Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1COCC1.C(Cl)(=O)C(Cl)=O.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:22])[CH2:20][CH3:21])=[C:15]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:14]=1>CN(C=O)C.O>[Cl:12][C:13]1[CH:14]=[C:15]2[C:16]([C:19](=[O:22])[C:20]([CH3:1])=[CH:21][N:23]2[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[CH:17][CH:18]=1
Reactant: C1CCOC1
Reactant: CCC(=O)c1ccc(Cl)cc1Nc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O
Temperature: 115 °C
Reaction time: 1.5 h
Yield: 81.6 %

Procedure:
To a mixture of THF (60 mL) and DMF (7.5 mL) at 0° C. under nitrogen was added oxalyl chloride (6.5 mL, 76.8 mmol) during which time a white precipitate formed. The temperature was slowly raised to room temp. and stirred for 1.5 hr. THF was distilled off from the reaction mixture under reduced pressure and under nitrogen. The gummy residue was further diluted with DMF (100 mL). A solution of 1-(4-chloro-2-phenylamino-phenyl)-propan-1-one (5.0 g, 19.30 mmol) in DMF (50 mL) was added to the reaction mixture at room temperature. The reaction was heated at 115° C. for 2 hr. The reaction mixture was brought down to room temperature, then diluted with water (750 mL), and the mixture was extracted with ethyl acetate (2×750 mL). The combined organic layers were washed with brine (500 mL), dried, and concentrated under reduced pressure to yield 7-chloro-3-methyl-1-phenyl-1H-quinolin-4-one (4.25 g, 81.6%) as an off-white solid. 1H NMR (DMSO-d6) δ ppm 8.24 (d, J=8.8 Hz, 1H) 8.01 (s, 1H) 7.52-7.80 (m, 5H) 7.40 (dd, J=8.8, 1.8 Hz, 1H) 6.87 (d, J=1.8 Hz, 1H) 2.01 (s, 3H). MS calcd. for C16H12ClNO [(M+H)+] 270.0, obsd. 269.8.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].O[C:17]1[CH:26]=[C:25]2[C:20]([CH:21]=[CH:22][CH:23]=[N:24]2)=[CH:19][CH:18]=1>N1C=CC=CC=1>[O:6]([C:17]1[CH:26]=[C:25]2[C:20]([CH:21]=[CH:22][CH:23]=[N:24]2)=[CH:19][CH:18]=1)[S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Oc1ccc2cccnc2c1
Solvent: c1ccncc1
Product: O=S(=O)(Oc1ccc2cccnc2c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Trifluoromethanesulfonic anhydride (28.5 mL) was added dropwise to a solution of 7-hydroxyquinoline (22.0 g) in anhydrous pyridine (100 mL) cooled on ice. After 10 minutes, the mixture was warmed to ambient temperature and stirred overnight. The mixture was poured into 1000 mL of ice-cold 1 N HCl and extracted three times with 500 mL of ether. The combined organic extracts were washed once with water and once with brine, then dried over MgSO4, filtered, and evaporated. The crude product was chromatographed on silica gel (1:1 ethyl acetate/hexanes), then crystallized from hot hexane, yielding 32.3 g of product as pale yellow crystals. 1H-NMR (CDCl3): δ 8.98 (1H, dd, J=1.6, 4.4 Hz), 8.21 (1H, d, J=7.6 Hz), 8.03 (1H, d, J=2.4 Hz), 7.91 (1H, d, J=8.8 Hz), 7.48 (2H, m). 13C-NMR (CDCl3): δ 151.4, 149.9, 146.9, 137.3, 130.4, 127.5, 122.3, 121.1, 120.2, 118.7 (q, JCF=320 Hz).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][OH:29]>CC(=O)CC>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][OH:29])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Reactant: OCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: N#Cc1ccc(-c2ccc(OCCCCCCO)cc2)cc1
Yield: 66.4 %

Procedure:
A solution of 0.10 g (0.51 mmol) of 4-cyano-4'-hydroxybiphenyl and 0.10 g (0.72 mmol) of potassium carbonate dissolved in 4 ml of 2-butanone was refluxed. After addition of 0.10 g (0.55 mmol) of 6-bromohexan-1-ol to the reaction mixture, the whole was refluxed overnight. After removal of the solvent by distillation, water was added to the residue and the whole was extracted with methylene chloride. The extract was purified by silica gel column chromatography. The resulting white solid was recrystallized from hexane to obtain 0.10 g of 4-cyano-4'(6-hydroxyhexyloxy)biphenyl (9) (yield: 66.4%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][NH:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[CH:14][C:13]=1[O:20][CH3:21].[F:23][C:24]([F:39])([F:38])[C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[C:28](O)=[O:29]>>[CH3:1][O:2][C:3](=[O:22])[CH2:4][N:5]([C:28](=[O:29])[C:27]1[CH:31]=[C:32]([C:34]([F:35])([F:36])[F:37])[CH:33]=[C:25]([C:24]([F:23])([F:38])[F:39])[CH:26]=1)[C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[CH:14][C:13]=1[O:20][CH3:21]
Reactant: COC(=O)CNc1cnccc1-c1cc(F)c(F)cc1OC
Reactant: O=C(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: COC(=O)CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1-c1cc(F)c(F)cc1OC

Procedure:
The title compound was prepared in analogy to example 90, from [4-(4,5-difluoro-2-methoxy-phenyl)-pyridin-3-ylamino]-acetic acid methyl ester (example 172, intermediate a) and 3,5-bis(trifluoromethyl)benzoic acid (CAS RN 725-89-3) after a reaction time of 72 hours. The compound was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). The product-containing fractions were pooled and evaporated and the residue purified by preparative HPLC (Gemini NX column) using a gradient of methanol:water with 0.05% formic acid (80:20 to 98:2). Colorless solid (10%). MS (ESI): m/z=549.105 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([C:9]([O:11]C(C)(C)C)=[O:10])[C:6](=O)[CH2:5][CH:4]([CH3:8])[O:3]1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH3:26][O:27][C:28]([CH2:30]P(OC)(OC)=O)=[O:29]>CO>[CH3:1][C:2]1([C:9]([OH:11])=[O:10])[CH:6]([CH2:30][C:28]([O:27][CH3:26])=[O:29])[CH2:5][CH:4]([CH3:8])[O:3]1
Reactant: CC1CC(=O)C(C)(C(=O)OC(C)(C)C)O1
Reactant: COC(=O)CP(=O)(OC)OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CO
Product: COC(=O)CC1CC(C)OC1(C)C(=O)O
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 48 %

Procedure:
2,5-Dimethyl-3-oxo-2-tetrahydrofuroic acid, t-butyl ester (64 mg, from Reference Example 23, Step D) was dissolved in anhydrous methanol (1 mL) and cooled to −78° C. Potassium bis(trimethylsilyl)amide 0.66 mL) was added dropwise over 10 minutes. After being stirred at 78° C. for 15 minutes, trimethyl phosphonoacetate (65 mg, dissolved in 1.5 mL tetrahydrofuran) was added dropwise over 25 minutes. Upon completion of addition, the cold bath was removed and the mixture was allowed to stir at room temperature for 3 h when TLC (4/1 hexane/ethyl acetate) showed formation of a new spot. At 0° C., the reaction was quenched by addition of 1.5 mL of saturated aqueous ammonium chloride and the product was extracted with ethyl acetate twice, washed with saturated sodium chloride and dried over anhydrous magnesium sulfate. The crude product obtained after filtration and removal of volatiles was flash chromatographed over silica get, using gradient elution (50-10/1 hexane/ethyl acetate) to give 31 mg of the desired compound, homogeneous by TLC (Rf=0.5 in 4/1 hexane/ethyl acetate). The NMR showed that all the diastereomers are present in this sample.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[CH2:9][CH2:10][CH2:11][NH:12][C:13]2[C:14]3[C:19]([N:20]=[C:21]4[C:26]=2[C:25](=[O:27])[CH2:24][CH2:23][CH2:22]4)=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[F:34][C:31]1[CH:30]=[CH:29][C:28]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:9][CH2:10][CH2:11][NH:12][C:13]2[C:14]3[C:19]([N:20]=[C:21]4[C:26]=2[CH:25]([OH:27])[CH2:24][CH2:23][CH2:22]4)=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:33][CH:32]=1
Reactant: O=C1CCCc2nc3ccccc3c(NCCCC(c3ccc(F)cc3)c3ccc(F)cc3)c21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OC1CCCc2nc3ccccc3c(NCCCC(c3ccc(F)cc3)c3ccc(F)cc3)c21
Reaction time: 0.5 h

Procedure:
To a cooled solution of 4.2 g of 3,4dihydro-9[4,4-bis(4-fluorophenyl)butylamino]acridin-1(2H)-one in tetrahydrofuran was added 5 ml of 1M solution of lithium aluminum hydride in tetrahydrofuran. This was stirred for 0.5 hour at ice bath temperature.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[N:17]1[CH2:22][CH2:21][CH:20]([CH:23]([N:25]([CH3:27])[CH3:26])[CH3:24])[CH2:19][CH2:18]1.[Cl:28][C:29]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[C:31]([F:44])[C:30]=1[OH:45]>>[Cl:28][C:29]1[CH:34]=[C:33]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:15][CH2:16]2)=[O:13])=[C:5]3[N:17]2[CH2:22][CH2:21][CH:20]([CH:23]([N:25]([CH3:27])[CH3:26])[CH3:24])[CH2:19][CH2:18]2)[CH:32]=[C:31]([F:44])[C:30]=1[OH:45]
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(C1CCN(c2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1)N(C)C
Product: CC(C1CCN(c2c(C(=O)C3CC3)cnc3ccc(-c4cc(F)c(O)c(Cl)c4)cc23)CC1)N(C)C
Yield: 60.5 %

Procedure:
Following general procedure F, (6-bromo-4-{4-[1-(dimethylamino)ethyl]piperidin-1-yl}quinolin-3-yl)(cyclopropyl)methanone (39 mg, 0.090 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (30 mg, 0.108 mmol) to afford the desired product (27 mg, 60%) as a light brown solid: 1H NMR (500 MHz, CD3OD) δ 8.81 (s, 1H), 8.26 (d, J=1.6 Hz, 1H), 8.08-7.99 (m, 2H), 7.57-7.51 (m, 1H), 7.46 (dd, J=11.6, 2.2 Hz, 1H), 3.55 (d, J=11.5 Hz, 2-H), 3.27-3.13 (m, 3H), 2.78 (s, 5H), 2.63-2.51 (m, 1H), 2.02 (s, 1H), 1.95 (d, J=12.8 Hz, 2H), 1.82-1.67 (m, 2H), 1.41-1.19 (m, 8H), 0.90 (s, 1H); ESI MS m/z 496 [C28H31ClFN3O2+H]+; HPLC 98.4% (AUC), tR=10.58 min.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:11]([N:19]1[CH2:24][CH2:23][CH:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:21][CH2:20]1)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O1CCCC1.Cl.C(OCC)(=O)C>[C:11]([N:19]1[CH2:24][CH2:23][C:22]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:21][CH2:20]1)(=[O:18])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)C1CCN(C(=O)c2ccccc2)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C1(Cc2ccccc2)CCN(C(=O)c2ccccc2)CC1
Temperature: -78 °C
Reaction time: 8 h

Procedure:
A stirred solution of 176 mL of commercial 1M lithium bistrimethylsilylamide in tetrahydrofuran was diluted with 100 mL of tetrahydrofuran and cooled to -78° C. under inert atmosphere. A solution of 44 g of ethyl 1-benzoyl-4-piperidinecarboxylate in 200 mL of tetrahydrofuran was added dropwise keeping the temperature below -60° C., followed by 21 mL of benzyl bromide. The resulting mixture was allowed to warm and stir overnight, diluted with 200 mL of 1N hydrochloric acid, 200 mL of ethyl acetate and separated. The organic layer was washed with 200 mL of 1N hydrochloric acid, dried over MgSO4, and concentrated. The residue was dissolved in 300 mL of toluene, filtered and concentrated under reduced pressure. Drying under reduced pressure gave 56.3 g of ethyl 1-benzoyl-4-(phenylmethyl)-4-piperidinecarboxylate as a viscous oil homogeneous by thin layer chromatography, eluting with 1:1 ethyl acetate: hexane, 1H NMR (300 MHz, CDCl3) 1.20 (t, 3H), 1.40 (m, 1H), 1.60 (m, 1H), 2.07 (m, 1H), 2.22 (m, 1H), 2.85 (d, 2H), 3.08 (m, 1H), 3.65 (m, 1H), 4.12 (q, 2H), 4.65 (m, 1H), 7.04 (m, 2H), 7.24 (m, 3H), 7.38 (m, 5H).
Reaction SMILES: [CH2:1]([C:3]1[N:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[C:16]1[CH:21]=[CH:20][C:19]([O:22]CC2C=CC=CC=2)=[CH:18][CH:17]=1)[CH3:2].CO.[H][H]>[Pd].C(O)(=O)C>[CH2:1]([C:3]1[N:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[C:16]1[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=1)[CH3:2]
Reactant: CCc1nc(C(F)(F)F)nc2c1ncn2-c1ccc(OCc2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: CCc1nc(C(F)(F)F)nc2c1ncn2-c1ccc(O)cc1
Reaction time: 5 h
Yield: 68.1 %

Procedure:
A mixture of 6-ethyl-9-(4-benzyloxyphenyl)-2-trifluoromethylpurine (0.1 mmol), palladium on active carbon (0.001 mol, methanol (50 mL) and acetic acid (3 mL) was shaken under 30 psi hydrogen. After 5 hours, the reaction mixture was filtered through celite and the filtrate was concentrated under vacuum. The resulting residue was dissolved in 30 mL of ethyl acetate and washed with 5% aqueous sodium bicarbonate (1×30 mL). Concentration and Chromatography (5% methanol in dichloromethane) gave 6-ethyl-9-(4-hydroxyphenyl)-2-trifluoromethylpurine (21 mg, 93%). 1H NMR (300 MHz, CDCl3) δ 8.37 (s, 1H), 7.45 (d, J=7.2 Hz, 2H), 6.96 (d, J=7.2 Hz, 2H), 3.29 (q, J=7.5 Hz, 2 H), 3.11 (s, 1H), 1.41 (t, J=7.5 Hz, 3H). [ESMS m/z (309.4 (M+H)+)]
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH2:10][O:11][C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl.CCOCC>CO.O>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH2:9][CH2:10][O:11][C:12]2[CH:13]=[CH:14][C:15]([C:16]([OH:18])=[O:17])=[CH:20][CH:21]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(OCCNc2ccc(Cl)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CCOCC
Product: O=C(O)c1ccc(OCCNc2ccc(Cl)cc2)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 144.4 %

Procedure:
Methyl 4-[2-[N-(4-chlorophenyl)amino]ethoxy]benzoate (0.4 g) was suspended in methanol (20 ml), and thereto a solution of sodium hydroxide (0.16 g) in water (5 ml) was added, and the mixture was heated with stirring at 60° C. for 3 hours. The reaction mixture was cooled, and neutralized with hydrochloric acid and concentrated under reduced pressure. After adding water thereto, the resulting residue was crushed, then, collected by filtration to give crude crystal. An equivalent amount of hydrochloric acid was added to the crude crystal in methanol, and the mixture was dried under reduced pressure to give a salt. The salt was suspended in a mixed solvent of methanol and ether, and collected by filtration to give the desired product (0.31 g). mp. 190°-193° C.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([NH:9][N:10]=[CH:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)[NH:4][C:3]1=[O:22].C(N(CC)CC)C.[CH:30]([C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=1)[C:35]([OH:37])=[O:36])=O>CN(C)C=O>[CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[C:30]([C:32]3[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=3)[C:35]([OH:37])=[O:36])[N:10]([CH2:11][C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=[CH:14][CH:13]=3)[N:9]=[C:5]2[NH:4][C:3]1=[O:22]
Reactant: O=Cc1cccc(C(=O)O)c1
Reactant: Cn1c(=O)cc(NN=Cc2cccc3ccccc23)[nH]c1=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1c(=O)[nH]c2nn(Cc3cccc4ccccc34)c(-c3cccc(C(=O)O)c3)c2c1=O
Temperature: 90 °C
Reaction time: 16 h

Procedure:
1-naphthaldehyde (1-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)hydrazone (2.12 g) and triethylamine (0.8 ml) was added to a suspension of Resin bound 3-formylbenzoic acid in dimethylformamide (15 ml), and the mixture was shaken at 90° C. for 16 hours. The resin was filtered and washed (3 times) DMF, CH2Cl2, MeOH, CH2Cl2, and dried in vacuum to give the subtitle compound.
Reaction SMILES: C([N:3]([CH2:6][CH3:7])CC)C.[C:8](Cl)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1(C)C=CC=CC=1>[C:9]1([C:8]2[O:15][C:10]3[CH:11]=[CH:7][C:6]([NH2:3])=[CH:14][C:9]=3[CH:8]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Nc1ccc2oc(-c3ccccc3)cc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Triethylamine (63.4 ml, 0.455 mol) is added to 2-hydroxy-5-nitrobenzylphsophonium bromide (50 g, 0.101 mol) in refluxing toluene (600 ml), followed by addition of benzoyl chloride (16.2 ml, 0.140 mol) in toluene (50 ml). The mixture is refluxed for 3 hours, cooled and stirred at room temperature for 2 hours. The resulting mixture is concentrated and the product is recrystallized from 2/1 isopropyl ether/hexane, and the 2-phenyl-5-nitrobenzofuran is filtered off. This product is hydrogenated in THF (300 ml) and methanol (150 ml), with Pd/C (10%; 3.2 g). The catalyst is filtered off and the filtrate is concentrated. The residue is taken up in isopropanol/MeOH/HCl, and the hydrochloride is precipitated. It is suspended in 1M NaOH and extracted with ethyl acetate. The extracts are washed with water and concentrated. The solid is recrystallized from isopropyl ether. Yield: 9.8 g (32%); Elem. anal. C14H11NO; theory C, 80.36; H, 5.30; N, 6.70. found C, 79.78; H, 5.16; N, 6.87. IR (KBr): 3400, 3325, 1595, 1465 cm−1.
Reaction SMILES: [N:1]12[CH2:14][CH2:13][N:7]([CH2:8][CH2:9][NH:10][CH2:11][CH2:12]1)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2.[CH2:15]1[O:18][CH:16]1[CH3:17]>>[OH:18][CH:16]([CH3:15])[CH2:17][N:10]1[CH2:9][CH2:8][N:7]2[CH2:13][CH2:14][N:1]([CH2:2][CH2:3][N:4]([CH2:15][CH:16]([OH:18])[CH3:17])[CH2:5][CH2:6]2)[CH2:12][CH2:11]1
Reactant: C1CN2CCNCCN(CCN1)CC2
Reactant: CC1CO1
Product: CC(O)CN1CCN2CCN(CC1)CCN(CC(C)O)CC2

Procedure:
From 1,4,7,10-tetraazabicyclo[5.5.2]tetradecane (1.1.4) and propylene oxide.
Reaction SMILES: O[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([C:12]([O:14][CH3:15])=[O:13])[CH2:4][CH2:3]1.P(Br)(Br)[Br:17]>ClCCl.C(=O)(O)[O-].[Na+]>[Br:17][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([C:12]([O:14][CH3:15])=[O:13])[CH2:4][CH2:3]1
Reactant: COC(=O)C1CCC(O)c2ccccc21
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)C1CCC(Br)c2ccccc21
Temperature: 25 °C

Procedure:
Methyl 4-hydroxy-1,2,3,4-tetrahydronaphthalene-1-carboxylate (3.68 g, 17.84 mmol) was taken-up in dichloromethane (17.8 ml) and the solution was purged and then evacuated with argon. Phosphorus tribromide (3.4 ml, 36 mmol) was added, and the resulting mixture was allowed to stir at room temperature over the weekend. The reaction was diluted with aqueous sodium bicarbonate and product was extracted with dichloromethane (3×). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0 to 100% EtOAc/hexanes) to afford racemic methyl 4-bromo-1,2,3,4-tetrahydronaphthalene-1-carboxylate as a light yellow oil.
Reaction SMILES: [NH2:1][C@H:2]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:3][N:4]1[C:9](=[O:10])[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:12]=2[F:19])=[C:7]([CH3:20])[N:6]([CH2:21][C:22]2[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:25]=[CH:24][C:23]=2[F:32])[C:5]1=[O:33].Br[CH2:41][CH2:42][CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45].CCN(C(C)C)C(C)C>C(#N)C>[CH2:47]([O:46][C:44]([CH2:43][CH2:42][CH2:41][NH:1][C@H:2]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:3][N:4]1[C:9](=[O:10])[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:12]=2[F:19])=[C:7]([CH3:20])[N:6]([CH2:21][C:22]2[C:27]([C:28]([F:29])([F:31])[F:30])=[CH:26][CH:25]=[CH:24][C:23]=2[F:32])[C:5]1=[O:33])=[O:45])[CH3:48]
Reactant: CCOC(=O)CCCBr
Reactant: COc1cccc(-c2c(C)n(Cc3c(F)cccc3C(F)(F)F)c(=O)n(C[C@H](N)c3ccccc3)c2=O)c1F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCCN[C@@H](Cn1c(=O)c(-c2cccc(OC)c2F)c(C)n(Cc2c(F)cccc2C(F)(F)F)c1=O)c1ccccc1
Temperature: 95 °C
Yield: 49.5 %

Procedure:
To compound 3-[2(R)-amino-2-phenylethyl]-5-(2-fluoro-3-methoxyphenyl)-1-[2-fluoro-6-trifluoromethyl)benzyl]-6-methyl-pyrimidine-2,4(1H,3H)-dione 1f (5 g, 9.4 mmol) in 100 mL of acetonitrile were added ethyl 4-bromobutyrate (4 mL, 28.2 mmol) and Hunig's base (1.6 mL, 9.4 mmol). After reflux at 95° C. overnight, the reaction mixture was cooled to ambient temperature and the volatiles were removed. The residue was chromatographed with 10:10:1 EtOAc/Hexane/Et3N to give 1g as a yellow oil (3.0 g, 4.65 mmol). MS (CI) m/z 646.2 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([O:14]C)=[O:13])[CH:6]=[C:5]2[N:16]1[CH2:21][CH2:20][CH:19]([NH:22][C:23]([C:25]2[NH:26][C:27]([CH3:32])=[C:28]([Cl:31])[C:29]=2[Cl:30])=[O:24])[CH2:18][CH2:17]1.[OH-].[Na+].Cl>C1COCC1.CO.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([OH:14])=[O:13])[CH:6]=[C:5]2[N:16]1[CH2:17][CH2:18][CH:19]([NH:22][C:23]([C:25]2[NH:26][C:27]([CH3:32])=[C:28]([Cl:31])[C:29]=2[Cl:30])=[O:24])[CH2:20][CH2:21]1
Reactant: COC(=O)c1cc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)c2cc(Cl)ccc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1[nH]c(C(=O)NC2CCN(c3cc(C(=O)O)nc4ccc(Cl)cc34)CC2)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 94.7 %

Procedure:
Methyl 6-chloro-4-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)quinoline-2-carboxylate (Example 134; 20 mg) was dissolved in 6 ml of 2:1 THF/MeOH, 0.20 ml of 1 N NaOH was added and the resulting solution was stirred at ambient temperature for 20 h. Following neutralization with 0.25 ml of 1 N HCl, the reaction was diluted with 5 ml of water and filtered. The solid was washed with water and dried under vacuum, giving 18.4 mg of a light yellow granular solid.
Reaction SMILES: Cl.[CH3:2][CH:3]1[CH2:8][CH:7]([C:9]2[NH:14][C:13]3=[CH:15][CH:16]=[N:17][C:12]3=[CH:11][N:10]=2)[CH2:6][CH:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[NH:4]1.[CH2:24]([Li])CCC.S(OC)(OC)(=O)=O>C1COCC1>[CH3:2][CH:3]1[CH2:8][CH:7]([C:9]2[NH:14][C:13]3=[CH:15][CH:16]=[N:17][C:12]3=[CH:11][N:10]=2)[CH:6]([CH3:24])[CH:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[NH:4]1
Reactant: CC1CC(c2ncc3nccc-3[nH]2)CC(c2ccccc2)N1
Reactant: [Li]CCCC
Agent: Cl
Solvent: COS(=O)(=O)OC
Solvent: C1CCOC1
Product: CC1CC(c2ncc3nccc-3[nH]2)C(C)C(c2ccccc2)N1
Temperature: -78 °C
Reaction time: 1 h
Yield: 34 %

Procedure:
A suspension of 2-methyl-6-phenyl-4-piperidylpyrrolo[3,2-d]pyridine (Example 35) (57 mg, 0.20 mmol) in THF (3 mL) was placed under a N2 atmosphere and cooled with a dry-ice bath to −78° C. n-Butyl lithium (Aldrich Chemical Company) (360 μL, 0.90 mmol, 4.5 equiv of a 2.5 M solution in hexanes) was added slowly. The reaction mixture was stirred at −78° C. for 1 h and allowed to warmed to 0° C. Dimethyl sulfate (Eastman Kodak Company) (73.8 mg, 0.60 mmol, 3.0) was added slowly at 0° C. The solution was allowed to warm to room temperature and stir overnight. The reaction was quenched by the addition of 10% NH4Cl (3 mL) and the THF was evaporated under reduced pressure. The solution was extracted with CHCl3 (3×50 mL), and the combined organic layers were washed with saturated NaCl, dried over Na2SO4, filtered and concentrated with a rotary evaporator. The crude material was purified by flash chromatography on silica gel with a gradient eluant of EtOAc(0-20%):hexanes(100-80%) to provide 20 mg (34%) of the title compound as a white solid [30 mg (53%) of recovered starting material was also obtained]. Mp: 131-132° C. 1H NMR (acetone-d6, 400 MHz): δ 7.68 (d, 2, J=7.0), 7.54 (t, 2, J=7.0), 7.47 (t, 1, J=7.0), 3.84 (s, 3), 3.40 (t, 4, J=4.9), 2.50 (s, 3), 1.78 (m, 4), 1.70 (m, 2). MS m/z: 307 (M+1).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([NH:12][C:13]1[C:18](O)=[C:17]([F:20])[C:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:15]([CH3:27])[C:14]=1[C:28]#[N:29])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH2:1]([O:8][CH2:9][C:10]1[O:11][C:18]2[C:13](=[C:14]([C:28]#[N:29])[C:15]([CH3:27])=[C:16]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:17]=2[F:20])[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(C#N)c(NC(=O)COCc2ccccc2)c(O)c(F)c1-c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: Cc1c(-c2ccccc2)c(F)c2oc(COCc3ccccc3)nc2c1C#N

Procedure:
Similarly, 2-(benzyloxy)-N-(3-cyano-6-fluoro-5-hydroxy-2-methyl[1,1′-biphenyl]-4-yl)acetamide (I-89) (418 mg, 1.07 mmol) was dissolve din toluene (8.4 ml), p-toluenesulfonic acid monohydrate (84 mg, 20 wt. %) was added, followed by heating under reflux for 18 hours.