Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.C([Li])CCC.[C:14]1([CH:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:22](=O)[O:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl>C1COCC1.CCCCCC>[Br:8][C:5]1([C:22]2[O:21][C:20]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[C:29]3[C:24]=2[CH:25]=[CH:26][CH:27]=[CH:28]3)[CH:6]=[CH:7][CH:2]=[CH:3][CH2:4]1
Reactant: Brc1ccc(Br)cc1
Reactant: O=C1OC(c2ccccc2)c2ccccc21
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: BrC1(c2oc(-c3ccccc3)c3ccccc23)C=CC=CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 69.7 %

Procedure:
Into a 200-cm3 Schlenk tube filled with argon, 5.0 g (2.12×10−2 mol) of 1,4-dibromobenzene was weighed. Into the Schlenk tube, 100 cm3 of dehydrated THF was poured, whereby a THF solution was prepared. After the THF solution was cooled to −50° C., 12.7 cm3 (1.9×10−2 mol) of a 1.5 mol/L hexane solution of n-butyllithium was added to the THF solution. The solution mixture was agitated for 1.5 hours while being cooled. To the resulting solution mixture, 4 g (1.9×10−2 mol) of 3-phenylphthalide was added. This mixture was cooled for two hours and then warmed to room temperature. To this mixture, 30 cm3 of a 35% aqueous solution of hydrochloric acid was added. This mixture was allowed to stand for one hour, transferred to a separatory funnel, and then subjected to extraction using toluene. The toluene layer in the separatory funnel was sufficiently washed with distilled water and then concentrated. The resulting toluene layer was fractionated by silica gel chromatography using a mixture containing toluene and hexane at a ratio of 1:4, whereby 4.65 g of 1-bromophenyl-3-phenylisobenzofuran was obtained as shown in FIG. 10. The yield of 1-bromophenyl-3-phenylisobenzofuran was 70%.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][NH:10][C:11]([CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[O:12].[N:21]1[C:28]([Cl:29])=[N:27][C:25](Cl)=[N:24][C:22]=1[Cl:23].C(N(C(C)C)CC)(C)C>C(#N)C>[Cl:23][C:22]1[N:21]=[C:28]([Cl:29])[N:27]=[C:25]([N:16]2[CH2:17][CH2:18][CH:13]([C:11]([NH:10][CH2:9][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:2]([F:1])([F:19])[F:20])=[O:12])[CH2:14][CH2:15]2)[N:24]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: O=C(NCc1ccccc1C(F)(F)F)C1CCNCC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1ccccc1C(F)(F)F)C1CCN(c2nc(Cl)nc(Cl)n2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of N-{[2-(trifluoromethyl)phenyl]methyl}-4-piperidinecarboxamide (950 mg, 3.32 mmol, 1.00 equiv) in acetonitrile (30 ml) at room temperature, cyanuric chloride (612 mg, 3.32 mmol, 1.00 equiv) and diisopropylethylamine (DIEA, 1.74 ml, 9.95 mmol, 3.00 equiv) were added dropwise. The reaction was stirred at room temperature for 3 h. Without workup or purification, the reaction mixture was carried forward to the next step. MS (ES+): m/e 435.9 [M+H]+
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([I:10])=[C:6]([CH2:8][OH:9])[CH:7]=1.[H-].[Na+].[C:13]([Si:17]([CH3:20])([CH3:19])Cl)([CH3:16])([CH3:15])[CH3:14].[I-].[K+]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([I:10])=[C:6]([CH:7]=1)[CH2:8][O:9][Si:17]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1cc(Br)ccc1I
Agent: [H-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1cc(Br)ccc1I
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 9.59 mmol (5-bromo-2-iodo-phenyl)-methanol [199786-58-8] in 10 ml of N,N-dimethylformamide is added at room temperature dropwise to a mixture of 11.5 mmol of sodium hydride (60% in paraffine) in 20 ml of N,N-dimethylformamide. The mixture is stirred for 1 h at room temperature. 10.6 mmol of tert-butyl-dimethylchloro silane and 1.00 mmol of potassium iodide are added and the mixture stirred for 30 minutes at room temperature. The reaction is quenched with water and extracted with toluene. The combined organics are washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue is purified by flash chromatography (SiO2 60 F) to afford the title compound as colourless oil. Rf=0.35 (dichloromethane); Rt=11.31 (gradient II).
Reaction SMILES: CO[C:3](=[O:26])[C@@H:4]([CH2:22][CH:23]([CH3:25])[CH3:24])[N:5]([P:13]([CH3:21])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:14])[CH2:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.Cl.[NH2:28][O:29][K]>>[OH:29][NH:28][C:3](=[O:26])[C@H:4]([N:5]([P:13]([CH3:21])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:14])[CH2:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)[CH2:22][CH:23]([CH3:25])[CH3:24]
Reactant: COC(=O)[C@@H](CC(C)C)N(Cc1cccnc1)P(C)(=O)c1ccccc1
Reactant: NO[K]
Agent: Cl
Product: CC(C)C[C@H](C(=O)NO)N(Cc1cccnc1)P(C)(=O)c1ccccc1
Reaction time: 16 h

Procedure:
Methylphenylphosphinic chloride (12.23 g, 70 mmol) is taken up in dichloromethane (100 mL) and cooled to 0° C. To this is added a solution of N-(3-picolyl) D-leucine methyl ester (15.5 g, 65.6 mmol) and N-methyl morpholine (19.24 mL, 175 mmol) in dichloromethane (100 mL). A catalytic amount of 4-dimethylaminopyridine is added and the reaction stirs for 16 hours at room temperature. More methylphenylphosphinic chloride is added (2 g, 11.46 mmol). The reaction continues to stir for 24 hours until complete. By TLC, the diastereomers do not separate. The product is purified by silica gel flash chromatography (5:95 ethanol:ethyl acetate) to give N-((R/S)-methylphenyl-phosphinyl)-N-(3-picolyl) D-leucine methyl ester as an oil. To this ester is added a solution of NH2OK (250 mL, 1.76M in methanol) prepared as described in Fieser and Fieser, Vol. 1, p. 478. The reaction is stirred for 16 hours at which time TLC indicates completion. The reaction mixture is neutralized with 1M aqueous HCl and the volatiles are removed. The product is purified by silica gel flash chromatography (10:90 ethanol:ethyl acetate) to give 8.6 g of N-hydroxy-2(R)-[[(R/S)-methylphenylphosphinyl]3-picolylamino]-4-methylpentanamide as a 60 (R)/40 (S) mixture of diastereomers: MS-IS m/z 376 [M+H]+, 398[M+Na]+. (R1 =3-pyridyl methyl, R2 =isobutyl, R3 =methyl, R4 =phenyl).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][C:12]3([CH2:23][C:22](=[O:24])[C:21]4[C:16](=[CH:17][CH:18]=[C:19](/[CH:25]=[CH:26]/[C:27](O)=[O:28])[CH:20]=4)[O:15]3)[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:30][O:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][O:33]1>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][C:12]3([CH2:23][C:22](=[O:24])[C:21]4[C:16](=[CH:17][CH:18]=[C:19](/[CH:25]=[CH:26]/[C:27]([NH:30][O:31][CH:32]5[CH2:37][CH2:36][CH2:35][CH2:34][O:33]5)=[O:28])[CH:20]=4)[O:15]3)[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(CCc3ccccc3)CC1)O2
Reactant: NOC1CCCCO1
Solvent: ClCCl
Product: O=C(/C=C/c1ccc2c(c1)C(=O)CC1(CCN(CCc3ccccc3)CC1)O2)NOC1CCCCO1

Procedure:
(E)-3-{1′-(2-Phenyl-ethyl)-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid (1.71 g, 4.00 mmol) obtained in Step B was suspended in DCM (50 ml). TEA (0.84 ml, 6.0 mmol) was added and the clear solution was treated with NH2OTHP following the procedure described in Example 1, Step B, giving (E)-3-{1′-(2-phenyl-ethyl)-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide (1.62 g) as a light yellow solid.
Reaction SMILES: [C:1](=[C:4]([C:10]([O:12]C)=O)[C:5]([O:7][CH2:8]Br)=[O:6])([CH3:3])[CH3:2].[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)C>[CH3:8][O:7][C:5]([C:4]1[C:10](=[O:12])[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:2][C:1]=1[CH3:3])=[O:6]
Reactant: COC(=O)C(C(=O)OCBr)=C(C)C
Reactant: Nc1ccccc1
Solvent: CCO
Product: COC(=O)C1=C(C)CN(c2ccccc2)C1=O
Yield: 52.4 %

Procedure:
A solution of 20.6 grams (82 mmol) of impure bromomethyl methyl isopropylidenemalonate and 15.2 grams (0.169 mol) of aniline in 25 mL of absolute ethanol were stirred at room temperature. Initially a homogeneous solution formed. After a mildly exothermic reaction a precipitate formed. The reaction was refluxed for 1 hour, cooled, and filtered. The collected product was washed with ethanol and water to give 10.0 grams (43 mmol, 52% yield) of crude product. An analytical sample was prepared by recrystallizing from methanol, m. p.=143°-145° C., Elemental Analysis: Calculated: C=67.5, H=5.7, N=6.1; Found: C=67.7, H=5.9, N=6.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[NH:23][N:24]=[C:25]([O:26][CH2:27][CH2:28][NH:29][CH2:30][CH2:31][OH:32])[C:18]=23)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.[C:33](C1NC=CN=1)(C1NC=CN=1)=[O:34]>CC(N(C)C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[NH:23][N:24]=[C:25]([O:26][CH2:27][CH2:28][N:29]4[CH2:30][CH2:31][O:32][C:33]4=[O:34])[C:18]=23)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: OCCNCCOc1n[nH]c2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Solvent: CC(=O)N(C)C
Product: O=C1OCCN1CCOc1n[nH]c2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.2 %

Procedure:
2-({2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}-1H-pyrazolo[3,4-d]pyrimidin-3-yl)oxy]ethyl}amino)ethanol (prepared as described in Example 36/27 mg, 0.06 mmol) was dissolved in DMA (0.7 ml) and carbonyl diimidazole (14 mg, 0.09 mmol) was added at −15° C. The temperature was slowly raised to room temperature and the reaction mixture was stirred for 1 hour. The crude mixture was purified by preparative HPLC (column beta-basic, Hypercil 5 μm, 21×100 mm) eluting with a mixture of water and acetonitrile containing 2g/l of ammonium carbonate (gradient) to give the title compound (20 mg, 69%); NMR Spectrum: 3.67-3.71 (m, 4H), 4.29 (t, 2H), 4.44 (t, 2H), 5.28 (s, 2H), 7.24 (d, 1H), 7.37 (t, 1H), 7.58 (d, 1H), 7.74 (dd, 1H), 7.88 (t, 2H), 8.11 (d, 1H), 8.13 (s, 1H), 8.33 (s, 1H), 8.59 (d, 1H); Mass Spectrum: 482 (MH+).
Reaction SMILES: C([O:3][C:4]([CH2:6][NH:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[CH:10][C:9]=1[C@@H:18]1[CH2:27][CH2:26][C:25]2[CH:24]=[C:23]([O:28]C(=O)C(C)(C)C)[CH:22]=[CH:21][C:20]=2[CH2:19]1)=O)C.C(O[C:40]([N:42]1[CH2:47][CH2:46][CH:45]([C:48]2[CH:53]=[CH:52][C:51]([C:54](O)=O)=[CH:50][CH:49]=2)[CH2:44][CH2:43]1)=O)(C)(C)C>>[OH:3][CH2:4][CH2:6][N:7]([CH2:54][C:51]1[CH:50]=[CH:49][C:48]([CH:45]2[CH2:44][CH2:43][N:42]([CH3:40])[CH2:47][CH2:46]2)=[CH:53][CH:52]=1)[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[CH:10][C:9]=1[C@@H:18]1[CH2:27][CH2:26][C:25]2[CH:24]=[C:23]([OH:28])[CH:22]=[CH:21][C:20]=2[CH2:19]1
Reactant: CCOC(=O)CNc1cc(OC)c(OC)cc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(C(=O)O)cc2)CC1
Product: COc1cc([C@@H]2CCc3cc(O)ccc3C2)c(N(CCO)Cc2ccc(C3CCN(C)CC3)cc2)cc1OC
Yield: 56.7 %

Procedure:
Synthesized from pivalic acid (R)-6-[2-(ethoxycarbonylmethylamino)-4,5-dimethoxyphenyl]-5,6,7,8-tetrahydronaphthalen-2-yl ester (39 mg) and 4-(4-carboxyphenyl)piperidine-1-carboxylic acid tert-butyl ester (38 mg) according to an analogous synthetic method to the above-mentioned Preparation Example 86 and Example 337, the title compound (25 mg) was obtained.
Reaction SMILES: N1C=CC=CC=1CC[O:9][C:10](=[O:35])[CH:11]([N:18]1[C:22]2[CH:23]=[CH:24][C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]#[N:34])=[CH:26][C:21]=2[N:20]=[CH:19]1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>CO.[OH-].[Na+]>[C:33]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:25]1[CH:24]=[CH:23][C:22]2[N:18]([CH:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:10]([OH:35])=[O:9])[CH:19]=[N:20][C:21]=2[CH:26]=1)#[N:34]
Reactant: CCCCCCC(C(=O)OCCc1ccccn1)n1cnc2cc(-c3ccccc3C#N)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCC(C(=O)O)n1cnc2cc(-c3ccccc3C#N)ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.6 %

Procedure:
2-[5-(2-Cyanophenyl)-1H-benzimidazol-1-yl]octanoic acid 2-pyridylethylester (0.042 moles, 19.6 g) was dissolved in 20 ml of methanol and 8 ml of 1N NaOH. The solution was stirred at room temperature for 3 hours. The reaction was concentrated under vacuum, dissolved in water, and washed with ether. The pH was adjusted to 3.0 with 5N HCl. The intermediate was extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate, and concentrated. The reaction produced 13.0 g of 2-[5-(2-cyanophenyl)-1H-benzimidazol-1-yl]octanoic acid. (MS).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]([N+:14]([O-])=O)[C:4]=1[C:5]([OH:7])=[O:6]>CCO.[Pd]>[NH2:14][C:8]1[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[C:4]=1[C:5]([OH:7])=[O:6]
Reactant: COc1ccc([N+](=O)[O-])c(C(=O)O)c1OC
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(N)c(C(=O)O)c1OC
Reaction time: 1 h

Procedure:
A slurry of 2,3-dimethoxy-6-nitrobenzoic acid (5 g, 22 mM) in EtOH (200 ml) was treated with Pd/C (5%, 0.5 g) and the mixture hydrogenated on a Parr apparatus at 45 psi for 1 hour. The reaction mixture was filtered and the solvent removed from the filtrate. An off-white semi-solid residue was isolated. Crystallization from isopropanol afforded the amine, 3.8 g (86.7%), mp 71°-72° C.
Reaction SMILES: [H-].[Li+].ClC1C=CC(NC2SC3N=CC=CC=3C(=O)N=2)=CC=1.BrCC[N:25]1[C:29](=[O:30])[C:28]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:27]2[C:26]1=[O:35]>CN(C=O)C>[C:26]1(=[O:35])[C:27]2[C:28](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29](=[O:30])[NH:25]1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Agent: O=c1nc(Nc2ccc(Cl)cc2)sc2ncccc12
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2ccccc21

Procedure:
The reaction and processing procedure of Example 127 was followed except that 30 mg (3.8 mmol) of lithium hydride, 17 ml of DMF, 800 mg (2.8 mmol) of 2-(4-chloroanilino)-4H-pyrido[3,2-e]-1,3-thiazin-4-one and 1.12 g of N-(2-bromoethyl)-phthalimide were used and post-treatment was carried out. The resulting residue was then purified through silica gel column chromatography (eluant: 1/2 mixture of ethyl acetate and normal hexane) to obtain 883 mg of 2-[2-[2-(4-chlorophenyl)imino]-4-oxo-2,3-dihydro-4H-pyrido[3,2-e]-1,3-thiazin-3-yl]ethyl]isoindol-1,3-dione.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([O:34][C:35](=[O:37])[CH3:36])[C:10]2[N:11]=[CH:12][N:13](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:14]=2)=[CH:5][C:4]=1[F:38])#[N:2].S(OC)(O[CH3:43])(=O)=O>CCOC(C)=O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([O:34][C:35](=[O:37])[CH3:36])[C:10]2[N:11]([CH3:43])[CH:12]=[N:13][CH:14]=2)=[CH:5][C:4]=1[F:38])#[N:2]
Reactant: COS(=O)(=O)OC
Reactant: CC(=O)OC(c1ccc(C#N)c(F)c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Solvent: CCOC(C)=O
Product: CC(=O)OC(c1ccc(C#N)c(F)c1)c1cncn1C
Temperature: 60 °C

Procedure:
Acetic acid (4-cyano-3-fluoro-phenyl)-(1-trityl-1H-imidazol-4-yl)-methyl ester (4.60 g, 9.17 mmol) and dimethyl sulfate (0.83 mL, 8.81 mmol) were dissolved in EtOAc (20 mL) and heated at 60° C. overnight under Ar. The reaction was concentrated in vacuo, diluted with MeOH (30 mL), and refluxed for 1 h. Concentrated in vacuo and purified using SiO2 chromatography (0.5-4% MeOH/CH2Cl2 with NH4OH) to give the title compound.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([S:11]([NH2:14])(=[O:13])=[O:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([SH:22])=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.C(Cl)Cl>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([S:22][C:2]2[CH:3]=[C:4]([S:11]([NH2:14])(=[O:13])=[O:12])[CH:5]=[CH:6][C:7]=2[N+:8]([O-:10])=[O:9])=[CH:18][CH:17]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: NS(=O)(=O)c1ccc([N+](=O)[O-])c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc([N+](=O)[O-])c(Sc2ccc(Cl)cc2)c1

Procedure:
3-Chloro-4-nitrobenzenesulphonamide (1.08 g; 4.53 mmol), 4-chlorothiophenol (0.66 g; 4.53 mmol) and K2CO3 (0.64 g; 4.60 mmol) were refluxed in dioxan (30 ml) for 3 hours. The mixture was then diluted with CH2Cl2, filtered and washed with water. The organic phase was dried over MgSO4 and evaporated down. The product was recrystallised from petroleum ether/ethyl acetate. Yield: 1.0 g=64% 13C (100 MHz, DMSO-d6) δ 148.57, 146.43, 138.07, 137.08, 135.76, 130.70, 128.74, 127.27, 125.43, 123.52
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:3]=1.[CH:16]1([C:19]2[CH:20]=[C:21]([CH3:31])[C:22]([N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[N:23][CH:24]=2)[CH2:18][CH2:17]1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:28]2[CH2:29][CH2:30][N:25]([C:22]3[C:21]([CH3:31])=[CH:20][C:19]([CH:16]4[CH2:17][CH2:18]4)=[CH:24][N:23]=3)[CH2:26][CH2:27]2)=[O:8])=[C:4]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:3]=1
Reactant: Cc1cc(C2CC2)cnc1N1CCNCC1
Reactant: CS(=O)(=O)Nc1cc(Br)ccc1C(=O)O
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)cc2NS(C)(=O)=O)CC1
Yield: 79.9 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 60 and using 4-bromo-2-methanesulfonylaminobenzoic acid (1 g) described in Preparation Example 122 and 1-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine (0.739 g) described in Preparation Example 96, the title compound (1.34 g) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][N:11]=[C:10]([C:13]([N:15]3[CH2:20][CH2:19][N:18]([C:21](OC(C)(C)C)=O)[CH2:17][CH2:16]3)=O)[C:9]=2[C:28]2[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=2)=[CH:4][CH:3]=1.[OH-].[K+].CO.C(OCC)(=O)C.[NH4+].[OH-]>O1CCCC1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:12][N:11]=[C:10]([CH2:13][N:15]3[CH2:16][CH2:17][N:18]([CH3:21])[CH2:19][CH2:20]3)[C:9]=2[C:28]2[CH:29]=[CH:30][N:31]=[CH:32][CH:33]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2n[nH]c(-c3ccc(F)cc3)c2-c2ccncc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: CN1CCN(Cc2n[nH]c(-c3ccc(F)cc3)c2-c2ccncc2)CC1
Reaction time: 1.5 h
Yield: 43 %

Procedure:
To a suspension of 1,1-dimethylethyl 4-[[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]carbonyl]-1-piperazinecarboxylate (0.451 g, 1.0 mL) in dry tetrahydrofuran (8 mL), 1.0N LiAlH4 in tetrahydrofuran (2.5 mL, 2.5 mmol) was added dropwise at such a rate as to maintain reflux over 15 minutes. Upon the addition, the suspension became a clear light yellow solution, which was kept boiling for an additional 1.5 hours. Excess LiAlH4 was decomposed by cautious addition of a solution of KOH (0.5611 g, 10.0 mmol) in water (3.5 mL). Upon hydrolysis, a white salt precipitated. After the addition was completed, the mixture was heated to reflux for 1 hour. The hot solution was filtered by suction through a buchner funnel. Any remaining product was extracted from the precipitate by refluxing with tetrahydrofuran (10 mL) for 1 hour, followed again by suction filtration. The combined filtrates were concentrated under reduced pressure to give a crude residue, which was then diluted with ethyl acetate and washed with water and brine. The organic layer was dried over MgSO4. After filtration, the solvent was removed under reduced pressure, and a crude product was obtained. The desired product 1-[[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]methyl]-4-methylpiperazine (0.1509 g, 50.1%) was obtained by chromatography (silica gel, 70:30:1 methanol/ethyl acetate/NH4OH). Anal. Calc'd for C20H22N5F.0.6H2O: C, 66.32; H, 6.46; N, 19.33; Found: C, 66.31; H, 5.96; N, 18.83. MS (MH+): 352 (base peak).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH2:12][CH2:11][N:10]([CH2:13][C:14](O)=[O:15])[C:9]2=[O:17])=[CH:4][CH:3]=1.[Br:25][C:26]1[CH:36]=[CH:35][C:29](/[C:30](=[N:33]/[H])/[NH:31]O)=[CH:28][CH:27]=1.C(N=C=NCCCN(C)C)C>ClC(Cl)C>[Br:25][C:26]1[CH:36]=[CH:35][C:29]([C:30]2[N:33]=[C:14]([CH2:13][N:10]3[CH2:11][CH2:12][C:8]([C:18]4[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=4)([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[C:9]3=[O:17])[O:15][N:31]=2)=[CH:28][CH:27]=1
Reactant: O=C(O)CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Reactant: [H]/N=C(\NO)c1ccc(Br)cc1
Agent: CCN=C=NCCCN(C)C
Solvent: CC(Cl)Cl
Product: O=C1N(Cc2nc(-c3ccc(Br)cc3)no2)CCC1(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 85 °C

Procedure:
2-(3,3-bis(4-fluorophenyl)-2-oxopyrrolidin-1-yl)acetic acid (0.300 g, 0.905 mmol; Example 58D), (Z)-4-bromo-N-hydroxybenzimidamide (0.214 g, 0.996 mmol) and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine (0.211 g, 1.358 mmol) were stirred together in dichloroethane (5 mL) at room temperature for 3 hours. The reaction was then heated to 85° C. for 18 hours. The reaction was cooled, loaded onto a GraceResolv 80 g silica gel column (Grace Davison Discovery Sciences) and the product eluted with a gradient of 5% ethyl acetate/hexanes to 40% ethyl acetate/hexanes (Flow=40 mL/minute) over 40 minutes to give the title compound. 1H NMR (300 MHz, CDCl3) δ 7.85 (d, J=8.6, 2H), 7.62 (d, J=8.6, 2H), 7.38-7.30 (m, 4H), 7.07-6.97 (m, 4H), 4.87 (s, 2H), 3.56 (t, J=6.5, 2H), 2.83 (t, J=6.4, 2H); MS (ESI+) m/z 512.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10]C)=O)=[N:6][CH:5]=[CH:4][N:3]=1.[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1>CO>[NH2:1][C:2]1[C:7]([C:8]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:10])=[N:6][CH:5]=[CH:4][N:3]=1
Reactant: C1CCNC1
Reactant: COC(=O)c1nccnc1N
Solvent: CO
Product: Nc1nccnc1C(=O)N1CCCC1

Procedure:
A solution of 10 g. (0.065 mol) of methyl 2-aminopyrazine-3-carboxylate in 100 ml. of methanol and 25 ml. of pyrrolidine was refluxed for 18 hours. The residue obtained after evaporation under reduced pressure was triturated with ether to yield 8.8 g. (70%) of the above-named product as yellow crystals, with m.p. 100°-105°. A second crop of 2.3 g. (18%) with m.p. 95°-105° was obtained from the mother liquors. The analytical sample was recrystallized from 2-propanol. The pale yellow prisms had a melting point of 104°-106°.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][O:10][C:11]3[CH:17]=[CH:16][C:15]([C:18](O)=[O:19])=[CH:14][C:12]=3[CH:13]=2)=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl.Cl.[CH3:45][N:46]([CH2:53][C@H:54]1[CH2:59][CH2:58][C@H:57]([NH2:60])[CH2:56][CH2:55]1)[CH:47]1[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1.C1CCN2C(=NCCC2)CC1>C(#N)C.C(N(CC)CC)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:9][O:10][C:11]3[CH:17]=[CH:16][C:15]([C:18]([NH:60][C@H:57]4[CH2:56][CH2:55][C@H:54]([CH2:53][N:46]([CH3:45])[CH:47]5[CH2:52][CH2:51][O:50][CH2:49][CH2:48]5)[CH2:59][CH2:58]4)=[O:19])=[CH:14][C:12]=3[CH:13]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(C2=Cc3cc(C(=O)O)ccc3OC2)cc1
Reactant: CN(C[C@H]1CC[C@H](N)CC1)C1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCN(CC)CC
Product: Cc1ccc(C2=Cc3cc(C(=O)N[C@H]4CC[C@H](CN(C)C5CCOCC5)CC4)ccc3OC2)cc1
Reaction time: 2 h

Procedure:
Into a suspension of 3-(4-methylphenyl)-2H-1-benzopyran-6-carboxylic acid (150 mg) and 1-hydroxybenzotriazole (114 mg) in acetonitrile (15 ml) was added at room temperature 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (162 mg), and the resulting mixture was stirred for 2 hours. Into the reaction mixture was added a solution of trans-4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]cyclohexylamine dihydrochloride (253 mg), 1,8-diazabicyclo[5,4,0]-7-undecene (257 mg) and triethylamine (0.16 ml) in acetonitrile (20 ml), and the resulting mixture was stirred for 4 hours. After the reaction mixture was concentrated under reduced pressure, water was added to the residue, and the resulting mixture was extracted with chloroform. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with magnesium sulfate. After the resulting organic layer was concentrated under reduced pressure to remove the solvent, the residue was subjected to purification using column chromatography (ethanol/ethyl acetate 1:2) and to recrystallization (ethanol) to obtain trans-3-(4-methylphenyl)-N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]cyclohexyl]-2H-1-benzopyran-6-carboxamide (compound 68) (190 mg) as colorless crystals.