Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3](B(O)O)=[N:4][CH:5]=[CH:6][CH:7]=1.C(O)C.C([O-])([O-])=O.[K+].[K+].Br[C:21]1[S:22][C:23]([N:26]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[CH:24][N:25]=1>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.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([C:21]2[S:22][C:23]([N:26]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:34]([O:36][C:37]([CH3:38])([CH3:39])[CH3:40])=[O:35])=[CH:24][N:25]=2)[CH:5]=[N:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1cnc(Br)s1
Reactant: OB(O)c1ncccc1F
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: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1cnc(-c2cncc(F)c2)s1
Reaction time: 0.75 h
Yield: 72.8 %

Procedure:
To a 3-neck round bottom flask was added fluoropyridine boronic acid (4.55 g, 32.3 mmol), ethanol (54 mL), and aqueous K2CO3 solution (27 mL, 2.0 M, 53.8 mmol), followed by 50 mL toluene. To this mixture was added di(tert-butyl) 2-bromo-1,3-thiazol-5-ylimidodicarbonate (10.2 g, 26.9 mmol). Next, tetrakis(triphenylphosphine)palladium(0) (6.2 g, 5.4 mmol) was added in one portion. The flask was fitted with a reflux condenser and was heated to reflux. After 45 minutes, the reaction was cooled in an ice bath and partitioned between aqueous saturated NaHCO3 and ethyl acetate. The layers were separated and the aqueous layer was extracted once with ethyl acetate. The combined organics were washed once with brine, dried over MgSO4, filtered, and then concentrated. This solid was triturated with 20% ethyl acetate/hexanes. The solids were filtered off and the filtrate evaporated to provide a residue which was purified via silica gel column chromatography (0 to 100% ethyl acetate/hexanes) to afford the desired product as an off-white solid (7.74 g, 73% yield): mp 94-96° C.; 1H NMR (300 MHz, CDCl3) δ 8.91 (app t, J=1.3 Hz, 1H), 8.52 (d, J=3.0 Hz, 1H), 7.96 (ddd, J=9.2, 3.0, 1.8 Hz, 1H), 7.66 (s, 1H), 1.48 (s, 18H); ESIMS m/z 396 (M+1).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[C:4]([CH3:11])[N:3]=1.[C:12]1([NH:18][C:19](=O)[CH3:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH3:20][C:19]1[N:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:2]2=[N:3][C:4]([CH3:11])=[CH:5][CH:6]=[C:7]2[N:8]=1
Reactant: CC(=O)Nc1ccccc1
Reactant: Cc1ccc([N+](=O)[O-])c(Cl)n1
Product: Cc1ccc2nc(C)n(-c3ccccc3)c2n1
Yield: 62.7 %

Procedure:
Method A applied to 2-chloro-6-methyl-3-nitropyridine (86 mg, 0.5 mmol) and N-phenylacetamide (81 mg, 0.6 mmol) afforded the title compound as brown viscous oil (70 mg, 63%). 1H NMR (DMSO) δ 2.42 (s, 3H), 3.31 (s, 3H), 7.11 (d, J=8.0Hz, 1H), 7.51-7.63 (m, 5H), 7.89 (d, J=8.0Hz, 1H); 13C NMR δ 14.6, 23.8, 118.0, 126.1, 127.7, 128.7, 129.4, 132.1, 134.8, 148.3, 150.9, 151.1. HRMS: cal. for C14H14N3 [M+H+]: 224.1188; found: 224.1184.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].[F:20][CH:21]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:22](Cl)=[O:23]>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:19])[N:2]([NH:1][C:22](=[O:23])[CH:21]([F:20])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:11]=2)=[CH:13][CH:14]=1
Reactant: Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O
Reactant: O=C(Cl)C(F)c1ccccc1
Product: O=C(Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O)C(F)c1ccccc1

Procedure:
The product of Example 86A and 2-fluoro-2-phenylacetyl chloride were treated using a method similar to that described in Example 1C to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 12.22 (s, 1H), 8.39-8.45 (m, 1H), 7.90-8.07 (m, 2H), 7.69-7.78 (m, 1H), 7.61-7.68 (m, 6H), 7.46-7.53 (m, 3H), 6.26 (d, J=47.1 Hz, 1H); MS (ESI+) M/Z 408 (M+H)+.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH3:7])=[O:5])#[N:2].[S:8]1CC(O)S[CH2:10][CH:9]1O.C(N(CC)CC)C>CCO>[NH2:2][C:1]1[S:8][CH:9]=[CH:10][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)CC#N
Reactant: OC1CSC(O)CS1
Solvent: CCN(CC)CC
Solvent: CCO
Product: COC(=O)c1ccsc1N
Temperature: 40 °C
Reaction time: 1 h

Procedure:
A mixture of methyl cyanoacetate (3.25 g, 32.3 mmol), 1,4 dithiane-2,5 diol (5 g, 32.8 mmol), triethylamine (1 mL, 7.71 mmol) in EtOH (50 mL) is stirred at 40° C. for 1 h. The cooled solution is eluted through a silica plug with CH2Cl2. The filtrate is stripped to dryness to give crude methyl 2-aminothiophene-3-carboxylate which is carried on to the next reaction. 1H NMR (DMSO) δ 7.26 (1H, s), 6.82 (1H, d, J=5.8 Hz), 6.28 (1H, d, J=5.8 Hz), 3.69 (3H, s).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[NH2:8])=[N:2]1.C(=O)([O-])[O-].[K+].[K+].[Cl:19][CH2:20][C:21](Cl)=O>O1CCCC1.C(OCC)C>[Cl:19][CH2:20][C:21]1[N:2]2[N:1]=[CH:5][CH:4]=[C:3]2[C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]=1
Reactant: O=C(Cl)CCl
Reactant: Nc1ccccc1-c1cc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: ClCc1nc2ccccc2c2ccnn12
Temperature: 5 °C
Reaction time: 0.17 h

Procedure:
2.1. 8.6 g of 2-(1H-pyrazol-3-yl)aniline are dissolved in 800 ml of tetrahydrofuran. 75.3 g of potassium carbonate are added thereto, the mixture is cooled to 5° C. and then a solution of 6.7 ml of chloroacetyl chloride in 40 ml of diethyl ether is added dropwise thereto within 10 min. The mixture is stirred at 5° C. for 30 min. and then a solution of 0.67 ml of chloroacetyl chloride in 5 ml of diethyl ether is again added dropwise thereto. The mixture is stirred for a further 15 min. and then the insoluble constituent is filtered off, The filtrate is evaporated in a vacuum. The residue is partitioned between saturated aqueous sodium hydrogen carbonate solution and dichloromethane. The aqueous phase is extracted several times with dichloromethane. The organic extracts are dried and evaporated in a vacuum. The residue is taken up in 560 ml of a 0.41N solution of hydrogen chloride in dioxan and stirred at 90° C. for 1 h. The solution is evaporated in a vacuum and the residue is partitioned between saturated aqueous sodium hydrogen carbonate solution and dichloromethane. The dichloromethane extract is evaporated in a vacuum. 11.4 g of 5-(chloromethyl)-pyrazolo[1,5-c]quinazoline are obtained. The m.p. is 135°-136° C. after recrystallization from diisopropyl ether.
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH:8]1[C:21]2NC3C(=CC=CC=3)SC=2C=C[CH:9]=1>C(O)CCC>[C:1]([O:6][CH2:7][CH2:9][CH2:8][CH3:21])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: c1ccc2c(c1)Nc1ccccc1S2
Reactant: C=C(C)C(=O)OC
Solvent: CCCCO
Product: C=C(C)C(=O)OCCCC
Reaction time: 6 h

Procedure:
Two hundred six grams of a reaction mix containing a 5:1 mole ratio of methyl methacrylate, 1-butanol, and 100 ppm phenothiazine as inhibitor were added to a 500 ml flask equipped with an agitatior, thermocouple, and a 10-tray Oldershaw fractional distillation column. Thirty grams of the heterogeneous zirconium vinylbenzyl acetylacetonate/styrene/divinylbenzene catalyst was added. The mixture was heated to reflux at atmospheric pressure while an azeotropic mixture of methyl methacrylate and methanol was removed from the upper portion of the fractionating column. The reaction was continued in this manner for 6 hours while the temperature at the column was 64°-67° C. and the temperature in the pot was 101°-107° C. Gas liquid chromatography (GLC) analysis showed 60% conversion of 1-butanol with a selectivity to butyl methacrylate of 99%.
Reaction SMILES: [C:1]([CH:4]1[CH2:9][NH:8][C:7](=[O:10])[CH2:6][CH2:5]1)([OH:3])=[O:2].S(Cl)(Cl)=O.[CH2:15](O)[CH3:16]>>[CH2:15]([O:2][C:1]([CH:4]1[CH2:9][NH:8][C:7](=[O:10])[CH2:6][CH2:5]1)=[O:3])[CH3:16]
Reactant: CCO
Reactant: O=C1CCC(C(=O)O)CN1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)C1CCC(=O)NC1
Reaction time: 18 h

Procedure:
To a suspension of 250 g of 5-carboxy-2-piperidone in 2.5 liters of punctilious ethanol were added 500 g of thionyl chloride at 22° C. Stir for 18 hours. The resulting solution was evaporated to dryness and the residue triturated with ether to give 233 g of the title compound: MS m/z 171 (M+), 142, 126, 115, 98; 300-MHz 1H NMR (DMSO-d6) δ1.21 (t, J=7 Hz, 3H), 1.78-1.92 (m, 1H), 1.95-2.08 (m, 1H), 2.15-2.31 (m, 2H), 2.78-2.89 (m, 1H), 3.25-3.40 (m, 2H), 4.12 (t, J=7 Hz, 2H), 7.95 (s, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C@@H:4]([N:16]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][C:22]=2[NH:26][C:27]([CH:29]2[CH2:31][CH2:30]2)=[O:28])[CH2:17]1)[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH2:14][CH3:15])[CH:6]=1.C(N(CC)CC)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C(Cl)Cl>[CH2:14]([O:13][C:7]1[CH:6]=[C:5]([C@H:4]([N:16]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][C:22]=3[NH:26][C:27]([CH:29]3[CH2:31][CH2:30]3)=[O:28])[CH2:17]2)[CH2:3][CH2:2][NH:1][S:40]([CH3:39])(=[O:42])=[O:41])[CH:10]=[CH:9][C:8]=1[O:11][CH3:12])[CH3:15]
Reactant: CS(=O)(=O)Cl
Reactant: CCOc1cc([C@@H](CCN)N2Cc3cccc(NC(=O)C4CC4)c3C2=O)ccc1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOc1cc([C@@H](CCNS(C)(=O)=O)N2Cc3cccc(NC(=O)C4CC4)c3C2=O)ccc1OC
Reaction time: 3 h
Yield: 58 %

Procedure:
To a solution of (1R)-cyclopropanecarboxylic acid {2-[3-amino-1-(3-ethoxy-4-methoxy-phenyl)-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide (0.45 g, 1.1 mmol) and triethylamine (0.3 mL, 2 mmol) in methylene chloride (10 mL) was added methane sulfonyl chloride (0.10 mL, 1.3 mmol) at 0° C. After 3 hrs, the mixture was extracted with methylene chloride (20 mL) and water (20 mL). The organic layer was washed with HCl (1N, 20 mL), sodium hydrogen carbonate (sat 20 mL), brine (20 mL), and dried over MgSO4. The solvent was removed in vacuo to give a solid, which was purified with chromatography (Silica Gel) to give (1R)-cyclopropanecarboxylic acid {2-[1-(3-ethoxy-4-methoxy-phenyl)-3-methanesulfonylamino-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide as a white solid (320 mg, 58% yield): mp, 93-95° C.; 1H NMR (CDCl3) δ 0.89-0.93 (m, 2H, CH2), 1.08-1.10 (m, 2H, CH2), 1.42 (t, J=7 Hz, 3H, CH3), 1.65-1.72 (m, 1H, CH), 2.27-2.32 (m, 2H, CH2), 2.94 (s, 3H, CH3), 2.97-3.06 (m, 1H, CHH), 3.85 (s, 3H, CH3), 3.50 (d, J=17 Hz, 1H, NCHH), 4.04 (q, J=7 Hz, 2H, CH2), 4.18 (d, J=17 Hz, 1H, NCHH), 5.51 (dd, J=6, 9 Hz, 1H, NCH), 5.60-5.62 (m, 1H, NH), 6.81-6.99 (m, 4H, Ar), 7.42 (t, J=8 Hz, 1H, Ar), 8.42 (d, J=8 Hz, 1H, Ar), 10.47 (s, 1H, NH); 13C NMR (CDCl3) 8.35, 14.76, 16.19, 32.26, 40.24, 40.65, 46.05, 51.12, 55.98, 64.63, 111.50, 112.83, 116.86, 116.94, 117.84, 119.64, 130.31, 133.43, 138.02, 141.44, 148.72, 149.41, 170.07, 172.72; Anal Calcd for C25H31N3O6S+0.35H2O: C, 59.12; H, 6.29; N, 8.27, H2O 1.26. Found: C, 59.42; H, 6.16; N, 8.05, H2O 1.24.
Reaction SMILES: C[O:2][C:3](=[O:38])[CH2:4][CH2:5][CH2:6]/[CH:7]=[CH:8]\[CH2:9][C@H:10]1[C@@H:14]([O:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[CH2:13][C@@H:12]([O:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)[C@@H:11]1[CH2:29][O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32].[Li+].[OH-]>C1COCC1>[Si:31]([O:30][CH2:29][C@H:11]1[C@H:12]([O:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)[CH2:13][C@H:14]([O:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[C@@H:10]1[CH2:9]/[CH:8]=[CH:7]\[CH2:6][CH2:5][CH2:4][C:3]([OH:38])=[O:2])([C:34]([CH3:37])([CH3:35])[CH3:36])([CH3:33])[CH3:32]
Reactant: COC(=O)CCC/C=C\C[C@@H]1[C@@H](CO[Si](C)(C)C(C)(C)C)[C@H](OC2CCCCO2)C[C@@H]1OC1CCCCO1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1[C@@H](C/C=C\CCCC(=O)O)[C@@H](OC2CCCCO2)C[C@H]1OC1CCCCO1
Reaction time: 12 h

Procedure:
To (Z)-7-[(1R,2S,3R,5S)-2-(tert-Butyldimethylsilanyloxymethyl)-3,5-bis-(tetrahydropyran-2-yloxy)cyclopentyl]hept-5-enoic acid methyl ester (1.5 g, 2.71 mmol) stirring in THF was added LiOH (4 mL, 1 M in H2O, 4.0 mmol) and the stirring was continued at 23° C. for 12 h. The THF was evaporated and the mixture was acidified with cold 1% HCl and extracted with CH2Cl2 (3×). The combined organics were washed with brine, dried (Na2SO4) filtered and concentrated in vacuo. FCC (silica gel, 30% EtOAc/hex) afforded 1.23 g of the above named acid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][OH:6].O[N:8]1[C:12](=[O:13])[C:11]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:10]2[C:9]1=[O:18]>>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][N:8]1[C:12](=[O:13])[C:11]2[C:10](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]1=[O:18]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: COCCCO
Product: COCCCON1C(=O)c2ccccc2C1=O
Yield: 94.9 %

Procedure:
2-(3-Methoxypropoxy)isoindoline-1,3-dione (2C) was prepared from 3-methoxypropan-1-ol and N-hydroxyphthalimide by a procedure analogous to Example 2A, Step 1 (3.71 g, 94.9% yield). ESI-MS: m/z 236.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9](=[O:22])[CH:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])C(OC)=O)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[Cl-].[Na+].CS(C)=O>O>[Cl:1][C:2]1[C:3]([C:9](=[O:22])[CH2:10][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: COC(=O)C(C(=O)c1ncc(Cl)cc1Cl)c1ccccc1F
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(Cc1ccccc1F)c1ncc(Cl)cc1Cl
Temperature: 150 °C

Procedure:
A mixture of 4.50 g (13.2 mmol) of methyl 3-(3,5-dichloropyridin-2-yl)-2-(2-fluorophenyl)-3-oxopropanoate from example 1A, 845 mg (14.5 mmol) of sodium chloride, 474 mg (26.3 mmol) of water and 13.5 ml of DMSO is heated in a microwave at 150° C. for 10 min and then stirred into water and extracted with ethyl acetate. The organic phase is dried over sodium sulfate and concentrated. The residue is purified by chromatography on silica gel (eluent: dichloromethane) to result in a yellow oil which gradually crystallizes and affords 3.18 g (85% of theory) of the title compound.
Reaction SMILES: C[OH:2].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]#N)=[C:6]([F:13])[CH:5]=1.O.[C:15]([O-])([O-])=[O:16].[Na+].[Na+]>C(Cl)Cl>[CH3:15][O:16][C:11](=[O:2])[CH2:10][C:7]1[CH:8]=[CH:9][C:4]([Br:3])=[CH:5][C:6]=1[F:13]
Reactant: O=C([O-])[O-]
Reactant: N#CCc1ccc(Br)cc1F
Reactant: CO
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COC(=O)Cc1ccc(Br)cc1F
Temperature: 50 °C
Yield: 34.4 %

Procedure:
MeOH (16 mmol, 0.81 ml), TMSCI (20 mmol, 2.13 g) and (4-bromo-2-fluorophenyl) acetonitrile (10 mmol, 2.13 g) were sequentially added to a dry flask under a nitrogen atmosphere at room temperature. The reaction mixture was heated at 50° C. for 4 hours. After being cooled to room temperature, water (20 mmol, 0.36 ml) was added to the mixture, followed by the addition of Na2CO3 (10 mmol, 1.06 g) and CH2Cl2 (10 ml). Drying over MgSO4 and concentrating at low pressure afforded product (0.85 g, 35% yield). 1H NMR (300 MHz, CDCl3) δ: 3.57 (s, 2H), 3.65 (s, 3H), 7.08 (t, J=8.3 Hz, 1H), 7.16-7.21 (m, 2H).
Reaction SMILES: [CH2:1]([C:5]12[CH2:17][CH2:16][C:15](=[O:18])[C:14]([C:19]([F:22])([F:21])[F:20])=[C:13]1[C:12]1[C:7](=[C:8]([Cl:26])[C:9]([O:24]C)=[C:10]([F:23])[CH:11]=1)[CH2:6]2)[CH2:2][CH2:3][CH3:4].B(Br)(Br)Br>ClCCl>[CH2:1]([C:5]12[CH2:17][CH2:16][C:15](=[O:18])[C:14]([C:19]([F:21])([F:20])[F:22])=[C:13]1[C:12]1[C:7](=[C:8]([Cl:26])[C:9]([OH:24])=[C:10]([F:23])[CH:11]=1)[CH2:6]2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC12CCC(=O)C(C(F)(F)F)=C1c1cc(F)c(OC)c(Cl)c1C2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCCCC12CCC(=O)C(C(F)(F)F)=C1c1cc(F)c(O)c(Cl)c1C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 9a-butyl-8-chloro-6-fluoro-7-methoxy-4-(trifluoromethyl)-1,2,9,9a-tetrahydro-3H-fluoren-3-one (39 mg, 0.10 mmol) in anhydrous dichloromethane (1.0 mL) was cooled in a dry ice-acetone bath (−78° C.) and the solution was treated with 1M boron tribromide in dichloromethane (0.3 mL, 0.3 mmol). The cooling bath was removed and the mixture was stirred at room temperature for one hour. The mixture was partitioned between EtOAc (20 mL) and water (20 mL) containing 2N HCl (1 mL). The organic phase was washed with brine (10 mL), dried over MgSO4, filtered, and evaporated under vacuum. The residue was purified by preparative layer chromatography on a 0.1×20×20 cm silica gel GF plate, developing with 10% EtOAc in CH2Cl2. The product band was eluted with 10% MeOH in CH2Cl2, the eluent evaporated under vacuum, and the residue lyophilized from benzene plus a few drops of EtOH to afford 9a-butyl-8-chloro-6-fluoro-7-hydroxy-4-(trifluoromethyl)-1,2,9,9a-tetrahydro-3H-fluoren-3-one as an amorphous solid.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[Br:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27](O)=[O:28])=[CH:22][CH:21]=1>>[Br:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH:1][N:2]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:18])=[O:28])=[CH:22][CH:21]=1
Reactant: O=C(O)Cc1ccc(Br)cc1
Reactant: Nn1nc(N2CCOCC2)c2ccccc2c1=O
Product: O=C(Cc1ccc(Br)cc1)Nn1nc(N2CCOCC2)c2ccccc2c1=O

Procedure:
The product of Example 1B and 2-(4-bromophenyl)acetic acid were treated using a method similar to that described in Example 111 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.30 (dd, J=7.9, 1.3 Hz, 1H), 8.03 (dd, J=8.1, 1.3 Hz, 1H), 7.97-8.01 (m, 1H), 7.91 (td, J=7.5, 1.3 Hz, 1H), 7.54-7.56 (m, 2H), 7.33-7.36 (m, 2H), 3.78-3.83 (m, 4H), 3.65 (s, 2H), 3.08-3.13 (m, 4H); MS (ESI−) M/Z 441 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([OH:20])=[C:5]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:12]=[CH:11][CH:10]=2)[N:6]=[N:7][CH:8]=1.[H-].[Na+].Br[CH:24]1[CH2:27][CH2:26][CH2:25]1.CO>CN(C=O)C>[CH:24]1([N:7]2[CH:8]=[C:3]([O:2][CH3:1])[C:4](=[O:20])[C:5]([C:9]3[N:13]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[N:12]=[CH:11][CH:10]=3)=[N:6]2)[CH2:27][CH2:26][CH2:25]1
Reactant: BrC1CCC1
Reactant: COc1cnnc(-c2ccnn2-c2ccccc2)c1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: COc1cn(C2CCC2)nc(-c2ccnn2-c2ccccc2)c1=O
Reaction time: 1.5 h

Procedure:
Under an argon atmosphere, to a solution of 5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4-ol (2.0 g) in DMF (40 mL) was added under ice-cooling 60% sodium hydride (596 mg), and the mixture was stirred for 1.5 hr. Then, bromocyclobutane (1.05 mL) was added, and the mixture was stirred at room temperature for 16 hr. To the reaction mixture was added methanol, and the mixture was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate/methanol) and further purified by HPLC to give the title compound (0.92 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:26]([N:28]([CH2:32][CH2:33]O)[CH:29]([CH3:31])[CH3:30])=[O:27])=[N:11][C:12]([CH2:16][C:17]([CH3:25])([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH3:18])=[N:13][C:14]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]=[C:12]([CH2:16][C:17]([CH3:25])([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH3:18])[N:11]2[CH2:33][CH2:32][N:28]([CH:29]([CH3:31])[CH3:30])[C:26](=[O:27])[C:10]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)N(CCO)C(=O)c1nc(CC(C)(C)c2ccccc2)nc(O)c1OCc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)N1CCn2c(CC(C)(C)c3ccccc3)nc(=O)c(OCc3ccccc3)c2C1=O
Reaction time: 0.17 h
Yield: 53.5 %

Procedure:
To a stirred solution of 5-(benzyloxy)-6-hydroxy-N-(2-hydroxyethyl)-N-isopropyl-2-(2-methyl-2-phenylpropyl)pyrimidine-4-carboxamide (58) (35 mg, 75.5 μmol, Eq: 1.00) in dichloromethane (5.00 ml) was added triphenylphosphine (29.7 mg, 113 μmol, Eq: 1.5) at room temperature and the reaction mixture was stirred for 10 min. Then diisopropyl azodicarboxylate (22.9 mg, 22.0 μl, 113 μmol, Eq: 1.5) was added and the reaction mixture was stirred for 18 hrs at room temperature. The reaction mixture was concentrated on a rotary evaporator and chromatographed (silica gel, gradient, 2 to 5% methanol-dichloromethane) to obtain 9-(benzyloxy)-2-isopropyl-6-(2-methyl-2-phenylpropyl)-3,4-dihydro-1H-pyrazino[1,2-c]pyrimidine-1,8(2H)-dione (59) (18 mg, 53.5% yield).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[CH:10]2)=[CH:5][CH:4]=1)#[N:2].[CH3:18][I:19]>C1COCC1>[I-:19].[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N+:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]([CH3:18])[CH:10]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CI
Reactant: N#Cc1ccc(-n2cnc3ccccc32)cc1
Solvent: C1CCOC1
Product: Cn1c[n+](-c2ccc(C#N)cc2)c2ccccc21
Product: [I-]
Temperature: 40 °C

Procedure:
1-(4-Cyanophenyl)benzimidazole (90 g, slightly contaminated with mineral oil) together with THF (250 ml) is placed in a reaction vessel, admixed with methyl iodide (116 g, 0.82 mol) and maintained at 40° C. for 25.5 hours. The residue formed is filtered off, washed with ethanol and dried under reduced pressure. This gives 123 g of 1-(4-cyanophenyl)-3-methylbenzimidazolium iodide.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][C:17]([F:20])([F:19])[F:18])[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21]([O:24][C:25]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)=[O:26])[CH2:22][CH3:23].C(N1CCOCC1)C.[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O>CN(C=O)C.C(OCC)(=O)C>[CH2:21]([O:24][C:25]([N:27]1[CH2:32][CH2:31][N:30]([C:13](=[O:15])[C@@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:16][C:17]([F:20])([F:19])[F:18])[CH2:29][CH2:28]1)=[O:26])[CH2:22][CH3:23]
Reactant: CCCOC(=O)N1CCNCC1
Reactant: O=C(N[C@@H](CC(F)(F)F)C(=O)O)OCc1ccccc1
Agent: CCN1CCOCC1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCOC(=O)N1CCN(C(=O)[C@H](CC(F)(F)F)NC(=O)OCc2ccccc2)CC1
Reaction time: 12 h

Procedure:
To a solution of 118 mg (S)-2-Benzyloxycarbonylamino-4,4,4-trifluoro-butyric acid in 2 ml DMF were added 70 mg 1-propoxycarbonylpiperazine, 0.18 ml N-ethylmorpholine and 238 mg TOTU. After stirring for 12 h it was diluted with ethyl acetate and extracted with aqueous LiCl (4% w/w), aqueous NaHCO3, 0.1 M HCl and brine. The organic layer was dried over MgSO4 and concentrated to furnish the crude coupling product which was used without further purification in the next step.
Reaction SMILES: [OH:1][C:2]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)([CH3:11])[CH2:3][NH:4][S:5]([CH:8]([CH3:10])[CH3:9])(=[O:7])=[O:6].[H-].[Na+].[F:21][C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([F:30])[CH:29]=1)[CH2:25]Br.[Na+].[I-]>CN(C=O)C.O>[F:21][C:22]1[CH:23]=[C:24]([CH2:25][O:18][C:15]2[CH:14]=[CH:13][C:12]([C:2]([OH:1])([CH3:11])[CH2:3][NH:4][S:5]([CH:8]([CH3:10])[CH3:9])(=[O:7])=[O:6])=[CH:17][CH:16]=2)[CH:27]=[C:28]([F:30])[CH:29]=1
Reactant: CC(C)S(=O)(=O)NCC(C)(O)c1ccc(O)cc1
Reactant: Fc1cc(F)cc(CBr)c1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)S(=O)(=O)NCC(C)(O)c1ccc(OCc2cc(F)cc(F)c2)cc1
Temperature: 25 °C
Yield: 140.3 %

Procedure:
Into a 100 mL-3 neck flask fitted with a stirrer and thermometer, 200 mg of [2-hydroxy-2-(4-hydroxyphenyl)propyl][(methylethyl)sulfonyl]amine in DMF (5 mL) was added dropwise to 35 mg of NaH in DMF (20 mL) while stirring at room temperature under a nitrogen atmosphere. After stirring at this temperature for 30 minutes, 153 mg of 3,5-difluorobenzyl bromide in DMF (5 mL) was added dropwise followed by the addition of 92 mg of NaI portion wise. The reaction was then heated at 100° C. for 2 hours. The mixture was cooled to room temperature and poured into H2O and the desired product was extracted with ethyl acetate. This organic layer was washed with H2O, dried over K2CO3, and concentrated under reduced vacuum to yield 410 mg of a brown oil. This two spot material was purified via silica gel chromatography employing the Chromatotron and using a 4000 micron rotor while eluting with a solvent of hexane/ethyl acetate 1:1. Collection of the bottom spot provided the intermediate title compound (70 mg, 24%) as an oil. Ion spray M.S. 398.1 (M*−1).