Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]4[CH:25]([OH:26])[C:24]5[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=5)[CH2:18]4)[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C.C([O-])(O)=O.[Na+]>ClCCl>[F:1][C:2]1[CH:28]=[CH:27][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]4[CH2:18][C:19]5[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=5)[C:25]4=[O:26])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: OC1c2ccccc2CN1CCN1CCC(c2noc3cc(F)ccc23)CC1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1c2ccccc2CN1CCN1CCC(c2noc3cc(F)ccc23)CC1
Reaction time: 18 h
Yield: 79 %

Procedure:
To 2-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-2,3-dihydro-3-hydroxy-1H-isoindol! -1-one (2.2 g, 5.6 mmol) was added a solution of trifluoroacetic acid (11.0 ml) in dichloromethane (30 ml) at room temperature, under nitrogen. Triethylsilane (1.5 ml) was then added and the reaction mixture was allowed to stir for 18 hours at which time it was poured into a NaHCO3 (sat.). The layers were separated and the aqueous phase was extracted with DCM (3×). The combined organics were washed with brine and dried (Na2SO4). Filtration and concentration gave the crude product as a solid which was recrystallized from EtOAc to give 1.6 g (79%) of the desired product as a white solid, m.p.=166°-168° C.
Reaction SMILES: [C:1]([O:4]C(=O)C)(=[O:3])[CH3:2].[CH:8]([O:11][C:12]([N:14]1[CH2:20][CH2:19][CH2:18][CH:17]([NH:21][CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([C:33]([F:36])([F:35])[F:34])[CH:24]=2)[C:16]2[C:37]([F:42])=[C:38]([CH3:41])[CH:39]=[CH:40][C:15]1=2)=[O:13])([CH3:10])[CH3:9].N1C=CC=CC=1.Cl>ClCCl>[C:1]([O-:4])(=[O:3])[CH3:2].[C:1]([N:21]([CH2:22][C:23]1[CH:24]=[C:25]([C:33]([F:35])([F:36])[F:34])[CH:26]=[C:27]([C:29]([F:32])([F:30])[F:31])[CH:28]=1)[CH:17]1[CH2:18][CH2:19][CH2:20][N:14]([C:12]([O:11][CH:8]([CH3:10])[CH3:9])=[O:13])[C:15]2[CH:40]=[CH:39][C:38]([CH3:41])=[C:37]([F:42])[C:16]1=2)(=[O:3])[CH3:2]
Reactant: Cc1ccc2c(c1F)C(NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCN2C(=O)OC(C)C
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2ccc(C)c(F)c21
Product: CC(=O)[O-]
Temperature: 0 °C
Reaction time: 12 h
Yield: 46.2 %

Procedure:
Add 3,5-bis(trifluoromethyl)benzylamine (23 mg, 0.095 mmol) followed by titanium isopropoxide (0.035 mL, 0.12 mmol) to isopropyl 6-fluoro-7-methyl-5-oxo-2,3,4,5-tetrahydro benzo[b]azepine-1-carboxylate (24 mg, 0.086 mmol) at room temperature under an atmosphere of nitrogen and stir the solution for 2 days. Filter the residue over silica cartridge, eluting with hexanes/ethyl acetate (8:1) to afford 5-(3,5-Bis-trifluoromethyl-benzylamino)-6-fluoro-7-methyl-2,3-dihydro-benzo[b]azepine-1-carboxylic (34 mg, 79%). Add methanol (1 mL) and platinum oxide (2 mg, 0.007 mmol) and hydrogenate the mixture at 1 atmosphere and room temperature for 7 h. Filter through celite and remove the solvent under reduced pressure to afford 5-(3,5-Bis-trifluoromethyl-benzylamino)-6-fluoro-7-methyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid isopropyl ester (36 mg, quantitative). Add acetic anhydride (0.1 mL, 1.07 mmol) dropwise to a suspension of the amine (36 mg, 0.071 mmol) and pyridine (0.1 mL g, 1.07 mmol) in dichloromethane (0.5 mL) under nitrogen cooled to 0° C. After the addition is complete, remove the cooling bath and warm the reaction to room temperature and stir for 12 h. Add 1 N hydrochloric acid and extract with dichloromethane (3×10 mL). Dry the organic layer over anhydrous sodium sulfate, filter and remove the solvent under reduced pressure. Chromatograph the residue over silica cartridge, eluting with hexanes/ethyl:acetate (6:1), to afford the title compound (18 mg, 46%); MS (ES+): 549 (M+H)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12](O)=O)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[C:15](Cl)(=O)[C:16](Cl)=[O:17].[OH:21][NH:22][C:23](=[NH:50])[C:24]1[C:25]([CH3:49])=[C:26]2[C:31](=[CH:32][CH:33]=1)[CH:30]([CH2:34][CH2:35][CH2:36][C:37](=[O:41])CCC)[N:29]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:28][CH2:27]2.C(N(CC)CC)C>ClCCl.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:21][N:22]=[C:23]([C:24]3[C:25]([CH3:49])=[C:26]4[C:31](=[CH:32][CH:33]=3)[CH:30]([CH2:34][CH2:35][CH2:36][C:37]([O:17][CH2:16][CH3:15])=[O:41])[N:29]([C:42]([O:44][C:45]([CH3:47])([CH3:48])[CH3:46])=[O:43])[CH2:28][CH2:27]4)[N:50]=2)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCC(=O)CCCC1c2ccc(C(=N)NO)c(C)c2CCN1C(=O)OC(C)(C)C
Reactant: CC(C)Oc1ncc(C(=O)O)cc1Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CCCC1c2ccc(-c3noc(-c4cnc(OC(C)C)c(Cl)c4)n3)c(C)c2CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.1 %

Procedure:
To a suspension of 5-chloro-6-[(1-methylethyl)oxy]-3-pyridinecarboxylic acid (for example available from UkrOrgSynthesis Building Blocks; 264 mg, 1.22 mmol) in dichloromethane (5.00 ml) at room temperature was added oxalyl chloride (0.292 ml, 3.33 mmol) followed by one drop of N,N-dimethylformamide (DMF) and the resulting mixture was stirred for 1 h at room temperature. The solvent was removed in vacuo and the residue co-evaporated with toluene then left for 5 min under vacuum. To a solution of 1,1-dimethylethyl 6-[(hydroxyamino)(imino)methyl]-5-methyl-1-(4-oxoheptyl)-3,4-dihydro-2(1H)-isoquinolinecarboxylate (Preparation 27; 232 mg, 0.556 mmol) in DMF (5 ml) was added triethylamine (0.116 ml, 0.833 mmol) then half of the acid chloride (i.e. 2 ml out of the 4 ml of DMF used to dissolve it). The mixture was stirred for 1 h at room temperature and heated at 120° C. for 100 min. The mixture was cooled to room temperature and most of the solvent concentrated in vacuo. The residue was dissolved in ethyl acetate and the solution washed with saturated sodium bicarbonate, dried over MgSO4 and concentrated in vacuo to give a residue (ca. 310 mg) which was purified by flash chromatography, eluting with 5-25% ethyl acetate in cyclohexane to give the title compound (102 mg) as a white foam
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:26])[NH:10][CH:11]1[CH2:23][C:22]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:24]#[N:25])[CH:20]=3)[NH:15][C:14]=2[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO>C(Cl)(Cl)Cl.CO>[CH2:1]([O:8][C:9](=[O:26])[NH:10][C@H:11]1[CH2:23][C:22]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:24]#[N:25])[CH:20]=3)[NH:15][C:14]=2[CH2:13][CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ccc2[nH]c3c(c2c1)CC(NC(=O)OCc1ccccc1)CC3
Solvent: ClC(Cl)Cl
Solvent: CO
Product: N#Cc1ccc2[nH]c3c(c2c1)C[C@H](NC(=O)OCc1ccccc1)CC3

Procedure:
Resolve racemic (6-cyano-2,3,4,9-tetrahydro-1H-carbazol-3-yl)-carbamic acid benzyl ester (Preparation 61) (43.28 g) using preparative HPLC under the following conditions: Chiralcel OD column (8×35 cm), MeOH/0.2% dimethylethyl amine (DMEA) mobile phase at 350 ml/min flow rate with UV detection at 240 nM. Use 20 mL (666 mg) injections in 1:3 CHCl3/MeOH diluent with a runtime of 18.2 min and a stacked recycle injection (2 passes through the column to completely remove both isomers). First isomer to elute is is S isomer (21.34 g) with 98.2% ee. Second isomer to elute is R isomer (20.45 g) with 95.0% ee to give the title compound.
Reaction SMILES: [I-].C[N+]([CH2:6][C:7]1[N:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]2=[N:9][C:8]=1[C:16]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]2[C:17]=1[CH:18]=[CH:19][C:20](=[O:28])[NH:21]2)(C)C.[C-:29]#[N:30].[Na+]>O>[C:29]([CH2:6][C:7]1[N:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]2=[N:9][C:8]=1[C:16]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]2[C:17]=1[CH:18]=[CH:19][C:20](=[O:28])[NH:21]2)#[N:30]
Reactant: COc1ccc(-c2nc3ccccn3c2C[N+](C)(C)C)c2ccc(=O)[nH]c12
Reactant: [C-]#N
Agent: [I-]
Agent: [Na+]
Solvent: O
Product: COc1ccc(-c2nc3ccccn3c2CC#N)c2ccc(=O)[nH]c12
Yield: 28.7 %

Procedure:
A solution of 5-{3-trimethylammoniomethylimidazo[1,2-a]pyridine-2-yl}-8-methoxycarbostyril iodide (4.39 g) in water (40 ml) was refluxed while adding dropwise 10 ml of an aqueous solution having dissolved therein 440 mg of sodium cyanide. After completion of addition, the mixture was reacted for 30 minutes and then allowed to cool. Crystals which precipitated were collected by filtration and isolated by passing through a silica gel column. The crude crystals thus formed were recrystallized from methanol to give 0.85 g of 5-{3-cyanomethylimidazo[1,2-a]pyridine-2-yl}-8-methoxycarbostyril.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]([CH2:13][CH2:14][N:15]([CH3:17])[CH3:16])[C:7]2=[O:12].[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH3:16][N:15]([CH3:17])[CH2:14][CH2:13][N:6]1[CH:5]=[CH:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[NH:1][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:7]1=[O:12]
Reactant: CN(C)CCn1ccc2c(N)cccc2c1=O
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CCn1ccc2c(NC(=O)c3ccccc3)cccc2c1=O

Procedure:
5-Amino-2-(2-dimethylamino-ethyl)-2H-isoquinolin-1-one (50 mg, 0.0002 mol), benzoyl chloride (36 mg, 0.00026 mol) and N,N-diisopropylethylamine (110 mg, 0.00086 mol) were stirred in methylene chloride (3 mL, 0.05 mol) at room temperature for 2 hours. The mixture was diluted with CH2Cl2 (20 mL) and the organic layer was separated and washed with NaHCO3 (10 mL), dried over Na2SO4, and purified via flash column chromatography (12 g of silica gel, 10% MeOH/CH2Cl2) to give the product as a light yellow solid.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25](Cl)[N:24]=2)[CH:18]=1)[S:12]([CH3:15])(=[O:14])=[O:13])(C)(C)C.[CH2:31]([NH2:39])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[NH2:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25]([NH:39][CH2:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:24]=2)[CH:18]=1)[S:12]([CH3:15])(=[O:13])=[O:14]
Reactant: CC(C)(C)OC(=O)NCCCN(Cc1cccc(-c2ccnc(Cl)n2)c1)S(C)(=O)=O
Reactant: NCCc1ccccc1
Product: CS(=O)(=O)N(CCCN)Cc1cccc(-c2ccnc(NCCc3ccccc3)n2)c1

Procedure:
Intermediate 4 was coupled to phenethylamine following procedure F and the resulting product deprotected following procedure G. LC-MS showed the product had the expected M+H+ of 440. 1H NMR (Varian 300 MHz, CDCl3—CD3OD, shifts relative to the solvent peak at 7.24 ppm) δ 8.1 (m, 3H) 7.7 (m, 1H) 7.5 (m, 2H) 7.2 (m, 5H) 4.5 (d, 2H) 3.8 (m, 2H) 3.6 (m, 1H) 3.3 (m, 3H) 3.0 (m, 2H) 2.9 (s, 3H) 1.8 (m, 2H).
Reaction SMILES: ClC(Cl)(Cl)[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:20])[C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][CH:14]=2)=[CH:8][C:7]=1[C:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=1)=[O:4].C([O-])(=O)C.[NH4+:36]>CS(C)=O>[Cl:28][C:24]1[CH:23]=[C:22]([C:21]2[C:7]3[C:6](=[CH:11][CH:10]=[C:9]([C:12](=[O:20])[C:13]4[CH:18]=[CH:17][C:16]([I:19])=[CH:15][CH:14]=4)[CH:8]=3)[NH:5][C:3](=[O:4])[N:36]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: [NH4+]
Reactant: O=C(c1ccc(I)cc1)c1ccc(NC(=O)C(Cl)(Cl)Cl)c(C(=O)c2cccc(Cl)c2)c1
Agent: CC(=O)[O-]
Solvent: CS(C)=O
Product: O=C(c1ccc(I)cc1)c1ccc2[nH]c(=O)nc(-c3cccc(Cl)c3)c2c1
Temperature: 120 °C
Reaction time: 2 h
Yield: 74.3 %

Procedure:
A mixture of intermediate (37) (0.0285 mol) and ammonium acetate (0.057 mol) in DMSO (180 ml) was stirred at 120 ° C. for 2 hours. The mixture was poured out into ice water. The precipitate was filtered, washed with water (several times) then with CH3CN/diethyl ether and dried at 60° C. under vacuum, yielding 10.3 g (74%) of 4-(3-chlorophenyl)-6-(4-iodobenzoyl)-2(1H)-quinazolinone (intermediate 38).
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:11])([CH3:10])[C@:4]([C:13]2[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][C:14]=2[F:20])([CH3:12])[N:3]=1.[Cl:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[C:27](=O)[CH2:26][C:25]2([CH3:33])[CH3:32].[B][B][B][B][B][B][B][B][B][B]>>[NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:10])([CH3:11])[C@:4]([C:13]2[CH:18]=[C:17]([NH:19][CH:27]3[C:28]4[C:24](=[CH:23][C:22]([Cl:21])=[CH:30][CH:29]=4)[C:25]([CH3:33])([CH3:32])[CH2:26]3)[CH:16]=[CH:15][C:14]=2[F:20])([CH3:12])[N:3]=1
Reactant: CC1(C)CC(=O)c2ccc(Cl)cc21
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(N)ccc2F)N=C1N
Agent: [B][B][B][B][B][B][B][B][B][B]
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(NC3CC(C)(C)c4cc(Cl)ccc43)ccc2F)N=C1N

Procedure:
The reductive amination of (S)-2-amino-6-(5-amino-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (intermediate J) and 5-chloro-3,3-dimethyl-indan-1-one (prepared according to Claiborne, C. F. et al., Int. patent application WO 2008/019124) using decaborane yielded a mixture of epimers of the title compound as a colorless waxy solid. MS (ESI): m/z=457.4 [M+H]+.
Reaction SMILES: Cl.[OH:2][C@@H:3]([C@H:5]1[C:25](=[O:26])[N:7]2[C:8]([C:22]([O-:24])=[O:23])=[C:9]([S:12]/[CH:13]=[CH:14]\[C:15]3[S:19][CH:18]=[N:17][C:16]=3[CH2:20][OH:21])[C@H:10]([CH3:11])[C@H:6]12)[CH3:4].[Na+]>>[OH:2][C@@H:3]([C@H:5]1[C:25](=[O:26])[N:7]2[C:8]([C:22]([OH:24])=[O:23])=[C:9]([S:12]/[CH:13]=[CH:14]\[C:15]3[S:19][CH:18]=[N:17][C:16]=3[CH2:20][OH:21])[C@H:10]([CH3:11])[C@H:6]12)[CH3:4]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Agent: Cl
Agent: [Na+]
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Reaction time: 0.05 h
Yield: 63.1 %

Procedure:
1 N Hydrochloric acid (7.10 ml) was added to 120 ml of an aqueous solution of 2.73 g of sodium (1R,5S,6S)-6-((1R)-1-hydroxyethyl)-2-[[(Z)-2-(4-hydroxymethylthiazol-5-yl)ethen-1-yl]thio]-1-methyl-1-carbapen-2-em-3-carboxylate at room temperature, and the mixture was stirred for 3 min. The reaction mixture was extracted twice with 150 ml of ethyl acetate. The extract was dried over anhydrous magnesium sulfate and was filtered, and ethyl acetate was removed by distillation under the reduced pressure until the amount of ethyl acetate was reduced to 50 ml. Hexane (200 ml) was added, and the precipitated solid was collected by filtration to give 1.63 g of the title compound.
Reaction SMILES: [CH3:1][NH2:2].[Cl:3][C:4]1[N:9]=[C:8](Cl)[CH:7]=[C:6]([CH2:11][O:12][CH2:13][CH:14]2[CH2:16][CH2:15]2)[N:5]=1>CCO.C(#N)C>[Cl:3][C:4]1[N:9]=[C:8]([NH:2][CH3:1])[CH:7]=[C:6]([CH2:11][O:12][CH2:13][CH:14]2[CH2:16][CH2:15]2)[N:5]=1
Reactant: Clc1cc(COCC2CC2)nc(Cl)n1
Reactant: CN
Solvent: CCO
Solvent: CC#N
Product: CNc1cc(COCC2CC2)nc(Cl)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Methanamine (0.124 mL, 0.99 mmol) in EtOH was added to a solution of 2,4-dichloro-6-((cyclopropylmethoxy)methyl)pyrimidine (77 mg, 0.33 mmol) in acetonitrile (6 mL). The mixture was stirred at 0° C. for 30 minutes. The mixture was concentrated and the residue was purified by preparative HPLC give the title compound, 42 mg (56%).
Reaction SMILES: Cl[C:2](=[N:13][OH:14])[C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.[C:15]([C:17]1[C:18]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)=[N:19][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)=[N:21][CH:22]=1)#[CH:16].C(N(CC)CC)C>C1COCC1>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][O:29][C:18]2[C:17]([C:15]3[O:14][N:13]=[C:2]([C:3]4[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=4)[CH:16]=3)=[CH:22][N:21]=[C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[N:19]=2)=[CH:36][CH:35]=1
Reactant: COC(=O)c1ccc(C(Cl)=NO)cc1
Reactant: C#Cc1cnc(-c2ccccn2)nc1OCc1ccc(OC)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(-c2cc(-c3cnc(-c4ccccn4)nc3OCc3ccc(OC)cc3)on2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.4 %

Procedure:
To a mixture of compound 37-e (517 mg, 2.43 mmol), compound 37-j (700 mg, 2.21 mmol) in THF (5 mL) was added triethylamine (335 mg, 3.31 mmol) dropwise. The mixture was stirred overnight at room temperature. The residue obtained from removal of the solvent was purified by flash chromatography (PE:EA=1:2) to afford compound 37-k (420 mg, 38%) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.786 (s, 1H), 8.753-8.731 (d, J=6.6 Hz, 1H), 8.172-8.144 (d, J=8.4 Hz, 2H), 8.004-7.976 (d, J=8.4 Hz, 2H), 7.838-7.806 (m, 1H), 7.645 (s, 1H), 7.615 (s, 1H), 7.495-7.470 (s, 1H), 6.875-6.846 (d, J=8.7 Hz, 2H), 6.697-6.668 (d, J=8.7 Hz, 2H), 5.786 (s, 2H), 3.960 (s, 3H), 3.723 (s, 3H), LC-MS (ESI): 495 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:3]([O:24][CH3:25])=[C:4]([C:8]([CH3:23])([CH3:22])[CH2:9][C:10]([C:18]([F:21])([F:20])[F:19])([O:13][Si](C)(C)C)[CH2:11][OH:12])[CH:5]=[CH:6][CH:7]=1.[N+](CCCC)(CCCC)(CCCC)CCCC.[F-].O.O.O.O>C1COCC1>[F:1][C:2]1[C:3]([O:24][CH3:25])=[C:4]([C:8]([CH3:23])([CH3:22])[CH2:9][C:10]([OH:13])([C:18]([F:21])([F:20])[F:19])[CH2:11][OH:12])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1c(F)cccc1C(C)(C)CC(CO)(O[Si](C)(C)C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: COc1c(F)cccc1C(C)(C)CC(O)(CO)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.2 %

Procedure:
4.11 g (10.75 mmol) of 4-(3-fluoro-2-methoxyphenyl)-4-methyl-2-trifluoromethyl-2-trimethylsilyloxy-pentan-1-ol is dissolved in 61 ml of THF, mixed with 3.39 g (10.746 mmol) of Bu4NF trihydrate, and stirred for one hour at room temperature. The reaction mixture is poured into water and extracted twice with diethyl ether. The organic phases are washed as usual with water and brine. After the desiccant is dried and filtered off, and after the solvent is spun in, the remaining residue is chromatographed on silica gel (mobile solvent:ethyl acetate/hexane). 2.71 g (81.4%) of the desired compound is isolated.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=O.[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18](=O)[CH2:19][CH3:20].P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:4]1[C:3]2[C:2](=[CH:10][CH:9]=[CH:8][CH:7]=2)[N:1]=[C:18]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[F:11])[C:19]=1[CH3:20]
Reactant: CCC(=O)c1ccccc1F
Reactant: Nc1ccccc1C(=O)O
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1c(-c2ccccc2F)nc2ccccc2c1Cl

Procedure:
Prepared according to Procedure J using 2-aminobenzoic acid (1.5 equiv.) and 1-(2-fluorophenyl)propan-1-one (1 equiv.) in phosphorous oxychloride to afford 4-chloro-2-(2-fluorophenyl)-3-methylquinoline upon purification by chromatography on silica gel. Mass Spectrum (ESI) m/e=272.0 (M+1).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][CH:12]=[C:11]([CH:14](O)C)[CH:10]=2)=[CH:5][CH:4]=1.CC1C=C(C2C=CC(C(F)(F)F)=CC=2)S[C:21]=1[CH:35]=[O:36].C[Mg]Br>>[CH3:14][C:11]1[CH:10]=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:17])[F:18])=[CH:8][CH:7]=2)[S:13][C:12]=1[CH:35]([OH:36])[CH3:21]
Reactant: CC(O)c1csc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)sc1C=O
Agent: C[Mg]Br
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)sc1C(C)O

Procedure:
The title compound was prepared using a method analogous to that used for the preparation of 1-{5-[4-(trifluoromethyl)phenyl]thien-3-yl}ethanol (intermediate 126) using 3-methyl-5-[4-(trifluoromethyl)phenyl]thiophene-2-carbaldehyde (intermediate 74) and methyl magnesium bromide.
Reaction SMILES: [Br:1][C:2]1[S:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2Cl)[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:18][C:19]1[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[CH:21][C:20]=1[OH:28]>O(C1C=CC=CC=1)C1C=CC=CC=1.C(Cl)Cl>[Br:1][C:2]1[S:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2[O:28][C:20]2[CH:21]=[CH:22][C:23]([N+:25]([O-:27])=[O:26])=[CH:24][C:19]=2[F:18])[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Reactant: Clc1ccnc2cc(Br)sc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(Oc2ccnc3cc(Br)sc23)c(F)c1
Temperature: 25 °C
Yield: 71.4 %

Procedure:
A mixture of 49 (5.1 g, 20.5 mmol), potassium carbonate (5.65 g, 4 mmol) and 2-fluoro-4-nitrophenol (4.82 g, 30.7 mmol) was heated at 190° C. in Ph2O (25 ml) for 3 hrs. After cooling to room temperature it was diluted with DCM and filtered. The filtrate was concentrated and the residue was purified by column chromatography (eluent ethyl acetate/hexane 3:1) to afford title compound 50 as a yellow solid (5.4 g, 71% yield). 1H NMR (DMSO-d6) δ (ppm): 8.55 (d, J=5.28 Hz, 1H), 8.46 (dd, J=2.5 and 10.4 Hz, 1H), 8.19 (d, J=8.8 Hz, 1H), 7.87 (s, 1H), 7.72 (t, J=8.4 Hz), 6.99 (d, J=5.47 Hz, 1H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][CH:8]1[CH2:12][CH2:11][CH:10]([CH3:13])[N:9]1[C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][C:15]=1[N+:23]([O-:25])=[O:24].[F:26][C:27]1[CH:28]=[CH:29][C:30]([O:37][CH3:38])=[C:31]([C:33](=[N:35]O)[NH2:34])[CH:32]=1.CCN(C(C)C)C(C)C>>[CH3:13][CH:10]1[CH2:11][CH2:12][CH:8]([CH3:7])[N:9]1[C:14]1[CH:22]=[CH:21][C:17]([C:18]2[O:20][N:34]=[C:33]([C:31]3[CH:32]=[C:27]([F:26])[CH:28]=[CH:29][C:30]=3[O:37][CH3:38])[N:35]=2)=[CH:16][C:15]=1[N+:23]([O-:25])=[O:24]
Reactant: COc1ccc(F)cc1C(N)=NO
Reactant: CC1CCC(C)N1c1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(F)cc1-c1noc(-c2ccc(N3C(C)CCC3C)c([N+](=O)[O-])c2)n1

Procedure:
Oxalyl chloride (152 μL; 1.2 mmol; 3 eq.), Intermediate 25 (106 mg; 0.4 mmol; 1 eq.), Intermediate 23 (74 mg; 0.4 mmol, 1 eq.) and DIEA (155 μL; 1.2 mmol; 3 eq.) were reacted according to general procedure 2. Purification by crystallisation from ethyl acetate/n-pentane afforded the title compound as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1([CH2:22][OH:23])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[CH2:3]1.[H-].[Na+].Cl[CH2:27][CH2:28][N:29]([CH3:31])[CH3:30]>CN(C=O)C>[CH3:30][N:29]([CH3:31])[CH2:28][CH2:27][O:21][C:18]1[CH:17]=[CH:16][C:15]([C:4]2[CH2:3][C:2]([CH2:22][OH:23])([CH3:1])[CH2:7][CH2:6][C:5]=2[C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:20][CH:19]=1
Reactant: CN(C)CCCl
Reactant: CC1(CO)CCC(c2ccc(O)cc2)=C(c2ccc(O)cc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCOc1ccc(C2=C(c3ccc(O)cc3)CCC(C)(CO)C2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (1-methyl-3,4-di(4-hydroxy-phenyl)-cyclohex-3-enyl)-methanol (30 mg, 1 eq.) in DMF (1 mL) was added NaH (10 mg, 1 eq.), and the reaction mixture was then stirred for 2 h at 25° C. To the reaction mixture was then added (2-chloro-ethyl)-dimethyl-amine (12 mg, 1 eq) and the mixture stirred for 16 hours. The reaction mixture was then partitioned between H2O/ethyl acetate (5 mL/5 mL). The organic layer was separated, dried over MgSO4, concentrated and purified HPLC (20%˜80% CH3CN/H2O with 0.1% TFA) to yield 4-{2-[4-(2-dimethylamino-ethoxy)-phenyl]-4-hydroxymethyl-4-methyl-cyclohex-1-enyl}-phenol.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][NH:5][CH2:4][C@@H:3]1[CH2:8][NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CO.[F:22][C:23]1[CH:32]=[C:31]2[C:26]([CH:27]=[CH:28][C:29](=[O:36])[N:30]2[CH2:33][CH:34]=O)=[CH:25][CH:24]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[F:22][C:23]1[CH:32]=[C:31]2[C:26]([CH:27]=[CH:28][C:29](=[O:36])[N:30]2[CH2:33][CH2:34][N:5]2[CH2:6][CH2:7][C@@H:2]([OH:1])[C@@H:3]([CH2:8][NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:4]2)=[CH:25][CH:24]=1
Reactant: O=C(NC[C@H]1CNCC[C@H]1O)OCc1ccccc1
Reactant: O=CCn1c(=O)ccc2ccc(F)cc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: O=C(NC[C@H]1CN(CCn2c(=O)ccc3ccc(F)cc32)CC[C@H]1O)OCc1ccccc1
Reaction time: 18 h
Yield: 25 %

Procedure:
To a mixture of phenylmethyl {[(3R,4R)-4-hydroxy-3-piperidinyl]methyl}carbamate (for a preparation see Example 135(f); 0.72 g; 2.72 mmol) in anhydrous DCM (10 mL) and anhydrous MeOH (2 mL) was added (7-fluoro-2-oxo-1(2H)-quinolinyl)acetaldehyde (for a preparation see Example 88(a)) (0.559 g; 2.72 mmol) and activated 4A sieves. The reaction was stirred under N2 for 18 h. The crude intermediate was treated with sodium triacetoxyborohydride (2.72 mmol; 577 mg) and stirred for 2 h. The product was obtained as a pale yellow oil after column:chromatography (90:10:DCM:MeOH) to yield 306 mg (25%) of the product as its free base.