C:13](=O)[C:14](OCC)=[O:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(O)C>[OH:15][C:14]1[C:13]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:5][S:1](=[O:3])(=[O:2])[N:4]=1
Reactant: NS(N)(=O)=O
Reactant: CCOC(=O)C(=O)c1ccccc1
Agent: [Na]
Solvent: CCO
Product: O=S1(=O)N=C(O)C(c2ccccc2)=N1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 40 %

Procedure:
Sulfamide (4.8 g, 50 mmoles) in ethanol (90 ml) was added slowly with stirring under nitrogen to a solution of sodium (1.15 g, 50 mmoles) dissolved in ethanol (35 ml). The suspension was stirred for 15 minutes at room temperature and then ethyl phenylglyoxylate (8.9 g, 50 mmoles) in ethanol (15 ml) was added. After stirring 15 minutes, the mixture was refluxed overnight and concentrated under vacuum. The residue was suspended in diethyl ether, filtered and the collected solid dissolved in water (25 ml). Acidification with hydrochloric acid precipitated the product which was collected by filtration, washed with water and recrystallized from a mixture of acetonitrile (12 ml) and toluene (8 ml) to obtain 4.2 g (40%) of the title compound, mp 202°-4°. Nmr (DMSO-d6): δ 7.29-7.89 (m, 3H), 8.19-8.49 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[N:3]=1.[CH2:18]([CH2:20][NH2:21])[OH:19]>O>[N:13]1([C:4]2[N:3]=[C:2]([NH:21][CH2:20][CH2:18][OH:19])[CH:7]=[C:6]([N:8]3[CH2:12][CH2:11][CH2:10][CH2:9]3)[N:5]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: NCCO
Reactant: Clc1cc(N2CCCC2)nc(N2CCCC2)n1
Solvent: O
Product: OCCNc1cc(N2CCCC2)nc(N2CCCC2)n1

Procedure:
A mixture of 4-chloro-2,6-di-1-pyrrolidinyl-pyrimidine (II, J. Med. Chem., 33, 1145 (1990), 300 g) in ethanolamine (1000 mL) is heated at 140° for 66 hr. The reaction mixture is cooled, diluted with water (1700 mL) and the product is isolated by filtration, to give the title compound, mp=150.5-151.50°; NMR (CDCl3) 6.55, 4.83, 4.75, 3.75-3.72, 3.54-3.38 and 1.93-1.85 δ.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:9]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:10]=2[C:11]([NH2:20])=[N:12][C:13]([NH2:19])=[N:14]3)[CH2:3][CH2:2]1.[C:21]1([CH3:30])[CH:26]=[CH:25][C:24]([C:27](Cl)=[O:28])=[CH:23][CH:22]=1>>[NH2:19][C:13]1[N:12]=[C:11]([NH2:20])[C:10]2[C:15](=[CH:16][CH:17]=[CH:18][C:9]=2[O:8][CH2:7][CH:4]2[CH2:5][CH2:6][N:1]([C:27]([C:24]3[CH:25]=[CH:26][C:21]([CH3:30])=[CH:22][CH:23]=3)=[O:28])[CH2:2][CH2:3]2)[N:14]=1
Reactant: Nc1nc(N)c2c(OCC3CCNCC3)cccc2n1
Reactant: Cc1ccc(C(=O)Cl)cc1
Product: Cc1ccc(C(=O)N2CCC(COc3cccc4nc(N)nc(N)c34)CC2)cc1
Yield: 64 %

Procedure:
The amidation of 5-(piperidin-4-ylmethoxy)quinazoline-2,4-diamine (50 mg; 0.18 mmol) was carried out using p-toluoyl chloride (57 mg; 0.37 mmol) via Method AA to yield 93 mg. (64% yield). 1HNMR (400 MHz, DMSO-d6) δ 7.35 (t, J=8.0 Hz, 1H), 7.25 (m, 4H), 7.2 (br s, 2H), 6.77 (d, J=8.0 Hz, 1H), 6.54 (d, J=8.0 Hz, 1H), 5.94 (br s, 2H), 4.53 (br s, 1H), 4.03 (d, J=6.0 Hz, 2H), 3.67 (br s, 1H), 3.07 (br s, 1H), 2.844 (br s, 1H), 2.34 (s, 3H), 2.18 (m, 1H), 1.82 (m, 2H), 1.29 (m, 2H). MS m/z (ESI) 392 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:35])[C@@H:10]([NH:25][C@H:26]([C:28]([O:30]C(C)(C)C)=[O:29])[CH3:27])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=2)=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:35])[C@@H:10]([NH:25][C@H:26]([C:28]([OH:30])=[O:29])[CH3:27])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=2)=[CH:14][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](N[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)C(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](N[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)C(=O)OCc1ccccc1)C(=O)O
Reaction time: 3 h

Procedure:
To a solution of (S)-2-((S)-1-tert-butoxycarbonyl-ethylamino)-3-(3′-chloro-biphenyl-4-yl)-propionic acid benzyl ester (1.12 g, 2.27 mmol) in DCM (5 mL) was added TFA (5 mL). After being stirred for 3 hours, the reaction mixture was concentrated and purified by silica gel column chromatography (eluent: 10% MeOH in DCM) to give (S)-2-((S)-1-carboxy-ethylamino)-3-(3′-chloro-biphenyl-4-yl)-propionic acid benzyl ester. MS: m/z (MH+) 438; HPLC retention time 0.73 min (HPLC condition C).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.[NH2:18][C:19]1[CH:20]=[N:21][C:22]([N:25]2[CH2:30][CH2:29][CH2:28][CH:27]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:26]2)=[N:23][CH:24]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:18][C:19]1[CH:24]=[N:23][C:22]([N:25]2[CH2:30][CH2:29][CH2:28][CH:27]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:36])([CH3:35])[CH3:37])[CH2:26]2)=[N:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)NC1CCCN(c2ncc(N)cn2)C1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Product: CC(C)(C)OC(=O)NC1CCCN(c2ncc(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)cn2)C1
Yield: 81.4 %

Procedure:
Following General procedure C, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (311 mg, 1 mmol) was reacted with tert-butyl 1-(5-aminopyrimidin-2-yl)piperidin-3-ylcarbamate (440 mg, 1.5 mmol) to afford the desired product (462 mg, 80%) as a yellow solid: ESI MS m/z 567 [C27H31BrN6O3+H]+.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:11]([OH:13])=O)=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1.S(Cl)([Cl:16])=O>>[CH3:1][C:2]1[S:3][C:4]([C:11]([Cl:16])=[O:13])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1nc(C(F)(F)F)c(C(=O)O)s1
Product: Cc1nc(C(F)(F)F)c(C(=O)Cl)s1
Reaction time: 2 h

Procedure:
0.50 g of 2-methyl-4-trifluoromethylthiazole-5-carboxylic acid was added to 5 ml of thionyl chloride and reaction was carried out for 2 hours under reflux. After the reaction, the reaction mixture was concentrated to obtain 0.54 g of 2-methyl-4-trifluoromethylthiazole-5-carbonyl chloride.
Reaction SMILES: [C:1]([CH2:5][CH2:6][CH2:7]/[CH:8]=[C:9]1\[CH2:10][C@@H:11]2[C@H:15]([CH2:16]\1)[C@@H:14]([CH2:17][CH2:18][CH:19]([OH:26])[CH:20]([F:25])[CH2:21][CH2:22][CH2:23][CH3:24])[C@H:13]([O:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][O:29]1)[CH2:12]2)([O:3]C)=[O:2]>CO.[OH-].[Na+]>[C:1]([CH2:5][CH2:6][CH2:7]/[CH:8]=[C:9]1\[CH2:10][C@@H:11]2[C@H:15]([CH2:16]\1)[C@@H:14]([CH2:17][CH2:18][CH:19]([OH:26])[CH:20]([F:25])[CH2:21][CH2:22][CH2:23][CH3:24])[C@H:13]([O:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][O:29]1)[CH2:12]2)([OH:3])=[O:2]
Reactant: CCCCC(F)C(O)CC[C@@H]1[C@H]2C/C(=C/CCCC(=O)OC)C[C@H]2C[C@H]1OC1CCCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCC(F)C(O)CC[C@@H]1[C@H]2C/C(=C/CCCC(=O)O)C[C@H]2C[C@H]1OC1CCCCO1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(1S,2R,3R,5S)-7(E)-(4-Carbomethoxybutylidene)-2-[4(RS)-fluoro-3(RS)-hydroxy-octyl]-3-tetrahydropyranyloxybicyclo[3.3.0]octane (12) (0.185 g) was dissolved in methanol, to which an aqueous solution of 1N sodium hydroxide (6.5 ml) was added. The mixture was stirred at room temperature for 4 hours. After a usual work-up a crude product (1S,2R,3R,5S)-7(E)-(4-carboxybutylidene)-2-[4(RS)-fluoro-3(RS)-hydroxyoctyl]-3-tetrahydropyranyloxybicyclo[3.3.0]octane (13) was obtained. Yield: 0.184 g
Reaction SMILES: [CH3:1][CH:2]([CH3:7])[CH2:3][C:4](Cl)=[O:5].[CH3:8][C:9]1([CH3:17])[O:16][C:14](=[O:15])[CH2:13][C:11](=[O:12])[O:10]1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:8][C:9]1([CH3:17])[O:16][C:14](=[O:15])[CH:13]([C:4](=[O:5])[CH2:3][CH:2]([CH3:7])[CH3:1])[C:11](=[O:12])[O:10]1
Reactant: CC(C)CC(=O)Cl
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)CC(=O)C1C(=O)OC(C)(C)OC1=O
Reaction time: 1.75 h

Procedure:
3-Methyl-butyryl chloride (7.40 mL, 60 mmol) was mixed at 0° C. with Meldrum's acid (2,2-dimethyl-1,3-dioxane-4,6-dione; 8.7 g, 60 mmol), and 4-dimethylaminopyridine (DMAP, 15.1 g, 124 mmol) in DCM. The reaction mixture was allowed to reach r.t. over 1.75 hr. and completion of the reaction was verified by TLC. The reaction mixture was diluted with DCM, was washed 3× with 5% aq. solution of potassium bisulfate and brine. The organic phase was than dried with MgSO4. Crude product 9, 13.36 g) obtained after evaporation was used for next reaction without purification. 1H NMR (500 MHz, CDCl3): δ 1.02 (d, 6H), 1.74 (s, 6H), 2.21 (hp, 1H), 2.99 (d, 2H).
Reaction SMILES: [CH3:1][C:2]([OH:6])([C:4]#[CH:5])[CH3:3].[Si:7](OS(C(F)(F)F)(=O)=O)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]>C(Cl)Cl>[C:10]([Si:7]([O:6][C:2]([CH3:3])([CH3:1])[C:4]#[CH:5])([CH3:9])[CH3:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: C#CC(C)(C)O
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: C#CC(C)(C)O[Si](C)(C)C(C)(C)C
Reaction time: 2 h
Yield: 79.3 %

Procedure:
2-Methyl-but-3-yn-2-ol (2.20 g, 26.2 mmol) in DCM (50 mL) was mixed with 2,6-lutadine (9.1 mL, 78.6 mmol). TBSOTf (6.6 mL, 28.8 mmol) was added to the reaction mixture slowly. After 2 hours at room temperature, an extra amount of TBSOTf (1.5 mL) was added. After 16 hours at room temperature, the reaction was quenched with 10% HOAc aqueous solution (400 mL). The product was extracted with DCM (2×200 mL). The combined organic layers were washed with brine, dried and concentrated. Purification of the crude on silica gel column (Foxy, 3:7 EtOAc/Hexane) provided desired product as colorless liquid (4.12 g, 80%). 1H NMR (CDCl3) δ 2.58 (s, 1H), 0.82 (s, 6H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7](O)[CH3:8])=[CH:3][CH:2]=1.[C:10]1(=[O:20])[NH:14][C:13](=[O:15])[C:12]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:11]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(OCC)(=O)C.O1CCCC1>[N:1]1[CH:6]=[CH:5][C:4]([CH:7]([N:14]2[C:10](=[O:20])[C:11]3[C:12](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:13]2=[O:15])[CH3:8])=[CH:3][CH:2]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(O)c1ccncc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(c1ccncc1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 29 h
Yield: 48.4 %

Procedure:
A tetrahydrofuran solution (10 mL) of 1-(pyridin-4-yl)ethanol (283 mg, 2.32 mmol), phthalimide (375 mg, 2.55 mmol) and triphenylphosphine (686 mg, 2.55 mmol) was mixed with diisopropyl azodicarboxylate (40% in toluene, 1.34 mL, 2.55 mmol) and stirred at room temperature for 29 hours. After completion of the reaction, the reaction solution was mixed with ethyl acetate, and the organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform/ethyl acetate=10/1) to give the desired product (283 mg, 48% yield).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][CH:6]=1.[C:7]([C:10]1[O:11][CH:12]=[CH:13][CH:14]=1)(=[O:9])[CH3:8]>>[O:11]1[CH:12]=[CH:13][CH:14]=[C:10]1[C:7]([C:6]1[S:5][CH:4]=[N:3][C:2]=1[CH3:1])([OH:9])[CH3:8]
Reactant: Cc1cscn1
Reactant: CC(=O)c1ccco1
Product: Cc1ncsc1C(C)(O)c1ccco1

Procedure:
Starting with 4-methylthiazole and 2-acetylfuran and following the general method of Example 15 the title compound was prepared. M.p. 127°-128° C.
Reaction SMILES: C(O)(=O)/C=C/C(O)=O.[Cl:9][C:10]1[N:15]=[N:14][C:13]([O:16]C(O)C)=[C:12]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:11]=1>Br>[Cl:9][C:10]1[N:15]=[N:14][C:13]([OH:16])=[C:12]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:11]=1
Reactant: CC(O)Oc1nnc(Cl)cc1N1CCNCC1
Agent: Br
Agent: O=C(O)/C=C/C(=O)O
Product: Oc1nnc(Cl)cc1N1CCNCC1
Reaction time: 1 h
Yield: 221.2 %

Procedure:
15 g (6-chloro-4-piperazin-1-yl-pyridazin-3-yloxy)-ethanol fumarate are suspended in 90 ml hydrobromic acid (48%). The reaction mixture is stirred for 1 hour at reflux temperature and evaporated to dryness. 19 g product are obtained as the hydrobromide. M.p=35° C.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:10]1([CH3:19])[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C(C)=CC=CC=1>O>[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[C:13]1[CH:14]=[CH:15][C:10]([CH3:19])=[CH:11][CH:12]=1)#[N:5]
Reactant: N#Cc1ccccc1Cl
Reactant: Cc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: O
Product: Cc1ccc(-c2ccccc2C#N)cc1
Yield: 90.3 %

Procedure:
15 g of 2-chlorobenzonitrile, 14.8 g of p-tolueneboronic acid and 28.9 g of sodium carbonate were heated to 120° C. in 40 ml of glycol and 10 ml of water. At 80° C., 0.1 mol % of a catalyst solution prepared as described in C.3.1 was added. After the reaction was complete, 50 ml of xylene were added and the organic phase was separated off. Distillation gave 19 g of 2-cyano-4'-methylbiphenyl (mp. 140° C./mbar).