Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][C:13](=[CH:16][CH3:17])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:23].S([O-])([O-])=O.[Na+].[Na+]>ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][C:13]2([O:23][CH:16]2[CH3:17])[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC=C1CCN(C(=O)OCc2ccccc2)C1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC1OC12CCN(C(=O)OCc1ccccc1)C2
Yield: 44.8 %

Procedure:
A solution of 3-ethylidenepyrrolidine-1-carboxylic acid benzyl ester (Example A8, 0.65 g, 2.8 mmol) and 3-chloroperoxybenzoic acid (0.86 g, 5 mmol) in dichloromethane (15 mL) is stirred at room temperature for 3 hours. The excess peracid is decomposed by the addition of 10% sodium sulfite. The organic layer is washed with 5% sodium bicarbonate solution, dried over Na2SO4 and evaporated. The residue is purified by column chromatography (1:1 hexanes/ethyl acetate) to afford the title compound (0.310 g). 1H NMR (200 MHz, CDCl3): δ 7.36-7.26 (m, 5H), 5.14 (s, 2H), 3.73-3.55 (m, 3H), 3.34 (d. 1H), 3.20-3.13 (m, 1H), 2.26-2.11 (m, 1H), 1.90-1.62 (m, 1H), 1.33 (d, 3H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][C@@H:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C@@H:5]([CH3:14])[N:4]2[C:15]([C:18]([OH:21])([CH3:20])[CH3:19])=[CH:16][N:17]=[C:3]12.[O:22]=[C:23]1[NH:31][C:26]2[N:27]=[CH:28][N:29]=[CH:30][C:25]=2[C@@:24]21[CH2:42][C:34]1=[N:35][CH:36]=[C:37]([C:39](O)=[O:40])[CH:38]=[C:33]1[CH2:32]2.ON1C2N=CC=CC=2N=N1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.O>[OH:21][C:18]([C:15]1[N:4]2[C@H:5]([CH3:14])[C@H:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:7][C@H:2]([NH:1][C:39]([C:37]3[CH:38]=[C:33]4[CH2:32][C@@:24]5([C:25]6[CH:30]=[N:29][CH:28]=[N:27][C:26]=6[NH:31][C:23]5=[O:22])[CH2:42][C:34]4=[N:35][CH:36]=3)=[O:40])[C:3]2=[N:17][CH:16]=1)([CH3:20])[CH3:19]
Reactant: C[C@@H]1[C@H](c2ccccc2)C[C@H](N)c2ncc(C(C)(C)O)n21
Reactant: O=C(O)c1cnc2c(c1)C[C@@]1(C2)C(=O)Nc2ncncc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: C[C@@H]1[C@H](c2ccccc2)C[C@H](NC(=O)c2cnc3c(c2)C[C@@]2(C3)C(=O)Nc3ncncc32)c2ncc(C(C)(C)O)n21
Reaction time: 2 h
Yield: 13.4 %

Procedure:
To a solution of 2-[(5R,6S,8S)-8-amino-5-methyl-6-phenyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-3-yl]propan-2-ol (6.7 mg, 0.023 mmol) in N,N-dimethylformamide (195 μL) was added (6S)-6′-oxo-5,6′,7,7′-tetrahydrospiro[cyclopenta[b]pyridine-6,5′-pyrrolo[2,3-d]pyrimidine]-3-carboxylic acid (5.5 mg, 0.019 mmol), 1-hydroxy-7-azabenzotriazole (0.2 mg, 0.002 mmol), N-methylmorpholine (10.7 μL, 0.097 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.5 mg, 0.023 mmol). The mixture was stirred 2 h. Water was added, and the mixture was purified by reverse phase chromatography (C-18, 85% water/acetonitrile→5% water/acetonitrile with 0.1% trifluoroacetic acid) giving the title compound (1.4 mg). HRMS 550.2546 (M+1). NMR (500 MHz, CD3OD): δ 8.95 (s, 1H); 8.70 (s, 1H); 8.22 (s, 1H); 8.15 (s, 1H); 7.41−7.27 (m, 5H); 6.86 (s, 1H); 5.43 (dd, J=10.7, 7.5 Hz, 1H); 5.04 (dd, J=7.0, 4.8 Hz, 1H); 3.70−3.41 (m, 5H); 2.70−2.67 (m, 1H); 2.52−2.49 (m, 1H); 1.64 (d, J=13.6 Hz, 6H); 1.32 (d, J=6.4 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10](I)[CH:9]=[CH:8][C:3]=1[O:4][CH2:5][CH2:6][OH:7].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[C:22]([F:28])[C:23]([C:26]#[CH:27])=[N:24][CH:25]=2)=[CH:16][CH:15]=1.BrCl>>[Br:1][C:2]1[CH:11]=[C:10]([C:27]#[C:26][C:23]2[C:22]([F:28])=[CH:21][C:20]([C:17]3[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=3)=[CH:25][N:24]=2)[CH:9]=[CH:8][C:3]=1[O:4][CH2:5][CH2:6][OH:7]
Reactant: OCCOc1ccc(I)cc1Br
Reactant: C#Cc1ncc(-c2ccc(Cl)cc2)cc1F
Agent: ClBr
Product: OCCOc1ccc(C#Cc2ncc(-c3ccc(Cl)cc3)cc2F)cc1Br

Procedure:
The product was prepared analogously to Example 7.1e starting from 2-(2-bromo-4-iodophenoxy)ethanol and 5-(4-chlorophenyl)-2-ethynyl-3-fluoropyridine. Yield: 1.60 g (82% of theoretical); C21H14BrClFNO2 (M=446.697); calc.: molpeak (M+H)+: 446/448/450 (BrCl); found: molpeak (M+H)+: 446/448/450 (BrCl); HPLC-MS: 6.38 minutes (method B).
Reaction SMILES: [CH2:1]([C:5]1(O)[C:10]([CH3:12])(C)[CH2:9][C:8](=[O:13])[CH:7]=[C:6]1[CH3:14])[CH2:2][CH2:3][CH3:4].Cl.[C:17]1(=O)C=CCC=C1>CCCCCC>[CH2:1]([C:5]1([CH3:17])[C:6]([CH3:14])=[CH:7][C:8](=[O:13])[CH:9]=[C:10]1[CH3:12])[CH2:2][CH2:3][CH3:4]
Reactant: O=C1C=CCC=C1
Reactant: CCCCC1(O)C(C)=CC(=O)CC1(C)C
Agent: Cl
Solvent: CCCCCC
Product: CCCCC1(C)C(C)=CC(=O)C=C1C

Procedure:
A solution of 7 g of 4-butyl-4-hydroxy-3,5,5-trimethyl-2-cyclohexen-1-one (prepared by the procedure of Example IV) in hexane is stirred overnight with 10 ml of a 5% solution of HCl. The hexane is separated and evaporated, and the residue is distilled through a micro column using triethanolamine as a still base. The product obtained is 4-butyl-3,4,5-trimethyl-(2,5-cyclohexadien-1-one, boiling point 112°-119° C. at 0.1 mm Hg. The compound exhibits the following spectral characteristics:
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][Cl:5].Cl[C:7]([O:9][CH2:10][C:11]([Cl:14])([Cl:13])[Cl:12])=[O:8].C(N(CC)CC)C>CN(C)C=O.O>[Cl:5][CH2:4][CH2:3][NH:2][C:7](=[O:8])[O:9][CH2:10][C:11]([Cl:14])([Cl:13])[Cl:12]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: NCCCl
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NCCCl)OCC(Cl)(Cl)Cl

Procedure:
One mole of 1-amino-2-chloroethane hydrochloride in 500 ml of dimethylformamide at 0° C is treated with 1 mole of β,β,β-trichloroethyl chloroformate after which a solution of 2 moles of triethylamine in 200 ml of dimethylformamide is slowly added. Upon completion of the addition, the reaction is diluted with 2 liters of water and extracted twice with 750 ml of ether. The ether extracts are washed twice with 500 ml of water then twice with 500 ml of 1 M HCl, dried over sodium sulfate and evaporated to dryness to give β,β,β-trichloroethyl N-(2-chloroethyl)carbamate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([O:12][CH3:13])[CH:6]=1.[Li][CH2:16]CCC.C(NC(C)C)(C)C.CI>C1COCC1>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([CH:4]([CH3:16])[C:3]([O:2][CH3:1])=[O:14])=[CH:6][C:7]=1[O:12][CH3:13]
Reactant: COC(=O)Cc1ccc(Cl)c(OC)c1
Reactant: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)C(C)c1ccc(Cl)c(OC)c1
Reaction time: 1 h

Procedure:
The product of step (i) (0.5 g) was added to a solution of nBuLi (1.75 ml, 1.6 M in THF) and diisopropylamine (0.4 ml) in THF (10 ml) at −78° C. and stirred for 1 h, then methyl iodide (0.18 ml) was added, stirred for 1 h at −78° C. then at room temperature for 1 h and quenched with water. The product was extracted with ether, dried (MgSO4) and evaporated under reduced pressure. The residue was purified by flash column chromatography (eluent 1:1 isohexane/ether) to give the subtitle compound (0.21 g).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:21].Cl[CH2:23][C:24]1[O:25][CH:26]=[C:27]([C:29]([O:31][CH3:32])=[O:30])[N:28]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1>[O:21]=[C:2]1[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:1]1[CH2:23][C:24]1[O:25][CH:26]=[C:27]([C:29]([O:31][CH3:32])=[O:30])[N:28]=1
Reactant: COC(=O)c1coc(CCl)n1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: COC(=O)c1coc(CN2C(=O)C3(COc4cc5c(cc43)OCO5)c3ccccc32)n1
Yield: 91.4 %

Procedure:
A suspended mixture of spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (1.60 g, 5.70 mmol), methyl 2-(chloromethyl)oxazole-4-carboxylate (1.00 g, 5.70 mmol) and cesium carbonate (3.71 g, 11.4 mmol) in tetrahydrofuran (10 mL) was refluxed for 16 h. The reaction mixture was cold down to ambient temperature and concentrated in vacuo. The residue was treated with water (20 mL) and extracted with ethyl acetate (3×20 mL). The combined organic solution was dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was purified by column chromatography with a 20% to 30% gradient of ethyl acetate in hexanes to afford methyl 2-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]-1,3-oxazole-4-carboxylate (2.19 g, 92%) as a colorless solid: mp 183-185° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.86 (s, 1H), 7.28 (t, J=7.2 Hz, 1H), 7.16 (d, J=7.0 Hz, 1H), 7.09 (d, J=7.8 Hz, 1H), 7.03 (t, J=7.5 Hz, 1H), 6.66 (s, 1H), 6.41 (S, 1H), 5.90 (d, J=2.1 Hz, 2H), 5.23-5.17 (m, 2H), 4.74 (ABq, 2H), 3.74 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ177.2, 161.3, 160.2, 155.6, 148.8, 146.9, 142.3, 142.0, 132.8, 132.4, 129.4, 124.1, 123.9, 120.4, 109.7, 103.9, 101.9, 93.7, 80.0, 57.9, 52.3, 37.4; MS (ES+) m/z 421.2 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([I:11])=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1.IC1C2C(=NC=C([C:32]3[CH:33]=[C:34]([NH:38][S:39]([CH3:42])(=[O:41])=[O:40])[CH:35]=[CH:36][CH:37]=3)C=2)NC=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[H-].[Na+]>CN(C=O)C>[I:11][C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:32]3[CH:33]=[C:34]([NH:38][S:39]([CH3:42])(=[O:40])=[O:41])[CH:35]=[CH:36][CH:37]=3)[CH:3]=2)[N:8]([S:12]([C:15]2[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(Br)cnc32)cc1
Reactant: CS(=O)(=O)Nc1cccc(-c2cnc3[nH]cc(I)c3c2)c1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4cccc(NS(C)(=O)=O)c4)cnc32)cc1

Procedure:
Using similar reaction conditions as described in, step ii of Intermediate 1, N-(3-(3-iodo-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)methanesulfonamide (800 mg, 1.93 mmol) was tosylated with p-toluene sulfonylchloride (100 mg, 2.09 mmol) and 60% suspension of sodium hydride in paraffin (193 mg, 4.82 mmol) in DMF (10 mL) to afford 800 mg of the titled compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22]([C:26](Cl)=[O:27])=[CH:21][CH:20]=[CH:19]2.[F:29][C@H:30]1[CH2:32][C@H:31]1[NH2:33]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22]([C:26]([NH:33][C@@H:31]1[CH2:32][C@@H:30]1[F:29])=[O:27])=[CH:21][CH:20]=[CH:19]2
Reactant: N[C@@H]1C[C@@H]1F
Reactant: COc1cc2nccc(Oc3ccc4c(C(=O)Cl)cccc4c3)c2cc1OC
Solvent: ClCCl
Product: COc1cc2nccc(Oc3ccc4c(C(=O)N[C@@H]5C[C@@H]5F)cccc4c3)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6-(6,7-Dimethoxyquinolin-4-yloxy)-1-naphthoyl chloride (200 mg, 0.50 mmol) was suspended in CH2Cl2 and TEA (210 μL, 1.5 mmol) was added. The mixture was blanketed with nitrogen, cis-2-fluorocyclopropylamine (131 mg, 0.54 mmol) was added and the reaction was stirred at RT for 1 h. The mixture was washed with water, dried with Na2SO4, filtered and concentrated in-vacuo. The residue was purified by column chromatography to give the title compounds. MS (ESI pos. ion) m/z: 433.2 (M+H). Calc'd for C28H21FN2O4−432.46.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[NH:14]1[C:22]2[CH2:21][CH2:20][NH:19][CH2:18][C:17]=2[CH:16]=[CH:15]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:19]3[CH2:20][CH2:21][C:22]4[NH:14][CH:15]=[CH:16][C:17]=4[CH2:18]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: c1cc2c([nH]1)CCNC2
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: O=C(c1cc2ncc(Br)cn2n1)N1CCc2[nH]ccc2C1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine to provide the title compound in moderate yield.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([P:20]([OH:22])[OH:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[O-:25][Mn](=O)(=O)=O.[K+].P(O)O.Cl.S(=O)(O)[O-].[Na+]>CC(C)=O.O>[CH2:1]([O:8][C:9]([NH:11][CH:12]([P:20](=[O:25])([OH:21])[OH:22])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NC(Cc1ccccc1)P(O)O)OCc1ccccc1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: Cl
Agent: O=S([O-])O
Agent: OPO
Solvent: O
Solvent: CC(C)=O
Product: O=C(NC(Cc1ccccc1)P(=O)(O)O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 1-benzyloxycarbonylamino2-phenylethyl phosphonous acid (0.5 g, 0.0016 mole) in acetone (20 ml) and water (10 ml) was added a 10% solution of sodium hydroxide in water until a pH of about 7 was reached. A solution of KMnO4 (0.14 g, 0.00086 mole, 0.55 equiv.) in water (10 ml) was added slowly to the vigorously stirred solution of phosphonous acid at 20-25° C. After the addition (5 minutes), the reaction mixture was stirred for 5 minutes at ambient temperature and acidified with concentrated HCl acid until a pH of 1 was reached. Saturated sodium bisulfite solution was added to the reaction mixture thereby resulting in formation of a white precipitate.
Reaction SMILES: CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[C:22]([CH2:29][CH2:30][CH2:31][C:32]([NH2:44])([CH2:36][C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=1)[C:33]([OH:35])=O)([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].Cl.Cl.[N:47]1([C:53]2[C:62]3[C:57](=[CH:58][CH:59]=[CH:60][CH:61]=3)[N:56]=[CH:55][N:54]=2)[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1>CN(C=O)C.O>[C:22]([CH2:29][CH2:30][CH2:31][C:32]([NH2:44])([CH2:36][C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=1)[C:33]([N:50]1[CH2:51][CH2:52][N:47]([C:53]2[C:62]3[C:57](=[CH:58][CH:59]=[CH:60][CH:61]=3)[N:56]=[CH:55][N:54]=2)[CH2:48][CH2:49]1)=[O:35])([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23]
Reactant: CC(C)(C)OC(=O)CCCC(N)(Cc1ccc(Cl)cc1)C(=O)O
Reactant: c1ccc2c(N3CCNCC3)ncnc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)CCCC(N)(Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ncnc3ccccc23)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of EDCI (100 mg, 0.54 mmol), HOBt.H20 (82 mg, 0.54 mmol), 5-Boc-amino-2-(4-chlorobenzyl)-pentanoic acid (170 mg, 0.50 mmol), and TEA (190 μL, 1.4 mmol) in 3 mL DMF was stirred 10 minutes, and solid 4-piperazin-1-yl-quinazoline dihydrochloride (130 mg, 0.45 mmol) was added. The reaction mixture was stirred at room temperature 15 hours, after which water was added. The reaction mixture was extracted with DCM, and combined extracts washed with sat NaHCO3, dried (Na2SO4), filtered, and concentrated. The crude was purified on silica gel (1:1 to 1:9 DCM:EtOAc) to give 5-Boc-amino-2-(4-chlorobenzyl)-1-(4-quinazolin-4-yl-piperazin-1-yl)-pentan-1-one. LCMS (APCI+) m/z 538 [M+H]+; Rt: 3.12 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=3)[N:13]=[C:12]2[CH3:28])[CH:5]=1.[Cl:30]N1C(=O)CCC1=O>C(O)(C)C.ClC(Cl)C(O)=O>[CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:16](=[O:17])[C:15]([Cl:30])=[C:14]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=3)[N:13]=[C:12]2[CH3:28])[CH:5]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)c1ccc(C)c(-n2c(C)nc(OCc3cccc(OC)c3)cc2=O)c1
Agent: O=C(O)C(Cl)Cl
Solvent: CC(C)O
Product: COC(=O)c1ccc(C)c(-n2c(C)nc(OCc3cccc(OC)c3)c(Cl)c2=O)c1
Temperature: 60 °C
Yield: 106.4 %

Procedure:
To a solution of 3-[4-(3-methoxy-benzyloxy)-2-methyl-6-oxo-6H-pyrimidin-1-yl]-4-methyl-benzoic acid methyl ester from Step A (226 mg, 0.57 mmol) in isopropanol (2 mL) was added N-chlorosuccinimide (84 mg, 0.63 mmol) and 2 drops of dichloroacetic acid. The solution was heated at 60° C. for two hours. The solution was allowed to cool to room temperature and concentrated in vacuo and the residue was partitioned between ethyl acetate and water. The organic layer was washed with water and brine and dried over magnesium sulfate. The slurry was filtered and concentrated to provide the chlorinated product as a light yellow semi-solid (260 mg, quantitative yield). MS (M+H): 429
Reaction SMILES: CCCCCC.[CH2:7]([N:9]([Al](C)C)[CH2:10][CH3:11])[CH3:8].[CH2:15]([NH:17][C:18](=[O:49])[NH:19][C:20]1[S:24][C:23]2[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=2[C:21]=1[C:29]([N:31]1[CH2:48][CH2:47][C:34]2([N:38]=[C:37]([CH2:39][CH2:40][C:41]([O:43]CC)=O)[NH:36][C:35]2=[O:46])[CH2:33][CH2:32]1)=[O:30])[CH3:16]>C1C=CC=CC=1.C1COCC1>[CH2:7]([N:9]([CH2:10][CH3:11])[C:41](=[O:43])[CH2:40][CH2:39][C:37]1[NH:36][C:35](=[O:46])[C:34]2([CH2:33][CH2:32][N:31]([C:29]([C:21]3[C:22]4[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=4[S:24][C:20]=3[NH:19][C:18]([NH:17][CH2:15][CH3:16])=[O:49])=[O:30])[CH2:48][CH2:47]2)[N:38]=1)[CH3:8]
Reactant: CCN(CC)[Al](C)C
Reactant: CCNC(=O)Nc1sc2ccccc2c1C(=O)N1CCC2(CC1)N=C(CCC(=O)OCC)NC2=O
Solvent: c1ccccc1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCNC(=O)Nc1sc2ccccc2c1C(=O)N1CCC2(CC1)N=C(CCC(=O)N(CC)CC)NC2=O
Temperature: 80 °C
Reaction time: 1 h
Yield: 20 %

Procedure:
To a 2.0 M hexane solution of (diethylamino)dimethylaluminum (3.2 equivalents) in dry benzene (0.26 M) was cooled to −15° C., a solution of ethyl 3-(8-(2-(3-ethylureido)benzo[b]thiophene-3-carbonyl)-4-oxo-1,3,8-triazaspiro[4.5]dec-1-en-2-yl)propanoate (10 (Example 10), 12 mg, 1.0 equivalent) in THF (0.16M) was added; the mixture was heated to 80° C. for 6 hrs. The mixture was cooled in an ice bath; then a saturated aqueous Rochelle's solution was added and stirred for 1 hr, then partitioned between ethyl acetate and water and the separated organics was washed with brine and dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparatory LCMS to afford N,N-diethyl-3-(8-(2-(3-ethylureido)benzo[b]thiophene-3-carbonyl)-4-oxo-1,3,8-triazaspiro[4.5]dec-1-en-2-yl)propanamide (10, 20%). Two rotamers observed (ratio 1.3:1).
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][CH2:9][Si:10]([O:15]C)([O:13]C)[O:11]C)(=[O:5])[C:2]([CH3:4])=[CH2:3].Cl[Si:18]([CH3:21])([CH3:20])[CH3:19]>>[C:1]([O:6][CH2:7][CH2:8][CH2:9][Si:10]([O:13][Si:18]([CH3:21])([CH3:20])[CH3:19])([O:11][Si:18]([CH3:21])([CH3:20])[CH3:19])[O:15][Si:10]([CH2:9][CH2:8][CH2:7][O:6][C:1](=[O:5])[C:2]([CH3:4])=[CH2:3])([O:11][Si:18]([CH3:21])([CH3:20])[CH3:19])[O:13][Si:18]([CH3:21])([CH3:20])[CH3:19])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C[Si](C)(C)Cl
Reactant: C=C(C)C(=O)OCCC[Si](OC)(OC)OC
Product: C=C(C)C(=O)OCCC[Si](O[Si](C)(C)C)(O[Si](C)(C)C)O[Si](CCCOC(=O)C(=C)C)(O[Si](C)(C)C)O[Si](C)(C)C

Procedure:
1.3-Bis(γ-methacryloxypropyl)-1,1,3,3-tetra(trimethylsiloxy)disiloxane (TETRA) was prepared following the same procedure as in Example (b) with 0.1 mole of γ-methacryloxypropyltrimethoxysilane (MEMO) and 0.2 mole of chlorotrimethylsilane.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10](I)=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1.[F:22][C:23]1[CH:43]=[CH:42][C:41]([F:44])=[CH:40][C:24]=1[CH2:25][N:26]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[N:27]1.C(=O)([O-])[O-].[Na+].[Na+]>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.C1(C)C=CC=CC=1.C(O)C.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:29]3[CH:28]=[N:27][N:26]([CH2:25][C:24]4[CH:40]=[C:41]([F:44])[CH:42]=[CH:43][C:23]=4[F:22])[CH:30]=3)=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1
Reactant: CC1(C)OB(c2cnn(Cc3cc(F)ccc3F)c2)OC1(C)C
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(Br)cnc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cc(F)ccc4F)c3)c3cc(Br)cnc32)cc1
Yield: 42.63 %

Procedure:
Using similar reaction conditions as described in step-i of example 1,5-bromo-3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridine (Intermediate 1) (1 g, 2.37 mmol) was coupled with 1-(2,5-difluorobenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Intermediate 6) (688 mg, 3.3 mmol) in sodium carbonate (749 mg, 7.07 mmol), bis(triphenyl phosphine)palladium(ii) dichloride (83 mg, 0.11 mmol) and toluene/ethanol/water (10/10/5 ml) to afford 550 mg (42.63% yield) of the pure product after column purification using 30% ethyl acetate in hexane as eluent. 1H NMR (DMSO-d6, 300 MHz): δ 8.59-8.51 (m, 3H), 8.29 (s, 1H), 8.13 (s, 1H), 7.98-7.95 (d, 2H), 7.42-7.40 (d, 2H), 7.35-7.10 (m, 4H), 5.52 (s, 2H), 2.33 (s, 3H). MS: m/z=542.6 (M−1).
Reaction SMILES: [N:1]1([C:7]([O:9]C(C)(C)C)=O)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20]([S:25]([CH2:28][CH2:29]C(O)=O)(=[O:27])=[O:26])[CH:19]=[CH:18]2.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.C(=O)([O-])[O-].[K+].[K+]>ClCCl.C(N(CC)CC)C>[Cl:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20]([S:25]([CH2:28][CH2:29][C:7]([N:1]1[CH2:2][CH2:3][NH:4][CH2:5][CH2:6]1)=[O:9])(=[O:27])=[O:26])[CH:19]=[CH:18]2
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)CCS(=O)(=O)c1ccc2cc(Cl)ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])[O-]
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCS(=O)(=O)c1ccc2cc(Cl)ccc2c1)N1CCNCC1
Yield: 88.6 %

Procedure:
tert-Butyl 1-piperazine carboxylate (5.0 g) was dissolved in dichloromethane (20 mL), and triethylamine (3.8 mL) was added thereto. With ice cooling, 3-((6-chloro-2-naphthyl)sulfonyl)propionic acid (8.0 g), HOBt (4.5 g) and WSC (5.7 g) were added thereto, and the mixture was mixed at room temperature for 16 hours. The reaction solution was basified with an aqueous potassium carbonate solution, then extracted with chloroform, and the extract was dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was dissolved in trifluoroacetic acid (25 mL) and mixed at room temperature for 1 hour. After concentrating the reaction solution, the residue was basified with an aqueous potassium carbonate solution and extracted with chloroform. The extract was dried over anhydrous magnesium sulfate, and then the solvent was concentrated to give the title compound (8.7 g) as a pale brown oily matter.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[C:18]([Cl:22])=[CH:17][C:16]=1[SH:23].N1C=CC=CC=1.C(OCC)(=O)C>C(#N)C>[C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([S:23][C:16]2[CH:17]=[C:18]([Cl:22])[C:19]([Cl:21])=[CH:20][C:15]=2[Cl:14])=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: Sc1cc(Cl)c(Cl)cc1Cl
Reactant: CC(=O)Oc1ccc(C(=O)Cl)cc1
Solvent: CC#N
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)Oc1ccc(C(=O)Sc2cc(Cl)c(Cl)cc2Cl)cc1
Yield: 97 %

Procedure:
A solution of 4-acetoxybenzoyl chloride (8.37 g) in dry acetonitrile (20 ml) was added to a solution of 2,4,5-trichlorothiophenol (9.00 g) in dry acetonitrile (120 ml) and the mixture stirred at room temperature whilst pyridine (3.41 ml) was added dropwise over 10 minutes. Stirring was continued until the reaction was complete, when ethyl acetate was added and the solution washed with water. Evaporation of the solution, which had been dried over magnesium sulphate, afforded the desired thioester (15.36 g).