Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1]/[C:2](/[CH2:6][CH2:7]/[CH:8]=[C:9](\[CH3:16])/[CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])=[CH:3]\[CH2:4][OH:5].CC(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-].BrC1C=CC=CC=1C=O.Cl>C1CCCCC1.CCCCCC>[CH3:1]/[C:2](/[CH2:6][CH2:7]/[CH:8]=[C:9](\[CH3:16])/[CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])=[CH:3]\[CH:4]=[O:5]
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CO
Agent: CC(C)[O-]
Agent: Cl
Agent: O=Cc1ccccc1Br
Solvent: CCCCCC
Solvent: C1CCCCC1
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/C=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 96 %

Procedure:
(2E,6E)-3,7,11-Trimethyl-2,6,10-dodecatrien-1-ol (266 mg, 1.2 mmol) was dissolved in cyclohexane (1 mL), added with aluminum isopropoxide (24.5 mg, 0.1 eq, 0.12 mmol) and 2-bromobenzaldehyde (289 mg, 1.3 eq, 1.56 mmol) and stirred at room temperature for 1.5 hours. The reaction mixture was added with hexane, then made acidic with addition of 1 N hydrochloric acid and extracted twice with ethyl acetate. Subsequently, the organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated in vacuo, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to obtain 256 mg (yield: 96%, E:Z=99:1) of the title compound as yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[F-:10].[K+]>CN1CCCC1=O.O>[F:10][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1
Reactant: N#Cc1ccc(Br)cn1
Reactant: [F-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: N#Cc1ccc(F)cn1
Temperature: 175 °C
Reaction time: 18 h

Procedure:
The mixture of 5-bromo-pyridine-2-carbonitrile (0.50 g, 2.73 mmol), and KF (0.48 g, 8.20 mmol) in 10 ml of 1-methyl-2-pyrrolidinone was stirred at 175° C. for 18 h, cooled to RT, diluted with H2O, extracted with EtOAc, the combined organic portions were washed with H2O, brine, dried with Na2SO4, filtered, condensed, the crude compound was purified by flash column chromatography (5 to 20% of EtOAc in hexanes). The titled compound was obtained as an off-white solid.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[CH2:16]([N:23]1[CH2:28][CH2:27][CH:26]([NH:29][C:30]2[CH:38]=[C:37]3[C:33]([CH2:34][CH2:35][N:36]3[C:39](=[O:41])[CH3:40])=[CH:32][CH:31]=2)[CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1(C)C=CC=CC=1>[C:39]([N:36]1[C:37]2[C:33](=[CH:32][CH:31]=[C:30]([N:29]([CH:26]3[CH2:25][CH2:24][N:23]([CH2:16][C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:28][CH2:27]3)[C:9](=[O:11])[C:8]#[C:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:38]=2)[CH2:34][CH2:35]1)(=[O:41])[CH3:40]
Reactant: CC(=O)N1CCc2ccc(NC3CCN(Cc4ccccc4)CC3)cc21
Reactant: O=C(O)C#Cc1ccccc1
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: CC(=O)N1CCc2ccc(N(C(=O)C#Cc3ccccc3)C3CCN(Cc4ccccc4)CC3)cc21
Temperature: 25 °C
Yield: 84.2 %

Procedure:
A mixture of phenyl-propynoic acid (220 mg, 1.5 mmol) and thionyl chloride (3.0 mL) in toluene (3.0 mL) was heated at reflux for 4 h. The reaction mixture was cooled to rt and the excess thionyl chloride and toluene were removed under reduced pressure. The resulting crude acid chloride was dissolved in CH2Cl2 (5 mL) and treated with 1-[6-(1-benzyl-piperidin-4-ylamino)-2,3-dihydro-indol-1-yl]-ethanone (349 mg, 1.0 mmol) and TEA (0.28 mL, 2.0 mmol) at rt for 20 h. The reaction mixture was concentrated, and the residue was purified on silica gel (60-70% EtOAc/hexanes) to afford the title compound (402 mg, 84%). 1H NMR (500 MHz, CDCl3): 8.12 (s, 1H), 7.28-7.18 (m, 9H), 7.09 (d, J=7.8 Hz, 2H), 6.86 (dd, J=8.0, 1.7 Hz, 1H), 4.65-4.59 (m, 1H), 4.13 (t, J=8.5 Hz, 2H) 3.44 (s, 2H), 3.24 (t, J=8.5 Hz, 2H), 2.89 (d, J=10.7 Hz, 2H), 2.22 (s, 3H), 2.10 (t, J=10.8 Hz, 2H), 1.90-1.78 (m, 2H), 1.63-1.58 (m, 2H). MS: exact mass calculated for C31H31N3O2, 477.24; m/z found, 478.3 [M+H]+.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH:13]1[CH2:17][CH2:16][O:15][C:14]1=[O:18].C(=O)([O-])[O-].[K+].[K+].CC(C)=O>C(OCC)(=O)C.O>[C:1]1([CH2:7][CH2:8][C:9]([O:11][CH:13]2[CH2:17][CH2:16][O:15][C:14]2=[O:18])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1OCCC1Br
Reactant: O=C(O)CCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: O=C(CCc1ccccc1)OC1CCOC1=O

Procedure:
A mixture comprising 13.65 g (90.9 mmol) of 3-phenyl-propanoic acid, 15.0 g (90.9 mmol) of 3-bromo-dihydrofuran-2(3H)-one, 37.7 g of potassium carbonate, and 150 ml of acetone was refluxed under nitrogen current for 9 hours. To the reaction mixture were added 200 ml of water and 400 ml of ethyl acetate, the organic layer was washed with water, a saturated sodium hydrogencarbonate aqueous solution, a saturated sodium chloride aqueous solution, and water in the order, and the organic layer was dried with sodium sulfate. The solvent was concentrated to obtain 24.3 g of brown and oily tetrahydro-2-oxofuran-3-yl 3-phenylpropanoate. The oily compound (5.00 g) (21.3 mmol), 4.32 g (21.3 mmol) of diphenyl sulfoxide, 6 ml of trifluoroacetic anhydride, and 6.7 g (22.3 mmol) of 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonic acid were stirred with ice-cooling for 3 hours, and further at room temperature for 2 hours. Chloroform (200 ml) was added to the reaction solution, the organic layer was washed with water, and the residue was purified by column chromatography (SiO2, chloroform/methanol: 10/1) to obtain 8.2 g of oily compound (A-34).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7][CH2:6]2>Br>[CH2:1]([O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7][CH2:6]2)[C:3]1[CH:4]=[CH:5][CH:10]=[CH:11][CH:12]=1
Reactant: COc1ccc2c(c1)CCCC2=O
Agent: Br
Product: O=C1CCCc2cc(OCc3ccccc3)ccc21
Temperature: 120 °C
Reaction time: 8 h
Yield: 155.2 %

Procedure:
A suspension of 6-methoxy-1-tetralone (99 g) in 48% hydrobromic acid (800 ml) was stirred overnight at 120° C. The reaction mixture was poured into ice water, the resulting solid was sequentially washed with water and hexane-diethyl ether system. To a solution of the resulting 6-hydroxy-3,4-dihydro-2H-naphthalen-1-one (76 g) in N,N-dimethylformamide (400 ml) were sequentially added potassium carbonate (76 g) and benzyl bromide (59 ml), and the solution was stirred for 4 hours at room temperature. The reaction mixture was poured into water, the resulting solid was sequentially washed with water and hexane-diethyl ether system to provide the title compound (110 g).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[C:12]([N:19]1[CH2:24][CH2:23][CH:22]([CH2:25][CH2:26]I)[CH2:21][CH2:20]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]>CN(C=O)C.CCOC(C)=O>[C:12]([N:19]1[CH2:20][CH2:21][CH:22]([CH2:25][CH2:26][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=2)[CH2:23][CH2:24]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]
Reactant: COC(=O)c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(CCI)CC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of methyl 4-hydroxybenzoate (Aldrich) (0.4 g, 2.6 mmoles) 9-1 in DMF (10 ml) was treated with 2-(N-Boc-4-piperidinyl)ethyl iodide 1-4 (0.6 g, 1.77 mmoles) and CS2CO3 (1.15 g, 3.5 mmoles) with stirring at room temperature for 48 hours. The reaction mixture was diluted with EtOAc, washed with H2O, saturated NaHCO3, 10% KHSO4, brine dried (MgSO4) and concentrated. The residue was purified by flash chromatography on silica gel eluting with 20% EtOAc/hexanes to give pure 9-2. Rf 0.3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[CH:12]([N:15]1[C:19]2[N:20]=[CH:21][N:22]=[CH:23][C:18]=2[C:17]([C:24]([C:26]2[CH:27]=[N:28][CH:29]=[C:30]([NH:32][CH3:33])[CH:31]=2)=[O:25])=[CH:16]1)([CH3:14])[CH3:13].F[P-](F)(F)(F)(F)F.CN(C(=[N+](C)C)ON1C2=NC=CC=C2N=N1)C>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([N:32]([C:30]2[CH:29]=[N:28][CH:27]=[C:26]([C:24]([C:17]3[C:18]4[CH:23]=[N:22][CH:21]=[N:20][C:19]=4[N:15]([CH:12]([CH3:14])[CH3:13])[CH:16]=3)=[O:25])[CH:31]=2)[CH3:33])=[O:11])=[CH:6][CH:7]=1
Reactant: CNc1cncc(C(=O)c2cn(C(C)C)c3ncncc23)c1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: c1ccncc1
Product: CC(C)n1cc(C(=O)c2cncc(N(C)C(=O)Cc3ccc(Cl)cc3)c2)c2cncnc21
Temperature: 50 °C
Yield: 42.4 %

Procedure:
(4-chlorophenyl)acetic acid (22 mg, 0.13 mmol) was added to a stirring mixture of (7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)[5-(methylamino)pyridin-3-yl]methanone (30 mg, 0.10 mmol) (Preparation 149) and N-[(dimethylamino)(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methylmethanaminium hexafluorophosphate (57 mg, 0.15 mmol) in pyridine (1.0 mL). The mixture was heated to 50° C. for 16 hours, evaporated in vacuo and partitioned between saturated aqueous sodium bicarbonate (10 mL) and EtOAc (10 mL). The aqueous layer was washed with further EtOAc (2×10 mL). The combined organics were dried over Na2SO4, filtered and concentrated in vacuo and purified by preparative HPLC to afford the title compound 43% yield, 19 mg, 1H NMR (400 MHz, DMSO) δ: 1.52 (d, 6H), 3.40 (br. s, 3H), 3.59 (s, 2H), 5.00-5.18 (m, 1H), 7.00-7.42 (m, 4H), 8.21 (s, 1H), 8.50 (s, 1H), 8.86 (s, 1H), 8.90-9.12 (m, 2H), 9.48 (s, 1H);
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH3:11])=[N:9][C:8]2[N:4]([N:5]=[C:6]3[CH2:14][N:13]([C:15]([C:17]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:18]=4[O:19][CH2:20][C:21](=O)[CH3:22])=[O:16])[CH2:12][C:7]3=2)[C:3]=1[CH3:29].[CH2:30]([NH:33][CH3:34])[CH:31]=[CH2:32].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.CC(=O)OCC>[CH2:30]([N:33]([CH3:34])[CH:21]([CH3:22])[CH2:20][O:19][C:18]1[CH:24]=[C:25]([F:28])[CH:26]=[CH:27][C:17]=1[C:15]([N:13]1[CH2:12][C:7]2=[C:8]3[N:4]([N:5]=[C:6]2[CH2:14]1)[C:3]([CH3:29])=[C:2]([Cl:1])[C:10]([CH3:11])=[N:9]3)=[O:16])[CH:31]=[CH2:32]
Reactant: CC(=O)COc1cc(F)ccc1C(=O)N1Cc2nn3c(C)c(Cl)c(C)nc3c2C1
Reactant: C=CCNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: C=CCN(C)C(C)COc1cc(F)ccc1C(=O)N1Cc2nn3c(C)c(Cl)c(C)nc3c2C1
Yield: 55.9 %

Procedure:
A mixture of Example 164 (150 mg; 0.36 mmol; 1 eq.) allyl-methyl-amine (51 mg; 0.72 mmol; 2 eq.) and sodium triacetoxyborohydride (99 mg; 0.47 mmol; 1.3 eq.) in DCE (5 mL) was stirred at 70° C. for 2 hours. The suspension was diluted with EA, washed with water, dried over magnesium sulfate and concentrated in vacuo. Purification by column chromatography (EA to 12% MeOH in EA) afforded the title compound (95 mg, 56%) as a white solid. 1H NMR (DMSO-d6) δ 7.45-7.29 (m, 1H), 7.17-7.02 (m, 1H), 6.87 (td, J=8.5, 2.4 Hz, 1H), 5.57-5.37 (m, 1H), 4.92 (dd, J=16.8, 5.8 Hz, 1H), 4.86-4.71 (m, 3H), 4.70-4.46 (m, 2H), 4.13-3.90 (m, 2H), 3.09-2.89 (m, 3H), 2.84 (s, 1.6H), 2.80 (s, 1.4H), 2.61 (s, 1.4H), 2.55 (s, 1.6H), 2.02 (d, J=4.9 Hz, 3H), 0.88 (dd, J=6.5, 1.9 Hz, 3H). HPLC (max plot) 94.9%, Rt 2.97 min. UPLC/MS: (MS+) 472.2 ([M+H]+).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[I:8].C(=O)([O-])[O-].[Na+].[Na+].[CH3:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.OO.[Cl-].[Na+]>C1(C)C=CC=CC=1.O.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>[I:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:19]1[CH:20]=[CH:21][C:16]([CH3:15])=[CH:17][CH:18]=1
Reactant: Ic1ccccc1I
Reactant: Cc1ccc(B(O)O)cc1
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: OO
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(-c2ccccc2I)cc1
Temperature: 25 °C
Yield: 44.2 %

Procedure:
A mixture of 1,2-diiodobenzene (6.6 g) and tetrakis(triphenylphosphine)palladium(0) (0.34 g) in AR toluene (100 ml) was stirred under a nitrogen atmosphere at ambient temperature. A solution of sodium carbonate (2 g) in water (15 ml) was added. The resulting orange mixture was stirred and heated under reflux while a solution of 4-methylbenzeneboronic acid (1.36 g) in industrial methylated spirit (40 ml) was added dropwise over a period of 40 minutes. The mixture obtained was heated under reflux for an additional 4 hours, then cooled to ambient temperature. Aqueous hydrogen peroxide (30%; 1 ml) was added and the resulting mixture was stirred for 1 hour at ambient temperature. Saturated aqueous sodium chloride solution (50 ml) was then added and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (2×50 ml) and the combined organic phases were washed with saturated aqueous sodium chloride solution (1×70 ml), dried over magnesium sulphate and evaporated to give an orange oil. This oil was triturated with petroleum ether (b.p. 40°-60° C.) (200 ml) to give a gum which was partially purified by flash chromatography on silica gel (eluting with petroleum ether (b.p. 40°-60° C.): ethyl acetate (4:1)) then further purified by high performance liquid chromatography on a silica column (eluting with petroleum ether (b.p. 60°-80° C.) at 200 ml/minute), to give the intermediate compound 2'-iodo-4-methylbiphenyl as a colourless oil (1.3 g).
Reaction SMILES: [F:1][C:2]1[C:3]([CH:22]([C:30]#[N:31])C(OC(C)(C)C)=O)=[C:4]2[C:9]3=[C:10]([C:12](=[O:20])[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:14][N:8]3[N:7]([CH3:21])[CH2:6][CH2:5]2)[CH:11]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[C:30]([CH2:22][C:3]1[C:2]([F:1])=[CH:11][C:10]2[C:12](=[O:20])[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:14][N:8]3[C:9]=2[C:4]=1[CH2:5][CH2:6][N:7]3[CH3:21])#[N:31]
Reactant: CCOC(=O)c1cn2c3c(c(C(C#N)C(=O)OC(C)(C)C)c(F)cc3c1=O)CCN2C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cn2c3c(c(CC#N)c(F)cc3c1=O)CCN2C
Reaction time: 1.5 h
Yield: 33.4 %

Procedure:
1.60 g of the compound (162) obtained in Example 39 (2) was added to 20 ml of methylene chloride, and 6 ml of trifluoroacetic acid was added to the solution. The solution was stirred for 1.5 hours. 4 ml of trifluoroacetic acid was added to the solution, and the solution was stirred overnight. The solvent was removed by distillation, and the residue was crystallized from ethyl ether. Crystals were filtered off to obtain 410 mg of the subject compound (165).
Reaction SMILES: C([O-])(=O)C.[NH4+].C([BH3-])#[N:7].[Na+].C(C1C=C(O)C(=CC=1)O)(C)(C)C.[CH2:22]([C:29]([C:31]1[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][Br:39])=[CH:33][CH:32]=1)=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[ClH:40]>CO.O1CCOCC1.C(OCC)(=O)C>[ClH:40].[Br:39][CH2:38][CH2:37][C:34]1[CH:35]=[CH:36][C:31]([C@@H:29]([NH2:7])[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:32][CH:33]=1
Reactant: O=C(Cc1ccccc1)c1ccc(CCBr)cc1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: CC(C)(C)c1ccc(O)c(O)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CO
Product: N[C@@H](Cc1ccccc1)c1ccc(CCBr)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 50 g (0.66 mol) of ammonium acetate in 200 ml of methanol, 2.7 g (0.43 mol) of sodium cyanoborohydride and about 100 mg of 4-tert-butylpyrocatechol are added to a solution of 20 g (0.066 mol) of 4-(2-bromoethyl)-phenyl benzyl ketone in 100 ml of dioxane. After the mixture has been stirred for 48 hours at room temperature, it is acidified with 50 ml of concentrated hydrochloric acid (pH 2). Thereafter, methanol and dioxane are substantially distilled off under about 2 kPa and are replaced by ethyl acetate. The solution is washed with twice 100 ml of water and evaporated down under about 2 kPa. The residue is taken up with ethanol/diethyl ether (1:1). The white precipitate formed is filtered off, and the filtrate is evaporated down to give an oil. After the addition of 50 ml of ethyl acetate, the product begins to crystallize. It is filtered off under suction and dried. Yield: 10.8 g (48% of theory) of white crystals. Melting point: 165°-168° C./decomposition.
Reaction SMILES: C(OC([N:8]1[C:16]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]=2[CH:10]=[C:9]1[CH2:17][N:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]2[N:33](C(OC(C)(C)C)=O)[C:32]3[CH:31]=[CH:30][N:29]=[CH:28][C:27]=3[CH:26]=2)[CH2:20][C:19]1=[O:41])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]1[C:16]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]=2[CH:10]=[C:9]1[CH2:17][N:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]2[NH:33][C:32]3[CH:31]=[CH:30][N:29]=[CH:28][C:27]=3[CH:26]=2)[CH2:20][C:19]1=[O:41]
Reactant: CC(C)(C)OC(=O)n1c(CN2CCN(Cc3cc4cnccc4n3C(=O)OC(C)(C)C)C(=O)C2)cc2cnccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CN(Cc2cc3cnccc3[nH]2)CCN1Cc1cc2cnccc2[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution containing 2-[4-(1-tert-Butoxycarbonyl-1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)-2-oxo-piperazin-1-ylmethyl]-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester (85 mg, 0.14 mmol) in CH2Cl2 (5 mL) is added TFA (1 mL) at 0° C. and the solution is allowed to slowly warm to ambient temperature. After 16 h, the reaction mixture is concentrated to dryness, diluted with water and purified by reverse-phase HPLC [Buffer A: water w/0.1% TFA; Buffer B: CH3CN w/0.1% TFA; Gradient: 0% B to 45% B over 30 min] to provide 35 mg (36%, two steps) of the title compound as a pale yellow, lyophilized solid.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][N:8]1[C:13](=[O:14])[C:12]([N+:15]([O-])=O)=[C:11](/[CH:18]=[CH:19]/[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=2)[N:10]([CH3:27])[C:9]1=[O:28])(=[O:3])[CH3:2].[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(O)=O.CC(=O)OCC.O>[Cl:26][C:22]1[CH:21]=[C:20]([C:19]2[NH:15][C:12]3[C:13](=[O:14])[N:8]([CH2:7][CH2:6][CH2:5][O:4][C:1](=[O:3])[CH3:2])[C:9](=[O:28])[N:10]([CH3:27])[C:11]=3[CH:18]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: CC(=O)OCCCn1c(=O)c([N+](=O)[O-])c(/C=C/c2cccc(Cl)c2)n(C)c1=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: O=CO
Product: CC(=O)OCCCn1c(=O)c2[nH]c(-c3cccc(Cl)c3)cc2n(C)c1=O
Temperature: 110 °C
Yield: 92.8 %

Procedure:
To a solution of (E)-3-(4-(3-chlorostyryl)-3-methyl-5-nitro-2,6-dioxo-2,3-dihydropyrimidin-1(6H)-yl)propyl acetate (70 mg, 0.172 mmol) in HCOOH (3 mL) was added Na2S2O4 (180.0 mg, 1.032 mmol). The reaction was heated at 110° C. for 5 h, cooled to RT then diluted with EA (20 mL) and water (20 mL). The organic layer was dried over Na2SO4 and concentrated to give 3-(6-(3-chlorophenyl)-1-methyl-2,4-dioxo-1H-pyrrolo[3,2-d]pyrimidin-3(2H,4H,5H)-yl)propylacetate (60 mg, 93.0% yield) as an oil. LCMS: MH+ 375 and TR=1.467 min. Used without further purification.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:43])[C:15]2([CH:18]3[CH2:22][CH2:21][N:20]([C:23]4[C:32]([O:33][CH3:34])=[C:31]5[C:26]([C:27](=[O:41])[C:28]([C:38]([OH:40])=[O:39])=[CH:29][N:30]5[CH:35]5[CH2:37][CH2:36]5)=[CH:25][C:24]=4[F:42])[CH2:19]3)[CH2:17][CH2:16]2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClC(Cl)C>[CH:35]1([N:30]2[C:31]3[C:26](=[CH:25][C:24]([F:42])=[C:23]([N:20]4[CH2:21][CH2:22][CH:18]([C:15]5([N:14]([CH3:43])[CH:11]6[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]6)[CH2:17][CH2:16]5)[CH2:19]4)[C:32]=3[O:33][CH3:34])[C:27](=[O:41])[C:28]([C:38]([OH:40])=[O:39])=[CH:29]2)[CH2:37][CH2:36]1
Reactant: COc1c(N2CCC(C3(N(C)C4CCN(C(=O)OC(C)(C)C)CC4)CC3)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Solvent: O=C(O)C(F)(F)F
Solvent: CC(Cl)Cl
Product: COc1c(N2CCC(C3(N(C)C4CCNCC4)CC3)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 7-(3-{1-[(1-tert-butoxycarbonyl-piperidin-4-yl)-methyl-amino]-cyclopropyl}-pyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid in dichloroethane (2.0 mL) was added trifluoroacetic acid (1.0 mL, ˜13 mmol) at 0° C. during a period of 5-6 minutes. The resulting solution was stirred at room temperature for one hour. The solvent was removed to yield yellow oil, which was partitioned between CH2Cl2 and sat. aq NaHCO3. The separated aqueous phase was extracted with CH2Cl2. The combined organic layer was with brine, dried over sodium sulfate and concentrated in vacuo. Title compound was achieved as a yellow solid (85 mg, 100%). ESI MS m/z 499.4 (M+H+).
Reaction SMILES: [ClH:1].C(OC([NH:9][CH2:10][C@H:11]([N:16]1[CH2:21][CH2:20][N:19]([S:22]([CH3:25])(=[O:24])=[O:23])[CH2:18][CH2:17]1)[C:12]([O:14][CH3:15])=[O:13])=O)(C)(C)C>C(O)(C)C.CO>[ClH:1].[NH2:9][CH2:10][C@H:11]([N:16]1[CH2:21][CH2:20][N:19]([S:22]([CH3:25])(=[O:24])=[O:23])[CH2:18][CH2:17]1)[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)[C@H](CNC(=O)OC(C)(C)C)N1CCN(S(C)(=O)=O)CC1
Agent: Cl
Solvent: CC(C)O
Solvent: CO
Product: COC(=O)[C@H](CN)N1CCN(S(C)(=O)=O)CC1
Temperature: 40 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
15 ml of a solution of hydrochloric acid in isopropanol, having a concentration of 5-6N are added dropwise to a solution of 2.7 g (7.4 mmol) of methyl (S)-3-tert-butoxycarbonylamino-2-(4-methanesulfonylpiperazin-1-yl)propanoate in 30 ml of methanol. The reaction medium is stirred at 40° C. for 2 h, concentrated under vacuum, and then taken up in 20 ml of methanol and 150 ml of diethyl ether. The product precipitates, and is filtered off under vacuum, rinsed with diethyl ether and then dried under vacuum. 2.3 g (100%) of methyl (S)-3-amino-2-(4-methanesulfonylpiperazin-1-yl)propanoate hydrochloride are obtained in the form of a white solid.
Reaction SMILES: I[C:2]1[S:6][C:5]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[N:9]=2)=[C:4]([C:15]([NH2:17])=[O:16])[CH:3]=1.[CH3:18][N:19]1[CH:23]=[C:22](B2OC(C)(C)C(C)(C)O2)[CH:21]=[N:20]1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[CH3:18][N:19]1[CH:23]=[C:22]([C:2]2[S:6][C:5]([NH:7][C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[N:9]=3)=[C:4]([C:15]([NH2:17])=[O:16])[CH:3]=2)[CH:21]=[N:20]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cc1cccc(Nc2sc(I)cc2C(N)=O)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1cccc(Nc2sc(-c3cnn(C)c3)cc2C(N)=O)n1
Temperature: 100 °C

Procedure:
A suspension of 5-iodo-2-[(6-methylpyridin-2-yl)amino]thiophene-3-carboxamide (300 mg, 0.84 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (619 mg, 2.97 mmol), dichlorobis(triphenylphosphine)palladium (29.3 mg, 0.04 mmol), and sodium carbonate (7.5 mL, 15.0 mmol) in 1,2-dimethoxyethane (7.5 mL) sealed in a 20 mL microwave reaction vessel was purged of oxygen by doing 5 vacuum/argon flush cycles. The reaction solution was heated in a microwave for five minutes at 100° C., and then partitioned between ethyl acetate (50 mL) and water (30 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. Purification by silica gel chromatography (12-100% ethyl acetate/hexanes) yielded the title compound.