Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:25])[C:10]([C:16]1[CH:17]=[C:18]([CH3:24])[C:19](=[O:23])[N:20]([CH3:22])[CH:21]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].C([O:28][C:29](=[O:41])[C:30]1[CH:35]=[CH:34][C:33](Cl)=[N:32][C:31]=1[C:37]([F:40])([F:39])[F:38])C.[Li+].[OH-].Cl>CN(C)C(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[CH:9]([CH3:25])[C:10]([C:16]1[CH:17]=[C:18]([CH3:24])[C:19](=[O:23])[N:20]([CH3:22])[CH:21]=1)([OH:15])[C:11]([F:13])([F:14])[F:12])[O:8][C:33]1[CH:34]=[CH:35][C:30]([C:29]([OH:41])=[O:28])=[C:31]([C:37]([F:38])([F:40])[F:39])[N:32]=1
Reactant: Cc1cc(C(O)(C(C)c2ccc(O)cc2Cl)C(F)(F)F)cn(C)c1=O
Reactant: CCOC(=O)c1ccc(Cl)nc1C(F)(F)F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)N(C)C
Product: Cc1cc(C(O)(C(C)c2ccc(Oc3ccc(C(=O)O)c(C(F)(F)F)n3)cc2Cl)C(F)(F)F)cn(C)c1=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 5-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1,3-dimethyl-1H-pyridin-2-one (Example 203, step 5, 60 mg) in N,N-dimethylacetamide (2 ml) were added potassium-tert.-butylate (21.5 mg) and 6-chloro-2-trifluoromethyl-nicotinic acid ethyl ester (81 mg). The mixture was stirred at room temperature for 1.5 h. A 0.2 M aqueous LiOH solution (4.79 ml) was added and the mixture was stirred at room temperature for 3 h and then cooled in an ice bath. The mixture was acidified with 1 M aqueous HCl and extracted with ethyl acetate. The organic phase was concentrated to dryness and the product was purified by chromatography ((SiO2, CH2Cl2/MeOH 1:0=>3:1). Off-white solid (22 mg). MS (m/e)=565.2 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:17]=[C:16]3[C:11]([N:12]=[CH:13][C:14]([N:18]4[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]4)=[N:15]3)=[CH:10][CH:9]=2)=[CH:4][C:3]=1[NH:31][S:32]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)(=[O:34])=[O:33].FC(F)(F)C(O)=O>C(#N)C>[Cl:1][C:2]1[C:3]([NH:31][S:32]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)(=[O:33])=[O:34])=[CH:4][C:5]([C:8]2[CH:17]=[C:16]3[C:11](=[CH:10][CH:9]=2)[N:12]=[CH:13][C:14]([N:18]2[CH2:19][CH2:20][NH:21][CH2:22][CH2:23]2)=[N:15]3)=[CH:6][N:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cnc3ccc(-c4cnc(Cl)c(NS(=O)(=O)c5ccccc5)c4)cc3n2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: O=S(=O)(Nc1cc(-c2ccc3ncc(N4CCNCC4)nc3c2)cnc1Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.1 %

Procedure:
To a solution of 1,1-dimethylethyl 4-(7-{6-chloro-5-[(phenylsulfonyl)amino]-3-pyridinyl}-2-quinoxalinyl)-1-piperazinecarboxylate (0.83 mmol) in acetonitrile (6 ml) was added concentrated trifluoroacetic acid (3 ml). The reaction stirred at ambient temperature for 3 hours and was then concentrated to an orange oil. The residue was neutralized with saturated sodium bicarbonate solution upon which a precipitate was formed. The product was filtered and dried to give the title compound (260 mg, 65%) as an off-white solid. MS(ES)+ m/e 481.2 [M+H]+.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([NH:12][C:13]1[NH:21][C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]=2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].Br[CH2:26][CH2:27][CH2:28][CH2:29][CH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>>[CH2:8]([NH:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:26][CH2:27][CH2:28][CH2:29][CH:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: BrCCCCC1CCOCC1
Reactant: CCCCNc1nc(N)c2nc(OC)nc-2[nH]1
Solvent: O=C(O)C(F)(F)F
Product: CCCCNc1nc(N)c2nc(OC)n(CCCCC3CCOCC3)c2n1

Procedure:
Prepared similarly to Intermediate 220 from N2-butyl-8-(methyloxy)-3H-purine-2,6-diamine trifluoroacetate and 4-(4-bromobutyl)tetrahydro-2H-pyran.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C([Li])CCC.I[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Br:20]>C1COCC1>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:18]2[CH:17]=[CH:16][C:15]([Br:20])=[CH:14][CH:19]=2)[CH:3]=1
Reactant: Brc1cccnc1
Reactant: Brc1ccccc1I
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Brc1ccc(-c2cccnc2)cc1
Yield: 47 %

Procedure:
3-Bromopyridine (6 g, 38 mmol) is treated as described in EXAMPLE 53, Part A with n-butyl lithium (28.5 mL of a 1.6 M solution in THF, 45.6 mmol) and iodobromobenzene (8.96 g, 31.7 mmol). The crude product is purified by chromatography (30% EtOAc/hexanes) to obtain the title compound (3.5 g, 14.9 mmol).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][C@H:7]3[N:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:16][C@@:13]4([C:14]=2[CH:15]=1)[C@H:8]3[CH2:9][CH2:10][CH2:11][CH2:12]4.C(N(CC)CC)C.[C:33]1([N:39]=[C:40]=[O:41])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>ClCCl>[NH:39]([C:40]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][C@H:7]3[N:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:16][C@@:13]4([C:14]=2[CH:15]=1)[C@H:8]3[CH2:9][CH2:10][CH2:11][CH2:12]4)=[O:41])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@]23CCCC[C@H]2[C@H]1Cc1ccc(O)cc13
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC[C@]23CCCC[C@H]2[C@H]1Cc1ccc(OC(=O)Nc2ccccc2)cc13
Reaction time: 1 h
Yield: 91.5 %

Procedure:
To a stirred solution of 3-hydroxy-N-(tert-butyloxycarbonyl)morphinan (9 mg, 0.026 mmol) and triethylamine (10 μL, 0.04 mmol) in dry dichloromethane (0.3 mL) was added phenyl isocyanate (4 μL, 0.045 mmol) and the mixture was stirred for 1 h. After starting material disappeared on TLC, solvent was removed and column chromatography gave 11 mg (90%) of the title compound: 1H NMR (300 MHz, CDCl3) δ7.4 (2H, d); 7.3 (2H, t); 7.1 (3H, m); 6.9 (2H, m); 4.3 (1H, m); 3.8 (1H, m); 3.1 (1H, d. d.); 2.4˜2.8 (2H, m); 2.3 (1H, m); 1.3 (9H, s); 1.0˜1.7 (10H, m).
Reaction SMILES: C[O-].[Na+].[NH2:4][C:5]([NH:7][N:8]([CH2:16][C:17]([O:19]C)=O)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=1)=[O:6].O.P([O-])([O-])([O-])=O>CO>[CH3:15][C:11]1[CH:10]=[C:9]([N:8]2[CH2:16][C:17](=[O:19])[NH:4][C:5](=[O:6])[NH:7]2)[CH:14]=[CH:13][CH:12]=1
Reactant: COC(=O)CN(NC(N)=O)c1cccc(C)c1
Agent: C[O-]
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1cccc(N2CC(=O)NC(=O)N2)c1
Reaction time: 1 h
Yield: 60.4 %

Procedure:
A solution of sodium methoxide (2.17M in methanol; 3 ml) was added to a stirred solution of methyl [2-(aminocarbonyl)-1-(3-methylphenyl)hydrazino]acetate (0.5 g) in methanol (1 ml), and the mixture was stirred at 20° for 1.0 h. Water (20 ml) was added, followed by pH 6.5 phosphate buffer solution (30 ml), and the mixture was extracted with ethyl acetate (3×80 ml). The combined extracts were washed with water (2×80 ml) and saturated brine (80 ml), dried, and evaporated in vacuo to give a solid which was triturated with ether (30 ml) to give the title compound (261 mg), m.p. 245°-247°.
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH:4]=[CH2:5].ClC1C=CC=C(C(OO)=[O:30])C=1>C(Cl)Cl>[O:30]1[CH2:5][CH:4]1[CH2:3][CH2:2][CH2:1][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[CH:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=2)=[CH:9][CH:8]=1
Reactant: C=CCCCOc1ccc(-c2ccc([N+](=O)[O-])cc2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(-c2ccc(OCCCC3CO3)cc2)cc1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
To 250 ml of methylene chloride is added 28.3 g of 4-(4-penteneoxy)-4'-nitrobiphenyl. The solution is cooled to 0° C., and 18 g of meta-chloroperbenzoic acid is added slowly. The mixture is stirred at 0° C. for 24 hours, and allowed to warm to room temperature.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[NH:4][C:5]1[S:6][C:7]2[C:13]([C:14]3[O:15][CH2:16][CH2:17][O:18][CH:19]=3)=[CH:12][CH:11]=[C:10]([O:20][CH3:21])[C:8]=2[N:9]=1.[H][H]>O1CCOCC1.C(O)(=O)C.[Pd]>[CH3:1][O:2][C:3](=[O:22])[NH:4][C:5]1[S:6][C:7]2[C:13]([CH:14]3[CH2:19][O:18][CH2:17][CH2:16][O:15]3)=[CH:12][CH:11]=[C:10]([O:20][CH3:21])[C:8]=2[N:9]=1
Reactant: COC(=O)Nc1nc2c(OC)ccc(C3=COCCO3)c2s1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: COC(=O)Nc1nc2c(OC)ccc(C3COCCO3)c2s1
Yield: 79.1 %

Procedure:
To a stirred solution of 4.90 g (15.2 mmol) [7-(5,6-dihydro-[1,4]dioxin-2-yl)-4-methoxy-benzothiazol-2-yl]-carbamic acid methyl ester in 250 ml dioxane and 5 ml acetic acid was added 4.9 g of 10% palladium on charcoal and the mixture was then stirred for 24 h at room temperature under a 10 bar atmosphere of hydrogen. The mixture was then filtered, washing with dioxane, and the filtrate concentrated in vacuo. Trituration in acetone afforded 3.90 g (79%) (±)-(7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-yl)-carbamic acid methyl ester as a white solid. ES-MS m/e (%): 325 (M+H+, 100).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:12](O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.CN(C=O)C.C(OCC)(=O)C>[CH2:12]([O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([CH3:11])=[N:10][C:2]=1[Cl:1])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OCc1ccccc1
Reactant: Cc1ccc(C(=O)O)c(Cl)n1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)OCc2ccccc2)c(Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.7 %

Procedure:
To a solution of 2-chloro-6-methylnicotinic acid (3.0 g), benzyl alcohol (2.27 g), 4-dimethylaminopyridine (2.56 g) in DMF (10 mL) was added 1-ethyl-3-(3′-dimethylaminopropyl) carbodiimide (WSC) hydrochloride (4.02 g). The mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed successively with water, saturated aqueous sodium bicarbonate, water, and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=4:1, v/v) to give the title compound (3.6 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][OH:8].Br[CH2:10][C:11]#[CH:12].O>C1COCC1>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:12][C:11]#[CH:10]
Reactant: COCCOCCO
Reactant: C#CCBr
Solvent: O
Solvent: C1CCOC1
Product: C#CCOCCOCCOC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 2 g 2-(2-Methoxy-ethoxy)-ethanol in 20 ml THF 1.8 g KOt-Bu were added at 0° C. After stirring for 10 min 8.1 ml 3-Bromo-propyne (75% in toluene) were added and the mixture was warmed to RT and stirred for 4 h. Then 10 ml of water were added and the mixture was filtered through a Chem Elut® cartridge by elution with CHCl3. This solution containing the desired product was subjected to the next reaction step.
Reaction SMILES: [CH2:1]([N:8]1[C@@H:13]2[CH2:14][CH2:15][C@@:9]1([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C@H:10]([OH:16])[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[F:25][C:26]([F:40])([F:39])[C:27]1[CH:28]=[C:29]([CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1)[CH2:30]Br.O>C1COCC1>[CH2:1]([N:8]1[C@@H:13]2[CH2:14][CH2:15][C@@:9]1([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C@H:10]([O:16][CH2:30][C:29]1[CH:32]=[C:33]([C:35]([F:37])([F:38])[F:36])[CH:34]=[C:27]([C:26]([F:25])([F:39])[F:40])[CH:28]=1)[CH2:11][CH2:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O[C@@H]1CC[C@H]2CC[C@]1(c1ccccc1)N2Cc1ccccc1
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: FC(F)(F)c1cc(CO[C@@H]2CC[C@H]3CC[C@]2(c2ccccc2)N3Cc2ccccc2)cc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 61 %

Procedure:
(1R*,2R*,5R*)-8-Benzyl-1-phenyl-8-azabicyclo[3.2.1]octan-2-ol (Description 9; 1.69 g, 3.90 mmol) in THF (25 ml) at 0° C. was treated with sodium hydride (217 mg, 9.02 mmol) and allowed to warm to room temperature. The mixture was recooled to 0° C. then 3,5-bis(trifluoromethyl)benzyl bromide added and the mixture heated to 50° C. overnight. The mixture was poured into water then extracted with ethyl acetate (×2), dried (MgSO4) and concentrated in vacuo to give a yellow oil. This was purified by flash column chromatography [5% ethyl acetate in iso-hexane] to give the title compound as a yellow oil (1.43 g, 61%).
Reaction SMILES: CN(S(F)(F)[F:5])C.O[C:9]1([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:27][C@H:26]([CH2:28][NH:29][C:30](=[O:32])[CH3:31])[O:25][C:24]3=[O:33])=[CH:19][C:18]=2[F:34])[CH:14]=[CH:13][S:12](=[O:16])(=[O:15])[CH2:11][CH2:10]1>C(Cl)Cl.C(OCC)(=O)C>[F:34][C:18]1[CH:19]=[C:20]([N:23]2[CH2:27][C@H:26]([CH2:28][NH:29][C:30](=[O:32])[CH3:31])[O:25][C:24]2=[O:33])[CH:21]=[CH:22][C:17]=1[C:9]1([F:5])[CH:14]=[CH:13][S:12](=[O:16])(=[O:15])[CH2:11][CH2:10]1
Reactant: CN(C)S(F)(F)F
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3(O)C=CS(=O)(=O)CC3)c(F)c2)C(=O)O1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(=O)NC[C@H]1CN(c2ccc(C3(F)C=CS(=O)(=O)CC3)c(F)c2)C(=O)O1
Temperature: 25 °C

Procedure:
(N,N-Dimethylamino)sulfur trifluoride (2.5 μL, 0.019 mmol) is added to a cooled (−78° C.) solution of the product of Example 12 (6.0 mg, 0.014 mmol) in DCM (0.75 mL). The solution is warmed slowly to room temperature over 4 hours and diluted with ethyl acetate. The organic solution is extracted with satd NaHCO3, H2O, brine and dried (Na2SO4). The crude product is purified by preparative TLC (7% MeOH-DCM) to provide the title compound as a mixture of diastereomers.
Reaction SMILES: [C:1](O[BH-](OC(=O)C)OC(=O)C)(=O)[CH3:2].[Na+].[N+:15]([C:18]1[CH:23]=[CH:22][C:21]([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:20][CH:19]=1)([O-:17])=[O:16].C(=O)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:1]([N:27]1[CH2:26][CH2:25][CH:24]([C:21]2[CH:22]=[CH:23][C:18]([N+:15]([O-:17])=[O:16])=[CH:19][CH:20]=2)[CH2:29][CH2:28]1)[CH3:2]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: O=[N+]([O-])c1ccc(C2CCNCC2)cc1
Agent: CC=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCN1CCC(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
Sodium triacetoxyborohydride (3.1 g, 14.6 mmol, 3 equiv) is added to a cold (5° C.) solution of 4-(4-nitro-phenyl)-piperidine (1 g, 4.9 mmol) and acetaldehyde (0.82 mL, 14.6 mmol, 3 equiv) in DCM (20 mL). The reaction mixture is stirred for 1 h at 5° C. and then diluted with DCM and a saturated aqueous solution of NaHCO3. The layers are separated and the aqueous layer is extracted with DCM. The organic phase is washed with brine, dried (Na2SO4), filtered and concentrated. The residue is purified by silica gel column chromatography (DCM/MeOH+1% NH3aq, 98:2) to provide the title compound as a yellow oil. ESI-MS: 235.1 [MH]+; tR=2.64 min (purity: 85%, system 1); TLC: Rf=0.14 (DCM/MeOH+1% NH3aq, 98:2).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH2:10])=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[C:32]([C:33](Cl)=[O:34])=[C:31]([CH3:36])[N:30]=[CH:29][CH:28]=2)=[C:23]([F:37])[C:22]=1[O:38][CH3:39]>C(Cl)Cl>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[C:32]([C:33]([NH:10][CH2:9][C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[O:34])=[C:31]([CH3:36])[N:30]=[CH:29][CH:28]=2)=[C:23]([F:37])[C:22]=1[O:38][CH3:39]
Reactant: COc1ccc(CN)cc1
Reactant: COc1c(Cl)ccc(-c2ccnc(C)c2C(=O)Cl)c1F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CNC(=O)c2c(-c3ccc(Cl)c(OC)c3F)ccnc2C)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 34.9 %

Procedure:
To a stirred solution of (4-methoxyphenyl)methanamine (0.437 g, 3.18 mmol) in CH2Cl2 (25 mL) was added DIEA (0.556 mL, 3.18 mmol) and the reaction mixture was stirred at 0° C. for 15 min. 4-(4-chloro-2-fluoro-3-methoxyphenyl)-2-methylnicotinoyl chloride (1 g, 3.18 mmol) (prepared by treatment of carboxylic acid with thionyl chloride) dissolved in 10 mL of DCM was then added to the reaction mixture and the reaction was stirred at rt for 10 h. The reaction was quenched by addition of water (50 mL) and the solution was extracted with DCM (2×50 mL). The combined organic layers were washed with brine solution 50 mL, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using ethyl acetate in hexanes as eluant to yield 4-(4-chloro-2-fluoro-3-methoxyphenyl)-N-(4-methoxybenzyl)-2-methylnicotinamide (800 mg, 1.109 mmol, 35% yield) as a brown oil. LC/MS (ESI) m/e 415.1 [(M+H)+, calcd for C22H21ClFN2O3 415.1]; LC/MS retention time (method D): tR=0.78 min.
Reaction SMILES: [C:1]1(CO)CCCCC=1.[Cl:9][C:10]1[C:11]([O:21][CH:22]2[CH2:27][CH2:26][C:25](=[CH2:28])[CH2:24][CH2:23]2)=[CH:12][C:13]([F:20])=[C:14]([CH:19]=1)[C:15]([O:17][CH3:18])=[O:16]>>[Cl:9][C:10]1[C:11]([O:21][CH:22]2[CH2:27][CH2:26][C:25]3([CH2:1][CH2:28]3)[CH2:24][CH2:23]2)=[CH:12][C:13]([F:20])=[C:14]([CH:19]=1)[C:15]([O:17][CH3:18])=[O:16]
Reactant: C=C1CCC(Oc2cc(F)c(C(=O)OC)cc2Cl)CC1
Reactant: OCC1=CCCCC1
Product: COC(=O)c1cc(Cl)c(OC2CCC3(CC2)CC3)cc1F

Procedure:
Following the procedure as described in Example 342 Step 2 and making non-critical variations to replace cyclohexenylmethanol with methyl 5-chloro-2-fluoro-4-((4-methylenecyclohexyl)oxy)benzoate, the title compound was obtained as a colorless syrup (0.769 g, 85% yield): 1H NMR (300 MHz, CDCl3) δ 7.95 (d, J=7.7 Hz, 1H), 6.68 (d, J=12.4 Hz, 1H), 4.49-4.41 (m, 1H), 3.88 (s, 3H), 1.99-1.78 (m, 4H), 1.53-1.32 (m, 4H), 0.33-0.27 (m, 4H).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[C:13]=1[CH2:20][C:21]([O:23][CH3:24])=[O:22].[C:25](Cl)(=[O:27])[CH3:26].O>O1CCCC1>[C:25]([CH:20]([C:13]1[C:12]([F:11])=[CH:17][C:16]([F:18])=[CH:15][C:14]=1[F:19])[C:21]([O:23][CH3:24])=[O:22])(=[O:27])[CH3:26]
Reactant: COC(=O)Cc1c(F)cc(F)cc1F
Reactant: CC(=O)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C(C(C)=O)c1c(F)cc(F)cc1F
Temperature: -65 °C
Reaction time: 0.5 h

Procedure:
To a commercially obtained tetrahydrofuran solution of lithium bis(trimethyl-silyl)amide (1.0 M, 21.0 mL) stirred under a nitrogen atmosphere and cooled to an internal temperature of −65° C., was added dropwise over 30 minutes a solution of methyl 2,4,6-trifluorobenzeneacetate (i.e. the product of Step A) (2.04 g, 10.0 mmol) dissolved in dry tetrahydrofuran (10 mL). The reaction mixture was stirred for an additional 30 minutes, and then while maintaining the −65° C. temperature, a solution of freshly distilled acetyl chloride (0.80 mL, 11 mmol) in dry tetrahydrofuran (3 mL) was added dropwise. The reaction mixture was allowed to warm slowly to ambient temperature, and then water (30 mL) was added. The resultant mixture was extracted with ethyl acetate (60 mL). The aqueous phase was acidified with 1 N hydrochloric acid and extracted with ethyl acetate (60 mL). Only the first ethyl acetate extract was retained, because thin layer chromatographic analysis showed the second extract to contain apparent polar impurities besides additional desired product. The first ethyl acetate extract was further sequentially washed with 1 N hydrochloric acid, water and brine, dried (MgSO4), and concentrated to provide the title compound as a clear oil (1.86 g).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][C:6]([Cl:13])=[CH:7][CH:8]=2)[N:3]=1.[CH2:14]([O:16][C:17]1[CH:18]=[C:19]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([NH2:27])[CH2:23][CH2:22]1)[CH3:15]>CC(N(C)C)=O>[Cl:1][C:2]1[N:11]=[C:10]([NH:27][CH:24]2[CH2:25][CH2:26][N:21]([CH2:20][C:19]3[CH:28]=[CH:29][C:30]([O:31][CH3:32])=[C:17]([O:16][CH2:14][CH3:15])[CH:18]=3)[CH2:22][CH2:23]2)[C:9]2[C:4](=[CH:5][C:6]([Cl:13])=[CH:7][CH:8]=2)[N:3]=1
Reactant: CCOc1cc(CN2CCC(N)CC2)ccc1OC
Reactant: Clc1ccc2c(Cl)nc(Cl)nc2c1
Solvent: CC(=O)N(C)C
Product: CCOc1cc(CN2CCC(Nc3nc(Cl)nc4cc(Cl)ccc34)CC2)ccc1OC
Yield: 2.6 %

Procedure:
A solution of 2,4,7-trichloro-quinazoline (35.0 mg, 0.15 mmol, 1.0 equiv) and 1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-ylamine (47.6 mg, 0.18 mmol, 1.2 equiv; intermediate A1) in DMAc (2 mL) was heated by microwave irradiation to 200° C. for 30 min. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 1.8 mg (3%) of the title compound. MS (ISP): 461.3 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].F[C:15]1[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=1>CC#N.CCOC(C)=O>[OH:7][CH:4]1[CH2:5][CH2:6][N:1]([C:15]2[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1ccc(F)cc1
Reactant: OC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(N2CCC(O)CC2)cc1
Temperature: 95 °C
Yield: 19.7 %

Procedure:
In a 200 mL round bottom flask, piperidin-4-ol (2.165 g, 21.41 mmol) and K2CO3 (2.96 g, 21.41 mmol) were suspended in MeCN (51.0 mL). Ethyl 4-fluorobenzoate (2.62 mL, 17.84 mmol) was added and the reaction mixture was stirred under reflux (95° C.) for 96 hr. The reaction was cooled to RT, diluted with EtOAc (100 mL) and washed with water (50 mL). Dried organic layer with MgSO4, filtered, and concentrated in vacuo. The product was purified by re-crystallization using EtOAc/hexanes, affording the title compound as a white solid (0.878 g, 19.74% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.28 (t, J=7.07 Hz, 3H) 1.34-1.47 (m, 2H) 1.73-1.85 (m, 2H) 3.03 (ddd, J=13.14, 9.98, 3.16 Hz, 2H) 3.63-3.77 (m, 3H) 4.23 (q, J=7.07 Hz, 2H) 4.72 (d, J=4.04 Hz, 1H) 6.86-7.05 (m, 2H) 7.66-7.85 (m, 2H). ESI-MS: m/z 250.2 (M+H)+.
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([CH2:12][CH2:13][CH:14]=[CH:15][C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[H][H]>[Pd].C(OCC)(=O)C>[CH2:1]([C@H:6]1[CH2:7][CH2:8][C@H:9]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:20]#[N:21])=[CH:22][CH:23]=2)[CH2:10][CH2:11]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCC[C@H]1CC[C@H](CCC=Cc2ccc(C#N)cc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCC[C@H]1CC[C@H](CCCCc2ccc(C#N)cc2)CC1
Yield: 89.4 %

Procedure:
A mixture of 40 g of 4-[4-(trans-4-pentylcyclohexyl)-1-butenyl]benzonitrile, 2 g of palladium/carbon (5%) and 250 ml of ethyl acetate was stirred while gassing with hydrogen. Subsequently, the inorganic material was filtered off and the filtrate was concentrated. The residue was purified by chromatography on silica gel with toluene/ethyl acetate (vol. 9:1). Recrystallization from ethanol gave 36 g of pure 4-[4-(trans-4-pentylcyclohexyl)-1-butyl]benzonitrile with m.p. 51° C.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:30])=[C:10]([N:14]3[CH2:19][CH2:18][N:17]([CH2:20][C:21]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)=O)[CH2:16][CH2:15]3)[C:11]=2[F:13])[C:6](=[O:31])[C:5]([C:32]([OH:34])=[O:33])=[CH:4]1)[CH3:2].Cl.[NH2:36][OH:37]>>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:30])=[C:10]([N:14]3[CH2:15][CH2:16][N:17]([CH2:20][C:21]([C:23]4[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=4)=[N:36][OH:37])[CH2:18][CH2:19]3)[C:11]=2[F:13])[C:6](=[O:31])[C:5]([C:32]([OH:34])=[O:33])=[CH:4]1)[CH3:2]
Reactant: NO
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(CC(=O)c4ccc(F)cc4)CC3)c(F)c21
Agent: Cl
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(CC(=NO)c4ccc(F)cc4)CC3)c(F)c21

Procedure:
1-Ethyl-6,8-difluoro-7-{4-[2-(4-fluorophenyl)-2-hydroxyiminoethyl]-1-piperazinyl}-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid was prepared from 1-ethyl-6,8-difluoro-7-{4-[2-(4-fluorophenyl)-2-oxoethyl]-1-piperazinyl}-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid (0.24 g, 0.5 mmole) and hydroxylamine hydrochloride (0.07 g, 1 mmol) by a method similar to that described for Example 3 (70% yield). Mp: 201° C. (dec). 1H NMR (DMSO-d6) δ 1.42 (t, 3H, J=7.0), 2.58 and 3.29 (two m, 8H), 3.41 and 3.73 (two s, 2H), 4.57 (q, 2H, J=7.0), 7.44-7.87 (m, 4 H), 7.90 (d, 1H, J=12.0), 8.95 (s, 1H), 11.18 and 11.65 (two s, 1H), 14.92 (br s, 1H). Anal. Calcd. for C24H23F3N4O4•0.5 H2O: C, 57.95; H, 4.86; N, 11.26. Found: C, 57.91; H, 4.83; N, 11.12.