Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:2]([C:15]2[N:19]([CH:20]([CH3:22])[CH3:21])[N:18]=[C:17]([CH:23]=O)[N:16]=2)=[CH:3][N:4]2[C:10]=1[C:9]1[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=1[O:7][CH2:6][CH2:5]2.Cl.[CH3:26][NH:27][CH3:28].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.C1COCC1.C(Cl)Cl>[N:1]1[C:2]([C:15]2[N:19]([CH:20]([CH3:21])[CH3:22])[N:18]=[C:17]([CH2:23][N:27]([CH3:28])[CH3:26])[N:16]=2)=[CH:3][N:4]2[C:10]=1[C:9]1[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=1[O:7][CH2:6][CH2:5]2
Reactant: CNC
Reactant: CC(C)n1nc(C=O)nc1-c1cn2c(n1)-c1ccccc1OCC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)n1nc(CN(C)C)nc1-c1cn2c(n1)-c1ccccc1OCC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 14.2 %

Procedure:
A mixture of 5-(4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-2-yl)-1-isopropyl-1H-[1,2,4]triazole-3-carbaldehyde (85 mg, 0.26 mmol), acetic acid (catalytic, 2 drops), 4 Å molecular sieves and dimethylamine hydrochloride (24 mg, 0.29 mmol) in THF (5 mL) was stirred at RT for 10 min before the addition of sodium triacetoxyborohydride (66 mg, 0.31 mmol). After stirring at RT for a further 18 h the reaction mixture was diluted with DCM, the organic layer washed with saturated aqueous sodium bicarbonate followed by water and then brine, then dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to RPHPLC (C18 column, gradient 5 to 98% methanol in water+0.1% HCO2H) to give 318 as a white solid (13 mg, 14%). LCMS: RT=3.18 min, [M+H]+353. 1H NMR 400 MHz (DMSO-d6) δ: 8.45 (1H, dd, J=8.02, 1.76 Hz), 7.97 (1H, s), 7.39-7.32 (1H, m), 7.19-7.19 (1H, m), 7.09 (1H, dd, J=8.15, 1.25 Hz), 5.89 (1H, m), 4.54 (4H, d, J=2.46 Hz), 3.47 (2H, s), 2.24 (6H, s), 1.51 (6H, d, J=6.59 Hz)
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[C:17]([NH:18][C:19](=[O:27])[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)=[CH:16][C:15]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:14][N:13]=2)[CH2:8][CH2:7]1)C.O1CCCC1.CO.[OH-].[Li+]>O>[Cl:26][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=1)[C:19]([NH:18][C:17]1[C:12]([N:9]2[CH2:10][CH2:11][CH:6]([CH2:5][C:4]([OH:34])=[O:3])[CH2:7][CH2:8]2)=[N:13][CH:14]=[C:15]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:16]=1)=[O:27]
Reactant: CCOC(=O)CC1CCN(c2ncc(-c3ccccc3)cc2NC(=O)c2cccc(Cl)c2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CC1CCN(c2ncc(-c3ccccc3)cc2NC(=O)c2cccc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 83 %

Procedure:
To a solution of 0.115 g (0.241 mmol) of [3′-(3-chloro-benzoylamino)-5′-phenyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]-acetic acid ethyl ester in a 5:2 mixture of tetrahydrofuran:methanol (7 mL) is added a solution of 0.028 g (1.2 mmol) of lithium hydroxide in water (1 mL). The reaction mixture is stirred at room temperature for 3 days and then concentrated under reduced pressure to remove volatile organics. The residue is diluted with water and the pH of the mixture is adjusted to approximately pH 2 by the addition of concentrated hydrochloric acid causing a solid to precipitate. The formed yellow solid is collected by filtration and dried under vacuum to provide 0.090 g (83%) of [3′-(3-chloro-benzoylamino)-5′-phenyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]-acetic acid.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([O:9][CH2:10][C@@H:11]2[CH2:15][CH2:14]C[NH:12]2)[CH:6]=[N:7][CH:8]=1)=[CH2:2].[ClH:16].CO>CCOCC>[ClH:16].[ClH:16].[NH:12]1[CH2:14][CH2:15][C@H:11]1[CH2:10][O:9][C:5]1[CH:6]=[N:7][CH:8]=[C:3]([CH:1]=[CH2:2])[CH:4]=1
Reactant: C=Cc1cncc(OC[C@@H]2CCCN2)c1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: C=Cc1cncc(OC[C@@H]2CCN2)c1

Procedure:
To a solution of 5-ethenyl-3-(2-(S)-pyrrolidinylmethoxy)pyridine in Et2O was added hydrogen chloride (1.0 M in Et2O) carefully to afford the tittle compound: mp 88-90° C. 1H NMR (D2O) δ 2.64-2.78 (m, 2H), 4.04-4.22 (m, 2H), 4.50 (d, 1H, J=4.0 Hz), 4.80 (m, 1H), 4.96 (m, 1H), 5.58 (dd, 1H, J=11.0 Hz), 6.04 (d, 1H, J=18.0 Hz), 6.83 (dd, 1H, J=11.0, 18.0 Hz), 7.85 (t, 1H, J=2.0 Hz), 8.31 (br s, 1H), 8.36 (br s, 1H); MS (CI/NH3) m/z 191 (M+H)+. Anal. Calcd for C11H14N2O.1.8 HCl: C, 51.64; H, 6.22; N, 10.95. Found: C, 51.59; H, 5.92; N, 10.75. [α]25D +2.58 (c 0.62, MeOH).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.CN1[CH:15]=[CH:14][C:12](=[O:13])N(C)C1=O.[O-]CC.[Na+:20].C(O)C>CO.ClCCl>[N:4]1[N:3]2[CH:15]=[CH:14][C:12]([O-:13])=[N:1][C:2]2=[CH:6][CH:5]=1.[Na+:20]
Reactant: Cn1ccc(=O)n(C)c1=O
Reactant: Nc1cc[nH]n1
Agent: CC[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Solvent: ClCCl
Product: [O-]c1ccn2nccc2n1
Yield: 95 %

Procedure:
A mechanically stirred mixture of 3-aminopyrazole (9.38 g, 0.11 mM, 1.0 equiv), 1,3-dimethyluracil (14.7 g, 0.11 mM, 1.0 equiv) and 21% sodium ethoxide in ethanol (170 mL, 5.0 equiv) was heated to reflux. Within minutes, a heavy precipitate formed. After refluxing for 1 hour, 1,3-dimethyluracil could no longer be detected by thin layer chromatography (tlc) (92:8 dichloromethane (dichloromethane):MeOH). The reaction mixture was cooled, filtered, washed with cold ethanol and vacuum dried to give 13.47 g (95%) of sodium pyrazolo[1,5-a]pyrimidin-5-olate. LCMS (ESI) m+H=136.0; 1H NMR (400 MHz, DMSO-d6) δ: 8.0 (d, 1H), 7.43 (d, 1H), 5.65 (d, 1H), 5.37 (d, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].[Cl:10][C:11]([F:19])([F:18])[C:12]([C:14]([F:17])([F:16])[F:15])=[O:13].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)(Cl)Cl>[F:15][C:14]([F:17])([F:16])[C:12]([C:7]1[CH:8]=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=1)([OH:13])[C:11]([F:19])([F:18])[Cl:10]
Reactant: CCOc1ccccc1
Reactant: O=C(C(F)(F)F)C(F)(F)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: CCOc1ccc(C(O)(C(F)(F)F)C(F)(F)Cl)cc1
Temperature: 120 °C

Procedure:
A mixture of ethoxybenzene (67 g), chloropentafluoroacetone (100 g) and aluminium chloride (7 g) was charged to a Hastalloy lined cell at -78° C, the cell sealed and heated to 120° C for 8 hours. After cooling and venting, the residue was taken up in chloroform and filtered through silica gel. After removal of the solvent by evaporation the residual solid was recrystallised from n-hexane to yield several crops of 1,1,1,3,3-pentafluoro-2-(4-ethoxyphenyl)-3-chloropropan-2-ol. (Total 70 g) mp. 84°-86° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)(=[O:4])[CH2:2][CH3:3].[C:15](OC(=O)C)(=[O:17])[CH3:16]>>[C:15]([N:10]1[C:11]2[C:7](=[CH:6][C:5]([C:1](=[O:4])[CH2:2][CH3:3])=[CH:13][CH:12]=2)[CH2:8][C:9]1=[O:14])(=[O:17])[CH3:16]
Reactant: CCC(=O)c1ccc2c(c1)CC(=O)N2
Reactant: CC(=O)OC(C)=O
Product: CCC(=O)c1ccc2c(c1)CC(=O)N2C(C)=O

Procedure:
Prepared from 5-propionyl-2-indolinone and acetic anhydride
Reaction SMILES: [NH2:1][C:2](=[O:25])[CH2:3][O:4][CH2:5][C:6]1[N:10]=[C:9]([C@H:11]([CH2:16][CH2:17][CH2:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:12][C:13](O)=[O:14])[O:8][N:7]=1.CN1CCOCC1.ClC(OCC(C)C)=O.C[Si](C)(C)[O:43][NH2:44]>O1CCCC1.CO>[NH2:1][C:2](=[O:25])[CH2:3][O:4][CH2:5][C:6]1[N:10]=[C:9]([C@H:11]([CH2:16][CH2:17][CH2:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:12][C:13]([NH:44][OH:43])=[O:14])[O:8][N:7]=1
Reactant: NC(=O)COCc1noc([C@H](CCCC2CCCCC2)CC(=O)O)n1
Reactant: C[Si](C)(C)ON
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: CO
Solvent: C1CCOC1
Product: NC(=O)COCc1noc([C@H](CCCC2CCCCC2)CC(=O)NO)n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 32.6 %

Procedure:
A solution of (3R)-3-{3-[(2-amino-2-oxoethoxy)methyl]-1,2,4-oxadiazol-5-yl}-6-cyclohexylhexanoic acid (Preparation 91) (178 mg, 0.50 mmol) and N-methylmorpholine (100 μl, 0.91 mmol) in anhydrous tetrahydrofuran (8 ml) was cooled to 0° C., treated with isobutyl chloroformate (70 μl, 0.54 mmol) and stirred under a nitrogen atmosphere for 2.5 hours. O-(Trimethylsilyl)hydroxylamine (200 μl, 1.63 mmol) was added and the mixture was stirred for 18 hours, being allowed to warm to room temperature over this time. The mixture was then treated with methanol and stirred at room temperature for 1 hour. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate and washed with water and brine, dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure. The oil was purified by column chromatography on silica gel eluting with a gradient system of 98:2 (dichloromethane:methanol) gradually changing to 90:10 (dichloromethane:methanol) and then neat methanol to afford the title compound as a colourless oil (60 mg).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[C:10]1([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]([NH:26][C:27]3[CH:42]=[CH:41][C:30]([O:31][C:32]4[C:37](B(O)O)=[CH:36][CH:35]=[CH:34][N:33]=4)=[CH:29][CH:28]=3)=[N:18][N:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>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.CO.C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([C:37]2[C:32]([O:31][C:30]3[CH:29]=[CH:28][C:27]([NH:26][C:19]4[C:20]5[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=5)[C:16]([C:10]5[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=5)=[N:17][N:18]=4)=[CH:42][CH:41]=3)=[N:33][CH:34]=[CH:35][CH:36]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: OB(O)c1cccnc1Oc1ccc(Nc2nnc(-c3ccccc3)c3ccccc23)cc1
Reactant: Fc1cnc(Cl)nc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: COCCOC
Product: Fc1cnc(Cl)nc1-c1cccnc1Oc1ccc(Nc2nnc(-c3ccccc3)c3ccccc23)cc1
Temperature: 85 °C
Reaction time: 3 h
Yield: 92.7 %

Procedure:
Under an argon atmosphere, 2,4-dichloro-5-fluoropyrimidine (390 mg, 2.34 mmol) and 2-(4-(4-phenylphthalazin-1-ylamino)phenoxy)pyridin-3-ylboronic acid (1.01 g, 2.34 mmol) were dissolved in 1,2-dimethoxyethane (15.6 ml, 2.34 mmol) in a screw capped test tube. Sodium carbonate (4.67 ml, 9.34 mmol) was added followed by Pd(PPh3)4 (0.270 g, 0.234 mmol). The tube was purged with argon, sealed, and heated to 85° C. After 3 h, LCMS showed mostly product, a small amount of starting material left. 100 mg of Dichlorofluoropyrimidine was added, and the reaction was stirred overnight. After 22 h, LCMS showed complete conversion to product. Water was added. The product was extracted with DCM. The organic phase was dried over MgSO4, filtered, and concentrated. Hexane was added to the residue. A tan solid precipitated and was filtered off with an aid of hexane. The product was purified using an ISCO column chromatography on silica gel eluting with 80:20 DCM:(90:10:1 DCM:MeOH:NHOH) and was obtained as a yellow solid, N-(4-(3-(2-chloro-5-fluoropyrimidin-4-yl)pyridin-2-yloxy)phenyl)-4-phenylphthalazin-1-amine (1.13 g, 93% yield). MS Calcd for C29H18ClFN6O: [M]+=520. Found: [M+1]+=521.
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[CH2:11][CH:10]([CH2:12][S:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])(=[O:15])=[O:14])[CH2:9]2)C=CC=CC=1.[H][H].[ClH:31]>C(O)C.O.[OH-].[OH-].[Pd+2]>[ClH:31].[F:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[S:13]([CH2:12][CH:10]1[CH2:11][NH:8][CH2:9]1)(=[O:14])=[O:15]
Reactant: O=S(=O)(CC1CN(C(c2ccccc2)c2ccccc2)C1)c1ccccc1F
Reactant: [H][H]
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=S(=O)(CC1CNC1)c1ccccc1F
Yield: 91 %

Procedure:
1-(Diphenylmethyl)-3-{[(2-fluorophenyl)sulfonyl]methyl}azetidine (1.33 g, 3.37 mmol) was dissolved in ethanol (80 mL). The solution was diluted with 2M hydrochloric acid (1.8 mL) and water (20 mL). 20% Palladium hydroxide on carbon (0.63 g) was added and the mixture shaken on a Parr apparatus under 50 psi of hydrogen for 3.5 h. The catalyst was removed by filtration and the filtrate concentrated to a small volume. The solid present was redissolved by adding ethanol and the solution filtered. The filtrate was concentrated to a small volume once again to give a crystalline solid which was collected under suction, washed with cold ethanol and dried in vacuo to afford the title compound as colourless crystals (0.81 g, 91%); 1H NMR (500 MHz, CD3OD) δ 3.34–3.42 (1H, m), 3.80 (2H, d, J=7.6 Hz), 4.07 (2H, t, J=10 Hz), 4.14 (2H, t, J=10 Hz), 7.41–7.49 (2H, m), 7.80–7.84 (1H, m), 7.90–7.92 (1H, m); 19F NMR (471 MHz, CD3OD) δ −110.6; m/z (ES+) 230 ([M+H]+, 100%).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([OH:29])([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH3:22])[CH:9]=2)=[O:5])C.[OH-].[Na+]>C1COCC1.C(O)C>[OH:29][C:7]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:21][CH3:22])[CH:9]=2)[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:6]1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)C1=C(c2ccccc2)c2ccc(OC)cc2C1(O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc2c(c1)C(O)(c1ccccc1)C(C(=O)O)=C2c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 96.9 %

Procedure:
1-Hydroxy-6-methoxy-1,3-diphenyl-1H-indene-2-carboxylic acid ethyl ester (110 mg, 0.285 mmol) prepared in Example 1 was dissolved in THF, and an excess amount of sodium hydroxide dissolved in aqueous ethanol was added thereto in such a way not to cause layer separation. The mixture was stirred for 24 hrs at RT, and the pH was adjusted to 3˜4 using 2N hydrochloric acid. The resulting mixture was extracted with ethyl acetate. The organic layer was separated, dried over anhydrous MgSO4 and concentrated under a reduced pressure, to obtain 99 mg of the titled compound (yield: 97%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][N:5]1[C:11](=[O:12])[C@@H:10]([NH2:13])[C:9]2[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=2[C:7]2[CH:18]=[CH:19][CH:20]=[CH:21][C:6]1=2.[CH3:23][CH:24]([C:28]([NH:30][CH2:31][C:32]([F:38])([F:37])[C:33]([F:36])([F:35])[F:34])=[O:29])[C:25](O)=[O:26].ON1C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C.C(Cl)CCl>C1COCC1>[CH3:1][O:2][C:3](=[O:22])[CH2:4][N:5]1[C:11](=[O:12])[C@@H:10]([NH:13][C:25](=[O:26])[CH:24]([C:28](=[O:29])[NH:30][CH2:31][C:32]([F:37])([F:38])[C:33]([F:34])([F:36])[F:35])[CH3:23])[C:9]2[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=2[C:7]2[CH:18]=[CH:19][CH:20]=[CH:21][C:6]1=2
Reactant: COC(=O)CN1C(=O)[C@@H](N)c2ccccc2-c2ccccc21
Reactant: CC(C(=O)O)C(=O)NCC(F)(F)C(F)(F)F
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CN1C(=O)[C@@H](NC(=O)C(C)C(=O)NCC(F)(F)C(F)(F)F)c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 70 %

Procedure:
((S)-7-Amino-6-oxo-6,7-dihydro-dibenzo[b,d]azepin-5-yl)-acetic acid methyl ester (25 mg, 0.85 mmol) were dissolved in THF and subsequently treated with 2-methyl-N-(2,2,3,3,3-pentafluoro-propyl)-malonamic acid (25 mg, 0.1 mmol), 1-hydroxybenzotriazole (11.6 mg, 0.85 mmol), N-ethyldiisopropylamine (0.03 ml, 0.17 mmol) and EDC (16.5 mg, 0.85 mmol). After stirring for 2.5 h at ambient temperature, the reaction mixture is quenched with water and extracted with ethyl acetate. The aqueous phase is extracted twice with ethyl acetate and the combined organic layers are extracted with water (2×5 ml) and saturated aqueous sodium chloride (5 ml), combined, dried over anhydrous sodium sulfate and evaporated to dryness. Chromatography (silica, eluent cyclohexane/ethyl acetate 65/35) afforded the product as colorless solid (70%). MS: m/e=528 (M+H+).
Reaction SMILES: [N:1]1[N:2]([CH2:6][C:7]([OH:9])=O)[N:3]=[CH:4][CH:5]=1.[F:10][C:11]1[CH:41]=[CH:40][C:14]([O:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]([C@@H:25]3[CH2:29][C@@H:28]([CH2:30][C:31]4[C:36]([F:37])=[CH:35][C:34]([F:38])=[CH:33][C:32]=4[F:39])[CH2:27][NH:26]3)=[O:24])=[CH:18][CH:17]=2)=[CH:13][CH:12]=1>>[N:3]1[N:2]([CH2:6][C:7]([N:26]2[CH2:27][C@H:28]([CH2:30][C:31]3[C:36]([F:37])=[CH:35][C:34]([F:38])=[CH:33][C:32]=3[F:39])[CH2:29][C@H:25]2[C:23]([NH:22][C:19]2[CH:18]=[CH:17][C:16]([O:15][C:14]3[CH:13]=[CH:12][C:11]([F:10])=[CH:41][CH:40]=3)=[CH:21][CH:20]=2)=[O:24])=[O:9])[N:1]=[CH:5][CH:4]=1
Reactant: O=C(O)Cn1nccn1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2c(F)cc(F)cc2F)CN1
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2c(F)cc(F)cc2F)CN1C(=O)Cn1nccn1

Procedure:
Proceeding as in Example 1, but substituting 2-(2H-1,2,3-triazol-2-yl)acetic acid and (2S,4R)—N-(4-(4-fluorophenoxy)phenyl)-4-(2,4,6-trifluorobenzyl)pyrrolidine-2-carboxamide, gave Compound 169, (2S,4R)-1-(2-(2H-1,2,3-triazol-2-yl)acetyl)-N-(4-(4-fluorophenoxy)phenyl)-4-(2,4,6-trifluorobenzyl)pyrrolidine-2-carboxamide. Major isomer: 1H-NMR (400 MHz, CDCl3): δ 9.12 (s, 1H), 7.72 (s, 2H), 7.43-7.38 (m, 2H), 7.03-6.86 (m, 6H), 6.72-6.64 (m, 2H), 5.12 (s, 2H), 4.82 (d, 1H), 3.63-3.57 (m, 1H), 3.22 (t, 1H), 2.92-2.74 (m, 3H), 2.59 (dd, 1H), 1.78-1.69 (m, 1H). MS (EI) for C28H23F4N5O3 found 554 (MH+).
Reaction SMILES: [Na].Cl[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.C(=O)=O.[CH2:12]([OH:15])[CH2:13][OH:14]>>[OH:14][CH2:13][CH2:12][O:15][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1
Reactant: OCCO
Reactant: Clc1ccncc1
Agent: O=C=O
Agent: [Na]
Product: OCCOc1ccncc1
Temperature: -15 °C
Reaction time: 1 h

Procedure:
To a solution of sodium (9.2 g) in ethylene glycol (100 ml) was added portionwise 4-chloropyridine (39.6 g) under heating at 120° to 130° C. and stirring, which was continued for one hour at 130° C. after the addition. The mixture was cooled to -15° C. and dry ice (5.2 g) was added thereto. The mixture was warmed to 45° C. and allowed to stand at room temperature. The resulting precipitates were removed by filtration and washed with diisopropyl ether. The filtrate and washings were combined and evaporated. The residual oil was distilled to give 4-(2-hydroxyethoxy)pyridine (9 g), bp. 138° to 145° C. at 5 to 6 mmHg, which solidified and recrystallized from ethyl acetate. mp. 113° to 115° C. (dec.).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][C@H:5]([CH2:24][O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[N:6]([C:13](=[O:23])[CH2:14][C:15]1[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:22])[C@H:7]2[CH3:12].[CH2:33](OB(C=C)OCCCC)[CH2:34]CC.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Si:26]([O:25][CH2:24][C@H:5]1[CH2:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[CH:33]=[CH2:34])[C@H:7]([CH3:12])[N:6]1[C:13](=[O:23])[CH2:14][C:15]1[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:22])([C:29]([CH3:30])([CH3:32])[CH3:31])([CH3:28])[CH3:27]
Reactant: C=CB(OCCCC)OCCCC
Reactant: C[C@H]1c2cccc(Br)c2C[C@H](CO[Si](C)(C)C(C)(C)C)N1C(=O)Cc1c(F)cccc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: C=Cc1cccc2c1C[C@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)Cc1c(F)cccc1Cl)[C@H]2C
Temperature: 80 °C
Reaction time: 2 h
Yield: 94.6 %

Procedure:
Dissolve 1-((1S,3R)-5-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-(2-chloro-6-fluorophenyl)ethan-1-one (1.8 g, 3.33 mmol) and vinylboronic acid dibutyl ester (1.5 mL, 6.65 mmol) in 1,4-dioxane (22 mL). Add aqueous Na2CO3 solution (11 mL, 2M in water). Degas with nitrogen 10 min Add bis(triphenylphosphine)palladium(II) chloride (467 mg, 0.67 mmol). Heat to 80° C. Stir 2 hours. Add water and extract with ethyl acetate three times. Combine the ethyl acetate extracts, dry over sodium sulfate, filter, and concentrate under reduced pressure to give a residue. Purify the residue by silica gel chromatography, eluting with ethyl acetate: hexanes (gradient, 5-40%) to give the title compound as a white foam (1.54 g, 3.15 mmol). MS (m/z): 488.2 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.O>[C:9]1([C:2]2[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Brc1ccc(Br)nc1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: Brc1ccc(-c2ccccc2)nc1

Procedure:
A mixture is prepared of 2,5-dibromopyridine (10 g, 42.21 mmol), phenylboronic acid (5.1 g, 42.21 mmol), and potassium carbonate (11.7 g, 84.42 mmol) in 100 mL dimethoxyethane and 40 mL of water. Nitrogen is bubbled directly into the mixture for 30 minutes. Next, tetrakis(triphenylphosphine)palladium(0) was added (244 mg, 2.11 mmol) and the mixture is heated to reflux under nitrogen overnight. The mixture is cooled and diluted with ethyl acetate and water. The layers are separated and the aqueous layer is extracted with ethyl acetate. The organic layers are washed with brine, dried over magnesium sulfate, filtered, and evaporated to a residue. The residue is purified by column chromatography eluting with 0, 2, and 5% ethyl acetate/hexanes.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH3:9].II.[C:12]([C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1)#N.C1C[O:23]CC1>CCOCC>[C:12]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH3:9])(=[O:23])[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1
Reactant: C1CCOC1
Reactant: Cc1ccccc1Br
Reactant: N#Cc1ccncc1
Agent: II
Agent: [Mg]
Solvent: CCOCC
Product: Cc1ccccc1C(=O)c1ccncc1
Temperature: 25 °C

Procedure:
To a warmed mixture of ether (500 mL) and magnesium turnings (14.9 g, 0.614 mol) was added dropwise 2-bromotoluene (105 g, 0.614 mol) and then a crystal of iodine. The reaction mixture was refluxed for 1 hour, then 4-cyanopyridine (30.2 g, 0.29 mol) in THF (130 mL) was added dropwise over 45 minutes. The mixture was refluxed for 1.5 hours, cooled to room temperature and quenched with 6N HCl (200 mL). The organic phase was separated, the aqueous phase was extracted with Et2O, and the combined ether phases were extracted with 2N HCl. The aqueous acidic phases were combined, basified with concentrated NH40OH, extracted with Et2O (3×750 mL) and the combined organic layers were dried over Na2SO4 and the solvent was removed in vacuo to afford 54 g of crude 2-isonicotinoyltoluene.
Reaction SMILES: [CH:1]1[CH:10]=[C:9]2[C:11]([O:13][C:14](=[O:15])[C:7]3=[C:8]2[C:3](=[C:4]([Cl:16])[CH:5]=[CH:6]3)[CH:2]=1)=O.[OH-].[Na+].[NH2:19][CH2:20][C:21]([OH:23])=[O:22].Cl>>[Cl:16][C:4]1[CH:5]=[CH:6][C:7]2[C:14](=[O:15])[N:19]([CH2:20][C:21]([OH:23])=[O:22])[C:11](=[O:13])[C:9]3[C:8]=2[C:3]=1[CH:2]=[CH:1][CH:10]=3
Reactant: O=C1OC(=O)c2ccc(Cl)c3cccc1c23
Reactant: NCC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CN1C(=O)c2cccc3c(Cl)ccc(c23)C1=O
Yield: 74.3 %

Procedure:
4-Chloro-1,8-naphthalic anhydride (20.0 g, 0.086 mole; commercial material purified by crystallization from toluene) was suspended in an aqueous 1 N sodium hydroxide solution (95 ml) of glycine (3.8 g, 0.095 mole). The mixture was stirred and refluxed for one hr, after which time a clear solution had resulted. The mixture was rendered acidic with conc hydrochloric acid. The resulting precipitate was collected and dried. Crystallization of the precipitate from anhydrous ethanol afforded 18.5 g of 6-chloro-1,3-dioxo-1H-benz[de]isoquinoline-2(3H)-acetic acid, mp 260° C.; UV (MeOH) 235,339 and 352 nm, ε=41,310, 15,190 and 13,700, respectively; IR (CHCl3) 1725, 1705 and 1670 cm-1 ; NMR (DMSO-d6) δ4.6 (s, 2H), 6.0 (m, 1H), 7.9 (m, 2H), 8.45 (m, 3H); Anal. Calc'd.: C, 58.05%; H, 2.78%; N, 4.83%; Found: C, 58.16%; H, 2.74%; N, 4.69%.