Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][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][CH2:13][N:14]1[CH2:19][CH2:18][N:17]([C:20]2[C:25]([O:26][CH3:27])=[CH:24][N:23]=[CH:22][N:21]=2)[CH2:16][CH2:15]1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:34][CH2:35][CH2:36][CH2:37][C:38](Cl)=[O:39]>CC(C)=O>[Cl:34][CH2:35][CH2:36][CH2:37][C:38]([NH: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][CH2:13][N:14]1[CH2:19][CH2:18][N:17]([C:20]2[C:25]([O:26][CH3:27])=[CH:24][N:23]=[CH:22][N:21]=2)[CH2:16][CH2:15]1)=[O:39]
Reactant: COc1cncnc1N1CCN(CCCc2c[nH]c3ccc(N)cc23)CC1
Reactant: O=C(Cl)CCCCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1cncnc1N1CCN(CCCc2c[nH]c3ccc(NC(=O)CCCCl)cc23)CC1
Temperature: 0 °C
Reaction time: 19 h
Yield: 66.7 %

Procedure:
To a mixture of 1-[3-[5-amino-1-H-indol-3-yl]propyl]-4-(5-methoxy-4-pyrimidinyl)piperazine (2.3g, 6.3 mmol), and sodium carbonate (0.67 g, 6.3 mmol) in 25 mL of acetone, cooled to 0° C., was added dropwise 4-chlorobutyryl chloride (0.89 g, 6.3 mmol). Additional acetone (10 mL) was added and the suspension was stirred for 19 h at 23° C. The insoluble material was separated by filtration and the acetone was removed in vacuo. The crude material was dissolved in EtOAc, and the solution was washed with water, dried (brine, MgSO4), filtered, and concentrated in vacuo to give crude 1-[3-[5-[4-chlorobutyrylamino]-1-H-indol-3-yl]propyl]-4-(5-methoxy-4-pyrimidinyl)piperazine (1.98 g, 4.2 mmol, 67%) as a gum. Sodium ethoxide (0.67 mL, 2.1 mmol, 21% in ethanol) was added dropwise to a solution of crude 1-[3-[5-[4-chlorobutyrylamino]-1-H-indol-3-yl]propyl]-4-(5-methoxy-4-pyrimidinyl)piperazine (1.0 g, 2.1 mmol) in ethanol (5 mL). After the addition, the reaction mixture was heated at 78° C. for 90 min and then cooled to room temperature. The insoluble solid was separated and the filtrate was concentrated in vacuo. Silica gel column chromatography (95:5:0.5 CH2Cl2 -MeOH-30% NH4OH) afforded 1-[3-[5-[2-pyrrolidinone-1-yl]-1-H-indol-3-yl]propyl]-4-(5-methoxy-4-pyrimidinyl)piperazine (0.33 g, 0.76 mmol, 36%). The free base (0.25 g, 0.58 mmol) was dissolved in a minimum volume of acetonitrile. A concentrated solution of oxalic acid (0.052 g, 0.58 mmol) in CH3CN was added with stirring. The precipitate was separated by filtration, washed sparingly with CH3CN, and dried at 70° C. in vacuo overnight to give the title compound (0.17 g, 56%): mp 100°-101° C. Anal. Calcd for C24H30N6O2.1.0 C2H2O4.1.15 H2O: C, 57.26; H, 6.34; N, 15.41. Found: C, 56.90; H, 5.96; N, 15.51.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[NH:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[C:5]([O:7][CH3:8])=[O:6].[C:22](OCC)(=[O:28])[C:23](OCC)=[O:24]>CCOCC>[CH3:21][O:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][N:12]2[C:11]3[C:2](=[CH:3][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:9][CH:10]=3)[NH:1][C:23](=[O:24])[C:22]2=[O:28])=[CH:19][CH:18]=1
Reactant: COC(=O)c1ccc(NCc2ccc(OC)cc2)c(N)c1
Reactant: CCOC(=O)C(=O)OCC
Solvent: CCOCC
Product: COC(=O)c1ccc2c(c1)[nH]c(=O)c(=O)n2Cc1ccc(OC)cc1
Reaction time: 3 h
Yield: 74 %

Procedure:
A mixture of methyl 3-amino-4-(4-methoxybenzylamino)benzoate (3 g, 10.48 mmol) and diethyl oxalate (100 ml) was stirred for 3 h at reflux and then cooled with a water/ice bath, and diluted with ether (500 ml). Tthe product was collected by filtration to afford methyl 1-(4-methoxybenzyl)-2,3-dioxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate as a green solid (2.64 g, 74%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])[NH:10][N:9]=1.[CH2:23](Br)[CH3:24]>>[CH2:23]([N:10]1[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:20])[F:21])=[N:12][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])=[N:9]1)[CH3:24]
Reactant: Fc1ccccc1-c1n[nH]c(-c2ccccc2C(F)(F)F)n1
Reactant: CCBr
Product: CCn1nc(-c2ccccc2F)nc1-c1ccccc1C(F)(F)F

Procedure:
starting from 3-(o-fluorophenyl)-5-(o-trifluoromethyl-phenyl)-1H-1,2,4-triazole and ethyl bromide there is obtained a mixture of isomeric N-ethyltriazoles and therefrom there are obtained pure 1-ethyl-3-(o-fluorophenyl)-5-(o-trifluoromethyl-phenyl)-1H-1,2,4-triazole, m.p. 72°-74° C.; and pure 1-ethyl-5-(o-fluorophenyl)-3-(o-trifluoromethyl-phenyl)-1H-1,2,4-triazole, 1H-NMR(CDCl3): 1.51 (t, CH3), 4.23 (q, CH2), 7.05-8.1 (8 aromatic H);
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH2:10][CH2:9][CH2:8][C:7]=1[NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)=[O:5])[CH3:2].B.N1C=CC=CC=1>C(O)(=O)C>[CH2:1]([O:3][C:4]([CH:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(NCc2ccccn2)CCC1
Agent: B
Solvent: c1ccncc1
Solvent: CC(=O)O
Product: CCOC(=O)C1CCCC1NCc1ccccn1
Reaction time: 0.5 h
Yield: 68.6 %

Procedure:
A solution of 2-[(pyridin-2-ylmethyl)-amino]-cyclopent-1-enecarboxylic acid ethyl ester (4.78 g, 19.4 mmol) in acetic acid (70 mL) was treated with a 8.0 M solution of borane in pyridine (2.67 mL, 21.4 mmol) and stirred under a nitrogen atmosphere for 30 min. The reaction was quenched with 1.0 M aqueous hydrochloric acid solution (40 mL) for 16 h. The reaction was then poured into a mixture of saturated aqueous sodium bicarbonate solution (200 mL) and ethyl acetate (200 mL) and extracted. The organic layer was dried over sodium sulfate, filtered, concentrated in vacuo, and purified by flash column chromatography (Teledyne Isco RediSep Flash Column 40 g; 0-10% methanol in dichloromethane) to afford the desired product, 2-[(pyridin-2-ylmethyl)-amino]-cyclopentanecarboxylic acid ethyl ester (3.30 g, 13.3 mmol, 68.6%), as a light yellow oil. 1H NMR (400 MHz, DMSO-d6) δ: 1.16 (3H, t, J=7.4 Hz), 1.38-1.79 (4H, m), 1.82-1.96 (2H, m), 2.56 (1H, dd, J1=15.5 Hz, J2=7.0 Hz), 2.88 (1H, dd, J1=14.9 Hz, J2=7.1 Hz), 3.21 (1H, dd, J1=13.7 Hz, J2=6.7 Hz), 4.04 (2H, q, J=7.0 Hz), 3.78 (2H, s), 7.19-7.22 (2H, m), 7.38 (1H, d, J=7.6 Hz), 7.68-7.73 (1H, m), 8.45 (1H, d, J=4.7 Hz). LC-MS (ESI) calcd for C14H20N2O2 248.15, found 249.2 [M+H+].
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:16]=[C:17]([O:21][CH3:22])[C:18]=1[O:19][CH3:20])[C:13](Cl)=[O:14].[CH3:23][O:24][C:25]1[CH:26]=[C:27]([NH2:37])[C:28](=[CH:33][C:34]=1[O:35][CH3:36])[C:29]([O:31][CH3:32])=[O:30]>C(Cl)(Cl)Cl>[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:16]=[C:17]([O:21][CH3:22])[C:18]=1[O:19][CH3:20])[C:13]([NH:37][C:27]1[C:28](=[CH:33][C:34]([O:35][CH3:36])=[C:25]([O:24][CH3:23])[CH:26]=1)[C:29]([O:31][CH3:32])=[O:30])=[O:14]
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: COC(=O)c1cc(OC)c(OC)cc1N
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(OC)c(OC)cc1NC(=O)c1cc(OC)c(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 79.2 %

Procedure:
In a mixture of 3.2 g of methyl 4,5-dimethoxyanthranilate in 30 ml of chloroform is dissolved 3 ml of triethylamine, and to this solution is added a solution of 3.45 g of 3,4,5-trimethoxybenzoylchloride in chloroform under cooling. The mixture is stirred at room temperature for 4 hours. The reaction mixture is concentrated under a reduced pressure and to the residue is added water. The precipitated crystals are recrystallized from a mixture of dimethylformamide and ethanol to obtain 4.8 g of methyl N-(3,4,5-trimethoxybenzoyl)-4,5-dimethoxyanthranilate as pale yellow prisms.
Reaction SMILES: [CH2:1]([NH:4][CH:5]([CH3:10])[C:6]([O:8]C)=O)[C:2]#[CH:3].[Cl:11][C:12]1[CH:13]=[C:14]([N:19]=[C:20]=[O:21])[CH:15]=[C:16]([Cl:18])[CH:17]=1>C1(C)C=CC=CC=1.CCCCC(C([O-])=O)CC.CCCCC(C([O-])=O)CC.[Sn+2]>[Cl:11][C:12]1[CH:13]=[C:14]([N:19]2[C:6](=[O:8])[CH:5]([CH3:10])[N:4]([CH2:1][C:2]#[CH:3])[C:20]2=[O:21])[CH:15]=[C:16]([Cl:18])[CH:17]=1
Reactant: C#CCNC(C)C(=O)OC
Reactant: O=C=Nc1cc(Cl)cc(Cl)c1
Agent: CCCCC(CC)C(=O)[O-]
Agent: [Sn+2]
Solvent: Cc1ccccc1
Product: C#CCN1C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)C1C
Yield: 86.5 %

Procedure:
To a solution of 10 g (0.07 mole) of methyl 2-propargylaminopropionate in 100 ml of toluene with 2 drops of stannous octoate is added 14.5 g (0.077 mole) of 3,5-dichlorophenylisocyanate in small portions. The resulting mixture is heated at 100° for 3 hours. It is then washed with water twice and dried over sodium sulfate. Solvent is evaporated to give a thick yellow oil. Material is further purified by passing it through a silica gel column using 30/70 ethyl acetate/hexane as solvent to give 18 g of a light yellow oil which solidifies on standing. The solids are triturated in boiling hexane and collected by filtration, mp 105°-6°. NMR and elemental analysis confirm the desired structure.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[Cl:22])[C:9](=[O:23])[N:8]([CH2:24][C:25]([OH:27])=[O:26])[C:7]2=[O:28].[CH2:29](Br)[CH2:30][OH:31].Cl>O.CN(C)C=O>[Cl:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[Cl:22])[C:9](=[O:23])[N:8]([CH2:24][C:25]([O:27][CH2:29][CH2:30][OH:31])=[O:26])[C:7]2=[O:28]
Reactant: OCCBr
Reactant: O=C(O)Cn1c(=O)c2cc(Cl)ccc2n(Cc2ccc(Cl)cc2Cl)c1=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Cn1c(=O)c2cc(Cl)ccc2n(Cc2ccc(Cl)cc2Cl)c1=O)OCCO
Yield: 54.2 %

Procedure:
Into 10 ml of dried dimethylformamide were suspended 60 mg of sodium hydride (60%), and, to this was added dropwise a solution dissolved 500 mg of 6-chloro-1-(2,4-dichlorophenyl)methyl-1,4-dihydro-2,4-dioxo-3-(2H)-quinazolineacetic acid into 3 ml of dried dimethylformamide under stirring. After stirring the mixture for 30 minutes at room temperature, 160 mg of ethylene bromohydrin were added and the mixture was stirred for 4 hours at 110° C. After cooling by allowing to stand, the reaction mixture was poured into 200 ml of water and acidified with hydrochloric acid, which was extracted with ethyl acetate. After dried over anhydrous magnesium sulfate, solvent was distilled off and the residue was recrystallized from ethanol to obtain 300 mg of title compound. m.p. 167°-168° C.
Reaction SMILES: C(OC(N[C@H:9]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]1)=O)(C)(C)C.[C:15]([O:19][C:20]([NH:22][C@H]1CCNC1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>>[C:15]([O:19][C:20]([NH:22][CH:14]1[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1
Product: CC(C)(C)OC(=O)NC1CCNCC1

Procedure:
3-(S)-tert-butoxycarbonylaminopiperidine (B=formula (2)) and 3-(S)-tert-butoxycarbonylaminopyrrolidine (B=formula (3)) (Synth. Comm. 1998, 28, 3919) in the last two cases Y=COOC(CH3)3; tert-butyl 8-azabicyclo[3.2.1]-oct-3-yl-exo-carbamate (B=formula (4), tert-butyl 8-azabicyclo[3.2.1]-oct-3-yl-endo-carbamate (B=formula (5)) (J. Med. Chem. 1991, 34, 656), tert-butyl 9-azabicyclo[3.3.1]-non-3-yl exo-carbamate (B=formula (6)) and tert-butyl 9-azabicyclo-[3.3.1]-non-3-yl-endo-carbamate (B=formula (7)), (J. Med. Chem. 1993, 36, 3720)) (Y=COOC(CH3)3).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:16]=[C:17]([NH:21][C:22](=[O:33])[C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=4)[CH:18]=[CH:19][CH:20]=3)=[N:10][N:9]2[CH:34]=1)=[O:4].[CH3:35][NH:36][CH3:37].C(=O)([O-])O.[Na+]>C(#N)C>[CH3:35][N:36]([CH3:37])[CH2:2][C:3]([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:16]=[C:17]([NH:21][C:22](=[O:33])[C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=4)[CH:18]=[CH:19][CH:20]=3)=[N:10][N:9]2[CH:34]=1)=[O:4]
Reactant: CNC
Reactant: O=C(CCl)Nc1cn2nc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)ccc2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CN(C)CC(=O)Nc1cn2nc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)ccc2n1
Temperature: 80 °C
Reaction time: 3 h
Yield: 70 %

Procedure:
A mixture of N-[3-({2-[(chloroacetyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)phenyl]-3-(trifluoromethyl)benzamide (120 mg, 0.244 mmol), aqueous dimethylamine (3 mL) solution and acetonitrile (3 mL) was heated to 80° C. and stirred for 3 hr. After the reaction mixture was allowed to cool to room temperature, saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was washed with ethanol to give the title compound (85 mg, 70%) as a pale-yellow powder.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:7]=[CH:6][C:5]=1[OH:16])([O-])=O.O.NN>C(O)C>[NH2:1][C:4]1[CH:9]=[C:8]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:7]=[CH:6][C:5]=1[OH:16]
Reactant: CCCCCCc1ccc(O)c([N+](=O)[O-])c1
Agent: NN
Solvent: O
Solvent: CCO
Product: CCCCCCc1ccc(O)c(N)c1
Temperature: 70 °C
Yield: 81.9 %

Procedure:
In a 50 ml-three-necked flask, 1.10 g (4.93 mM) of 2-nitro-4-hexylphenol, 0.30 g of activated carbon, 0.02 g of FeCl3.6H2O and 5 ml of ethanol were placed and heated to 55°-70° C. under stirring. To the mixture, 1.5 ml of 80% hydrazine hydrate was gradually added dropwise and heated to 70° C., followed by stirring for 30 min at 70°-75° C. After the reaction, the reaction mixture was filtered under heating to remove the activated carbon and the filtrate was poured into water to precipitate a crystal. The crystal was recovered by filtration, followed by drying under reduced pressure to obtain 0.78 g of 2-amino-4-hexylphenol (yield: 81.9%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:65][C:66]1[CH:67]=[C:68]([CH:72]=[CH:73][CH:74]=1)[C:69]([NH2:71])=[O:70]>C(Cl)Cl>[C:69]([C:68]1[CH:67]=[C:66]([NH:65][C:28]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[NH:10]2)=[O:29])[CH:74]=[CH:73][CH:72]=1)(=[O:70])[NH2:71]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: NC(=O)c1cccc(N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)Nc2cccc(C(N)=O)c2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (100 mg, 0.172 mmol) in methylene chloride (10 mL), HATU (Aldrich, 98 mg, 0.258 mmol) was added followed by the addition of DIPEA (90 uL, 0.52 mmol) and 3-amino benzamide (Oakwood, 35 mg, 0.26 mmol). The mixture was stirred at rt overnight. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (24 g column, eluent, 30% EtOAc/methylene chloride) to give a white solid. 58 mg.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[Br:11]N1C(=O)CCC1=O.O>CN(C=O)C>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[Br:11]
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccc(C(=O)O)cc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 70 %

Procedure:
4-Amino-benzoic acid (100 mmol) was dissolved in DMF (50 mL) and N-bromosuccinimide (100 mmol) was added. Stirred at ambient temperature for 18 h, the reaction mixture was then poured into water (100 mL). The product was removed by filtration, washed with water and dried in vacuo to give 4-amino-3-bromo-benzoic acid.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[NH:8][C:9]1[S:10][C:11]([CH2:18][CH2:19][OH:20])([CH2:15][CH2:16][OH:17])[C:12](=[O:14])[N:13]=1.C(N(C(C)C)CC)(C)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[NH:8][C:9]1[S:10][C:11]([CH2:15][CH2:16][O:17][S:31]([CH3:30])(=[O:33])=[O:32])([CH2:18][CH2:19][O:20][S:31]([CH3:30])(=[O:33])=[O:32])[C:12](=[O:14])[N:13]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C1N=C(NC2CC3CCC2C3)SC1(CCO)CCO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)OCCC1(CCOS(C)(=O)=O)SC(NC2CC3CCC2C3)=NC1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of 2-(bicyclo[2.2.1]heptan-2-ylamino)-5,5-bis(2-hydroxyethyl)thiazol-4(5H)-one (280 mg, 0.94 mmol) and diisopropylethylamine (Aldrich, 412 mg, 3.19 mmol) in CH2Cl2 (5 mL) was added methanesulfonyl chloride (344 mg, 3.00 mmol, 3.2 eq), and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was then concentrated in vacuo to providethe title compound which was used without further purification. MS (ESI, pos. ion) m/z: 455 (M+H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([Cl:15])[CH:9]=2)[C:5]([CH:16]2[CH2:18][CH2:17]2)=[CH:4][N:3]=1.[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([CH2:26][C:27]2[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=2)[CH2:22][CH2:21]1>C(Cl)Cl.CO>[Cl:15][C:10]1[CH:9]=[C:8]([C:6]2[C:5]([CH:16]3[CH2:18][CH2:17]3)=[CH:4][N:3]=[C:2]([NH:31][C:30]3[CH:29]=[CH:28][C:27]([CH2:26][N:23]4[CH2:22][CH2:21][N:20]([CH3:19])[CH2:25][CH2:24]4)=[CH:33][CH:32]=3)[N:7]=2)[CH:13]=[CH:12][C:11]=1[F:14]
Reactant: CN1CCN(Cc2ccc(N)cc2)CC1
Reactant: Fc1ccc(-c2nc(Cl)ncc2C2CC2)cc1Cl
Solvent: ClCCl
Solvent: CO
Product: CN1CCN(Cc2ccc(Nc3ncc(C4CC4)c(-c4ccc(F)c(Cl)c4)n3)cc2)CC1
Yield: 51 %

Procedure:
The title compound was prepared according to synthesis procedure B described above from 2-chloro-4-(3-chloro-4-fluorophenyl)-5-cyclopropylpyrimidine and 4-((4-methylpiperazin-1-yl)methyl)aniline in 51% yield (yellow solid) after flash chromatography (CH2Cl2/CH3OH 99:1 gradually increasing to 95:5). 1H NMR (400 MHz, CDCl3): δ 8.22 (s, 1H), 7.90 (dd, 1H, J=7.0, 2.0 Hz), 7.72 (m, 1H), 7.55 (d, 2H, J=8.6 Hz), 7.22 (d, 1H, J=8.6 Hz), 7.09 (d, 2H, J=8.6 Hz), 3.45 (s, 2H), 2.43 (bs, 8H), 2.26 (s, 3H), 1.86 (m, 1H), 0.92 (m, 2H), 0.63 (m, 2H); MS (ESI): 452.3 [M+H]+, 226.9 [M+2H]2+.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:7]=1.[CH2:12]([O:14][C:15]([O:21][CH2:22][CH3:23])([O:18][CH2:19][CH3:20])[C:16]#[CH:17])[CH3:13].C(N(CC)CC)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.[Cu]I.ClCCl>[CH3:11][S:8]([C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:17]#[C:16][C:15]([O:18][CH2:19][CH3:20])([O:14][CH2:12][CH3:13])[O:21][CH2:22][CH3:23])[CH:7]=1)(=[O:10])=[O:9]
Reactant: CS(=O)(=O)c1cncc(Br)c1
Reactant: C#CC(OCC)(OCC)OCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(C#Cc1cncc(S(C)(=O)=O)c1)(OCC)OCC
Temperature: 25 °C
Yield: 87.3 %

Procedure:
A solution of 3-bromo-5-methanesulfonyl-pyridine (1.00 g, 4.20 mmol), 3,3,3-triethoxypropyne (1.75 g, 9.4 mmol), dichlorobis(triphenylphospine)palladium(II) (0.15 g, 0.21 mmol), copper(I)iodide (0.08 g, 0.42 mmol), triethylamine (1.80 mL, 12.7 mmol) and dichloromethane (40 mL) was heated at reflux for 48 h. The mixture was cooled to room temperature and the solvent was removed under reduced pressure. The crude product was chromatographed on silica (30% ethyl acetate/hexanes) to give the title compound (1.2 g, 87% yield) as yellow solid. 1H NMR (CDCl3) δ 9.08(d, 1H, J=2.4 Hz), 8.91 (d, 1H J=2.0), 8.28 (t, 1H, J=2.0 Hz), 3.75 (q, 6H, J=7.2), 3.13 (s, 3H), 1.29 (t, 9H, J=7.2).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.[Li]CCCC.CN([CH:30]=[O:31])C>C1COCC1>[CH3:21][O:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][N:6]1[C:5]2[CH:4]=[CH:3][C:2]([CH:30]=[O:31])=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2
Reactant: CN(C)C=O
Reactant: COCCOCCn1c2ccccc2c2cc(Br)ccc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCCOCCn1c2ccccc2c2cc(C=O)ccc21
Temperature: -78 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
To a solution of 2a (1.5 g, 4.3 mmol) in dried THF (45 mL) was added n-BuLi (3.5 mL 5.2 mmol) at −78° C. The resulting mixture was stirred at −78° C. for 1 h and then added with dried DMF (3 mL). The reaction mixture was allowed to warm to room temperature and stirred overnight before quenched with aqueous ammonia chloride solution. Water was added and extracted with ethyl acetate three times. The combined organic phase was washed with brine and dried over anhydrous sodium sulfate. After removing the solvent, the residue was purified by silica gel chromatography using ethyl acetate and petroleum ether (EA:PE=1:2) as eluent to afford 3a (0.76 g) as yellow solid in 60% yield. 1H NMR (400 MHz, CDCl3) δ 10.07 (s, 1H), 8.58 (d, J=0.8 Hz, 1H), 8.13 (d, J=8.0 Hz, 1H), 7.98 (dd, J=8.8 Hz, 0.8 Hz, 1H), 7.51 (m, 3H), 7.30 (m, 1H), 4.53 (t, J=6.0 Hz, 2H), 3.87 (t, J=6.0 Hz, 2H), 3.49 (m, 2H), 3.38 (m, 2H), 3.26 (s, 3H). 13C NMR (400 MHz, CDCl3) δ 191.8, 144.3, 141.1, 128.5, 127.1, 126.6, 123.7, 123.0, 122.9, 120.6, 120.4, 109.4, 109.3, 71.8, 70.8, 69.1, 59.0, 43.4. MS (FAB) m/z Calcd for C18H19NO3 297.1 Found 297.3 [M]+.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:7]([C:9](=[CH:12]N(C)C)[C:10]#[N:11])=O)=[CH:5][CH:6]=1.Cl.[O:17]=[C:18]1[NH:22][CH2:21][CH2:20][N:19]1[CH2:23][CH2:24][NH:25][C:26]([NH2:28])=[NH:27].C(=O)([O-])[O-].[Cs+].[Cs+]>CN1CCCC1=O.CO>[Br:1][C:2]1[S:3][C:4]([C:7]2[C:9]([C:10]#[N:11])=[CH:12][N:28]=[C:26]([NH:25][CH2:24][CH2:23][N:19]3[CH2:20][CH2:21][NH:22][C:18]3=[O:17])[N:27]=2)=[CH:5][CH:6]=1
Reactant: CN(C)C=C(C#N)C(=O)c1ccc(Br)s1
Reactant: N=C(N)NCCN1CCNC1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: CO
Product: N#Cc1cnc(NCCN2CCNC2=O)nc1-c1ccc(Br)s1
Temperature: 100 °C

Procedure:
2-(2-Bromothiophene-5-carbonyl)-3-(dimethylamino)acrylonitrile) (3 g, 10 mmol) in N-methylpyrrolidone (15 mL) was treated with 1-(2-(2-oxoimidazolidin-1-yl)ethyl)guanidine hydrochloride (1 M solution in N-methylpyrrolidone, 15 mL, 15 mmol) and cesium carbonate (3.4 g, 10 mmol). The mixture was heated at 100° C. overnight. The reaction was then allowed to cool to room temperature and poured onto crushed ice. The resulting solid that formed was suspended in hot methanol to give a yellow solid (2.3 g). The filtrate was concentrated and purified by flash chromatography using a gradient of 3 to 10% methanol in dichloromethane to obtain an additional 0.9 g of the desired product. Total yield=3.2 g. MS (M+H)+ 394.
Reaction SMILES: O[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]([O:13][CH3:14])=[O:12])=[CH:10][C:4]=2[N:3]=1.P(Cl)(Cl)([Cl:17])=O>>[Cl:17][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]([O:13][CH3:14])=[O:12])=[CH:10][C:4]=2[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1ccc2[nH]c(O)nc2c1
Product: COC(=O)c1ccc2[nH]c(Cl)nc2c1
Temperature: 0 °C

Procedure:
3.9 g of methyl 2-hydroxy-1H-benzimidazole-5-carboxylate and 50 ml of phosphorus oxychloride are stirred at 10° C. for 6 hours. The resulting thick slurry is, after cooling, stirred cautiously into 500 ml of ice-water, and the solid is filtered off with suction after one hour, washed with water and dried under reduced pressure.