Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[C:6](N)[CH:5]=1)(=[O:3])[CH3:2].B(F)(F)[F:20].F.N([O-])=O.[Na+]>O1CCCC1.O>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[C:6]([F:20])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc(-c2ccc(C(C)=O)cc2N)cc1
Reactant: FB(F)F
Agent: F
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc(C(C)=O)cc2F)cc1
Temperature: 70 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of intermediate B (8.8 g.) in a mixture of tetrahydrofuran (28 ml.), water (9.5 ml.) and hydrofluoroboric acid (38.5 ml. of 42% w/v acid) was slowly added a solution of sodium nitrite (2.7 g.) in water (4.5 ml.) whilst maintaining the temperature of the reaction mixture below 5°C. The mixture was then stirred for a further period of 20 minutes at 0° - 5°C. The resulting diazonium fluoroborate was collected by filtration, washed with hydrofluoroboric acid (20 ml. of 10% w/v acid) and then with methanol/ether (60 ml. of 10% methanol in ether), and finally dried in vacuo. This product was suspended in xylene (85 ml.) and the suspension heated to 70°C. at which point decomposition took place. When the reaction had subsided the mixture was refluxed for 45 minutes, after which the xylene was removed by distillation in vacuo. The residue was extracted with hot benzene. The resulting extract was cooled, washed with dilute aqueous sodium carbonate and then water, dried over anhydrous sodium carbonate, and evaporated. The residue was distilled in vacuo to give a product, b.p. 146° - 156°C./0.2 mm. which solidified on cooling. This product was recrystallized from ethanol to give 4-acetyl-2-fluoro-4'-methoxybiphenyl, m.p. 103° - 106°C. (novel intermediate C).
Reaction SMILES: [CH2:1]([Mg]Cl)[CH2:2][CH2:3][CH3:4].[CH2:7]([O:14][C:15](=[O:19])[C:16]([O-])=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[C:15]([O:14][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:19])[CH2:16][CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: CCCC[Mg]Cl
Reactant: O=C([O-])C(=O)OCc1ccccc1
Product: CCCCCC(=O)OCc1ccccc1

Procedure:
Alternatively, the compound of Example 3 was prepared by the Grignard reaction of n-butylmagnesium chloride with excess benzyloxalate to obtain desired product in 27% yield. 1H NMR (CDCl3, TMS) δ0.91 (t,3H), 1.35 (m,2H), 1.6 (m,2H), 2.85 (t,2H), 5.29 (s,2H), 7.4 (m,5H). Rf value is identical to Example 3.
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:22][C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:8]=1)=[O:5].[CH2:32]([N:34]([CH2:49][CH3:50])[CH2:35][CH2:36][N:37]([CH2:39][C:40]1[CH:48]=[CH:47][C:43]([C:44](O)=[O:45])=[CH:42][CH:41]=1)[CH3:38])[CH3:33].CCN=C=NCCCN(C)C.Cl>ClCCl.CN(C)C1C=CN=CC=1>[CH2:49]([N:34]([CH2:32][CH3:33])[CH2:35][CH2:36][N:37]([CH2:39][C:40]1[CH:41]=[CH:42][C:43]([C:44]([NH:1][C:2]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:22][C:3]=2[C:4]([NH:6][C:7]2[CH:11]=[CH:10][N:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:20])([F:21])[F:19])[CH:13]=3)[N:8]=2)=[O:5])=[O:45])=[CH:47][CH:48]=1)[CH3:38])[CH3:50]
Reactant: CCN(CC)CCN(C)Cc1ccc(C(=O)O)cc1
Reactant: Nc1ccc(N2CCCCC2)cc1C(=O)Nc1ccn(-c2cccc(C(F)(F)F)c2)n1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCN(CC)CCN(C)Cc1ccc(C(=O)Nc2ccc(N3CCCCC3)cc2C(=O)Nc2ccn(-c3cccc(C(F)(F)F)c3)n2)cc1
Temperature: 30 °C
Reaction time: 8 h
Yield: 37.2 %

Procedure:
Into a 5-mL vial, was placed a solution of 2-amino-5-(piperidin-1-yl)-N-(1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)benzamide 8d (100 mg, 0.23 mmol, 1.00 equiv) in dichloromethane (5 mL), 4-(((2-(diethylamino)ethyl)(methyl)amino)methyl)benzoic acid (74 mg, 0.28 mmol, 1.20 equiv), EDC.HCl (90 mg, 0.47 mmol, 2.00 equiv), and 4-dimethylaminopyridine (43 mg, 0.35 mmol, 1.50 equiv). The resulting solution was stirred overnight at 30° C. in an oil bath. The reaction progress was monitored by LCMS. The resulting mixture was washed with 3×10 mL of water and 1×10 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product (150 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 57.8 mg (31%) of a light yellow solid. 1H-NMR (300 MHz, CD3OD, ppm): δ 8.684(d, J=9 Hz, 1H), 8.392-8.400(m, 1H), 8.179(s, 1H), 8.047-8.075(m, 3H), 7.991-7.999(m, 1H), 7.589-7.727(m, 5H), 7.078-7.087(m, 1H), 4.007(s, 2H), 3.556-3.615(m, 4H), 3.393-3.436(m, 2H), 3.171-3.263(m, 4H), 3.052-3.095(m, 2H), 2.538-2.560(m, 3H), 1.998(m, 4H), 1.788-1.804(m, 2H), 1.286-1.334(m, 6H). MS (ES, m/z): 676 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[NH2:24][C:25]1([C:28]#[N:29])[CH2:27][CH2:26]1>>[C:28]([C:25]1([NH:24][C:19](=[O:21])[C:18]2[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)=[N:5][O:6][C:2]=3[CH3:1])=[N:16][CH:17]=2)[CH2:27][CH2:26]1)#[N:29]
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Reactant: N#CC1(N)CC1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NC2(C#N)CC2)cn1
Yield: 51 %

Procedure:
As described for example 191, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32 mmol) was converted, using 1-amino-1-cyclopropanecarbonitrile instead of 2-aminoethyl isopropylether, to the title compound (61 mg, 51%) which was obtained as a white solid. MS: m/e=375.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][CH2:11]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:32]N1C(=O)CCC1=O>C(Cl)Cl>[Br:32][CH2:11][CH2:10][CH2:9][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=1[Cl:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: OCCCc1cccc(Cl)c1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Clc1cccc(CCCBr)c1Cl
Yield: 93.2 %

Procedure:
Compound 60-2 (2.67 g) was dissolved in methylene chloride (30 ml), triphenylphosphine (3.76 g) and N-bromosuccinimide (2.55 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 3 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (3.25 g) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:10])=[N:4][C:5]([NH2:9])=[N:6][C:7]=1Cl.C(N(CC)CC)C.[NH2:18][CH2:19][CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25]>CN(C=O)C>[NH2:9][C:5]1[N:6]=[C:7]([NH:18][CH2:19][CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:25])[CH3:27])[C:2]([Br:1])=[C:3]([Cl:10])[N:4]=1
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: Nc1nc(Cl)c(Br)c(Cl)n1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCNc1nc(N)nc(Cl)c1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.3 %

Procedure:
A stirred solution of 5-bromo-4,6-dichloropyrimidin-2-amine (Reference Example 1, 14.00 g, 0.0576 mole), and triethylamine (41.8 mL, 0.2997 mole) in DMF (55 mL) was treated with tert-butyl 2-aminoethylcarbamate (9.24 g, 0.0576 mole). The reaction mixture was stirred at ambient temperature for 18 hours, then volatiles were removed under reduced pressure and the residue was partitioned between ethyl acetate and saturated aqueous sodium carbonate. The organic layer was dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure to give a yellow solid that was triturated with ether to remove color. The ether-insoluble material was collected by filtration and dried under vacuum to provide tert-butyl 2-(2-amino-5-bromo-6-chloropyrimidin-4-ylamino)ethylcarbamate (18.02 g, 85.2% yield). 1H NMR (300 MHz, CD3OD) δ ppm 1.42 (s, 9H), 3.25 (t, J=6 Hz, 2H), 3.47 (t, J=6 Hz, 2H). MS (DCl—NH3) m/z=366 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[S:11](=[O:16])(=[O:15])[N:12]([CH3:14])[CH3:13].[N+:17](=[CH2:19])=[N-:18]>C(OCC)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](=[O:7])[CH:19]=[N+:17]=[N-:18])=[CH:4][C:3]=1[S:11](=[O:16])(=[O:15])[N:12]([CH3:14])[CH3:13]
Reactant: CN(C)S(=O)(=O)c1cc(C(=O)Cl)ccc1Cl
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: CN(C)S(=O)(=O)c1cc(C(=O)C=[N+]=[N-])ccc1Cl

Procedure:
14.1 g of 4-chloro-3-dimethylsulfamoylbenzoyl-chloride were reacted as prescribed in Example 66(b) with diazomethane in diethyl ether and the crystalline product was filtered off. Melting point: 136°-137° C. (decomposition).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]2[C:15]=1[CH2:14][N:13](CC1C=CC(OC)=CC=1OC)[C:12](=[O:27])[C:11]1[CH:28]=[C:29]([O:32][CH3:33])[CH:30]=[CH:31][C:10]2=1)=[O:5])[CH3:2].FC(F)(F)S(O)(=O)=O>C(Cl)Cl.FC(F)(F)C(O)=O>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]2[C:15]=1[CH2:14][NH:13][C:12](=[O:27])[C:11]1[CH:28]=[C:29]([O:32][CH3:33])[CH:30]=[CH:31][C:10]2=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncn2c1CN(Cc1ccc(OC)cc1OC)C(=O)c1cc(OC)ccc1-2
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1ncn2c1CNC(=O)c1cc(OC)ccc1-2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-(2,4-Dimethoxy-benzyl)-8-methoxy-6-oxo-5,6-dihydro-4H-2,5,10b-triaza-benzo[e]azulene-3-carboxylic acid ethyl ester (9.8 g, 22 mmol) was suspended in CH2Cl2 (50 mL), cooled in ice, and diluted sowly with trifluoroacetic acid (50 mL). The resulting clear solution was treated at 5° C. with trifluoromethanesulfonic acid (3.8 mL, 44 mmol). The now red solution was stirred at rt for 2 h, evaporated to dryness, and the residue extracted with CH2Cl2 (500 mL), and 2×10% NaHCO3 (500 mL). The crude product (ca. 10 g) was digested with hot ethyl acetate (100 mL), allowed to cool, and the white crystals (5.6 g, 85%) were filtered off. mp 240° C. m/z 301 (M).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][C:21]([CH3:27])([CH2:25][CH3:26])[C:22]([OH:24])=[O:23].N(C(OCC)=O)=NC(OCC)=O.[C:40]([CH:44]([O:66][SiH:67]([CH3:69])[CH3:68])[C:45]1[C:46]([CH:63]([CH3:65])[CH3:64])=[N:47][C:48]([CH:60]([CH3:62])[CH3:61])=[C:49]([CH2:58]O)[C:50]=1[C:51]1[CH:56]=[CH:55][C:54]([F:57])=[CH:53][CH:52]=1)([CH3:43])([CH3:42])[CH3:41]>O1CCCC1>[C:40]([CH:44]([O:66][SiH:67]([CH3:69])[CH3:68])[C:45]1[C:46]([CH:63]([CH3:64])[CH3:65])=[N:47][C:48]([CH:60]([CH3:61])[CH3:62])=[C:49]([CH2:58][O:23][C:22](=[O:24])[C:21]([CH3:27])([CH3:20])[CH2:25][CH3:26])[C:50]=1[C:51]1[CH:56]=[CH:55][C:54]([F:57])=[CH:53][CH:52]=1)([CH3:43])([CH3:42])[CH3:41]
Reactant: CC(C)c1nc(C(C)C)c(C(O[SiH](C)C)C(C)(C)C)c(-c2ccc(F)cc2)c1CO
Reactant: CCC(C)(C)C(=O)O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCC(C)(C)C(=O)OCc1c(C(C)C)nc(C(C)C)c(C(O[SiH](C)C)C(C)(C)C)c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
865 mg (3.3 mmol) of triphenylphosphine, 0.41 ml (3.3 mmol) of 2,2-dimethylbutyric acid and 0.52 ml (3.3 mmol) of diethyl azodicarboxylate are added successively at 0° C. to 1.29 g of the compound from Example 6 in 50 ml of absolute tetrahydrofuran and the mixture is stirred overnight at room temperature. The mixture is concentrated in vacuo and t he residue is chromatographed on a column (silica gel 70-230 mesh, using ethyl acetate/petroleum ether 1:9).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([C:17]1[CH:18]=[N:19][C:20]([N:23]2[CH2:28][CH2:27][N:26]([CH2:29][CH3:30])[CH2:25][CH2:24]2)=[CH:21][CH:22]=1)=[O:16].N1C=CC=CC=1.[S:37](Cl)([C:40]1[CH:46]=[CH:45][C:43]([CH3:44])=[CH:42][CH:41]=1)(=[O:39])=[O:38]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[S:37]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([C:17]1[CH:18]=[N:19][C:20]([N:23]2[CH2:28][CH2:27][N:26]([CH2:29][CH3:30])[CH2:25][CH2:24]2)=[CH:21][CH:22]=1)=[O:16])([C:40]1[CH:46]=[CH:45][C:43]([CH3:44])=[CH:42][CH:41]=1)(=[O:39])=[O:38]
Reactant: CCN1CCN(c2ccc(C(=O)NCCCCCCCCCCCCO)cn2)CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCN1CCN(c2ccc(C(=O)NCCCCCCCCCCCCOS(=O)(=O)c3ccc(C)cc3)cn2)CC1
Yield: 76.2 %

Procedure:
To a suspension of 210 mg of N-(12-hydroxydodecyl)-6-(4-ethyl-1-piperazinyl)pyridine-3-carboxamide in 10 ml of methylene chloride were added 0.03 ml of pyridine, 115 mg of tosyl chloride and a catalytic amount of 4-dimethylaminopyridine and the mixture was stirred at room temperature for one hour. The reaction solution was washed with water and a saturated aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue thus obtained was chromatographed over a silica gel column to afford 219 mg of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].[CH2:10]([O:17][CH2:18][C:19](O)=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[CH2:10]([O:17][CH2:18][C:19]1[NH:8][C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([OH:9])[C:2]=2[N:1]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(O)COCc1ccccc1
Reactant: Nc1cccc(O)c1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Oc1cccc2[nH]c(COCc3ccccc3)nc12
Temperature: 140 °C
Yield: 67 %

Procedure:
A mixture of the 2,3-diaminophenol (5 g, 40.3 mmol, 1 eq) and benzyloxyacetic acid (5.6 g, 48.3 mmol, 1.2 eq) in 40 ml of a 10% aqueous solution of sodium bicarbonate was stirred and refluxed at 140° C. for one hour. The mixture was allowed to cool down to room temperature. Ethyl acetate was poured into the mixture. The organic fraction was extracted with ethyl acetate, washed with water, and then dried over sodium sulfate. The solvents were removed in vacuo. The crude product was further purified by flash chromatography to yield 6.87 grams (67% yield) of the desired title product.
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([NH:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[N:6]=[CH:5][CH:4]=1)#[N:2].[C:18](OC)(=[O:26])[C:19]1[C:20](=[CH:22][CH:23]=[CH:24][CH:25]=1)[SH:21].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:26]=[C:18]1[C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[S:21][C:1]([C:3]2[N:8]=[C:7]([NH:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[N:6]=[CH:5][CH:4]=2)=[N:2]1
Reactant: CC(C)(C)OC(=O)CNc1nccc(C#N)n1
Reactant: COC(=O)c1ccccc1S
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)CNc1nccc(-c2nc(=O)c3ccccc3s2)n1
Yield: 69 %

Procedure:
tert-Butyl [(6-cyano-2-pyrimidinyl)amino]acetate (1.00 g, 4.03 mmol) and methyl thiosalicylate (2.34 g, 13.9 mmol) were dissolved in toluene (50 ml), and triethylamine (1.95 ml, 13.9 mmol) was added thereto. The mixture was refluxed for 18 hrs. The solvent was evaporated, and the residue was recrystallized from ethanol to give the titled compound (1.03 g, 60%) as pale yellow crystals.
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].C([O-])([O-])=O.[Cs+].[Cs+].S(O[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][NH:32][C:33]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)(C1C=CC(C)=CC=1)(=O)=O.O>CN(C=O)C>[C:33]([NH:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][N:1]1[CH:8]=[CH:7][C:5](=[O:6])[NH:4][C:2]1=[O:3])([C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: O=c1cc[nH]c(=O)[nH]1
Reactant: Cc1ccc(S(=O)(=O)OCCCCCCNC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1ccn(CCCCCCNC(c2ccccc2)(c2ccccc2)c2ccccc2)c(=O)[nH]1
Temperature: 40 °C
Yield: 70 %

Procedure:
Uracil (0.087 g, 0.776 mmol) was stirred with Cs2CO3 (0.169 g, 0.519 mmol) in DMF (4 mL) at room temperature for 1 h. A solution of O-tosyl-6-tritylaminohexanol (0.250 g, 0.487 mmol) in DMF (2 mL) was then added dropwise. The reaction mixture was heated at 40° C. for 64 h, left to cool to room temperature, poured into cold water (15 mL) and extracted with EtOAc (25 mL). The organic extracts were washed with brine (10 mL), dried over Na2SO4 and concentrated in vacuo. Further purification was carried out by flash column chromatography (ISOLUTE SI column) using a gradient elution of 20→50% EtOAc in hexane. The fractions with Rf=0.49 (10% CH3OH/CHCl3) gave the title compound slightly contaminated with DMF as a white solid (0.111 g, ca 50%). Remaining traces of DMF could be removed by recrystallisation from CH3OH or alternatively by water wash with a purification yield of 70-80%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12](SCC)[N:11]3[CH:17]=[CH:18][N:19]=[C:10]3[CH:9]=2)=[CH:4][CH:3]=1.C[OH:21].[OH-].[K+].Cl>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:13][C:12](=[O:21])[N:11]3[CH:17]=[CH:18][N:19]=[C:10]3[CH:9]=2)=[CH:4][CH:3]=1
Reactant: CO
Reactant: CCSc1nc(-c2ccc(Br)cc2)cc2nccn12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=c1[nH]c(-c2ccc(Br)cc2)cc2nccn12
Reaction time: 48 h
Yield: 94.71 %

Procedure:
To a flask charged with 7-(4-bromophenyl)-5-(ethylthio)imidazo[1,2-c]pyrimidine (62.34 g, 186.5 mmol), methanol (250 mL), and potassium hydroxide (52.32 g, 932.6 mmol) was added water (250 mL) and the reaction was fitted with a condenser and heated to reflux for 4 hours. The reaction mixture was diluted with water (500 mL) and acidified with concentrated hydrochloric acid to a pH=5. The solids were collected by vacuum filtration and then washed with water (3×500 mL) and the cake was dried. The semi dry solids were placed in a vacuum desiccator under high vacuum for two days to afford 7-(4-bromophenyl)imidazo[1,2-c]pyrimidin-5(6H)-one (51.25 g, 176.7 mmol, 94.71% yield). MS (apci) m/z=290.0 (M+H).
Reaction SMILES: Cl.Br[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][N:7]=[C:6]2[NH:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]([Cl:21])[CH:15]=1.[S:22]1[CH:26]=[CH:25][C:24](B(OC(C)C)OC(C)C)=[CH:23]1>>[Cl:21][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][C:17]=1[F:20])[NH:13][C:6]1[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([C:24]3[CH:25]=[CH:26][S:22][CH:23]=3)[CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: CC(C)OB(OC(C)C)c1ccsc1
Reactant: Fc1ccc(Nc2ncnc3ccc(Br)cc23)cc1Cl
Agent: Cl
Product: Fc1ccc(Nc2ncnc3ccc(-c4ccsc4)cc23)cc1Cl
Yield: 51 %

Procedure:
Using an analogous procedure to that described in Example 5 except that the reaction mixture was heated to reflux for 2 hours, 6-bromo-4-(3-chloro-4-fluoroanilino)quinazoline hydrochloride salt was reacted with di-isopropyl 3-thienylboronate to give 4-(3-chloro-4-fluoroanilino)-6-(3-thienyl)quinazoline in 51% yield, m.p. 195-197° C.;
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([OH:14])[CH2:10][C@@H:9]1[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Br:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21](F)[CH:20]=1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([O:14][C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([Br:18])[CH:20]=2)[CH2:10][C@@H:9]1[CH3:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@H]1C[C@@H](O)CCN1C(=O)OC(C)(C)C
Reactant: Fc1cccc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@H]1C[C@@H](Oc2cccc(Br)c2)CCN1C(=O)OC(C)(C)C
Temperature: 65 °C
Reaction time: 0.5 h

Procedure:
Combine 4-hydroxy-cis-2-methyl-piperidine-1-carboxylic acid tert-butyl ester isomer 2 (preparation 3, 0.986 g) in DMF (10 mL) and add to a suspension of sodium hydride (95%, 0.127 g) in DMF (10 mL) and heat in an oil bath at 65° C. After 30 min., add 1-bromo-3-fluoro-benzene (0.96 g) and heat at 65° C. After 18 hr., partition between ethyl acetate-hexane (1:4) and saturated aqueous NaCl, dry over anhydrous sodium sulfate, evaporate and purify on a 35 g silica gel column eluting with ethyl acetate-hexane (1:9) to give the title compound as a colorless oil (0.759 g). 1H NMR (CDCl3): 7.13 (dd, 1H), 7.05 (ddd, 1H), 7.04 (m, 1H), 6.81 (ddd, 1H), 4.63 (m, 1H), 4.35 (m, 1H), 3.88 (m, 1H), 3.23 (m, 1H), 1.90 (m, 3H), 1.73 (m, 1H), 1.46 (s, 9H), 1.27 (d, J=7.0 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([NH:11][CH2:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[CH:7]=[C:8]([Cl:10])[CH:9]=1)=[O:4].[CH3:19][O:20][C:21](=[O:26])[CH2:22][C:23](Cl)=[O:24]>>[CH3:1][O:2][C:3]([C:5]1[N:6]([N:11]([C:23](=[O:24])[CH2:22][C:21]([O:20][CH3:19])=[O:26])[CH2:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[CH:7]=[C:8]([Cl:10])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(Cl)cn1NCc1cccnc1
Reactant: COC(=O)CC(=O)Cl
Product: COC(=O)CC(=O)N(Cc1cccnc1)n1cc(Cl)cc1C(=O)OC

Procedure:
Prepared according to the acylation condition used in Example 2 step f) from 4-chloro-1-[(pyridin-3-ylmethyl)-amino]-1H-pyrrole-2-carboxylic acid methyl ester and chlorocarbonyl-acetic acid methyl ester (1.5 eq.). 1H NMR (CDCl3, δ in ppm): 8.55 (dd, 1H, J=1.8 Hz, 4.8 Hz), 8.34 (1H, J=2.2 Hz), 7.57 (m, 1H), 6.84 (d, 1H, J=2.2 Hz), 6.50 (d, 1.8 Hz), 5.29 (d, 1H, J=14.6 Hz), 4.45 (d, J=14.6 Hz), 3.76 (s, 3H), 3.69 (s, 3H), 3.19 (m, 2H).
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[N:12][N:13]([C:17]3[CH:30]=[CH:29][C:20]([C:21]([NH:23][CH2:24][CH2:25][CH2:26][O:27][CH3:28])=[O:22])=[CH:19][N:18]=3)[C:14]=2[O:15]C)=[CH:6][C:5]=1[F:31])#[N:2].[Cl-].[Li+]>CC(N(C)C)=O.CS(C)=O>[C:1]([CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[N:12][N:13]([C:17]3[CH:30]=[CH:29][C:20]([C:21]([NH:23][CH2:24][CH2:25][CH2:26][O:27][CH3:28])=[O:22])=[CH:19][N:18]=3)[C:14]=2[OH:15])=[CH:6][C:5]=1[F:31])#[N:2]
Reactant: COCCCNC(=O)c1ccc(-n2ncc(-c3ccc(CC#N)c(F)c3)c2OC)nc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CC(=O)N(C)C
Solvent: CS(C)=O
Product: COCCCNC(=O)c1ccc(-n2ncc(-c3ccc(CC#N)c(F)c3)c2O)nc1
Yield: 57.2 %

Procedure:
Combined 6-(4-(4-(cyanomethyl)-3-fluorophenyl)-5-methoxy-1H-pyrazol-1-yl)-N-(3-methoxypropyl)nicotinamide (27 mg, 0.064 mmol) and lithium chloride (27.0 mg, 0.638 mmol) in DMA (1.0 mL) and heated at 60° C. for 24 h. The reaction mixture was diluted with 0.2 mL DMSO and purified by prep HPLC (formic acid conditions) to give the title compound (15 mg, 57.5% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.79 (quin, J=6.7 Hz, 2 H) 3.25 (s, 3 H) 3.30-3.37 (m, 2 H) 3.40 (t, J=6.3 Hz, 2 H) 4.03 (s, 2 H) 7.42 (br. s., 1 H) 7.52-8.06 (m, 2 H) 8.41 (br. s., 1 H) 8.50-8.82 (m, 3 H) 8.91 (d, J=1.5 Hz, 1 H) 13.28 (br. s., 1 H). MS m/z 410 [M+H]+.
Reaction SMILES: [C:1]([C:9]1[NH:10][C:11]2[C:16]([C:17]=1[CH2:18][C:19](O)=[O:20])=[CH:15][CH:14]=[C:13]([Cl:22])[CH:12]=2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:23]>C1COCC1>[C:1]([C:9]1[NH:10][C:11]2[C:16]([C:17]=1[CH2:18][C:19]([NH2:23])=[O:20])=[CH:15][CH:14]=[C:13]([Cl:22])[CH:12]=2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N
Reactant: O=C(O)Cc1c(C(=O)c2ccccc2)[nH]c2cc(Cl)ccc12
Solvent: C1CCOC1
Product: NC(=O)Cc1c(C(=O)c2ccccc2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 43 from (2-benzoyl-6-chloro-1H-indol-3-yl)acetic acid (Example 2) and a solution of ammonia in THF.
Reaction SMILES: BrC1C=CC(CC[C:10]([NH:12]C)=O)=CC=1.[Br:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]([OH:24])=O)=[CH:17][CH:16]=1.CN>>[Br:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]([NH:12][CH3:10])=[O:24])=[CH:17][CH:16]=1
Reactant: O=C(O)Cc1ccc(Br)cc1
Reactant: CNC(=O)CCc1ccc(Br)cc1
Agent: CN
Product: CNC(=O)Cc1ccc(Br)cc1
Yield: 75 %

Procedure:
Using a procedure analogous to that used to prepare 22A, 2-(4-bromophenyl)acetic acid (1.6 g, 7.0 mmol) was coupled to methylamine to yield 23A (2.0 g, 75%) as a white solid. MS (ESI) m/z 228.20/230.20 (M+H)+.