Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:8]2[CH2:9][C:10](=O)[C:11]3[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:12]=3[S:13][C:7]=2[CH:6]=[CH:5][CH:4]=1)#[N:2].O.[NH2:21][NH2:22]>C(O)C>[C:1]([C:3]1[C:8]2[CH2:9][C:10](=[N:21][NH2:22])[C:11]3[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:12]=3[S:13][C:7]=2[CH:6]=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1cccc2c1CC(=O)c1cc(F)ccc1S2
Reactant: NN
Solvent: O
Solvent: CCO
Product: N#Cc1cccc2c1CC(=NN)c1cc(F)ccc1S2
Yield: 95 %

Procedure:
The mixture of 0.3 g of 9-cyano-2-fluoro-10,11-dihydrodibenzo[b,f]thiepin-11-one, 0.3 g of 100% hydrazine hydrate and 10 ml of ethanol was heated under reflux on waterbath for 5 hours. The reaction mixture was concentrated to 5 ml to separate crystals on cooling, which was collected by filtration. Recrystallization from ethanol afforded 0.3 g of 9-cyano-2-fluoro-10,11-dihydrodibenzo[b,f]thiepin-11-one hydrazone as pale yellow needles having a melting point of 220°-222° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3]1.[C:8](OC(=O)C)(=[O:10])[CH3:9]>C(Cl)Cl>[C:8]([N:4]1[CH2:5][CH2:6][CH2:7][CH:2]([OH:1])[CH2:3]1)(=[O:10])[CH3:9]
Reactant: OC1CCCNC1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)N1CCCC(O)C1
Temperature: 10 °C
Reaction time: 2 h

Procedure:
3-Hydroxypiperidine (0.4 mole) is dissolved in 150 ml. of methylene chloride. The solution is cooled to 10° C. and acetic anhydride (0.46 mole) is added dropwise, maintaining the temperature under 20° C. The reaction mixture is allowed to come to room temperature,for 2 hours. The methylene chloride is evaporated off, and the remaining liquid is distilled under high vacuum. A thick yellow oil is collected at 122°-126° C. (0.3 mm Hg).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:16]=[N:17][C:18]([NH2:21])=[N:19][CH:20]=3)=[N:13][CH:14]=2)O1.Br[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30]([N:33]1[CH2:38][CH2:37][NH:36][C:35](=[O:39])[CH2:34]1)(=[O:32])=[O:31]>>[NH2:21][C:18]1[N:19]=[CH:20][C:15]([C:12]2[N:13]=[CH:14][C:9]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[S:30]([N:33]3[CH2:38][CH2:37][NH:36][C:35](=[O:39])[CH2:34]3)(=[O:32])=[O:31])=[CH:10][CH:11]=2)=[CH:16][N:17]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)nc2)OC1(C)C
Reactant: O=C1CN(S(=O)(=O)c2ccccc2Br)CCN1
Product: Nc1ncc(-c2ccc(-c3ccccc3S(=O)(=O)N3CCNC(=O)C3)cn2)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 427 using 5-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)pyrimidin-2-amine and 4-((2-bromophenyl)sulfonyl)piperazin-2-one. MS (ESI): mass calcd. for C19H18N6O3S, 410.12; m/z found, 411.1 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.97 (s, 2H), 8.60 (dd, J=2.2, 0.9, 1H), 8.18 (dd, J=8.0, 1.3, 1H), 7.91 (dd, J=8.2, 2.2, 1H), 7.87 (dd, J=8.2, 1.0, 1H), 7.80 (m, 1H), 7.70 (m, 1H), 7.50 (dd, J=7.5, 1.3, 1H), 3.42 (s, 2H), 3.15 (s, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([NH:12][CH:13]([CH3:15])[CH3:14])[C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][N:3]=1.O.[OH-].[K+].[C:19](=S)=[S:20]>CCO>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]2[O:7][C:19]([SH:20])=[N:9][N:8]=2)=[C:10]([NH:12][CH:13]([CH3:15])[CH3:14])[CH:11]=1
Reactant: S=C=S
Reactant: CC(C)Nc1cc(Cl)ncc1C(=O)NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)Nc1cc(Cl)ncc1-c1nnc(S)o1
Temperature: 90 °C

Procedure:
6-chloro-4-(isopropylamino)nicotinohydrazide (10) (1.5 g, 8.7 mmol) was taken in EtOH (10 mL): H2O (5 mL). Added KOH (13 mmol, 1.5 equiv.) followed by the addition of CS2 (87 mmol, 10 equiv.) to the reaction mixture and heated at 90° C., overnight. The reaction mass was concentrated under reduced pressure to remove solvents from the reaction mixture. The crude material obtained was taken to next step as such without purification. LC/MS: Purospher@star RP-18, 4×55 mm, 3 μm; Solvent A=10% ACN: 90% H2O: 20 mM NH4OAc; Solvent B=90% ACN: 10% H2O: 20 mM NH4COOAc; gradient 0-100% B over 1.5 min (3.2 min run time); retention time: 1.27 min; LCMS (ES-API), m/z 269.0 (M−H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)[CH:10]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].B>C1COCC1>[NH2:2][CH2:1][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]3[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:20][CH2:21]3)[CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc(-c3cccc(C#N)c3)c2)CC1
Agent: B
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(Cc2cccc(-c3cccc(CN)c3)c2)CC1
Temperature: 25 °C
Yield: 24.2 %

Procedure:
A solution of 1,1-dimethylethyl 4-[(3′-cyano-3-biphenylyl)methyl]-1-piperazinecarboxylate (4.5 g) in THF (30 mL) was treated with borane. THF (47.7 mL, 1M in THF) and the resulting mixture was heated at reflux for 1 hour. After cooling to room temperature, the reaction mixture was quenched with saturated ammonium chloride solution (20 mL) and extracted with ethyl acetate (3×30 mL). The combined organics were dried (MgSO4), concentrated under vacuum to give a residue which was purified by flash chromatography on silica (100 g) to yield the title compound (1.1 g). LC/MS: m/z, 382 (M+H), 1.86 min.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH2:36][C:37]1[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=1)[C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH:17]([C:29](=[O:32])[NH:30][CH3:31])[CH2:18][C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=2)[CH2:13][CH:12]1[CH2:33][O:34][CH3:35])=[O:10])(C)(C)C.[Cl:45]CCCl>Cl.O1CCOCC1>[ClH:45].[NH2:7][CH:8]([CH2:36][C:37]1[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=1)[C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH:17]([CH2:18][C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=2)[C:29]([NH:30][CH3:31])=[O:32])[CH2:13][CH:12]1[CH2:33][O:34][CH3:35])=[O:10]
Reactant: ClCCCl
Reactant: CNC(=O)C(Cc1ccc2ccccc2c1)N1CCN(C(=O)C(Cc2ccc(F)cc2)NC(=O)OC(C)(C)C)C(COC)C1
Agent: Cl
Solvent: C1COCCO1
Product: CNC(=O)C(Cc1ccc2ccccc2c1)N1CCN(C(=O)C(N)Cc2ccc(F)cc2)C(COC)C1
Reaction time: 1.5 h
Yield: 98 %

Procedure:
{1-(4-Fluoro-benzyl)2-[2-methoxymethyl-4-(1-methylcarbamoyl-2-naphthalen-2-yl-ethyl)-piperazin-1-yl]-2oxo-ethyl}-carbamic acid tert-butyl ester, 65, is dissolved in 4M HCl in dioxane (60 mL). The reaction mixture is stirred for 90 minutes then 1,2-dichloroethane (60 mL) is added. The solution is concentrated in vacuo to afford 3.6 g (98% yield) of the desired product.
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[C:15](=[O:21])[CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:22]([O:24][CH3:25])=[O:23])[CH2:3]1.[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1.O.Cl>N1C=CC=CC=1>[CH3:25][O:24][C:22]([C@H:11]1[CH2:10][CH2:9][C@H:8]2[C@H:7]3[C@H:16]([C:15](=[O:21])[CH2:14][C@:12]12[CH3:13])[C@:17]1([CH3:20])[C@H:4]([CH2:3][C@@H:2]([O:1][S:32]([C:29]2[CH:30]=[CH:31][C:26]([CH3:36])=[CH:27][CH:28]=2)(=[O:34])=[O:33])[CH2:19][CH2:18]1)[CH2:5][CH2:6]3)=[O:23]
Reactant: COC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H](OS(=O)(=O)c5ccc(C)cc5)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Reaction time: 96 h

Procedure:
3β-Hydroxy-17β-methoxycarbonyl-5α-androstan-11-one (4.75 g.) and toluene-p-sulphonyl chloride (5 g.) in pyridine (50 ml.) were allowed to stand at room temperature for four days. Water (10 ml.) was added, the resulting solution was stirred for an hour and was then poured into stirred water (1.1). The mixture was acidified with hydrochloric acid and the product collected, washed well with water and dried over sodium hydroxide in vacuo. Recrystallisation from chloroform/hexane containing a trace of ether afforded pure title compound (3.4 g.) as needles; m.p. 158°-160°; [α]D + 42.5°, (c 1.09).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:12][CH3:13])=[C:7]([N+:9]([O-])=O)[CH:8]=1)#[N:2]>C(O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:12][CH3:13])=[C:7]([CH:8]=1)[NH2:9])#[N:2]
Reactant: COc1ccc(C#N)cc1[N+](=O)[O-]
Solvent: CCO
Product: COc1ccc(C#N)cc1N
Yield: 94.3 %

Procedure:
A mixture of 8.8 g of Compound 18A and 46.8 g of stannous chloride dihydrate in 250 mL of 95% ethanol was refluxed for 1 hour. The solvent was evaporated off in vacuo and the residue was taken up with 200 mL of water. The mixture was acidified with 37% HCl, then alkalinised with 35% sodium hydroxide and extracted with 3×200 mL of diethyl ether. The combined organic layers were washed with 50 mL of water, dried over sodium sulphate and evaporated to dryness in vacuo to afford 6.90 g (94.2%) of Compound 18B as an ivory solid.
Reaction SMILES: [Mg].Br[CH:3]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)[CH2:4][CH3:5].[C:14]([C:22]1[CH:39]=[CH:38][C:25]([N:26]([CH2:31][CH2:32][N:33]([CH2:36][CH3:37])[CH2:34][CH3:35])[S:27]([CH3:30])(=[O:29])=[O:28])=[CH:24][CH:23]=1)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Cl-].[NH4+]>O1CCCC1.O>[CH2:36]([N:33]([CH2:34][CH3:35])[CH2:32][CH2:31][N:26]([S:27]([CH3:30])(=[O:28])=[O:29])[C:25]1[CH:38]=[CH:39][C:22]([C:14]([OH:21])([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:3]([C:6]2[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=2)[CH2:4][CH3:5])=[CH:23][CH:24]=1)[CH3:37]
Reactant: CCC(Br)c1ccc(OC)cc1
Reactant: CCN(CC)CCN(c1ccc(C(=O)c2ccccc2)cc1)S(C)(=O)=O
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CCC(c1ccc(OC)cc1)C(O)(c1ccccc1)c1ccc(N(CCN(CC)CC)S(C)(=O)=O)cc1
Reaction time: 16 h

Procedure:
Magnesium turnings (10.0 g., 0.411 mole) are employed to prepare the Grignard reagent from 0.333 mole of p-(1-bromopropyl)anisole in 500 ml. of tetrahydrofuran which has been previously dried by distillation for lithium aluminum hydride. The Grignard reaction is initiated by adding a small portion of the p-(1-bromopropyl)anisole to a small portion of the magnesium turnings in a beaker and when the reaction commences as evidenced by a rise in temperature of the mixture it is transferred to the main reaction flask containing the remaining magnesium turnings and tetrahydrofuran solvent. A nitrogen atmosphere is maintained over the reaction mixture which is cooled at 0°-5°C. The main portion of the p-(1-bromopropyl)anisole dissolved in 700 ml. of similarly dried tetrahydrofuran is then added dropwise to the reaction flask during a period of 30 min. The mixture is then agitated overnight (16 hr.) with cooling and then employed for reaction in the same flask with the substituted benzoylmethanesulfonanilide reactant. 4'-Benzoyl-N-(2-diethylaminoethyl)methanesulfonanilide (25.0 g., 0.0667 mole) dissolved in 200 ml. of dried tetrahydrofuran is added dropwise during 45 min. to the reaction mixture with cooling and stirring which is continued for 24 hr. after the material has been added. The reaction product is then recovered by removing the excess magnesium by filtration and treatment of the filtrate first with water (18.0 g., 1.00 mole) and then with a solution of 50 g. of ammonium chloride in 500 ml. of water. Stirring is continued for 1/2 hr. and the organic layer is then separated and concentrated under reduced pressure. The residual oil is dissolved in ether, the solution washed first with water, the with saturated sodium chloride, and dried over magnesium sulfate. Excess hydrogen chloride gas is then introduced into the solution with stirring and the precipitated hydrochloride salt is collected on a filter and washed with ether; yield 35.2 g. (66%), m.p. 75°-140°C.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C@@H:3]([OH:19])[CH2:4][N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([N+:16]([O-])=O)[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1>CO.[Pd]>[NH2:16][C:13]1[CH:14]=[CH:15][C:8]2[CH2:7][CH2:6][N:5]([CH2:4][C@H:3]([OH:19])[C:2]([F:21])([F:1])[F:20])[CH2:11][CH2:10][C:9]=2[CH:12]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)CCN(C[C@H](O)C(F)(F)F)CC2
Agent: [Pd]
Solvent: CO
Product: Nc1ccc2c(c1)CCN(C[C@H](O)C(F)(F)F)CC2
Reaction time: 0.5 h

Procedure:
(S)-1,1,1-Trifluoro-3-(7-nitro-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-propan-2-ol (582 mg, 1.91 mmol, 1.0 eq) was placed in methanol (20 mL) and 10% palladium on carbon (58 mg) was added. The reaction was hydrogenated at 25 psi for 30 minutes. The mixture was then filtered through celite and concentrated under reduced pressure to obtain (S)-3-(7-amino-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-1,1,1-trifluoro-propan-2-ol as a green amorphous solid (525 mg, 100%). 1H-NMR (CDCl3, 400 MHz) δ 6.90 (d, 1H, J=8.2 Hz), 6.53-6.39 (m, 2H), 4.49-4.35 (m, 1H), 4.12-3.93 (m, 1H), 3.63-3.47 (m, 2H), 2.96-2.75 (m, 6H), 2.75-2.60 (m, 4H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][C@@H:15]([C:26]([NH:28][C@H:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[C:34]([O:36]CC1C=CC(OC)=CC=1)=[O:35])=[O:27])[NH:16][C:17]([C:19]1[N:23]([CH3:24])[N:22]=[C:21]([CH3:25])[CH:20]=1)=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][C@@H:15]([C:26]([NH:28][C@H:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[C:34]([OH:36])=[O:35])=[O:27])[NH:16][C:17]([C:19]1[N:23]([CH3:24])[N:22]=[C:21]([CH3:25])[CH:20]=1)=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(COC(=O)[C@@H]2CCC[C@@H]2NC(=O)[C@H](CCCNC(=O)OCc2ccccc2)NC(=O)c2cc(C)nn2C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C(=O)N[C@@H](CCCNC(=O)OCc2ccccc2)C(=O)N[C@H]2CCC[C@H]2C(=O)O)n(C)n1
Reaction time: 1 h
Yield: 9.2 %

Procedure:
To a mixture of 4-methoxybenzyl (1R,2S)-2-({N5-[(benzyloxy)carbonyl]-N2-[(1,3-dimethyl-1H-pyrazole-5-yl)carbonyl]-L-ornithyl}amino)cyclopentanecarboxylate (0.50 g) and methylene chloride (5.0 ml) was added trifluoroacetic acid (5.0 ml) under ice-cooling, followed by stirring for 1 hour under ice-cooling. The reaction mixture was concentrated under reduced pressure, and diethyl ether and a saturated sodium bicarbonate solution were added to the residue. The organic layer was separated, the aqueous layer was then washed with diethyl ether, and citric acid was added thereto under ice-cooling. The solid precipitated was collected by filtration, washed with water, then purified by silica gel column chromatography (5% methanol/chloroform), solidified with a 50% aqueous ethanol solution, and washed to obtain (1R,2S)-2-({N5-[(benzyloxy)carbonyl]-N2-[(1,3-dimethyl-1H-pyrazole-5-yl)carbonyl]-L-ornithyl}amino)cyclopentanecarboxylic acid (37 mg).
Reaction SMILES: [CH3:1][N:2]([CH3:29])[CH2:3][CH2:4][CH2:5][NH:6][C:7]1[CH:12]=[C:11]([CH:13]([OH:28])[C:14]2[CH:19]=[CH:18][C:17]([NH:20]C(=O)OC(C)(C)C)=[CH:16][CH:15]=2)[CH:10]=[CH:9][N:8]=1.[SiH](CC)(CC)CC.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:20][C:17]1[CH:16]=[CH:15][C:14]([CH:13]([C:11]2[CH:10]=[CH:9][N:8]=[C:7]([NH:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:29])[CH:12]=2)[OH:28])=[CH:19][CH:18]=1
Reactant: CN(C)CCCNc1cc(C(O)c2ccc(NC(=O)OC(C)(C)C)cc2)ccn1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)CCCNc1cc(C(O)c2ccc(N)cc2)ccn1
Reaction time: 1 h
Yield: 49.9 %

Procedure:
To a solution of tert-butyl 4-((2-(3-(dimethylamino)propylamino)pyridin-4-yl)(hydroxy)methyl)phenylcarbamate (16 mg, 0.04 mmol) in 1 mL of DCM were added Et3SiH (0.1 mL)/TFA in DCM (10%, 0.2 mL). The mixture was stirred for 1 hr and no reaction was detected by LC-MS. Another 0.1 mL of Et3SiH and 0.8 mL of TFA in DCM (10%) were added and the mixture was stirred for 2 h. The solvent was removed and was purified by solid extraction (Waters Oasis®MCX extraction cartridge) to give (4-aminophenyl)(2-(3-(dimethylamino)propylamino)pyridin-4-yl)methanol (6.0 mg, 50% yield). MS(ESI+): m/z 301.40 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[N:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:18][CH:17]=3)=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[O:8]C.O>C(O)(=O)C.Br>[F:1][C:2]1[CH:3]=[C:4]([C:10]2[N:11]=[CH:12][C:13]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:18][CH:17]=3)=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: CCCCCCCc1ccc(-c2cnc(-c3ccc(OC)c(F)c3)nc2)cc1
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: CCCCCCCc1ccc(-c2cnc(-c3ccc(O)c(F)c3)nc2)cc1
Temperature: 25 °C
Yield: 87.2 %

Procedure:
2.5 g of the 2-(3-fluoro-4-methoxyphenyl)-5-(4-heptylphenyl)pyrimidine obtained in Example 1 was dissolved in a mixture of 200 ml of acetic acid and 100 ml of 47% hydrobromic acid. The obtained solution was heated under reflux for 18 hours. The reaction mixture was allowed to cool to room temperature and 500 ml of water was added thereto. The crystals thus precipitated were filtered. The product thus obtained was purified by column chromatography (developing solvent: hexane: ethyl acetate 5:1) to thereby give 2.1 g of 2-(3-fluoro-4-hydroxyphenyl)-5-(4-heptylphenyl)pyrimidine. Yield: 87%.
Reaction SMILES: [C:1]([C:3]1[CH:19]=[CH:18][C:6]([C:7]([N:9]([CH3:17])[CH2:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=O)=[CH:5][CH:4]=1)#[N:2].[C:20]([C:22]1[CH:30]=[CH:29][C:25](C(Cl)=O)=[CH:24][CH:23]=1)#[N:21]>>[C:1]([C:3]1[CH:19]=[CH:18][C:6]([C:7]2[N:9]([CH3:17])[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[C:20]([C:22]3[CH:30]=[CH:29][CH:25]=[CH:24][CH:23]=3)[N:21]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CN(Cc1ccncc1)C(=O)c1ccc(C#N)cc1
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Product: Cn1c(-c2ccc(C#N)cc2)nc(-c2ccccc2)c1-c1ccncc1

Procedure:
4-Cyano-N-methyl-N-(4-picolyl)benzamide The title compound was prepared using the same procedure as described in Example 2, step (b) except using 4-cyanobenzoyl chloride: 1H NMR (CDCl3): d 8.49 (dd, 2H); 7.86-7.04 (m, 6H); 4.70 and 4.43 (two br s, 2H); 3.08 and 2.89 (two br s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:13]([OH:15])=O)[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][CH:23]([C:26]2[CH:27]=[C:28]([NH:32][C:33](=[O:37])[CH:34]([CH3:36])[CH3:35])[CH:29]=[CH:30][CH:31]=2)[CH2:22][CH2:21]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:13]([NH:16][CH2:17][CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][C:33](=[O:37])[CH:34]([CH3:35])[CH3:36])[CH:27]=4)[CH2:22][CH2:21]3)=[O:15])[CH2:9][CH2:10][CH2:11][CH2:12]2)=[CH:6][CH:7]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CCCC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)C3(c4ccc(Cl)cc4)CCCC3)CC2)c1

Procedure:
Example 31 was prepared from 1-(4-chlorophenyl)cyclopentanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCl3) δ 7.45–7.42 (m, 1H), 7.33–7.24 (m, 7H), 6.94 (d, 1H, J=7.1 Hz), 6.58–6.52 (m, 1H), 3.26 (q, 2H, J=6.1 Hz), 2.90 (d, 2H, J=10.8 Hz), 2.56–2.40 (m, 4H), 2.29 (t, 2H, J=6.3 Hz), 2.03–1.87 (m, 6H), 1.83–1.76 (m, 4H), 1.60 (dd, 4H, J=6.8, 4.6 Hz), 1.25 (d, 6H, J=6.8 Hz); ESMS m/e: 510.4 (M+H)+.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:14])([CH3:13])[CH3:12])=[N:10][C:5]2=[N:4][CH:3]=1.[F:15][C:16]1[C:21]([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[C:20]([F:28])[CH:19]=[CH:18][C:17]=1B(O)O>O1CCCC1.C(=O)([O-])[O-].[Na+].[Na+].O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:28][C:20]1[C:21]([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[C:16]([F:15])[CH:17]=[CH:18][C:19]=1[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:14])([CH3:13])[CH3:12])=[N:10][C:5]2=[N:4][CH:3]=1
Reactant: OB(O)c1ccc(F)c(-c2cccnc2)c1F
Reactant: CC(C)(O)c1ccn2c(Br)cnc2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(-c4cccnc4)c3F)cnc2n1
Temperature: 65 °C

Procedure:
A mixture of 2-(3-bromoimidazo[1,2-α]pyrimidin-7-yl)propan-2-ol (256 mg, 1.0 mmol) and 2,4-difluoro-3-(pyridin-3-yl)benzeneboronic acid (352 mg, 1.5 mmol) in tetrahydrofuran (3 ml) and sodium carbonate (1.25 ml of a 2M solution in water, 2.5 mmol) was degassed with nitrogen for 10 min. Tetrakis(triphenylphosphine)palladium(0) (58 mg, 0.05 mmol) was added and this mixture was heated at 65° C. for 24 h. The reaction was cooled to ambient temperature then partitioned between dichloromethane and saturated aqueous sodium hydrogencarbonate. The organics were dried over anhydrous magnesium sulfate, filtered and pre-adsorbed onto silica. Purification by chromatography on silica gel eluting with dichloromethane (containing 1% conc. ammonia) on a gradient of methanol (1-5%) gave 2-[3-(2,4-difluoro-3-(pyridin-3-yl)phenyl)imidazo[1,2-α]pyrimidin-7-yl]propan-2-ol as a pale yellow oil which solidified on standing (200 mg, 44%). Bis-hydrochloride salt (from ethyl acetate/ethanol): δH (360 MHz, d6-DMSO) 1.56 (6H, s), 7.62 (1H, t, J 9), 7.79-7.84 (1H, m), 7.86 (1H, s), 7.88 (1H, s), 8.32 (1H, d, J 8), 8.54 (1H, s), 8.80 (1H, d, J 5), 8.98 (1H, s), 9.27 (1H, dd, J 7 and 3).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9]([N:12]([CH3:18])[NH:13][S:14]([CH3:17])(=[O:16])=[O:15])(=[O:11])=[O:10].Cl[C:20]([O:22][CH2:23][CH2:24][Br:25])=[O:21]>CC(C)=O>[CH3:8][S:9]([N:12]([CH3:18])[N:13]([S:14]([CH3:17])(=[O:15])=[O:16])[C:20]([O:22][CH2:23][CH2:24][Br:25])=[O:21])(=[O:10])=[O:11]
Reactant: O=C(Cl)OCCBr
Reactant: CN(NS(C)(=O)=O)S(C)(=O)=O
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CN(N(C(=O)OCCBr)S(C)(=O)=O)S(C)(=O)=O
Reaction time: 18 h

Procedure:
1,2-Bis(methylsulfonyl)-2-(2-bromoethoxycarbonyl)-1-methylhydrazine (compound 8) was synthesized as follows: Triethylamine (1.45 g, 0.014 mol) was added in portions to a stirred solution of 1,2-bis(methylsulfonyl)-1-methylhydrazine (2.02 g, 0.01 mol) and 2-bromoethyl chloroformate (3.49 g, 0.019 mol) in acetone (100 ml) over a period of 15 min. The reaction mixture was stirred for an additional 18 hr, filtered, and the filtrate evaporated to dryness in vacuo. The residue was taken up in chloroform (100 ml) and washed with water (3×20 ml). The chloroform layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate evaporated to dryness. The residue was triturated with petroleum ether until a solid separated. The solid was filtered and recrystallized from ethanol (1.52 g, 43.0%). Mp was approximately 81-82° C. 1H NMR (CDCl3): δ 4.7 and 3.6 (4H, 2t, CH2CH2Br), 3.5, 3.3 and 3.1 (9H, 3s, 2CH3SO2 and NCH3).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]([C:33]([O:35]C)=[O:34])=[CH:25][CH:24]=2)[C:7](/[CH:10]=[C:11](\[CH2:16][C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)/[C:12]([O:14]C)=[O:13])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].[OH-].[K+]>C(O)C.O>[CH2:1]([C:5]1[N:6]([CH2:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]([C:33]([OH:35])=[O:34])=[CH:25][CH:24]=2)[C:7]([CH:10]=[C:11]([CH2:16][C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)[C:12]([OH:14])=[O:13])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc(/C=C(\Cc2cccs2)C(=O)OC)n1Cc1ccc(C(=O)OC)c2ccccc12
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCc1ncc(C=C(Cc2cccs2)C(=O)O)n1Cc1ccc(C(=O)O)c2ccccc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A slurry containing 14.46 g (26.14 mmol) of methyl(E)-3-[2-n-butyl-1-{(4-carbomethoxynaphth-1-yl)methyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoate, 8.38 g (2.09 mmol) of potassium hydroxide in a mixture of 165 mL of ethanol and 85 mL of water was stirred at ambient temperature for 18 hours. Concentration under vacuum and dilution with water gave 400 mL of a clear solution. Adjustment of the pH to 4.03 with hydrochloric acid gave crystals which when recrystallized from methanol gave 9.89 g (80%) of colorless crystals; mp 218°-219° C. as a partial hydrate.