Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[CH:11]1[CH2:14][CH2:13][CH2:12]1.[H-].[Na+].I[CH2:18][CH3:19]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:18][CH3:19])[N:6]=[C:5]2[CH:11]1[CH2:14][CH2:13][CH2:12]1
Reactant: Brc1ccc2[nH]nc(C3CCC3)c2c1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1nc(C2CCC2)c2cc(Br)ccc21
Temperature: 0 °C
Reaction time: 8 h
Yield: 68.4 %

Procedure:
The 5-bromo-3-cyclobutyl-1H-indazole intermediate (1.501 g, 5.97 mmol) was dissolved in anhydrous DMF (25 mL), cooled to 0° C. and treated with a 60% dispersion of sodium hydride in mineral oil (330 mg, 8.26 mmol). The cold bath was removed and the reaction mixture was stirred at room temperature for 2 h after which time iodoethane (1.034 g, 6.62 mmol) was added and the reaction mixture was stirred 8 h. The reaction mixture was then cooled and quenched by addition of a saturated aqueous solution of NH4Cl (10 mL) then extracted with EtOAc (20 mL). The organic extract was dried over MgSO4, filtered, and evaporated to an oil, which was purified by silica gel flash chromatography with a 0-10% EtOAc/hexanes gradient to afford titled compound as a light yellow oil (1.14 g, 68%). 1H NMR (DMSO-d6) 7.90 (s, 1H), 7.58 (d, J=8.5, 1H), 7.44 (d, J=8.5, 1H), 4.35 (q, J=7.2, 2H), 3.85 (pent, J=7.6, 1H), 2.35-2.31 (m, 4H), 2.31-2.02 (m, 1H), 1.99 (m, 1H), 1.35 (t, J=7.6, 3H). LC/MS (Method B) 4.27 min, [M+1]+ 279/281.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH2:10][CH2:9][CH2:8][CH:7]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[C:5]=2[CH:6]=1.C([Li])CCC.CN(C)[CH:26]=[O:27].[Cl-].[NH4+]>O1CCCC1.CCCCCC.O>[Si:12]([O:11][CH:7]1[C:5]2[CH:6]=[C:2]([CH:26]=[O:27])[S:3][C:4]=2[CH2:10][CH2:9][CH2:8]1)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]
Reactant: CC(C)(C)[Si](C)(C)OC1CCCc2sc(Br)cc21
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: CC(C)(C)[Si](C)(C)OC1CCCc2sc(C=O)cc21
Yield: 92 %

Procedure:
To a solution of [(2-bromo-4,5,6,7-tetrahydro-1-benzothiophen-4-yl)oxy](t-butyl)dimethylsilane (5.6 g, 16 mmol) that was obtained in Example 8 (8b) in tetrahydrofuran (30 ml) was slowly added dropwise n-butyllithium (a 1.6 M solution in hexane, 11 ml, 18 mmol) at −78° C. with stirring, and the resulting mixture was stirred for 5 minutes. Subsequently, to the resulting mixture was added N,N-dimethylformamide (2.5 ml, 32 mmol) at the same temperature with stirring, and the resulting mixture was stirred for 30 minutes. After stirring, a saturated aqueous solution of ammonium chloride (10 ml) was added to the reaction mixture to quench the reaction, and the resulting mixture was poured into water (50 ml) and extracted with ether. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo, and the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:9) as the eluent to afford the title compound (4.4 g) in a yield of 92% as a colourless oily product.
Reaction SMILES: [NH:1]([C:8]1[N:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:16]2[N:15]=[C:14]([C:24]([O:26]CC)=O)[C:13]([F:29])=[CH:12][C:11]=2[C:10](=[O:30])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH4+:31].[Cl-]>N.CO>[NH:1]([C:8]1[N:17]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:16]2[N:15]=[C:14]([C:24]([NH2:31])=[O:26])[C:13]([F:29])=[CH:12][C:11]=2[C:10](=[O:30])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1nc2c(cc1F)c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Reactant: [NH4+]
Agent: N
Agent: [Cl-]
Solvent: CO
Product: NC(=O)c1nc2c(cc1F)c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.2 %

Procedure:
A suspension of ethyl 7-anilino-3-fluoro-5-oxo-8-phenyl-5,8-dihydro-1,8-naphthyridine-2-carboxylate (50 mg, 0.12 mmol), and NH4Cl (10 mg, 0.19 mmol) in concentrated NH3 (3 mL) and MeOH (8 drops) was stirred for 16 h at room temperature. The solid was collected by filtration washing with water. Trituration with Et2O, provided 7-anilino-3-fluoro-5-oxo-8-phenyl-5,8-dihydro-1,8-naphthyridine-2-carboxamide as a yellow solid (32 mg, 71%): LCMS RT: 1.93 min, MH+: 375.3. This transformation can also be accomplished using EDCI/HOBT coupling with NH3.
Reaction SMILES: [CH:1]1([C:4](=[O:21])[CH2:5][C:6]([C:8]2[CH:18]=[CH:17][C:11]3[S:12][CH:13]=[C:14]([O:15][CH3:16])[C:10]=3[C:9]=2[O:19][CH3:20])=[O:7])[CH2:3][CH2:2]1.[CH:22](OCC)(OCC)[O:23][CH2:24][CH3:25].C(OC(=O)C)(=O)C>C1(C)C=CC=CC=1>[CH:1]1([C:4](=[O:21])[C:5](=[CH:22][O:23][CH2:24][CH3:25])[C:6]([C:8]2[CH:18]=[CH:17][C:11]3[S:12][CH:13]=[C:14]([O:15][CH3:16])[C:10]=3[C:9]=2[O:19][CH3:20])=[O:7])[CH2:3][CH2:2]1
Reactant: COc1csc2ccc(C(=O)CC(=O)C3CC3)c(OC)c12
Reactant: CCOC(OCC)OCC
Solvent: Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)c1ccc2scc(OC)c2c1OC)C(=O)C1CC1

Procedure:
A mixture of 5-(3-cyclopropyl-1,3-dioxoprop-1-yl)-3,4-dimethoxybenzo[b]thiophene (0.5 g) and triethyl orthoformate (0.73 g) was heated under reflux with acetic anhydride (10 ml) for 3 hours. After cooling and addition of toluene the solution was evaporated to dryness to yield 5-(3-cyclopropyl-2-ethoxymethylene-1,3-dioxoprop-1-yl)-3,4-dimethoxybenzo[b]thiophene as a red oil.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[C:4](=[CH:8][C:9]2[CH:10]=[CH:11][C:12]([O:21][CH3:22])=[C:13]([CH2:15][C:16]([O:18]CC)=[O:17])[CH:14]=2)[S:3]1.Cl>C(O)(=O)C>[O:1]=[C:2]1[NH:6][C:5](=[O:7])[C:4](=[CH:8][C:9]2[CH:10]=[CH:11][C:12]([O:21][CH3:22])=[C:13]([CH2:15][C:16]([OH:18])=[O:17])[CH:14]=2)[S:3]1
Reactant: CCOC(=O)Cc1cc(C=C2SC(=O)NC2=O)ccc1OC
Agent: Cl
Solvent: CC(=O)O
Product: COc1ccc(C=C2SC(=O)NC2=O)cc1CC(=O)O
Temperature: 0 °C
Yield: 96.1 %

Procedure:
Ethyl 2-[5-[(2,4-dioxothiazolidin-5-ylidene)methyl]-2-methoxyphenyl]acetate (1.29 g, 4.01 mmol), concentrated hydrochloric acid (20 mL)and acetic acid (20 mL) were mixed and refluxed for 2.5 hours. After allowed to stand for cooling, ice water was added thereto and the precipitated crystals were collected by filtration, washed with water, and then dried to obtain 1.13 g (96%) of title compound as yellow powder.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][N:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[Br:11][C:12]1[CH:13]=[N:14][C:15](Cl)=[N:16][CH:17]=1.O>C1COCC1>[Br:11][C:12]1[CH:13]=[N:14][C:15]([O:3][CH2:4][CH2:5][N:6]2[CH2:10][CH2:9][CH2:8][CH2:7]2)=[N:16][CH:17]=1
Reactant: OCCN1CCCC1
Reactant: Clc1ncc(Br)cn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Brc1cnc(OCCN2CCCC2)nc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
50 mg (1.15 mmol, 60%) NaH are added to a solution of 0.17 mL (1.38 mmol) N-(2-hydroxyethyl)pyrrolidine in 10 mL THF at RT. The reaction solution is stirred for 15 min at RT and then 200 mg (1.03 mmol) 5-bromo-2-chloropyrimidine are added. The solution is stirred for 16 h at RT. 10 mL water are added and the aqueous phase is extracted with 20 mL EtOAc. The organic phase is dried over Na2SO4 and the solvent is eliminated i.vac. Further purification is carried out by column chromatography on silica gel (DCM/MeOH/NH3 9:1:0.1).
Reaction SMILES: [F:1][C:2]([S:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)([F:4])[F:3].BrBr.[Cl:15]Cl>C(Cl)(Cl)(Cl)Cl>[F:1][C:2]([S:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][Cl:15])=[CH:8][CH:7]=1)([F:4])[F:3]
Reactant: ClCl
Reactant: Cc1ccc(SC(F)(F)F)cc1
Agent: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: FC(F)(F)Sc1ccc(CCl)cc1
Yield: 87.6 %

Procedure:
700 g of 4-trifluoromethylmercapto-toluene in 2,000 ml of CCl4 were initially introduced into a glass chlorination apparatus and heated to the reflux temperature. The solution was irradiated with a UV lamp. 3 ml of bromine were added before the start of the chlorination. When the color of the bromine had disappeared, 200 g of chlorine were passed in over a period of 6 hours. By fractional distillation over a 40 cm packed column, in addition to non-chlorinated starting material, 560 g of 4-trifluoromethylmercaptobenzyl chloride were obtained. Boiling point=97°-8° C./14 mm Hg, nD20 =1.5072.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][CH:14]=[C:15]3[C:19]=2[CH2:18][C:17]([CH3:20])=[CH:16]3)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.[C:26]([C:30]1[CH:38]=[C:37]2[C:33]([CH:34]=[C:35]([CH3:43])[CH:36]2[Si:39](Cl)([CH3:41])[CH3:40])=[C:32]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:31]=1[O:50][CH3:51])([CH3:29])([CH3:28])[CH3:27].O>CCOCC.C([Cu])#N>[C:26]([C:30]1[CH:38]=[C:37]2[C:33]([CH:34]=[C:35]([CH3:43])[CH:36]2[Si:39]([CH:16]2[C:15]3[C:19](=[C:11]([C:8]4[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:6][CH:7]=4)[CH:12]=[CH:13][CH:14]=3)[CH:18]=[C:17]2[CH3:20])([CH3:41])[CH3:40])=[C:32]([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:31]=1[O:50][CH3:51])([CH3:27])([CH3:28])[CH3:29]
Reactant: CC1=Cc2cccc(-c3ccc(C(C)(C)C)cc3)c2C1
Reactant: COc1c(C(C)(C)C)cc2c(c1-c1ccccc1)C=C(C)C2[Si](C)(C)Cl
Agent: N#C[Cu]
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: COc1c(C(C)(C)C)cc2c(c1-c1ccccc1)C=C(C)C2[Si](C)(C)C1C(C)=Cc2c(-c3ccc(C(C)(C)C)cc3)cccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
To a solution of 11.5 g (43.8 mmol) of 7-(4-tert-butylphenyl)-2-methyl-1H-indene in 300 ml of ether, 17.0 ml (42.5 mmol) of 2.5 M nBuLi in hexanes was added in one portion at −78° C. This mixture was stirred overnight at room temperature, then cooled to −60° C., and 150 mg of CuCN was added. The resulting mixture was stirred for 1 h at −20° C., then cooled to −70° C., and 16.2 g of (6-tert-butyl-5-methoxy-2-methyl-4-phenyl-1H-inden-1-yl)(chloro)-dimethylsilane (42.08 mmol) in 150 ml of ether was added. Further on, this mixture was stirred overnight at ambient temperature, then 0.5 ml of water was added. This solution was filtered through a pad of silica gel 60 (40-63 um) which was additionally washed by dichloromethane. The combined organic elute was evaporated to dryness, and the obtained yellowish oil was purified by flash chromatography on silica gel 60 (40-63 um; eluent: hexane-dichloromethane, from 10:1 to 3:1, vol.). This procedure gave 23.4 g (91%) of the title compound as yellowish glass.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][N:6]1[C:10]([C:11]([O:13]C)=[O:12])=[C:9]([N+:15]([O-:17])=[O:16])[C:8]([C:18]([O:20][CH3:21])=[O:19])=[N:7]1)[CH3:2].[OH-].[K+]>CO>[CH3:21][O:20][C:18]([C:8]1[C:9]([N+:15]([O-:17])=[O:16])=[C:10]([C:11]([OH:13])=[O:12])[N:6]([CH2:5][CH2:4][O:3][CH2:1][CH3:2])[N:7]=1)=[O:19]
Reactant: CCOCCn1nc(C(=O)OC)c([N+](=O)[O-])c1C(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCOCCn1nc(C(=O)OC)c([N+](=O)[O-])c1C(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The ester of Step 1 (1.63 g, 5.4 mmol) was added to a solution of potassium hydroxide (330 mg, 5.9 mmol) in methanol (20 mL) and the reaction mixture stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and the crude product dissolved in water and washed with ether. The aqueous phase was acidified with 2M hydrochloric acid and extracted into dichloromethane (3×100 mL). The organics were combined, dried over magnesium sulphate and concentrated in vacuo to yield the title product.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C@@H:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[C@@H:3]1[C:11]([OH:13])=O.[Cl:15][C:16]1[C:17]([O:25][CH3:26])=[CH:18][C:19]([O:23][CH3:24])=[C:20]([CH:22]=1)[NH2:21]>>[Cl:15][C:16]1[C:17]([O:25][CH3:26])=[CH:18][C:19]([O:23][CH3:24])=[C:20]([NH:21][C:11]([C@H:3]2[C@H:4]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:2]2([CH3:1])[CH3:14])=[O:13])[CH:22]=1
Reactant: CC1(C)[C@@H](C(=O)O)[C@@H]1c1ccccc1
Reactant: COc1cc(OC)c(Cl)cc1N
Product: COc1cc(OC)c(NC(=O)[C@H]2[C@H](c3ccccc3)C2(C)C)cc1Cl
Yield: 65.5 %

Procedure:
2,2-Dimethyl-trans-3-phenylcyclopropanecarboxylic acid (500 mg, 2.63 mmol) and 5-chloro-2,4-dimethoxyaniline (493 mg, 2.63 mmol) were reacted as described under General Procedure D to furnish the title compound (620 mg, 66%) as a beige solid. 1H NMR (300 MHz, CDCl3) δ 8.49 (s, 1H), 7.78 (s, 1H), 7.30-7.19 (m, 5H), 6.53 (s, 1H), 3.94 (s, 3H), 3.89 (s, 3H), 2.83 (d, J=5.7 Hz, 1H), 1.86 (d, J=5.7 Hz, 1H), 1.42 (s, 3H), 0.97 (s, 3H). mp 160-162° C. ESIMS m/z [M+H]+ 360.2.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][C:8]1[CH:9]=[C:10]([CH:24]=[C:25]([CH3:28])[C:26]=1[OH:27])[C:11]([C:13]1[O:14][C:15]2[C:20]([C:21](=[O:23])[CH:22]=1)=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12].[Br:29][CH2:30][CH2:31][CH2:32]Br>CN(C)C=O>[Br:29][CH2:30][CH2:31][CH2:32][O:27][C:26]1[C:25]([CH3:28])=[CH:24][C:10]([C:11]([C:13]2[O:14][C:15]3[C:20]([C:21](=[O:23])[CH:22]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:12])=[CH:9][C:8]=1[CH3:7]
Reactant: Cc1cc(C(=O)c2cc(=O)c3ccccc3o2)cc(C)c1O
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)c2cc(=O)c3ccccc3o2)cc(C)c1OCCCBr
Reaction time: 15 h

Procedure:
27.6 g (0.2 mol) of potassium carbonate was added to a solution of 29.4 g (0.1 mol) of 2-(3,5-dimethyl 4-hydroxy benzoyl) chromone in 150 ml of dimethyl formamide, 101 g (0.5 mol) of 1,3-dibromo propane was added and the admixture left at ambient temperature for 15 hours with constant agitation. The potassium bromide precipitate was filtered, the dimethyl formamide was concentrated in vacuo and the residue dissolved in 300 ml of water. Extraction was effected with 200 ml of methylene chloride, and precipitation was then effected by adding 200 ml of ether. The product was 36 g of 2-[4-(3-bromo propoxy) 3,5-dimethyl benzoyl] chromone.
Reaction SMILES: C(O[C:4]([C:6]1[O:10][N:9]=[C:8]([CH2:11][NH:12][C:13]([C:15]2[S:16][C:17]([Cl:20])=[CH:18][CH:19]=2)=[O:14])[N:7]=1)=[O:5])C.[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][C:29]2=[O:34])=[CH:24][C:23]=1F>>[O:34]=[C:29]1[CH2:30][O:31][CH2:32][CH2:33][N:28]1[C:25]1[CH:24]=[CH:23][C:22]([NH:21][C:4]([C:6]2[O:10][N:9]=[C:8]([CH2:11][NH:12][C:13]([C:15]3[S:16][C:17]([Cl:20])=[CH:18][CH:19]=3)=[O:14])[N:7]=2)=[O:5])=[CH:27][CH:26]=1
Reactant: CCOC(=O)c1nc(CNC(=O)c2ccc(Cl)s2)no1
Reactant: Nc1ccc(N2CCOCC2=O)cc1F
Product: O=C(Nc1ccc(N2CCOCC2=O)cc1)c1nc(CNC(=O)c2ccc(Cl)s2)no1

Procedure:
In analogy to example 1E 3-{[(5-chloro-thiophene-2-carbonyl)-amino]-methyl}-[1,2,4]oxadiazole-5-carboxylic acid ethyl ester (example 1D) was reacted with 4-(4-amino-3-fluoro-phenyl)-morpholin-3-one (CAS 438056-69-0) to give 3-{[(5-chloro-thiophene-2-carbonyl)-amino]-methyl}-[1,2,4]oxadiazole-5-carboxylic acid [4-(3-oxo-morpholin-4-yl)-phenyl]-amide. Light yellow solid. MS 462.0 ([M+H]−)
Reaction SMILES: [C:1]([C:4]1[CH:30]=[CH:29][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12][CH2:13][CH:14]2[CH2:18][S:17][C:16]3([CH2:22][CH2:21][CH:20]([CH2:23][C:24]([O:26]CC)=[O:25])[CH2:19]3)[O:15]2)=[C:6]([CH2:31][CH2:32][CH3:33])[C:5]=1[OH:34])(=[O:3])[CH3:2].[Li+].[OH-]>CO>[C:1]([C:4]1[CH:30]=[CH:29][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12][CH2:13][CH:14]2[CH2:18][S:17][C:16]3([CH2:22][CH2:21][CH:20]([CH2:23][C:24]([OH:26])=[O:25])[CH2:19]3)[O:15]2)=[C:6]([CH2:31][CH2:32][CH3:33])[C:5]=1[OH:34])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCCSCC2CSC3(CCC(CC(=O)OCC)C3)O2)ccc(C(C)=O)c1O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CCCc1c(OCCCSCC2CSC3(CCC(CC(=O)O)C3)O2)ccc(C(C)=O)c1O

Procedure:
The ester of Example 15 (4.87 g, 10 mmol) is stirred overnight at room temperature under N2 with aqueous LiOH solution (2M, 13 ml) in methanol (60 ml). The reaction is concentrated on a rotary evaporator and the residue diluted with water. The resulting solution is washed once with ethyl ether and then acidified to pH 2.5 with 0.5N KHSO4 solution. The aqueous mixture is extracted with ethyl acetate and the organic layer dried over MgSO4.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[C:11]([CH:13]([S:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[F:21])[C:10]([Br:30])=[CH:9][N:8]=1.CN(C)[CH:33]=[O:34].[BH4-].[Na+]>CCCCCC.O.CO.C1(C)C=CC=CC=1>[Br:30][C:10]1[C:11]([CH:13]([S:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[F:21])=[CH:12][C:7]([CH2:33][OH:34])=[N:8][CH:9]=1
Reactant: Fc1ccc(F)c(C(Sc2ccc(Cl)cc2)c2cc(Br)ncc2Br)c1
Reactant: CN(C)C=O
Agent: [BH4-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: Cc1ccccc1
Product: OCc1cc(C(Sc2ccc(Cl)cc2)c2cc(F)ccc2F)c(Br)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.4 %

Procedure:
Under an argon atmosphere, n-butyl lithium (a 1.59M hexane solution, 0.27 ml, 0.435 mmol) was added to a toluene (10 ml) solution of 2,5-dibromo-4-[(4-chlorophenylthio)(2,5-difluorophenyl)methyl]pyridine (200 mg, 0.396 mmol) at −78° C. The reaction mixture was stirred for 2 hours. To the reaction mixture was added dropwise dimethylformamide (40 μl, 0.514 mmol), followed by stirring for 1 hour. To the reaction mixture were added methanol (10 ml) and sodium borohydride (30 mg, 0.791 mmol). The temperature of the resulting mixture was raised to room temperature. The reaction mixture was stirred for 1 hour. After addition of water, the resulting mixture was extracted with ethyl acetate. The extract was washed with brine. The organic layer thus obtained was dried over magnesium sulfate, and concentrated under reduced pressure. The residue thus obtained was subjected to flash silica gel column chromatography. The fraction obtained from the hexane:ethyl acetate=3:1 eluate was concentrated under reduced pressure to give the title compound (160 mg, 0.350 mmol, 89%) as a colorless amorphous substance.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][C:17]2[CH:26]=[C:25]3[C:20]([C:21](=[O:35])[N:22]([CH2:27][O:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])[CH:23]=[N:24]3)=[CH:19][C:18]=2[O:36][CH3:37])[CH2:10][CH2:9]1)=O)(C)(C)C.O.C(=O)([O-])O.[Na+]>C(Cl)Cl>[NH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][C:17]2[CH:26]=[C:25]3[C:20]([C:21](=[O:35])[N:22]([CH2:27][O:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:31])[CH3:32])[CH:23]=[N:24]3)=[CH:19][C:18]=2[O:36][CH3:37])[CH2:10][CH2:9]1
Reactant: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCCC1CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCCC1CCNCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
A solution of 7-(2-(1-tertbutoxycarbonylpiperidin-4-yl)ethoxy)-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (10.5 g, 20 mmol) in methylene chloride (100 ml) containing TPA (25 ml) was stirred for 1 hour at ambient temperature. Water (50 ml) and methylene chloride (100 ml) were added and the pH of the aqueous layer was adjusted to 8 with solid sodium hydrogen carbonate. The organic layer was separated, washed with water, brine, dried (MgSO4) and evaporated. The residue was triturated with ether and the solid was filtered and dried under vacuum to give 7-(2-(piperidin-4-yl)ethoxy)-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (8.3 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=O)[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][CH:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C([O-])(=O)C.[NH4+].C([BH3-])#[N:33].[Na+].O1CCCC1>CO.C(#N)C>[Cl:1][C:2]1[CH:11]=[C:10]([CH:12]([NH2:33])[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][CH:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: [BH3-]C#N
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCC(c2ccccc2)CC1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC#N
Solvent: C1CCOC1
Solvent: CO
Product: CC(N)c1cc(Cl)c2cccnc2c1N1CCC(c2ccccc2)CC1
Temperature: 65 °C

Procedure:
A mixture of 1-[5-chloro-8-(4-phenylpiperidin-1-yl)quinolin-7-yl]ethanone (0.0293 g, 0.0803 mmol) and ammonium acetate (0.0619 g, 0.803 mmol) in methanol (0.3 mL) and acetonitrile (0.3 mL) was heated at 65° C. in a sealed tube for 1 hour. After cooling to room temperature, to the resulting mixture was added 1.0 M sodium cyanoborohydride in tetrahydrofuran (0.20 mL, 0.20 mmol). The reaction was heated at 65° C. overnight. The mixture was cooled to room temperature, quenched with sat. NaHCO3 solution and extracted with dichloromethane. The organic layers were combined, dried over MgSO4 and concentrated to give the desired product. LCMS calculated for C22H25ClN3 (M+H)+: m/z=366.2; Found: 366.2.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:19]=[C:18](Br)[CH:17]=[CH:16][C:15]=2[O:21][CH3:22])[CH2:9][CH2:8]1.[C:23]1([Mg]Br)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O1CCCC1.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>[C:23]1([C:18]2[CH:17]=[CH:16][C:15]([O:21][CH3:22])=[C:14]([CH2:13][N:10]3[CH2:11][CH2:12][N:7]([C:2]4[N:3]=[CH:4][CH:5]=[CH:6][N:1]=4)[CH2:8][CH2:9]3)[CH:19]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COc1ccc(Br)cc1CN1CCN(c2ncccn2)CC1
Reactant: Br[Mg]c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(-c2ccccc2)cc1CN1CCN(c2ncccn2)CC1
Temperature: 25 °C

Procedure:
A solution of 182 mg 2-[(4-(2-pyrimidinyl)-piperazinyl)methyl]-4-bromoanisole in 1 mL of tetrahydrofuran heated to 60° C. and 6 mg of Pd(PPh3)4 was added. To this mixture 0.5 mL of a 1M solution of phenylmagnesium bromide in tetrahydrofuran was added dropwise. The reaction mixture was heated at relux temperature under nitrogen for 1 hr, cooled to room temperature and the solvent removed by evaporation under reduced pressure to yield 4-phenyl-2-[(4-(2-pyrimidinyl) -piperazinyl)methyl]anisole which was purified by chromatography on silica gel using 5% methanol in dichloromethane as eluent. Evaporation of the solvent yielded 140 mg of a solid which was treated with ethyl acetate-HCl to give 50 mg of 4-phenyl-2-[(4-(2-pyrimidinyl)-piperazinyl) methyl]anisole dihydrochloride (Compound 1), mp 205°-207° C.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][C@@H:17]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:18]([NH:20][CH2:21][CH2:22][CH3:23])=[O:19]>CS(C)=O>[Cl:15][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:16][C@H:17]([C:18](=[O:19])[NH:20][CH2:21][CH2:22][CH3:23])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:11]([C:12]([OH:14])=[O:13])=[CH:10]2
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Reactant: CCCNC(=O)[C@@H](N)Cc1ccccc1
Solvent: CS(C)=O
Product: CCCNC(=O)[C@H](Cc1ccccc1)Nc1nc2ccc(Cl)cc2cc1C(=O)O

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with (S)-2-amino-3-phenyl-N-propyl-propionamide [Chem. Lett. 2003, 32 (4), 372-373.] in DMSO to provide the title compound in good yield.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([C:24]3[CH2:25][CH2:26][NH:27][CH2:28][CH:29]=3)[NH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.Cl[C:33]1[C:38]([C:39]([F:42])([F:41])[F:40])=[CH:37][CH:36]=[CH:35][N:34]=1>>[F:31][C:2]([F:1])([F:30])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:10]=[C:11]([C:24]3[CH2:25][CH2:26][N:27]([C:33]4[C:38]([C:39]([F:42])([F:41])[F:40])=[CH:37][CH:36]=[CH:35][N:34]=4)[CH2:28][CH:29]=3)[NH:12][C:13]=2[C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:22])([F:23])[F:21])=[CH:18][CH:19]=2)=[CH:7][CH:8]=1
Reactant: FC(F)(F)c1ccc(-c2nc(C3=CCNCC3)[nH]c2-c2ccc(C(F)(F)F)cc2)cc1
Reactant: FC(F)(F)c1cccnc1Cl
Product: FC(F)(F)c1ccc(-c2nc(C3=CCN(c4ncccc4C(F)(F)F)CC3)[nH]c2-c2ccc(C(F)(F)F)cc2)cc1

Procedure:
4-[4,5-Bis-(4-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-1,2,3,6-tetrahydropyridine from step (b) above reacted with 2-chloro-3-trifluoromethyl-pyridine (352 mg, 1.95 mmol, TCI America) under the condition of Example 22(d) to give the title compound as a light-yellow solid. MS (ESI, positive ion) m/z: 583 (M+1).