Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][CH2:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16]3[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:17]=3[N:18]([CH3:34])[C:19](=[O:33])[CH:20]([CH2:22][C:23]3[CH:32]=[CH:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=3)[N:21]=2)=[CH:11][N:10]=1)=[O:7])(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.O>[Cl:39][C:37]1[CH:36]=[CH:35][C:17]2[N:18]([CH3:34])[C:19](=[O:33])[CH:20]([CH2:22][C:23]3[CH:32]=[CH:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=3)[N:21]=[C:15]([C:12]3[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[CH2:5][OH:4])=[N:10][CH:11]=3)[C:16]=2[CH:38]=1
Reactant: CC(=O)OCC(=O)Nc1ccc(C2=NC(Cc3ccc4ccccc4c3)C(=O)N(C)c3ccc(Cl)cc32)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CN1C(=O)C(Cc2ccc3ccccc3c2)N=C(c2ccc(NC(=O)CO)nc2)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 40.1 %

Procedure:
2-(5-(7-Chloro-1-methyl-3-(naphthalen-2-ylmethyl)-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl)pyridin-2-ylamino)-2-oxoethyl acetate (20 mg, 0.04 mmol) was dissolved in methanol (0.5 mL) and water (0.1 mL), potassium carbonate was added and the mixture was stirred at ambient temperature for 45 minutes. The crude mixture as partitioned between ethyl acetate and water, the layers were separated, and the organic layer was dried with sodium sulfate, decanted, then concentrated in the presence of silica gel. Column chromatography eluting with a step gradient of 20-80% ethyl acetate in hexanes in 5% increments every 3 minutes provided N-(5-(7-chloro-1-methyl-3-(naphthalen-2-ylmethyl)-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl)pyridin-2-yl)-2-hydroxyacetamide (8 mg, 43% yield). ESI m/z measured 521.1348 [M+H]+. calculated 521.1356.
Reaction SMILES: [NH2:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[O:7])=[C:4]([O:19][CH2:20][CH2:21][CH2:22][S:23][CH3:24])[CH:3]=1.Cl.I([O-])(=O)(=O)=[O:27].[Na+].[OH-].[Na+]>O>[NH2:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:11]([CH2:12][CH3:13])[CH2:14][CH3:15])=[O:7])=[C:4]([O:19][CH2:20][CH2:21][CH2:22][S:23]([CH3:24])=[O:27])[CH:3]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1OCCCSC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1OCCCS(C)=O
Reaction time: 2.5 h
Yield: 49.4 %

Procedure:
To a stirred solution of product from Example 49 (1.496 g, 4 mmoles) in 2N hydrochloric acid (5.0 ml, 10 mmoles) and water (20 ml) was added sodium periodate (856 mg. 4.0 mmoles) and the mixture stirred for 2.5 hours. It was then basified with 4N sodium hydroxide (3 ml) and extracted with methylene chloride (3×30 ml). The extracted was concentrated in vacuo and the residue flash-chromatographed on deactivated silica column using methylene chloride:methanol:ammonia (100:3.5:0.5) solvent system. The appropriate fractions were combined and concentrated to give a yellow oil which crystallized from methylene chloride-ether to give 770 mg of the title product as a light yellow solid, mp. 116°-117° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([C:13]([CH3:19])([CH3:18])[C:14]([O:16]C)=[O:15])=[CH:8][CH:7]=2.[Li+].[OH-].CO.Cl>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([C:13]([CH3:19])([CH3:18])[C:14]([OH:16])=[O:15])=[CH:8][CH:7]=2
Reactant: COC(=O)C(C)(C)c1ccc2ncc(OC)cc2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cnc2ccc(C(C)(C)C(=O)O)cc2c1

Procedure:
A solution of methyl 2-(3-methoxyquinolin-6-yl)-2-methylpropanoate (400 mg, 1543 μmol), LiOH (1928 μl, 7713 μmol) [4M], MeOH (2 mL), and THF (2 mL) was stirred at 50° C. overnight. LCMS suggests full conversion. Solution cooled, acidified to pH 1 with 5M HCl, and precipitate collected by filtration. White cake washed with water (2 mL) and EtOH (1 mL). Product air dried for 3 h and isolated as a white solid. MS (ESI pos. ion) m/z: 246 (MH+). Calc'd exact mass for C14H15NO3: 245.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH2:10]([N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)[CH3:11]>>[CH2:10]([N:12]1[CH2:17][CH2:16][N:15]([C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[C:4]#[N:5])[CH2:14][CH2:13]1)[CH3:11]
Reactant: N#Cc1ccccc1F
Reactant: CCN1CCNCC1
Product: CCN1CCN(c2ccccc2C#N)CC1

Procedure:
According to a similar manner to that in Reference Example 12, the title compound was synthesized from 2-fluorobenzonitrile and 4-ethylpiperazine.
Reaction SMILES: C([O-])(=[O:3])C.[Na+].[CH2:6]([CH:9]([C:13]([CH3:15])=[CH2:14])[C:10](=[O:12])[CH3:11])[CH:7]=[CH2:8].C(OO)(=O)C>ClCCl>[CH2:6]([CH:9]([C:13]1([CH3:15])[O:3][CH2:14]1)[C:10](=[O:12])[CH3:11])[CH:7]=[CH2:8]
Reactant: C=CCC(C(=C)C)C(C)=O
Reactant: CC(=O)[O-]
Agent: CC(=O)OO
Agent: [Na+]
Solvent: ClCCl
Product: C=CCC(C(C)=O)C1(C)CO1
Temperature: 30 °C
Reaction time: 1 h

Procedure:
2.5 Grams of sodium acetate was added at 30° C. to a mixture of 3-allyl-4-methyl-pent-4-en-2-one (5.0 g) and dichloromethane (100 ml), and then a 9% peracetic acid solution (153 g) was added dropwise thereto over 1 hour. After stirring at 30° C. for 4 hours, the reaction solution was treated in the same manner as in Example 3 to obtain 1.20 g of pure 3-allyl-4-methyl-4,5-epoxy-pentan-2-one.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]2[NH:7][C:8](=[O:19])[N:9]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH:13]3[CH3:18])[CH2:10][CH2:11][C:5]=2[CH:4]=1.Cl[C:23]1[N:28]=[CH:27][N:26]=[C:25]([C:29]([C:31]2[CH:41]=[C:40]([CH3:42])[C:34]3[N:35]([CH3:39])[C:36](=[O:38])[O:37][C:33]=3[CH:32]=2)=[O:30])[CH:24]=1.CO>CN(C=O)C>[CH3:39][N:35]1[C:34]2[C:40]([CH3:42])=[CH:41][C:31]([C:29]([C:25]3[N:26]=[CH:27][N:28]=[C:23]([N:15]4[CH2:16][CH2:17][CH:12]([N:9]5[CH2:10][CH2:11][C:5]6[CH:4]=[C:3]([O:2][CH3:1])[CH:21]=[CH:20][C:6]=6[NH:7][C:8]5=[O:19])[CH:13]([CH3:18])[CH2:14]4)[CH:24]=3)=[O:30])=[CH:32][C:33]=2[O:37][C:36]1=[O:38]
Reactant: Cc1cc(C(=O)c2cc(Cl)ncn2)cc2oc(=O)n(C)c12
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1C)C(=O)N2
Solvent: CN(C)C=O
Solvent: CO
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)c4cc(C)c5c(c4)oc(=O)n5C)ncn3)CC1C)C(=O)N2

Procedure:
60 mg (0.21 mmol) 7-methoxy-3-(3-methyl-piperidin-4-yl)-1,3,4,5-tetrahydro-benzo[d]-[1,3]diazepin-2-one, 60 mg (0.20 mmol) 6-(6-chloro-pyrimidine-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-one and 0.040 mL (0.29 mmol) TEA were stirred overnight in 1 mL DMF at RT. Then the reaction mixture was combined with 2 mL MeOH, the precipitate formed was suction filtered, washed with MeOH and diethyl ether and dried.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[C:5]([NH:7][C:8]([CH3:16])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:9])=[O:6].CN(CCN(C)C)C.C([Li])(CC)C.CCCCCC.CN([CH:42]=[O:43])C>C1COCC1>[F:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:4]2[C:3]=1[CH:42]([OH:43])[N:7]([C:8]([CH3:16])([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH3:9])[C:5]2=[O:6]
Reactant: CN(C)C=O
Reactant: CC(C)(NC(=O)c1cccc(F)c1)c1ccccc1
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(c1ccccc1)N1C(=O)c2cccc(F)c2C1O
Yield: 93.4 %

Procedure:
In a similar manner to Step 2 of Example 16, 3-fluoro-N-(1-methyl-1-phenylethyl)benzamide (2.00 g, 7.77 mmol) was dissolved in THF (80 mL), and the solution was treated with TMEDA (3.8 mL, 24.9 mmol), sec-butyllithium-hexane solution (1.01 mol/L, 24.6 mL, 24.9 mmol) and DMF (1.30 mL, 17.1 mmol). The mixture was purified by slurry using diisopropylether to obtain 4-fluoro-3-hydroxy-2-(1-methyl-1-phenylethyl)isoindolinone (2.07 g, yield 93%).
Reaction SMILES: [C:1]([O:5][CH2:6][C:7]#[N:8])(=[O:4])[CH:2]=[CH2:3].[CH2:9]([NH:11][CH2:12][CH3:13])[CH3:10]>>[CH2:9]([N:11]([CH2:12][CH3:13])[CH2:3][CH2:2][C:1]([O:5][CH2:6][C:7]#[N:8])=[O:4])[CH3:10]
Reactant: CCNCC
Reactant: C=CC(=O)OCC#N
Product: CCN(CC)CCC(=O)OCC#N
Reaction time: 10 h

Procedure:
At 20 to 30° C., 22.2 g of cyanomethyl acrylate was added to 14.6 g of diethylamine, which was stirred for 10 hours, obtaining cyanomethyl 3-diethylaminopropionate.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5](Br)[S:4][C:3]=1[CH3:8].[F:9][C:10]([F:21])([F:20])[C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[CH:15][CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCCC1>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.O>[Br:1][C:2]1[CH:6]=[C:5]([C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([C:10]([F:21])([F:20])[F:9])[CH:16]=2)[S:4][C:3]=1[CH3:8]
Reactant: Cc1sc(Br)cc1Br
Reactant: OB(O)c1cccc(C(F)(F)F)c1
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: [Cs+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1sc(-c2cccc(C(F)(F)F)c2)cc1Br
Yield: 85.7 %

Procedure:
Under a nitrogen atmosphere, a mixture of 3,5-dibromo-2-methylthiophene (2.00 g), 3-(trifluoromethyl)phenylboronic acid (2.23 g), tetrakis(triphenylphosphine)palladium (0.45 g), cesium carbonate (5.09 g) and tetrahydrofuran (40 mL) was heated under reflux for 16 hr. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (carrier: silica gel, eluent: hexane-ethyl acetate) to give the title compound (2.15 g) as a solid.
Reaction SMILES: I[C:2]1[C:7]([NH2:8])=[C:6]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:5]=[CH:4][N:3]=1.[CH2:16]([OH:21])[CH:17]=[CH:18][C:19]#[CH:20]>C(#N)C.C(N(CC)CC)C.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.[Cu]I>[NH2:8][C:7]1[C:2]([C:20]#[C:19]/[CH:18]=[CH:17]/[CH2:16][OH:21])=[N:3][CH:4]=[N:5][C:6]=1[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Nc1c(I)ncnc1Oc1ccccc1
Reactant: C#CC=CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Nc1c(C#C/C=C/CO)ncnc1Oc1ccccc1
Yield: 59.9 %

Procedure:
4-Iodo-6-phenoxypyrimidin-5-amine (3.5 g) was dissolved in a mixed solvent of acetonitrile (185 mL)/triethylamine (136 mL), and 2-penten-4-yn-1-ol (1.1 g), trans-dichlorobis(triphenylphosphine)palladium(II) (392 mg) and copper(I) iodide (127 mg) were sequentially added. The title compound (1.79 g) was obtained as a powder by the reaction in the same manner as in Example 9 (iv).
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)=[O:9].[N:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][CH:27]([CH2:30][NH2:31])[CH2:26][CH2:25]2)=[CH:20][CH:19]=1.S>CN(C)C=O.CO.[Cu]Br>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([NH:10][C:8]([C:7]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=2[NH:31][CH2:30][CH:27]2[CH2:26][CH2:25][N:24]([C:21]3[CH:22]=[CH:23][N:18]=[CH:19][CH:20]=3)[CH2:29][CH2:28]2)=[O:9])=[CH:12][CH:13]=1
Reactant: NCC1CCN(c2ccncc2)CC1
Reactant: O=C(Nc1ccc(Cl)cc1)c1ccncc1Cl
Agent: [Cu]Br
Agent: S
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(Nc1ccc(Cl)cc1)c1ccncc1NCC1CCN(c2ccncc2)CC1
Temperature: 110 °C
Reaction time: 18 h
Yield: 14 %

Procedure:
A mixture of 3-chloro-N-(4-chlorophenyl)pyridine-4-carboxamide (130 mg, 0.49 mmol), 1-(4-pyridyl)piperidine-4-methylamine (187 mg, 0.98 mmol), and copper(1) bromide (70 mg) in dimethylformamide (1 mL) was heated at 110° C. After 18 h, the mixture was diluted with MeOH, filtered, and concentrated. The residue was treated with 6:1 chloroform:water (10 mL) followed by MeOH until a homogenoeus solution resulted. The solution was treated with hydrogen sulfide(g), heated at reflux for 0.1 h, and filtered through diatomaceous earth. The filtrate was concentrated and the residue taken up in water, 1 N NaOH, and EtOAc. The aqueous layer was washed with EtOAc (3×), the combined extracts were dried (sodium sulfate), filtered and concentrated. The residue was purified by RPHPLC yielding 29 mg (13%) of the title compound as a hydrochloride salt.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=4)[CH2:15][CH2:14]3)[CH:10]=[N:11][C:5]=2[N:4]2[CH2:28][CH2:29][CH2:30][C@@H:3]12.Cl.[CH3:32][NH2:33].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:32][NH:33][C:23](=[O:24])[C:22]1[CH:26]=[CH:27][C:19]([N:16]2[CH2:15][CH2:14][N:13]([CH2:12][C:9]3[CH:10]=[N:11][C:5]4[N:4]5[CH2:28][CH2:29][CH2:30][C@H:3]5[C:2](=[O:1])[NH:7][C:6]=4[CH:8]=3)[CH2:18][CH2:17]2)=[CH:20][CH:21]=1
Reactant: O=C(O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)cc1
Reactant: CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)cc1
Temperature: 25 °C
Reaction time: 23 h
Yield: 47.2 %

Procedure:
(S)-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzoic acid (87 mg, 0.214 mmol) and methanamine hydrochloride (21.62 mg, 0.320 mmol) were suspended in DMF (1 ml) and treated with DIPEA (0.186 ml, 1.068 mmol) and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (162 mg, 0.427 mmol). The reaction mixture was stirred at room temperature for 23 h and purified using HPLC (25-95% acetonitrile in water, NH4HCO3 buffered) to afford (S)—N-methyl-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide (42.4 mg, 0.101 mmol, 47.2% yield) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.83-2.01 (m, 3H) 2.11-2.25 (m, 1H) 2.39-2.48 (m, 4H) 2.73 (d, J=4.55 Hz, 3H) 3.13-3.27 (m, 4H) 3.34-3.44 (m, 3H) 3.52-3.64 (m, 1H) 3.96-4.02 (m, 1H) 6.92 (d, J=9.09 Hz, 2H) 6.98 (d, J=2.02 Hz, 1H) 7.62 (d, J=1.77 Hz, 1H) 7.69 (d, J=9.09 Hz, 2H) 8.13 (q, J=4.29 Hz, 1H) 10.44 (s, 1H); [M+H] calc'd for C23H28N6O2, 421; found, 421.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][Si:6]([CH:13]([CH3:15])[CH3:14])([CH:10]([CH3:12])[CH3:11])[CH:7]([CH3:9])[CH3:8].[CH2:16]([O:18][C:19]([C:21]1[NH:29][C:28]2[CH:27]=[CH:26][N:25]=[CH:24][C:23]=2[C:22]=1[NH:30][C:31]1[CH:36]=[CH:35][C:34]([I:37])=[CH:33][C:32]=1[F:38])=[O:20])[CH3:17].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH2:16]([O:18][C:19]([C:21]1[N:29]([CH2:2][CH2:3][CH2:4][O:5][Si:6]([CH:13]([CH3:15])[CH3:14])([CH:10]([CH3:12])[CH3:11])[CH:7]([CH3:9])[CH3:8])[C:28]2[CH:27]=[CH:26][N:25]=[CH:24][C:23]=2[C:22]=1[NH:30][C:31]1[CH:36]=[CH:35][C:34]([I:37])=[CH:33][C:32]=1[F:38])=[O:20])[CH3:17]
Reactant: CCOC(=O)c1[nH]c2ccncc2c1Nc1ccc(I)cc1F
Reactant: CC(C)[Si](OCCCBr)(C(C)C)C(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(Nc2ccc(I)cc2F)c2cnccc2n1CCCO[Si](C(C)C)(C(C)C)C(C)C
Temperature: 80 °C
Yield: 28.9 %

Procedure:
(3-Bromo-propoxy)-triisopropyl-silane (209 mg, 0.71 mmol) was dissolved in DMF (5 ml) and 3-(2-fluoro-4-iodophenylamino)-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid ethyl ester (250 mg, 0.59 mmol) was added, followed by cesium carbonate (250 mg, 0.77 mmol). The mixture was heated at 80° C. under nitrogen for 3 hours, then allowed to cool, diluted with water and extracted with dichloromethane (×2). The combined organic layers were washed with 20% aqueous lithium chloride solution, dried over magnesium sulfate then concentrated in vacuo. Purification of the resultant residue by flash chromatography (Si-PPC, dichloromethane:methanol gradient 1:0 to 99:1) gave the title compound as a yellow oil (109 mg, 44%). LCMS (method B): RT 3.41, M+H+ 640.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH:6]1([CH2:12][CH2:13][CH:14]([OH:16])[CH3:15])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1>C(Cl)Cl>[CH3:1][S:2]([O:16][CH:14]([CH3:15])[CH2:13][CH2:12][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(O)CCC1CCCCC1
Solvent: ClCCl
Product: CC(CCC1CCCCC1)OS(C)(=O)=O
Yield: 107.5 %

Procedure:
A solution of 3.53 g methanesulfonyl chloride in 100 mL methylene chloride was added to a solution of 4.38 g 4-cyclohexylbutan-2-ol in 200 mL methylene chloride. The reaction mixture was stirred over night. Aqueous work-up yielded 7.06 g (96%) of a colourless oil.
Reaction SMILES: [CH3:1][O:2][NH:3][S:4]([CH3:7])(=[O:6])=[O:5].Cl[S:9]([N:12]=[C:13]=[O:14])(=[O:11])=[O:10]>ClC1C=CC=CC=1>[CH3:7][S:4]([N:3]([O:2][CH3:1])[S:9]([N:12]=[C:13]=[O:14])(=[O:11])=[O:10])(=[O:6])=[O:5]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CONS(C)(=O)=O
Solvent: Clc1ccccc1
Product: CON(S(C)(=O)=O)S(=O)(=O)N=C=O

Procedure:
3.4 g (0.0272 mol) of O-methyl-N -methylsulfonylhydroxylamine (prepared in accordance with Z. Naturforsch. 36b, 1673 (1981)) are suspended in 80 ml of anhydrous chlorobenzene, and 2.53 ml (4.10 g; 0.029 mol) of chlorosulfonyl isocyanate are added at 0° C. The reaction mixture is then heated slowly while nitrogen is passed through, during which process the suspension changes into a clear solution at 40° C. After the mixture has been refluxed for about 3 hours, it is cooled and evaporated in a rotary evaporator, and the residue is dried under a high vacuum. 6.18 g (99% of theory) of N-methylsulfonyl-methoxyamino-sulfonyl isocyanate which can be employed in the next step without further purification are obtained.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[CH:11][C:12](=[O:15])[NH:13][CH:14]=2)=[CH:5][CH:4]=1.Cl.O1[CH:22]=[CH:21][C:20](=[O:23])[CH:19]=[CH:18]1>O>[O:23]=[C:20]1[CH:21]=[CH:22][N:2]([C:3]2[CH:4]=[CH:5][C:6]([C:9]3[N:10]=[CH:11][C:12](=[O:15])[NH:13][CH:14]=3)=[CH:7][CH:8]=2)[CH:18]=[CH:19]1
Reactant: Nc1ccc(-c2c[nH]c(=O)cn2)cc1
Reactant: O=c1ccocc1
Agent: Cl
Solvent: O
Product: O=c1ccn(-c2ccc(-c3c[nH]c(=O)cn3)cc2)cc1

Procedure:
A stirred mixture of 5-(4-aminophenyl)-2(1H)pyrazinone hydrochloride (1.5 g, from hydrolysis of the corresponding acetamido derivative with hydrochloric acid), 4H-pyran-4-one (0.71 g) and water (15 ml) was heated under reflux for 21/2 hours under a nitrogen atmosphere. The resultant solution was neutralised to give a solid, 1.79 g, m.p. 345° C. (dec). Recrystallisation from aqueous ethanol gave the title compound, 0.93 g, m.p. 354°-357° C. (dec).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([SH:12])=[CH:8][CH:7]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:21][C:22](=[O:24])[CH3:23]>CC(C)=O.O>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][CH2:21][C:22](=[O:24])[CH3:23])=[CH:8][CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(S)cc1
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)Cc1ccc(SCC(C)=O)cc1
Temperature: 25 °C

Procedure:
To a solution of (4-mercaptophenyl)-acetic acid ethyl ester (10 g, 0.051 mol) in 150 mL of acetone is added potassium carbonate (anhydrous, 8.51 g, 0.061 mol) at 0° C., followed by dropwise addition of chloroacetone (5 mL, 0.061 mol) in 10 mL of acetone at 0° C. The reaction is then maintained at RT for 2 h. The reaction is filtered and the filtrate is concentrated under vacuum. The residue thus obtained is diluted with 15 mL of water and extracted with ethyl acetate (2×50 mL). The organic layer is then washed with water and brine, dried over sodium sulfate, filtered and evaporated under vacuum to give [4-(2-oxo-propylsulfanyl)-phenyl]-acetic acid ethyl ester as a yellow oil.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[S:4]([C:8]1[CH:16]=[CH:15][C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=1)([O-])(=[O:6])=[O:5].[N+:17]([C:20]1[CH:25]=[CH:24][C:23]([S:26]([Cl:29])(=[O:28])=[O:27])=[CH:22][CH:21]=1)([O-:19])=[O:18].N1(C2C=CN=CC=2)CCCC1.[N-]=[N+]=[N-].[Na+]>C(Cl)(Cl)Cl.CN(C)C=O>[N+:17]([C:20]1[CH:25]=[CH:24][C:23]([S:26]([Cl:29])(=[O:27])=[O:28])=[CH:22][CH:21]=1)([O-:19])=[O:18].[S:4]([N:1]=[N+:2]=[N-:3])([C:8]1[CH:16]=[CH:15][C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=1)(=[O:5])=[O:6]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)[O-])cc1
Reactant: [N-]=[N+]=[N-]
Agent: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: c1cc(N2CCCC2)ccn1
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: [N-]=[N+]=NS(=O)(=O)c1ccc([N+](=O)[O-])cc1

Procedure:
Secondary alcohol 7 was converted to azide 8 through the formation of a secondary nosylate using 4-nitrobenzenesulfonyl chloride and 4-pyrrolidinopyridine in chloroform followed by azide displacement with sodium azide in N,N-dimethylformamide at 50° C. The p-methoxy trityl protecting group was selectively removed using 1% p-toluenesulfonic acid in methylene chloride. Nosylation of the primary alcohol with 4-nitrobenzenesulfonyl chloride and pyridine in chloroform provided azido-nosylate 9.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]=[CH:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1)[CH3:2].[H][H]>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][CH2:6][CH:7]1[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH2:12]1)[CH3:2]
Reactant: CCOC(=O)C=CC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCC1CCN(C(=O)OC(C)(C)C)CC1
Yield: 69.5 %

Procedure:
To a solution of 1.0 g of t-butyl 4-(3-ethoxy-3-oxoprop-1-enyl)-tetrahydropyridine-1(2H)-carboxylate (cf. WO9501336) in 20 ml of ethanol, 300 mg of 10% palladium-on-carbon catalyst, and stirred for 3 hours in a hydrogen atmosphere, at ambient temperature and pressure. After filtering the catalyst off, the solvent was distilled off under reduced pressure to provide 700 mg of the title compound.
Reaction SMILES: [OH-:1].[K+].Br[CH:4]1[C:9]([CH3:11])([CH3:10])[CH2:8][C:7]([CH3:13])([CH3:12])[CH:6](Br)[C:5]1=[O:15]>O>[OH:15][C:5]1[C:6](=[O:1])[C:7]([CH3:13])([CH3:12])[CH2:8][C:9]([CH3:11])([CH3:10])[CH:4]=1
Reactant: CC1(C)CC(C)(C)C(Br)C(=O)C1Br
Reactant: [OH-]
Agent: [K+]
Solvent: O
Product: CC1(C)C=C(O)C(=O)C(C)(C)C1
Reaction time: 24 h

Procedure:
To a stirred solution of potassium hydroxide (50 g) in 1500 ml of distilled water was added the brominated compound of step 1 (50 g). Stirring was continued for 24 hours. The solution was filtered to remove brominated compound which had not dissolved. The filtrate was cooled in an ice bath and concentrated sulphuric acid added dropwise until a white solid precipitated. The mixture was stirred for 30 minutes, after which the white solid was collected and recrystallized from a hot mixture of 200 ml of methanol and 100 ml of water, giving 2-hydroxy-4,4,6,6-tetramethylcyclohex-2-enone as white crystals, 13.5 g, melting range 85°-86° C.
Reaction SMILES: [CH2:1]([Si:4](OC)([O:7][CH3:8])[O:5][CH3:6])[CH2:2][CH3:3].[C:11]1([Mg]Br)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[SiH4].Cl>CCOCC>[C:11]1([Si:4]([CH2:1][CH2:2][CH3:3])([O:7][CH3:8])[O:5][CH3:6])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Br[Mg]c1ccccc1
Reactant: CCC[Si](OC)(OC)OC
Agent: Cl
Agent: [SiH4]
Solvent: CCOCC
Product: CCC[Si](OC)(OC)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
A 500 mL round bottomed flask was charged with propyl-trimethoxysilane (19.3 mL, 1.10×10−1 mole, Hüls) and ether (250 mL, Aldrich). A pressure equalizing addition funnel was charged with phenylmagnesium bromide (33.3 mL of a 3M solution in ether, 99.9 mmol, Aldrich) and ether (50 mL). The contents of the addition funnel were added into the silane over a 20 minute period (exotherm). A white precipitate formed. The reaction was stirred for two hours at room temperature then poured into 0.2N HCl (300 mL). The layers were separated, the product extracted into ether (2×250 mL), dried (MgSO4), and filtered. The solvent was removed via rotary evaporation resulting in 23.5 grams of crude material. Distillation under reduced pressure (b.p. 71° C., 0.6 mm Hg) provided phenyl-propyl-dimethoxysilane (18.5 g, 88.0 mmol, 88% yield); C11H18SiO2 (mw=210.34); 1H NMR (CDCl3) δ 7.7 (m, 2H), 7.4 (m, 3H), 3.6 (s, 6H), 1.4 (m, 2H), 1.0 (t, 3H), 0.9 (t, 2H); 13C NMR (CDCl3) δ 134.3, 133.3, 130.1, 127.9, 50.6, 17.9, 16.3, 14.8; MS m/z (relative abundance) 210 (2), 167 (100), 137 (33), 107 (17), 91 (17), 59 (10).