Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH3:9][C:10]1[C:11]([N:18]2[CH2:27][CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C@H:19]2[CH3:28])=[N:12][C:13]([Cl:17])=[N:14][C:15]=1[CH3:16]>CN(C)C=O>[ClH:17].[CH3:9][C:10]1[C:11]([N:18]2[CH2:27][CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C@H:19]2[CH3:28])=[N:12][C:13]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=2)=[N:14][C:15]=1[CH3:16]
Reactant: Cc1nc(Cl)nc(N2CCc3ccccc3[C@H]2C)c1C
Reactant: Nc1ccc(F)cc1
Solvent: CN(C)C=O
Product: Cc1nc(Nc2ccc(F)cc2)nc(N2CCc3ccccc3[C@H]2C)c1C
Product: Cl
Yield: 62.7 %

Procedure:
After 4-fluoroaniline(1 ml, 10 mmol) was added to a mixture solution of (R)-5,6-dimethyl-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)-2-chloropyrimidine(1.4 g, 4.8 mmol) and dimethylformamide(10 ml), 1.20 g of the titled compound was obtained in accordance with the same procedure as in Step 2 of Example 1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][CH:19]3[CH2:23][CH:22]([CH2:24][NH:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:21][C:20]3=[O:32])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C[O:34]C1C=CC(C2C=CC(S(NC(CC3OC3)C(OC)=O)(=O)=O)=CC=2)=CC=1.NC1C=CC=CC=1.Cl([O-])(=O)(=O)=O.[Mg+2].Cl([O-])(=O)(=O)=O>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]([S:15]([NH:18][CH:19]([CH2:23][CH:22]([OH:34])[CH2:24][NH:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:20]([OH:21])=[O:32])(=[O:16])=[O:17])=[CH:13][CH:14]=2)=[CH:5][CH:4]=1
Reactant: COC(=O)C(CC1CO1)NS(=O)(=O)c1ccc(-c2ccc(OC)cc2)cc1
Reactant: COc1ccc(-c2ccc(S(=O)(=O)NC3CC(CNc4ccccc4)OC3=O)cc2)cc1
Agent: [Mg+2]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: O
Solvent: Nc1ccccc1
Product: COc1ccc(-c2ccc(S(=O)(=O)NC(CC(O)CNc3ccccc3)C(=O)O)cc2)cc1
Temperature: 80 °C

Procedure:
3-[(4′-Methoxy[1,1′-biphenyl]-4-yl)sulfonyl]amino-2-oxo-5-[(phenylamino)methyl]-tetrahydrofuran: To a solution of methyl 2-[(4′-methoxy[1,1′-biphenyl]-4-yl)sulfonyl]amino-4,5-epoxypentanoate 1d (0.5 g, 1.28 mmol) in aniline (0.17 mL, 1.92 mmol) is added magnesium perchlorate (2 mg, 0.009 mmol) and the resulting mixture is heated for 4 h at 80° C. The resulting mixture is cooled to room temperature, and then the mixture is diluted with water, and extracted three times with EtOAc. The combined EtOAc layer is washed with water, brine, dried over MgSO4 and concentrated to an oil which is purified by column chromatography eluting with hexane/EtOAc (7:3) to give the desired product.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH2:12][N:13]([CH3:29])[C:14]([C:16]1[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[O:18][C:17]=1[CH2:25][CH2:26][CH2:27][CH3:28])=[O:15])[CH:6]=[CH:5]2.Br[CH2:31][C:32]#[N:33].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[C:32]([CH2:31][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH2:12][N:13]([CH3:29])[C:14]([C:16]1[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[O:18][C:17]=1[CH2:25][CH2:26][CH2:27][CH3:28])=[O:15])[CH:6]=[CH:5]2)#[N:33]
Reactant: N#CCBr
Reactant: CCCCc1oc2ccccc2c1C(=O)N(C)Cc1ccc2cc(O)ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1oc2ccccc2c1C(=O)N(C)Cc1ccc2cc(OCC#N)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
A mixture of 2-butyl-benzofuran-3-carboxylic acid (6-hydroxy-naphthalen-2-ylmethyl)-methyl-amide (0.90 g, 2.32 mmol), prepared in step-4 of Example 31, bromoacetonitrile (0.194 mL, 2.79 mmol) and potassium carbonate (1.6 g, 11.6 mmol) in 10 mL DMF was stirred under nitrogen at room temperature for 24 h (overnight). The reaction was diluted with ethyl acetate and extracted five times with water. The organic layer was dried (MgSO4) and the solvent removed under reduced pressure to give 2-butyl-benzofuran-3-carboxylic acid (6-cyanomethoxy-naphthalen-2ylmethyl)-methyl-amide (0.94 g, 95%) as a brown oil, MS m/z: 427 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[N:13]=[N:14][NH:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=1[C:26]#[N:27])#[N:2].[C:28]1([N:34]=[C:35]=[O:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CCOCC>[C:28]1([NH:34][C:35]([N:13]([C:4]2[CH:5]=[C:6]([C:9]([F:12])([F:11])[F:10])[CH:7]=[CH:8][C:3]=2[C:1]#[N:2])[N:14]=[N:15][C:16]2[CH:21]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:19]=[CH:18][C:17]=2[C:26]#[N:27])=[O:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C=Nc1ccccc1
Reactant: N#Cc1ccc(C(F)(F)F)cc1N=NNc1cc(C(F)(F)F)ccc1C#N
Solvent: CCOCC
Product: N#Cc1ccc(C(F)(F)F)cc1N=NN(C(=O)Nc1ccccc1)c1cc(C(F)(F)F)ccc1C#N

Procedure:
A mixture of 2.0 g. (5.2 mmol.) of 1,3-bis(2-cyano-5-trifluoromethylphenyl)triazene and 1.6 ml. of phenyl isocyanate in 20 ml. of ether is stirred at 25° for 48 hours. The precipitate is collected and recrystallized from ether to give 3-(N-phenylcarbamoyl)-1,3-bis(2-cyano-5-trifluoromethylphenyl)-triazene, m.p. 157°-158°.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([C:11]2[CH:12]=[N:13][C:14]3[N:15]([C:17]([C:20]4([C:23]5[CH:24]=[C:25]6[C:30](=[CH:31][CH:32]=5)[N:29]=[CH:28][CH:27]=[CH:26]6)[CH2:22][CH2:21]4)=[CH:18][N:19]=3)[CH:16]=2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:33][O:34][CH2:35][CH:36]([NH2:38])[CH3:37].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[F:1][C:2]1[CH:10]=[C:9]([C:11]2[CH:12]=[N:13][C:14]3[N:15]([C:17]([C:20]4([C:23]5[CH:24]=[C:25]6[C:30](=[CH:31][CH:32]=5)[N:29]=[CH:28][CH:27]=[CH:26]6)[CH2:22][CH2:21]4)=[CH:18][N:19]=3)[CH:16]=2)[CH:8]=[CH:7][C:3]=1[C:4]([NH:38][CH:36]([CH3:37])[CH2:35][O:34][CH3:33])=[O:6]
Reactant: COCC(C)N
Reactant: O=C(O)c1ccc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3c2)cc1F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCC(C)NC(=O)c1ccc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3c2)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzoic acid (19 mg, 0.045 mmol), 1-methoxypropan-2-amine (8 mg, 0.090 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (40 mg, 0.090 mmol), and N,N-diisopropylethylamine (31 μL, 0.18 mmol) in N,N-dimethylformamide (0.5 mL) was stirred at RT for 2 h. The reaction mixture was purified by RP-HPLC (pH 10) to afford the desired product. LCMS: (M+H)=496.1
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][N:11]([CH3:24])[CH:12]1[CH2:17][CH2:16][CH:15]([CH2:18][C:19]([O:21]CC)=[O:20])[CH2:14][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO.C1COCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][N:11]([CH3:24])[CH:12]1[CH2:17][CH2:16][CH:15]([CH2:18][C:19]([OH:21])=[O:20])[CH2:14][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)CC1CCC(N(C)CCNC(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CN(CCNC(=O)OC(C)(C)C)C1CCC(CC(=O)O)CC1
Reaction time: 2.75 h

Procedure:
To a solution of ethyl 2-[4-[2-(tert-butoxycarbonylamino)ethyl-methyl-amino]cyclohexyl]acetate (231 mg, 0.67 mmol) in methanol (2 mL) and THF (2 mL) was added NaOH (1 mL, 2M aqueous solution). The resulting solution was stirred for 2.75 hours then concentrated under reduced pressure to approximately ¼ the original volume. The residue was acidified with HCl (3 mL, 1M aqueous solution). This solution was purified directly by reverse phase silica chromatography (30 g of C18 silica; eluted with 5-100% acetonoitrile/water/0.1% TFA) to give the title compound.
Reaction SMILES: [OH:1][N:2]=[CH:3][CH:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9](=[O:28])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])=[O:19])=[CH:13][CH:12]=1.C[O:30][C:31](=[O:44])[CH:32]([NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][C:34]#[CH:35].C(N(CC)CC)C.Cl[O-].[Na+]>ClCCl>[C:40]([O:39][C:37]([NH:36][CH:32]([CH2:33][C:34]1[O:1][N:2]=[C:3]([CH:4]2[CH2:8][CH2:7][CH2:6][N:5]2[C:9](=[O:28])[CH2:10][C:11]2[CH:12]=[CH:13][C:14]([NH:17][C:18]([NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[CH3:27])=[O:19])=[CH:15][CH:16]=2)[CH:35]=1)[C:31]([OH:44])=[O:30])=[O:38])([CH3:43])([CH3:42])[CH3:41]
Reactant: Cc1ccccc1NC(=O)Nc1ccc(CC(=O)N2CCCC2C=NO)cc1
Reactant: C#CCC(NC(=O)OC(C)(C)C)C(=O)OC
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccccc1NC(=O)Nc1ccc(CC(=O)N2CCCC2c2cc(CC(NC(=O)OC(C)(C)C)C(=O)O)on2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 14.1 %

Procedure:
A solution of 1-(4-{2-[2-(hydroxyimino-methyl)-pyrrolidin-1-yl]-2-oxo-ethyl}-phenyl)-3-o-tolyl-urea (300 mg, 0.789 mmol), 2-tert-butoxycarbonylamino-pent-4-ynoic acid methyl ester (359 mg, 1.182 mmol, crude mixture) and triethyl amine (12.9 μL) in dichloromethane (2 mL) was stirred 5 minutes. A sodium hypochlorite solution (5.25%, 2 mL) was added. The reaction was stirred at room temperature overnight. The aqueous portion was extracted 4 times with dichloromethane. The combined organic portions were washed with brine, dried over magnesium sulfate and concentrated. Chromatography of the crude mixture on a Biotage Flash 40S column eluting with ethyl acetate/hexane 1:5 gave the title compound (66 mg, 14%). MS (Cl) m/z 604.5 (M−1), 505.9 (M−99) C. 2-tert-Butoxycarbonylamino-pent-4-ynoic acid methyl ester
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:19]=[C:18]3[C:13]([C:14](=O)[CH2:15][CH2:16][O:17]3)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21](P(=O)(OCC)OCC)#[N:22].[C-]#N.[Li+].O>O1CCCC1>[C:1]1([S:7]([C:10]2[CH:19]=[C:18]3[C:13]([CH:14]([C:21]#[N:22])[CH2:15][CH2:16][O:17]3)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCOc2cc(S(=O)(=O)c3ccccc3)ccc21
Reactant: CCOP(=O)(C#N)OCC
Agent: [C-]#N
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: N#CC1CCOc2cc(S(=O)(=O)c3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 58 %

Procedure:
7-Benzenesulfonyl-chroman-4-one from Preparation 1 above (500 mg, 1.73 mmol) was dissolved in 10 mL of tetrahydrofuran (THF). Diethyl cyanophosphonate (789 uL, 5.21 mmol) and lithium cyanide (10.42 mL, 5.21 mmol) were added, and the reaction mixture was stirred for 10 minutes at room temperature. Water (150 (mL) was added, and the aqueous mixture was extracted twice with 200 mL of EtOAc. The combined organic layers were washed with brine, dried over MgSO4, and the solvent was evaporated under reduced pressure. The residue was dissolved in 5 mL THF, and 70 mL of MeOH was added. SmI2 (52 mL, 5.21 mmol) was then added over five minutes, and the reaction mixture was stirred for 10 minutes at room temperature. The reaction was quenched by addition of 20 mL 1 N HCl, and the resulting aqueous mixture was extracted with EtOAc and 1 N Na2S2O3. The organic phase was dried over MgSO4, and solvent was removed under reduced pressure. The residue eluted through silica gel using 40% EtOAc in hexanes, and solvent was removed under reduced pressure to yield 300 mg (1 mmol, 58%) of 7-benzenesulfonyl-chroman-4-carbonitrile. MS: 300 (M+H)+.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH:22]=O)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].C(O)C>[NH3:1].[N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3([CH2:22][N:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:14][CH:15]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=CC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Reactant: C1CCNCC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: CCO
Product: N
Product: c1cc(C2(CN3CCCCC3)CCOCC2)ccc1OCCCN1CCCC1
Yield: 58.6 %

Procedure:
4-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carbaldehyde (272 mg, 0.86 mmol), piperidine (0.161 mL, 1.63 mmol), absolute ethanol (11 mL), activated 4 Å molecular sieves, titanium (IV) isopropoxide (1.205 mL, 4.28 mmol) and STAB (1.54 g, 7.28 mmol) were reacted in accordance with the general procedure D. The isolated waxy solid was purified by column chromatography on silica eluting with a gradient of DCM:MeOH:NH3 (from 99:0:1 to 90:9:1) to give the title compound (97.4 mg, 25%). 1H NMR (400 MHz, CDCl3) δ 7.21 (d, 2H), 6.85 (d, 2H), 4.02 (t, 2H), 3.77-3.72 (m, 2H), 3.54-3.48 (t, 2H), 2.63 (t, 2H), 2.53 (m, 4H), 2.29 (s, 2H), 2.13-1.87 (m, 10H), 1.79 (quint, 4H), 1.41-1.36 (m, 4H), 1.30-1.26 (m, 2H).
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].C(O)=O.[CH:8]([C:10](=[N+:16]=[N-:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=O>CO>[OH:2][CH2:1][CH2:3][N:4]1[CH:8]=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:16]=[N:17]1
Reactant: CCOC(=O)C(C=O)=[N+]=[N-]
Reactant: NCCO
Solvent: CO
Solvent: O=CO
Product: CCOC(=O)c1cn(CCO)nn1
Temperature: 25 °C
Reaction time: 48 h
Yield: 74.9 %

Procedure:
A solution of ethanolamine (60 ml, 1 mole) in methanol (320 ml) at 5° was treated with formic acid until a pH of 5 was obtained. A solution of ethyl α-formyldiazoacetate (crude, approximately 0.3 mole) in methanol (320 ml) was then added and the mixture stirred at room temperature for two days. The mixture was then evaporated, chloroform (1 liter), then water (200 ml) was added and the mixture was treated with sodium bicarbonate until a pH of 7 was reached. The phases were separated and the aqueous phase saturated with sodium chloride and extracted with chloroform (6 x 300 ml). The combined organic phases were dried (MgSO4), filtered and evaporated. The residue was then dissolved in toluene (approximately 100 ml). The resulting crystalline solid was filtered, washed with ether and dried to provide the title compound (41.6 g) as a solid; λmax (nujol) 3320, 3140, 1725 cm-1 ; δ (CDCl3), 1.38 (3H, t, J 7.5Hz), 4.00-4.80 (7H, m, becomes 6H, m on D2O exch), 8.40 (1H, s). This material was pure enough for further synthetic progression.
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[NH:8][CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:11]=1.Cl[C:19]([O:21][CH2:22][CH3:23])=[O:20]>O1CCCC1>[CH3:6][C:7]1[N:8]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:9]=[C:10]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:11]=1
Reactant: CCOC(=O)Cl
Reactant: Cc1cc(-c2ccccc2)c[nH]1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)n1cc(-c2ccccc2)cc1C
Reaction time: 0.33 h
Yield: 106.9 %

Procedure:
n-Butyllithium (0.87 mL, 1.6M solution, 1.40 mmol) was added to a cold (below 0° C.) solution of 2-methyl-4-phenyl-1H-pyrrole (200 mg, 1.27 mmol) in tetrahydrofuran (6 mL) and stirred at below 0° C. for 20 min. Ethyl chloroformate (0.1 mL, 1.02 mmol) was added slowly to the reaction mixture and stirred at 0 to 10° C. for 90 min. The reaction mixture was quenched into saturated ammonium chloride solution and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution, brine, dried over anhydrous sodium sulphate and concentrated in vacuo to afford ethyl 2-methyl-4-phenyl-pyrrole-1-carboxylate (250 mg, 86%) as a brown solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][OH:12])=[N:9][CH:10]=2)[CH:7]=1.C(=O)(O)[O-].[Na+].[I:18]I>C(O)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][OH:12])=[N:9][C:10]=2[I:18])[CH:7]=1
Reactant: OCc1ncc2ccc(F)cn12
Reactant: II
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: OCc1nc(I)c2ccc(F)cn12
Temperature: 25 °C
Reaction time: 3 h
Yield: 46.7 %

Procedure:
In a round-bottomed flask, (6-fluoro-imidazo[1,5-a]pyridin-3-yl)-methanol (225 mg, 1.15 mmol) was dissolved in ethanol (2 ml) and water (1 ml). Sodium bicarbonate (341 mg, 4.06 mmol) was added followed by iodine (383 mg, 1.51 mmol). The dark brown suspension was stirred at room temperature for 3 h then quenched with 10% Na2S2O3-solution and extracted with EtOAc (2×). The organic layers were washed with water and brine then dried over sodium sulfate, filtered and concentrated. The residue was absorbed on silica gel and chromatographed with EtOAc/hexanes (gradient 0-40% EtOAc) to provide 157 mg (50%, 2 steps) of (6-fluoro-1-iodo-imidazo[1,5-a]pyridin-3-yl)-methanol as a light yellow solid.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([OH:11])=[CH:9][CH:10]=1.[CH3:12][C:13](OC(C)=O)=[O:14].N1C=CC=CC=1>ClCCl>[C:13]([O:11][C:8]1[CH:7]=[CH:6][C:5]([CH2:4][CH2:3][CH2:2][CH3:1])=[CH:10][CH:9]=1)(=[O:14])[CH3:12]
Reactant: CCCCc1ccc(O)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCc1ccc(OC(C)=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 10 g of 4-n-butylphenol, 10 ml of Ac2O and 8 ml of pyridine is stirred at reflux in 10 ml of dichloromethane. After 2 hours, the medium is cooled to room temperature, diluted with dichloromethane, washed with water, washed with 1M HCl solution, washed with saturated CuSO4 solution, washed with water and dried over MgSO4. After evaporation, 10.8 g of the expected compound are recovered in the form of an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:19])([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.Cl[CH2:21][CH2:22][NH:23][CH2:24][CH2:25]Cl.Cl>C1(C)C(C)=CC=CC=1>[CH3:19][C:8]([C:5]1[CH:6]=[CH:7][C:2]([N:1]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:3][CH:4]=1)([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)C(C)(C(=O)OCC)c1ccc(N)cc1
Reactant: ClCCNCCCl
Agent: Cl
Solvent: Cc1ccccc1C
Product: CCOC(=O)C(C)(C(=O)OCC)c1ccc(N2CCNCC2)cc1
Yield: 63.5 %

Procedure:
A suspension of diethyl 2-(4-aminophenyl)-2-methylmalonate (6.00 g, 22.6 mmol), Bis-(2-chloroethyl) amine.HCl (4.82 g, 27.2 mmol) in xylene (20 ml) was refluxed for 48 h. The reaction mixture was concentrated in vacuo and the residue was partitioned between saturated sodium bicarbonate solution and ethyl acetate. The separated organic layer was washed with water, brine solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product. Purification by column chromatography over neutral alumina using 5% MeOH in CHCl3 as eluent afford 4.80 g (63.5%) of diethyl 2-methyl-2-(4-(piperazin-1-yl)phenyl)malonate as brown oil.
Reaction SMILES: [NH2:1][C:2]([CH:4]1[CH2:9][N:8]([CH2:10][CH2:11][CH2:12][CH2:13][CH:14]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH2:7][CH2:6][N:5]1[CH2:29][C:30]([NH:32][C:33]1[C:38]([Cl:39])=[CH:37][C:36]([CH2:40][NH:41]C(=O)OC(C)(C)C)=[CH:35][C:34]=1[Cl:49])=[O:31])=[O:3].CO.Cl>CC(O)C>[NH2:1][C:2]([CH:4]1[CH2:9][N:8]([CH2:10][CH2:11][CH2:12][CH2:13][CH:14]([C:22]2[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=2)[C:15]2[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=2)[CH2:7][CH2:6][N:5]1[CH2:29][C:30]([NH:32][C:33]1[C:38]([Cl:39])=[CH:37][C:36]([CH2:40][NH2:41])=[CH:35][C:34]=1[Cl:49])=[O:31])=[O:3]
Reactant: CC(C)(C)OC(=O)NCc1cc(Cl)c(NC(=O)CN2CCN(CCCCC(c3ccc(F)cc3)c3ccc(F)cc3)CC2C(N)=O)c(Cl)c1
Agent: Cl
Solvent: CO
Solvent: CC(C)O
Product: NCc1cc(Cl)c(NC(=O)CN2CCN(CCCCC(c3ccc(F)cc3)c3ccc(F)cc3)CC2C(N)=O)c(Cl)c1
Yield: 44.9 %

Procedure:
A mixture of 8.7 parts of (1,1-dimethylethyl) [[4-[[2-[2-(aminocarbonyl)-4-[5,5-bis(4-fluorophenyl)pentyl]-1-piperazinyl]acetyl]amino]-3,5-dichlorophenyl]methyl]carbamate, 120 parts of methanol and 24 parts of 2-propanol, saturated with hydrogen chloride was stirred for 30 minutes at reflux temperature. The reaction mixture was evaporated and the residue was taken up in water. The whole was treated with an ammonium hydroxide solution and the product was extracted twice with dichloromethane. The combined extracts were washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (93:7 by volume) as eluent. The desired fraction was collected and the eluent was evaporated. The residue was suspended in 2,2'-oxybispropane. The product was filtered off and dried, yielding 3.34 parts (44.9%) of 2-(aminocarbonyl)-N-(4-(aminomethyl)-2,6-dichlorophenyl]-4-[5,5-bis(4-fluorophenyl)pentyl]-1-piperazineacetamide; mp. 160.8° C. (compound 100 ).
Reaction SMILES: [CH3:1][N:2]([CH2:8][CH2:9][OH:10])[C:3]1[S:4][CH:5]=[CH:6][N:7]=1.F[C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1>>[CH3:1][N:2]([CH2:8][CH2:9][O:10][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1)[C:3]1[S:4][CH:5]=[CH:6][N:7]=1
Reactant: CN(CCO)c1nccs1
Reactant: O=Cc1ccc(F)cc1
Product: CN(CCOc1ccc(C=O)cc1)c1nccs1

Procedure:
The-title compound was prepared from 2-[N-methyl-N-(2-thiazolyl)amino]ethanol (10.7 g) and 4-fluorobenzaldehyde (15.9 g) by an analogous procedure to that described in Preparation 5.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]2[N:4]([CH:5]=[N:6][C:7]3[CH:13]=[CH:12][S:11][C:8]=32)[N:3]=1.[Br:14]N1C(=O)CCC1=O>C(Cl)Cl>[Br:14][C:10]1[C:2]([CH3:1])=[N:3][N:4]2[C:9]=1[C:8]1[S:11][CH:12]=[CH:13][C:7]=1[N:6]=[CH:5]2
Reactant: Cc1cc2c3sccc3ncn2n1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: Cc1nn2cnc3ccsc3c2c1Br
Reaction time: 1 h

Procedure:
To a solution of 8-methylpyrazolo[1,5-c]thieno[2,3-e]pyrimidine (1.01 g, 5.34 mmol) in methylene chloride (30 mL) was added N-bromosuccinimide (0.959 g, 5.39 mmol). After stirring for 1 h, the reaction solution was concentrated, and the resultant residue was purified with flash chromatography (eluting with a gradient of 0-20% ethyl acetate in hexanes) to give the desired product as whited solid. 1H NMR (300 MHz, CD3OD) δ 9.11 (1H, s), 7.94 (1H, d, J=5.3 Hz), 7.52 (1H, d, J=5.3 Hz), 2.48 (3H, s) ppm. LCMS calculated for C9H7BrN3S (M+H)+: m/z=268.0. Found: 267.9.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:15]([C:20](O)=[O:21])=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:10][C:9]=2[F:23])=[CH:4][N:3]=1.[N:24]1([C:30](=[O:32])[CH3:31])[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>>[C:30]([N:24]1[CH2:29][CH2:28][N:27]([C:20]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[C:11]2[CH:12]=[CH:13][C:8]([C:5]3[N:6]=[CH:7][C:2]([NH2:1])=[N:3][CH:4]=3)=[C:9]([F:23])[CH:10]=2)=[O:21])[CH2:26][CH2:25]1)(=[O:32])[CH3:31]
Reactant: CC(=O)N1CCNCC1
Reactant: Nc1cnc(-c2ccc(-c3ccccc3C(=O)O)cc2F)cn1
Product: CC(=O)N1CCN(C(=O)c2ccccc2-c2ccc(-c3cnc(N)cn3)c(F)c2)CC1

Procedure:
The title compound was prepared using methods analogous to those described in Step C of Example 504 using 4′-(2-aminopyrazin-5-yl)-3′-fluoro-[1,1′-biphenyl]-2-carboxylic acid for and 1-(piperazin-1-yl)ethanone. MS (ESI): mass calcd. for C23H22FN5O2, 419.18; m/z found, 420.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.65-8.56 (m, 1H), 8.11 (d, J=1.5, 1H), 8.02 (dd, J=10.4, 5.8, 1H), 7.55-7.41 (m, 4H), 7.42-7.32 (m, 1H), 7.34-7.28 (m, 1H), 4.71 (s, 2H), 3.65 (s, 2H), 3.51-2.93 (m, 4H), 2.79 (s, 2H), 1.99 (d, 3H).