Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:2]=[C:3]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[N:21]=[N:20][C:19]([N:22]([CH3:33])[CH:23]4[CH2:28][C:27]([CH3:30])([CH3:29])[NH:26][C:25]([CH3:32])([CH3:31])[CH2:24]4)=[CH:18][CH:17]=3)=[C:12]([O:34]C)[CH:11]=2)[N:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=12.B(Br)(Br)Br.Cl>C(Cl)Cl>[CH3:33][N:22]([CH:23]1[CH2:28][C:27]([CH3:30])([CH3:29])[NH:26][C:25]([CH3:32])([CH3:31])[CH2:24]1)[C:19]1[N:20]=[N:21][C:16]([C:13]2[CH:14]=[CH:15][C:10]([C:3]3[N:4]4[CH2:9][CH2:8][NH:7][CH2:6][C:5]4=[N:1][CH:2]=3)=[CH:11][C:12]=2[OH:34])=[CH:17][CH:18]=1
Reactant: COc1cc(-c2cnc3cnccn23)ccc1-c1ccc(N(C)C2CC(C)(C)NC(C)(C)C2)nn1
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Product: CN(c1ccc(-c2ccc(-c3cnc4n3CCNC4)cc2O)nn1)C1CC(C)(C)NC(C)(C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 8.7 %

Procedure:
To a solution of 6-(4-(imidazo[1,2-a]pyrazin-3-yl)-2-methoxyphenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine (Example 42-3, 50 mg, 0.1 mmol) in DCM (2 mL) was added 1 M solution of BBr3 in DCM (0.52 mL) dropwise at 78° C. The crude reaction mixture was warmed to RT and stirred overnight. The reaction was quenched with NaHCO3 aq solution at 0° C. and extracted with DCM. The organic layer was dried over Na2SO4, filtered and concentrated to give the crude product. The crude product was acidified to pH 3 using 1N HCl and purified by catch and release using SiliaBond Propylsulfonic Acid® (1 g, MeOH as eluent and a 2 N ammonia solution in MeOH to release the material). After evaporation, the material was purified via reverse phase HPLC to afford 2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-yl)phenol (4 mg). MS: 462.4 [M+H+]; LCMS Rt=0.36 min [Method Q]; 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.03 (d, J=10.11 Hz, 1H), 7.74 (d, J=9.09 Hz, 1H), 7.22 (d, J=10.11 Hz, 1H), 6.96 (s, 2H), 6.99 (s, 1H), 5.02 (br. s., 1H), 3.88-4.09 (m, 4H), 3.11 (t, J=5.31 Hz, 2H), 2.92 (s, 3H), 1.62 (d, J=12.63 Hz, 2H), 1.51 (t, J=12.38 Hz, 2H), 1.31 (s, 6H), 1.16 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.COC1C=CC2[S:28]C3C(=CC=CC=3)NC=2C=1>>[CH3:1][O:2][C:3]1[C:8]2[S:28][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc(Nc2ccccc2)c1
Reactant: COc1ccc2c(c1)Nc1ccccc1S2
Product: COc1cccc2c1Sc1ccccc1N2

Procedure:
The conversion rate of the 3-methoxydiphenylamine is 91%, and the chemical yield of 2-methoxyphenothiazine is 91%.
Reaction SMILES: [OH:1][CH2:2][N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[C:13](=[O:31])[NH:14][C:15](=[O:30])[C:16]=2[C:17]2[C:25]3[C:20](=[CH:21][C:22]([N+:26]([O-:28])=[O:27])=[CH:23][CH:24]=3)[N:19]([CH3:29])[CH:18]=2)=[CH:4]1.[C:32](OC(=O)C)(=[O:34])[CH3:33]>O>[CH3:29][N:19]1[C:20]2[C:25](=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=2)[C:17]([C:16]2[C:15](=[O:30])[NH:14][C:13](=[O:31])[C:12]=2[C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[N:3]([CH2:2][O:1][C:32](=[O:34])[CH3:33])[CH:4]=2)=[CH:18]1
Reactant: CC(=O)OC(C)=O
Reactant: Cn1cc(C2=C(c3cn(CO)c4ccccc34)C(=O)NC2=O)c2ccc([N+](=O)[O-])cc21
Solvent: O
Product: CC(=O)OCn1cc(C2=C(c3cn(C)c4cc([N+](=O)[O-])ccc34)C(=O)NC2=O)c2ccccc21
Reaction time: 2.5 h
Yield: 53 %

Procedure:
A slurry of 3-(1-hydroxymethyl-1H-indol-3-yl)-4-(1-methyl-6-nitro-1H-indol-3-yl)-pyrrole-2,5-dione (120 mg, 0.288 mmol) (prepared as described in U.S. Ser. No. 09/268,887 (Compound II)) in 3 mL of acetic anhydride (Aldrich) was stirred at room temperature for 19 hours, and at 100° C. for 2.5 hours. The resulting solution was cooled, diluted with water, and extracted with EtOAc. The EtOAc layer was washed with water, brine, dried over magnesium sulfate, and evaporated. The residue was purified by flash chromatography using EtOAc/hexanes to give 77.1 mg of acetic acid 3-[4-(1-methyl-6-nitro-1H-indol-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3yl]-indol-1-ylmethyl ester. (Yield 53%).
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[N:16][C:5]2[NH:6][C:7]3[CH2:8][CH2:9][N:10]4[CH:14]([C:15]=3[C:4]=2[CH:3]=1)[CH2:13][CH2:12][CH2:11]4.[OH-].[K+].[F:20][C:21]([F:31])([F:30])[C:22]1[CH:27]=[CH:26][C:25]([CH:28]=[CH2:29])=[CH:24][N:23]=1>CN1C(=O)CCC1.O>[CH3:1][C:2]1[CH:17]=[N:16][C:5]2[N:6]([CH2:29][CH2:28][C:25]3[CH:24]=[N:23][C:22]([C:21]([F:31])([F:20])[F:30])=[CH:27][CH:26]=3)[C:7]3[CH2:8][CH2:9][N:10]4[CH:14]([C:15]=3[C:4]=2[CH:3]=1)[CH2:13][CH2:12][CH2:11]4
Reactant: C=Cc1ccc(C(F)(F)F)nc1
Reactant: Cc1cnc2[nH]c3c(c2c1)C1CCCN1CC3
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1cnc2c(c1)c1c(n2CCc2ccc(C(F)(F)F)nc2)CCN2CCCC12
Reaction time: 16 h

Procedure:
A solution of 10-methyl-2,3,5,6,7,11c-hexahydro-1H-pyrido[3′,2′:4,5]pyrrolo[2,3-g]indolizine (80 mg, 0.352 mmol) and powdered KOH (138 mg, 2.46 mmol) in NMP (2 mL) was stirred at RT for 5 min. 2-(Trifluoromethyl)-5-vinylpyridine (122 mg, 0.704 mmol) was added into the reaction mixture and stirring continued for 16 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue obtained was purified by silica gel flash chromatography to yield 10-methyl-7-(2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-2,3,5,6,7,11c-hexahydro-1H-pyrido[3′,2′:4,5]pyrrolo[2,3-g]indolizine;
Reaction SMILES: [Br:1]Br.C([O:6][CH2:7][CH2:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)(=[O:11])=[O:10])(=O)C.[O-]S([O-])=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>C(O)(=O)C.CC(=O)OCC>[Br:1][C:14]1[CH:13]=[C:12]([S:9]([CH2:8][CH2:7][OH:6])(=[O:11])=[O:10])[CH:17]=[CH:16][C:15]=1[O:18][CH3:19]
Reactant: BrBr
Reactant: COc1ccc(S(=O)(=O)CCOC(C)=O)cc1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1ccc(S(=O)(=O)CCO)cc1Br
Temperature: 50 °C
Yield: 29.5 %

Procedure:
Br2 (25 g, 155.0 mmol) was added dropwise over 30 min to the title compound of step 2 (8.0 g, 31.0 mmol) in acetic acid (100 mL) at 0° C. The mixture was heated at 50° C. for 12 h. Aqueous Na2SO3 (200 mL) was added and the pH was adjusted to 8 with sat. aq. NaHCO3. The mixture was subjected to EA extractive work up and silica gel chromatography (PE:EA=1:0-1:1) to give the title compound (2.7 g, 27.3%) as a white solid. 1H NMR (CDCl3, 400 MHz) δ 8.11 (d, J=2.4 Hz, 1H), 7.87 (dd, J1=8.8 Hz, J2=2.4 Hz, 1H), 7.04 (d, J=2.4 Hz, 1H), 4.05-4.00 (m, 5H), 3.34-3.67 (m, 3H). LCMS: 316.9, 318.9 (M+Na)+
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][CH2:14][O:15][CH:16]=[C:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:7]1)=[O:5])C.[OH-].[Na+].Cl.[Cl:33]CCl>C(O)C.CC(C)=O>[ClH:33].[C:24]1([C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:16][O:15][CH2:14][CH2:13][CH2:12][N:8]2[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4]([OH:5])=[O:3])[CH2:7]2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCOC(=O)[C@@H]1CCCN(CCCOC=C(c2ccccc2)c2ccccc2)C1
Reactant: ClCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(C)=O
Product: O=C(O)[C@@H]1CCCN(CCCOC=C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
(R)-1-[3-[[2,2-Diphenylethenyl]oxy]propyl]-3-piperidine carboxylic acid ethyl ester (0.60 g, 0.0015 mol) (prepared as described in Method A) was dissolved in ethanol (5 ml) and 12N sodium hydroxide solution (0.4 ml) was introduced. After stirring the solution at room temperature for 2 h, 37% hydrochloric acid (ca. 0.52 ml) was added with cooling followed by dichloromethane (250 ml). The mixture was dried (Na2SO4). Filtration and evaporation of the filtrate gave a residue, which was co-evaporated with acetone. The solid product was triturated with acetone, collected by filtration and dried in vacuo to give the title compound (0.30 g, 50%), m.p. 176°-180°.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([C:18](=[O:35])[NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][N:27]4[CH2:32][CH2:31][S:30](=[O:34])(=[O:33])[CH2:29][CH2:28]4)=[CH:22][CH:21]=3)=[CH:14][CH:13]=2)[C:8]([CH3:11])=[CH:9][CH:10]=1)=O.[BH4-].[Li+].CO>C1COCC1>[O:34]=[S:30]1(=[O:33])[CH2:31][CH2:32][N:27]([CH2:26][C:23]2[CH:24]=[CH:25][C:20]([NH:19][C:18]([C:15]3[CH:14]=[CH:13][C:12]([C:7]4[CH:6]=[C:5]([CH2:3][OH:2])[CH:10]=[CH:9][C:8]=4[CH3:11])=[CH:17][CH:16]=3)=[O:35])=[CH:21][CH:22]=2)[CH2:28][CH2:29]1
Reactant: COC(=O)c1ccc(C)c(-c2ccc(C(=O)Nc3ccc(CN4CCS(=O)(=O)CC4)cc3)cc2)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(CO)cc1-c1ccc(C(=O)Nc2ccc(CN3CCS(=O)(=O)CC3)cc2)cc1
Reaction time: 18 h
Yield: 94.8 %

Procedure:
4′-[4-(1,1-Dioxo-1lambda*6*-thiomorpholin-4-ylmethyl)-phenylcarbamoyl]-6-methyl-biphenyl-3-carboxylic acid methyl ester (565 mg) in dry THF (6 ml) was treated with a solution of lithium borohydride (2M in THF, 3.5 ml). The mixture was stirred at 20 C for 18 h. and was then treated with methanol (5 ml). The mixture was then evaporated and the residue partitioned between water and ethyl acetate. The dried extracts were evaporated giving the title compound as a colourless crystalline solid (505 mg).
Reaction SMILES: Br[C:2]1[C:15]([F:16])=[C:14]([F:17])[C:5]([CH2:6][O:7]C2CCCCO2)=[C:4]([F:18])[C:3]=1[F:19].[CH2:20](Cl)[C:21]#[CH:22]>>[CH2:22]([C:2]1[C:3]([F:19])=[C:4]([F:18])[C:5]([CH2:6][OH:7])=[C:14]([F:17])[C:15]=1[F:16])[C:21]#[CH:20]
Reactant: C#CCCl
Reactant: Fc1c(F)c(COC2CCCCO2)c(F)c(F)c1Br
Product: C#CCc1c(F)c(F)c(CO)c(F)c1F

Procedure:
4-(Prop-2-yn-1-yl)-2,3,5,6-tetrafluorobenzyl alcohol was prepared from 2-[4-bromo-2,3,5,6-tetrafluorobenzyloxy)-tetrahydropyran and propargyl chloride, by a two stage procedure similar to that described in Example 4.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].C(O)(C(F)(F)F)=O.[C:35]1([C:41](=[O:49])[CH2:42][C:43](=O)[CH2:44][CH2:45][CH2:46][CH3:47])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[CH2:44](/[C:43](/[NH:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4])=[CH:42]/[C:41](=[O:49])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:45][CH2:46][CH3:47]
Reactant: CCCCC(=O)CC(=O)c1ccccc1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C[C@H](N)C(=O)O)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCCC/C(=C/C(=O)c1ccccc1)N[C@@H](Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)C(=O)O

Procedure:
The title compound was prepared (as described above for the preparation of Example 2) from 1.0 g (2.05 mmol) of Intermediate 45 (as the TFA salt) and 0.86 g (4.2 mmol) of Intermediate 18 to yield 290 mg (25% yield) of Example 23 as a solid: TLC (EtOAc/MeOH , 7/3): Rf=0.55; 1H NMR (DMSO-d6, 400 MHz) δ11.59 (d, 1H, J=9.7), 7.86 (m, 2H), 7.76 (m, 2H), 7.48-7.34 (m, 6H), 7.10 (d, 2H, J=8.5), 7.10 (t, 2H, J=8.4), 6.8 (d, 2H, J=8.6), 5.52 (s, 1H), 4.12 (t, 2H, J=6.5), 4.02 (m, 1H), 3.16 (m, 1H), 2.86 (t, 2H, J=6.5), 2.75 (dd, 1H, J=13.5, 9.5), 2.31 (s, 3H), 1.9 (m, 2H), 1.3-1.1 (m, 4H), 0.73 (t, 3H, J=6.9); low resolution MS (ES+)m/e 553.2 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[CH2:4][CH:5]([C:11]([CH3:13])=O)[C:6]([O:8]CC)=O.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:24]=[C:25]([O:27][CH3:28])[CH:26]=1)[NH2:23].CS(O)(=O)=O.O>C1(C)C(C)=CC=CC=1>[CH3:28][O:27][C:25]1[CH:26]=[C:20]([O:19][CH3:18])[CH:21]=[C:22]2[C:24]=1[C:11]([CH3:13])=[C:5]([CH2:4][C:3]1[CH:14]=[CH:15][CH:16]=[CH:17][C:2]=1[F:1])[C:6](=[O:8])[NH:23]2
Reactant: CCOC(=O)C(Cc1ccccc1F)C(C)=O
Reactant: COc1cc(N)cc(OC)c1
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1C
Solvent: O
Product: COc1cc(OC)c2c(C)c(Cc3ccccc3F)c(=O)[nH]c2c1
Temperature: 160 °C
Reaction time: 0.5 h

Procedure:
Ethyl 2-(2-fluorobenzyl)acetoacetate (2.5 g) in xylene (1 ml) was heated to 150° C. and 3,5-dimethoxyaniline (1.46 g) in xylene (4 ml) was added in small portions during 30 minutes. The reaction mixture was heated at 160° C. for 3 hours and then cooled to room temperature. Methanesulfonic acid (1.7 ml) was added and the mixture was stirred at ambient temperature for 30 minutes. Water was added and the precipitate filtered and dried. The product was triturated with warm ethanol. Yield 0.64 g (21%).
Reaction SMILES: [CH2:1]([C:3]1[S:4][C:5]([CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:6][C:7]=1[CH:8]=[O:9])[CH3:2].[CH:16]1([Mg]Br)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.O1CCCC1.[Cl-].[NH4+]>O1CCCC1>[CH:16]1([CH:8]([C:7]2[CH:6]=[C:5]([CH:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[S:4][C:3]=2[CH2:1][CH3:2])[OH:9])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CCc1sc(C2CCOCC2)cc1C=O
Reactant: Br[Mg]C1CCCCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCc1sc(C2CCOCC2)cc1C(O)C1CCCCC1
Reaction time: 2 h
Yield: 77 %

Procedure:
To a solution of 2-ethyl-5-(tetrahydro-2H-pyran-4-yl)thiophene-3-carbaldehyde (692 mg) synthesized above in tetrahydrofuran (10 mL) was added dropwise 1.0M cyclohexylmagnesium bromide-tetrahydrofuran solution (4.64 mL) at 0° C., and the mixture was stirred for 2 hr. Saturated aqueous ammonium chloride solution was added to quench the reaction, tetrahydrofuran was evaporated using evaporator, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=3:7, volume ratio) to give the title compound (737 mg, 77%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-])=O)[CH:17]=2)[N:4]=[C:5]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[NH:8][C:7](=[O:15])[C:6]=12.O1CCCC1>[Pd].CO>[NH2:1][C:2]1[N:3]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=2)[N:4]=[C:5]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[NH:8][C:7](=[O:15])[C:6]=12
Reactant: Nc1c2c(=O)[nH]c3ccccc3c2nn1-c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1cccc(-n2nc3c(c2N)c(=O)[nH]c2ccccc23)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.2 %

Procedure:
A mixture of 3-amino-2-(3-nitrophenyl)-2,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one (150 mg), 10% palladium/active carbon (50% water, 40 mg), tetrahydrofuran (10 ml) and methanol (30 ml) was stirred under hydrogen atmosphere, at room temperature for 3 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. To the residue was added methanol, and the precipitated solid was collected by filtration, washed with methanol, and dried to obtain the target compound (120 mg).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N+:9]([O-:11])=[O:10].C(=O)([O-])[O-].[K+].[K+].[C:18]([O:25][CH3:26])(=[O:24])[CH2:19][C:20]([O:22][CH3:23])=[O:21]>CN(C)C=O>[F:8][C:4]1[C:3]([N+:9]([O-:11])=[O:10])=[C:2]([CH:19]([C:18]([O:25][CH3:26])=[O:24])[C:20]([O:22][CH3:23])=[O:21])[CH:7]=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1c(F)cccc1F
Reactant: COC(=O)CC(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C(=O)OC)c1cccc(F)c1[N+](=O)[O-]
Temperature: 65 °C
Reaction time: 24 h
Yield: 52 %

Procedure:
1,3-Difluoro-2-nitrobenzene (2.83 g, 17.79 mmol) was dissolved in N,N-dimethylformamide (25 mL). Potassium carbonate (2.49 g, 18.02 mmol) was added to the mixture followed by dimethyl malonate (2.033 ml, 17.79 mmol). Mixture was warmed to 65° C. and held for 24 hours. Mixture was cooled to room temperature. Reaction was quenched with 1N hydrochloric acid. Material was extracted three times with diethyl ether and the aqueous phase was discarded. Material was washed twice with water and the aqueous phase was discarded. Material was washed with brine and the aqueous phase was discarded. Organics were dried MgSO4, filtered and then concentrated to dryness. Residue was crystallized with hexanes. Solids were filtered off and washed with hexanes. Title compound was obtained as yellow crystals in 52% yield. MS (M−H)−=270.1.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([C:15]2[N:16](COCC[Si](C)(C)C)[CH:17]=[C:18]([C:20]#[N:21])[N:19]=2)=[O:14])=[C:8]([C:30]2[CH2:35][CH2:34][C:33]([CH3:37])([CH3:36])[CH2:32][CH:31]=2)[CH:7]=1)(=[O:3])[NH2:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.CCOC(C)=O>C1COCC1>[C:1]([CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([C:15]2[NH:16][CH:17]=[C:18]([C:20]#[N:21])[N:19]=2)=[O:14])=[C:8]([C:30]2[CH2:35][CH2:34][C:33]([CH3:37])([CH3:36])[CH2:32][CH:31]=2)[CH:7]=1)(=[O:3])[NH2:2]
Reactant: CC1(C)CC=C(c2cc(CCC(N)=O)ccc2NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(C)CC=C(c2cc(CCC(N)=O)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Temperature: 25 °C
Yield: 24 %

Procedure:
A solution of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid [4-(2-carbamoyl-ethyl)-2-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-amide (as prepared in the previous step, 160 mg, 0.307 mmol) and tetrabutylammonium fluoride (357 μL, 0.357 mmol, 1.0 M in THF) in 4.5 mL of THF was stirred at reflux for 1.5 h under Ar. After cooling to RT, the mixture was treated with EtOAc (40 mL), washed with saturated aq NaHCO3 (5 mL), brine (10 mL) and dried (Na2SO4). The organic layer was concentrated in vacuo and the residue was purified by flash chromatography on silica gel (5% MeOH/DCM) to give 29.2 mg (24%) of the title compound as a white solid. 1H-NMR (CD3OD; 400 MHz): δ 8.09 (d, 1H, J=8.3 Hz), 7.98 (s, 1H), 7.14 (dd, 1H, J=8.3, 2.1 Hz), 7.07 (d, 1H, J=2.1 Hz), 5.71 (m, 1H), 2.89 (t, 2H, J=7.7 Hz), 2.50 (t, 2H, J=7.7 Hz), 2.29 (m, 2H), 2.06 (m, 2H), 1.57 (t, 2H, J=6.3 Hz), 1.07 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C22H25N5O2, 392.2 (M+H). found 392.2.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5](I)=[CH:4][C:3]=1[CH3:10].[CH3:11][N:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][C:13]1=[O:21]>>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:15]2[CH:16]=[CH:17][N:12]([CH3:11])[C:13](=[O:21])[CH:14]=2)=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1cc(I)cc(C)c1Br
Reactant: Cn1ccc(B(O)O)cc1=O
Product: Cc1cc(-c2ccn(C)c(=O)c2)cc(C)c1Br

Procedure:
The title compound is prepared from 2-bromo-5-iodo-1,3-dimethylbenzene and 1-methyl-2-oxo-1,2-dihydropyridin-4-ylboronic acid following a procedure analogous to that described in Step 1 of Intermediate 56. LC (method 11): tR=1.04 min; Mass spectrum (ESI+): m/z=292, 294 [M+H]+.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]2[S:16][C:15]([S:17]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][C:21]3=[O:26])(=[O:19])=[O:18])=[N:14][C:13]=2[CH:27]=1.[CH:28]([O:41][C:42]([NH:44][C:45]1[CH:50]=[CH:49][N:48]([CH2:51][C:52](O)=[O:53])[C:47](=[O:55])[N:46]=1)=[O:43])([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]2[S:16][C:15]([S:17]([N:20]3[CH2:25][CH2:24][N:23]([C:52](=[O:53])[CH2:51][N:48]4[CH:49]=[CH:50][C:45]([NH:44][C:42]([O:41][CH:28]([C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=5)[C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)=[O:43])=[N:46][C:47]4=[O:55])[CH2:22][C:21]3=[O:26])(=[O:19])=[O:18])=[N:14][C:13]=2[CH:27]=1
Reactant: O=C1CNCCN1S(=O)(=O)c1nc2cc(Cl)ccc2s1
Reactant: O=C(O)Cn1ccc(NC(=O)OC(c2ccccc2)c2ccccc2)nc1=O
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccn(CC(=O)N2CCN(S(=O)(=O)c3nc4cc(Cl)ccc4s3)C(=O)C2)c(=O)n1)OC(c1ccccc1)c1ccccc1

Procedure:
The title compound was synthesized by the reaction of 1-(5-chloro-benzothiazole-2-sulfonyl)-piperazin-2-one trifluoroacetic acid salt with [4-N-(benzhydryloxycarbonyl)-cytosin-1-yl]-acetic acid as per the procedure of Example 52. 1H NMR (500 MHz; DMSO-d6) δ 10.98 (brs, 1H), 8.40 (m, 2H), 7.96 (s, 1H), 7.79 (m, 1H), 7.45 (d, 4H), 7.38 (t, 4H), 7.30 (t, 2H), 6.96 (t, 1H), 6.80 (s, 1H), 4.83 (s, 1.2H), 4.72 (s, 0.8H), 4.46 (s, 0.8H), 4.28 (s, 1.2H), 4.22 (t, 1.2H), 4.06 (t, 0.8H), 3.99 (t, 1.2H), 3.87 (t, 0.8H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:45]=[CH:44][C:9]([CH2:10][C@H:11]([NH:32][C:33](=[O:43])[O:34][C@@H:35]2[C@H:42]3[C@H:38]([O:39][CH2:40][CH2:41]3)[O:37][CH2:36]2)[C@H:12]([OH:31])[CH2:13][N:14]([S:19]([C:22]2[CH:30]=[CH:29][C:25]3[O:26][CH2:27][O:28][C:24]=3[CH:23]=2)(=[O:21])=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:8][CH:7]=1.[O:46]1[CH:50]=[CH:49][C:48]([C:51](O)=[O:52])=[CH:47]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C>[O:26]1[C:25]2[CH:29]=[CH:30][C:22]([S:19]([N:14]([CH2:15][CH:16]([CH3:17])[CH3:18])[CH2:13][C@@H:12]([OH:31])[C@@H:11]([NH:32][C:33](=[O:43])[O:34][C@@H:35]3[C@H:42]4[C@H:38]([O:39][CH2:40][CH2:41]4)[O:37][CH2:36]3)[CH2:10][C:9]3[CH:44]=[CH:45][C:6]([O:5][CH2:4][CH2:3][CH2:2][NH:1][C:51]([C:48]4[CH:49]=[CH:50][O:46][CH:47]=4)=[O:52])=[CH:7][CH:8]=3)(=[O:21])=[O:20])=[CH:23][C:24]=2[O:28][CH2:27]1
Reactant: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OCCCN)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Reactant: O=C(O)c1ccoc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OCCCNC(=O)c2ccoc2)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Yield: 75.1 %

Procedure:
A solution of 44 mg (0.068 mmol) of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-1-[4-(3-aminopropoxy)benzyl]-3-[(1,3-benzodioxol-5-ylsulfonyl)(isobutyl)amino]-2-hydroxypropylcarbamate, 15 mg (0.14 mmol) of 3-furoic acid, and 36 μL (0.20 mmol) of N,N-diisopropylethylamine in 2 mL of anhydrous DMF was treated with 52 mg (0.14 mmol) of O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) and the resulting solution was stirred at RT. After 18 hours the solution was concentrated in vacuo and the residue subjected to flash chromatography (SiO2, 97:3 CH2Cl2/MeOH) to afford 38 mg (75%) of the desired compound as a white foam. 1H NMR (CDCl3): 7.88 (s, 1H), 7.38 (s, 1H), 7.29 (d, 1H) t 7.10 (m, 3H), 6.84 (d, 1H), 6.76 (d, 2H), 6.56 (s, 1H), 6.34 (br s, 1H), 6.05 (s, 2H), 5.60 (d, 1H), 5.00 (m, 2H), 4.01 (t, 2H), 3.90 (dd, 1H), 3.80 (m, 3H), 3.64 (m, 2H), 3.55 (q, 2H), 3.17-2.63 (m, 8H), 2.03 (m, 2H), 1.80 (m, 1H), 1.61 (m, 1H), 1.49 (m, 1H), 0.89 (d, 3H), 0.83 (d, 3H). MS(ESI): 744(M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[C:6]([CH3:8])[CH:7]=1.O([Si](C)(C)C)S(C(F)(F)F)(=O)=O.C(N(CC)CC)C.[C:31]1([S:37][CH:38]([C:42](O)=[O:43])[C:39](O)=[O:40])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[O:11][C:39](=[O:40])[C:38]([S:37][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[C:42]([OH:43])[CH:10]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: O=C(O)C(Sc1ccccc1)C(=O)O
Reactant: CC(=O)c1cc(C)cc(C)c1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)cc(-c2cc(O)c(Sc3ccccc3)c(=O)o2)c1

Procedure:
The title compound was prepared by Method A using 3', 5'-dimethylacetophenone (1.43 g, 9.70 mmol), trimethylsilyl triflate (2.24 mL, 11.64 mmol), triethylamine (2.70 mL, 19.40 mmol), methylene chloride (24 mL), and diethyl ester of (phenylthio)-propanedioic acid (1.00 g, 7.46 mmol). m.p. 210-211° C.; 1H NMR (400 MHz, DMSO-d6) δ 2.35 (s, 6H), 6.83 (s, 1H), 7.12 (m, 3H), 7.21 (s, 1H), 7.27 (t, 2H), 7.46 (s, 2H).