Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[NH:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl.[Cl:19][C:20]1[C:29]2[C:24](=[C:25]([O:34][CH3:35])[C:26]([O:32][CH3:33])=[C:27](OC)[CH:28]=2)[N:23]=[CH:22][N:21]=1.[CH:36]([OH:39])(C)C>>[ClH:19].[C:10]([NH:9][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:2]=1[F:1])[NH:8][C:20]1([O:39][CH3:36])[C:29]2[C:24](=[C:25]([O:34][CH3:35])[C:26]([O:32][CH3:33])=[CH:27][CH:28]=2)[N:23]=[CH:22][NH:21]1)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Nc1ccc(F)c(NC(=O)c2ccccc2)c1
Reactant: COc1cc2c(Cl)ncnc2c(OC)c1OC
Reactant: CC(C)O
Agent: Cl
Product: COc1ccc2c(c1OC)N=CNC2(Nc1ccc(F)c(NC(=O)c2ccccc2)c1)OC
Temperature: 80 °C
Yield: 53 %

Procedure:
N-(2-Fluoro-5-aminophenyl)benzamide (276 mg) was added to a suspension of 4-chloro-6,7,8-trimethoxyquinazoline hydrochloride (293 mg) in isopropanol (8 ml) and the resultant mixture stirred and heated to 80° C. for 18 hours. The mixture was cooled to ambient temperature and the precipitated solid was isolated, washed with isopropanol then diethyl ether to yield the title compound as a solid (257 mg, 53%); NMR: 4.0 (s, 3H), 4.01 (s, 3H), 4.07 (s, 3H), 7.42 (t, 1H), 7.52 (m, 2H), 7.62 (m, 2H), 8.0 (m, 3H), 8.35 (s, 1H), 8.72 (s, 1H), 10.28 (s, 1H), 11.84 (broad s, 1H); m/s: M+H+ 449.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13](=[O:20])[CH2:12][CH2:11]1.C(N(CC)CC)C.O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13](=[O:20])[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCNc2ccccc21
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CCN(C(=O)c2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Benzoyl chloride (0.30 ml, 2.58 mmol) is added dropwise to a solution of 2,3-dihydro-1H-quinolin-4-one (260 mg, 1.77 mmol), triethylamine (0.32 ml, 2.30 mmol) and DMAP (10 mg) in CH2Cl2 at 0° C. The resulting mixture is stirred at room temperature for overnight. Water is added and the mixture is extracted with CH2Cl2 and washed with brine, dried over anhydrous sodium sulfate. After concentration, a residue is yielded, which is used “as is” for the next reaction without further purification.
Reaction SMILES: [S:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1.C(#N)C.C(=O)=O.C([Li])CCC.CON(C)[C:24](=[O:27])[CH2:25][CH3:26]>O1CCCC1>[S:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[C:2]1[C:24](=[O:27])[CH2:25][CH3:26]
Reactant: CCC(=O)N(C)OC
Reactant: c1cc2sccc2cn1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC#N
Product: CCC(=O)c1cc2cnccc2s1
Temperature: -78 °C
Reaction time: 14 h
Yield: 82.7 %

Procedure:
To a stirring mixture of thieno[3,2-c]pyridine (1.0 g) in anhydrous tetrahydrofuran (50 mL) at −40° C. (acetonitrile-dry ice bath) was added a solution of n-butyllithium (1.6 M, 4.7 mL) in hexanes. The mixture was cooled to −78° C. followed by the subsequent addition of a solution of N-methoxy-N-methyl-propionamide (0.97 g) in anhydrous tetrahydrofuran (10 mL). The cold bath was removed and the reaction mixture was allowed to warm gradually to room temperature. The mixture was stirred overnight (14 hours). The mixture was treated with saturated aqueous ammonium chloride (150 mL). The mixture was then extracted with ethyl acetate (500 mL), and the extract was washed with brine solution (100 mL). The organic phase was dried over anhydrous potassium carbonate and was concentrated under reduced pressure, reconstituted in chloroform, and concentrated again under reduced pressure to afford the orange-brown semisolid (1.17 g). The semisolid was purified by flash silica chromatography using an Analogix silica column (115 g silica), eluting with 0-30% ethyl acetate/heptane, then 30-60% ethyl acetate/heptane. Concentration of fractions containing product gave 0.49 g of product. Starting material (0.45 g) was also isolated by evaporation of appropriate fractions.
Reaction SMILES: C(N(CC)CC)C.C(Cl)(Cl)Cl.[C:12]([O:16][C:17]([NH:19][C@H:20]([C:33](O)=[O:34])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:24][CH:23]=1)=[O:18])([CH3:15])([CH3:14])[CH3:13].N#N.Cl.[CH3:39][NH:40][C@@H:41]([C:46]([NH:48][CH2:49][CH2:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:47])[CH2:42][CH2:43][S:44][CH3:45]>O1CCCC1>[NH:19]([C:17]([O:16][C:12]([CH3:14])([CH3:15])[CH3:13])=[O:18])[C@H:20]([C:33]([N:40]([CH3:39])[C@@H:41]([C:46]([NH:48][CH2:49][CH2:50][CH2:51][C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1)=[O:47])[CH2:42][CH2:43][S:44][CH3:45])=[O:34])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]([CH3:32])([CH3:30])[CH3:31])=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OC(C)(C)C)cc1)C(=O)O
Reactant: CN[C@H](CCSC)C(=O)NCCCc1ccccc1
Agent: Cl
Agent: N#N
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CSCC[C@H](C(=O)NCCCc1ccccc1)N(C)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)OC(C)(C)C

Procedure:
By the method of part A of Example 5 and using triethylamine instead of diisopropylethylamine and chloroform as a cosolvent with tetrahydrofuran, N-(tert-butyloxycarbonyl)-O-(tert-butyl)-L-tyrosine (2.13 g.) was condensed with N2 -methyl-N-(3-phenylpropyl)-D-methioninamide hydrochloride (2.0 g.). The product, [N-(tert-butyloxycarbonyl)-O-(tert-butyl-L-tyrosyl]-N2 -methyl-N-(3-phenylpropyl)-D-methioninamide, was purified by crystallization, the first crop (1.51 g., m.r. 129°-130° C.) from ethyl acetate, the second crop (0.53 g.) from ethyl acetate-hexane.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:11][C:10]2[NH:9][CH2:8][CH2:7][CH2:6][C:5]=2[C:4](=[O:12])[CH2:3]1.Br[CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18]>>[CH3:1][C:2]1([CH3:13])[CH2:11][C:10]2[N:9]([CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:8][CH2:7][CH2:6][C:5]=2[C:4](=[O:12])[CH2:3]1
Reactant: CC(C)CCBr
Reactant: CC1(C)CC(=O)C2=C(C1)NCCC2
Product: CC(C)CCN1CCCC2=C1CC(C)(C)CC2=O

Procedure:
7,7-Dimethyl-1,2,3,4,7,8-hexahydro-quinolin-5(6H)-one was reacted with 1-bromo-3-methylbutane according to the procedures of Part b) of Example 1 to give 7,7-dimethyl-1,2,3,4,7,8-hexahydro-1-(3-methylbutyl)-quinolin-5(6H)-one (18) as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:22]([CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:21]3[C:12]([C:13]4[CH:14]=[CH:15][C:16]([C:28](O)=[O:29])=[N:17][C:18]=4[CH2:19][CH2:20]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[CH3:31][NH:32][C@@H:33]1[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34]1.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>ClCCl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:22]([CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:21]3[C:12]([C:13]4[CH:14]=[CH:15][C:16]([C:28]([N:32]([CH3:31])[C@@H:33]5[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34]5)=[O:29])=[N:17][C:18]=4[CH2:19][CH2:20]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: CN[C@@H]1CCN(C)C1
Reactant: N#Cc1ccc(N2N=C3c4ccc(C(=O)O)nc4CCC3C2C2CCCC2)cc1Cl
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
Solvent: ClCCl
Product: CN1CC[C@@H](N(C)C(=O)c2ccc3c(n2)CCC2C3=NN(c3ccc(C#N)c(Cl)c3)C2C2CCCC2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 15.5 %

Procedure:
In a dried reaction flask, 2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-pyrazolo[3,4-f]quinoline-7-carboxylic acid (0.421 g, 1.0 mmol), (R)—N,1-dimethylpyrrolidine-3-amine (0.308 g, 2.697 mmol), DIEA (0.4 mL, 2.30 mmol), and HATU (0.836 g, 2.2 mmol) were added to a mixed solvent of DMF (3 mL) and dichloromethane (6 mL). The mixture was stirred at room temperature for 18 hr and was concentrated under reduced pressure. Water was added to the residue. The mixture was washed with water, and was purified by a preparative chromatography to produce a purified product as pale yellow solid (80 mg) in 15.5% yield.
Reaction SMILES: [Cl:1][CH2:2][CH:3]([OH:28])[CH2:4][NH:5][C:6]1[C:19]2[C:18](=[O:20])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:21])[C:10]=2[C:9]([NH:22][CH2:23][CH:24]([OH:27])[CH2:25]Cl)=[CH:8][CH:7]=1.[CH2:29]([NH2:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>ClCCl.CO>[ClH:1].[CH2:29]([NH:36][CH2:2][CH:3]([OH:28])[CH2:4][NH:5][C:6]1[C:19]2[C:18](=[O:20])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:21])[C:10]=2[C:9]([NH:22][CH2:23][CH:24]([OH:27])[CH2:25][NH:5][CH2:6][C:19]2[CH:18]=[CH:17][CH:12]=[CH:11][CH:10]=2)=[CH:8][CH:7]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: NCc1ccccc1
Reactant: O=C1c2ccccc2C(=O)c2c(NCC(O)CCl)ccc(NCC(O)CCl)c21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: Cl
Product: O=C1c2ccccc2C(=O)c2c(NCC(O)CNCc3ccccc3)ccc(NCC(O)CNCc3ccccc3)c21
Yield: 86 %

Procedure:
To a solution of 1,4-bis-(3-chloro-2-hydroxypropylamino)-9, 10-anthracenedione (1 g, 2.36 mmole), benzylamine (2.02 g, 18.88 mmole), and potassium iodide (0.25 g, 153 mmole) in a solution of methanol (40 mL) and dichloromethane (5 mL), which had been heated at reflux for 5 hours, was added potassium carbonate (0.7 g, 5.06 mmole). The reaction was heated at reflux for an additional 16 hours. Solvent was removed and the blue product was dissolved in dichloromethane and washed three times with water. The organic layer was dried over magnesium sulfate and the solvent was removed under reduced pressure. The blue free base product was purified by column chromatography (silica gel, dichloromethane with an increasing methanol gradient). The title product 1,4-Bis-(3-Benzylamino-2-Hydroxypropylamino)-9, 10 anthracenedione. Hydrochloride salt (610 mg, 42% yield) was formed by bubbling hydrochloride gas through a stirring solution of the free base in acetone until a color change was noted, mp 86°-89° C.; NMR (CDCl3) δ 2.76 (m, 2H, CH2) 2.90 (m, 2H CH2), 3.43 (m, 6H, CH2 and OH), 3.85 (d, J=4.3 Hz, 4H, CH2), 4.04 (m, 2H, CH), 7.15 (s, 2H, Ar (2, 3)), 7.31 (m, 10H, Ar (Benzyl)), 7.64 (m, 2H, Ar (6 ,7)), 8.22 (m, 2H, Ar (5, 8)), 10.82 (b, 2H, NH); Anal. Calcd for C34H37N4O4 ×HCl: C, 67.93; H, 6.20; N, 9.32. Found: C, 68.21; H, 6.14; N, 9.02.
Reaction SMILES: [Mg].Br[C:3]1[CH:4]=[C:5]([CH3:9])[CH:6]=[CH:7][CH:8]=1.II.[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#N)=[CH:16][CH:15]=1.[OH:22]S(O)(=O)=O>CCOCC.O>[CH3:9][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[C:18]([C:17]1[CH:20]=[CH:21][C:14]([O:13][CH3:12])=[CH:15][CH:16]=1)=[O:22]
Reactant: O=S(=O)(O)O
Reactant: COc1ccc(C#N)cc1
Reactant: Cc1cccc(Br)c1
Agent: II
Agent: [Mg]
Solvent: CCOCC
Solvent: O
Product: COc1ccc(C(=O)c2cccc(C)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.5 %

Procedure:
A 3-neck flask equipped with a condenser, mechanical stirrer and dropping funnel is charged under nitrogen with 1.925 g (79.19 g.a.) of magnesium turnings and enough ether to cover the turnings. A few drops of a solution of 3-bromotoluene (15.79 g, 92.28 mmole) in ether (40 mL) is then added along with a crystal of iodine to initiate the reaction. The remainder of the solution is then added dropwise and the mixture is refluxed until most of the magnesium has disappeared. After cooling, a solution of 4-methoxybenzonitrile (10 g, 75.1 mmole, dried in vacuo over P2O5) is added in one portion. The mixture is refluxed for 2 hours CFLC, no starting material present), cooled (ice bath) and slowly treated with cold water (130 mL) followed by dilute H2SO4 (1:1, v/v, 25 mL). The decomposition of the complex is completed by refluxing the mixture for 4 hours (followed by TLC, 8:2 ether-ethyl acetate). Following stirring overnight at room temperature, the layers are separated and extracted with ether (3x). The extracts are washed with 5% NaHCO3, dried (MgSO4) and evaporated to dryness. The crude material (amber oil, 13.93 g) is purified by flash chromatography (on silica Merck-60, eluted with 8:2 petrolether-ethyl acetate) to provide the title compound as a light yellow oil (12.5 g, 73.5%).
Reaction SMILES: CC(C)([O-])C.[K+].[OH:7][C@H:8]1[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:10]([C:20]([OH:22])=[O:21])[CH2:9]1.[Br:23][C:24]1[CH:33]=[C:32]2[C:27]([CH:28]=[CH:29][N:30]=[C:31]2Cl)=[CH:26][C:25]=1[O:35][CH3:36]>CS(C)=O>[Br:23][C:24]1[CH:33]=[C:32]2[C:27]([CH:28]=[CH:29][N:30]=[C:31]2[O:7][C@H:8]2[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[C@H:10]([C:20]([OH:22])=[O:21])[CH2:9]2)=[CH:26][C:25]=1[O:35][CH3:36]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Reactant: COc1cc2ccnc(Cl)c2cc1Br
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1cc2ccnc(O[C@@H]3C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C3)c2cc1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Potassium tert-butoxide (14.1 g, 125 mmol) was added to a solution of trans 4-hydroxy L-BOC-proline (9.67 g, 41.8 mmol) in DMSO (180 mL) at RT. The reaction mixture was stirred at RT for 30 min and cooled to 15° C. The product from step 3 (11.4 g, 41.8 mmol) was added to the reaction mixture as a solution in DMSO (45 mL); the reaction mixture was allowed to warm to RT and stirred for 30 min. The reaction mixture was quenched with ice-cold 10% citric acid solution and partitioned with EtOAc. The organic layer was washed with aqueous citric acid solution, water and brine, and the aqueous phases were back-extracted with EtOAc. The combined organic phases were dried over anhydrous Na2SO4, and the solvent was evaporated. LRMS ESI+ (M+H-tBu)+411.2.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([C:11]2[S:15][C:14]([NH2:16])=[N:13][C:12]=2[CH3:17])[CH:8]=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:18](OC(=O)C)(=[O:20])[CH3:19].CN(C)CCN(C)C1N=C(C2SC(NC(=O)C)=NC=2C)C=C(C)N=1>>[C:1]([C:5]1[N:10]=[C:9]([C:11]2[S:15][C:14]([NH:16][C:18](=[O:20])[CH3:19])=[N:13][C:12]=2[CH3:17])[CH:8]=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1nc(N)sc1-c1ccnc(C(C)(C)C)n1
Agent: CC(=O)Nc1nc(C)c(-c2cc(C)nc(N(C)CCN(C)C)n2)s1
Product: CC(=O)Nc1nc(C)c(-c2ccnc(C(C)(C)C)n2)s1

Procedure:
This material is prepared by acylating 5-(2-tert-Butyl-pyrimidin-4-yl)-4-methyl-thiazol-2-ylamine (Intermediate AG) with acetic anhydride as described for N-(5-{2-[(2-dimethylamino-ethyl)-methyl-amino]-6-methyl-pyrimidin-4-yl}-4-methyl-thiazol-2-yl)-acetamide (Example 39, step 2).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([NH:7][C:8]2[S:9][C:10]3[N:18]=[CH:17][CH:16]=[CH:15][C:11]=3[C:12](=[O:14])[N:13]=2)=[CH:5][CH:4]=1.[H-].[Li+].[CH2:23](I)[CH2:24][CH3:25]>>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([N:7]=[C:8]2[N:13]([CH2:23][CH2:24][CH3:25])[C:12](=[O:14])[C:11]3[CH:15]=[CH:16][CH:17]=[N:18][C:10]=3[S:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Nc2nc(=O)c3cccnc3s2)cc1
Reactant: CCCI
Agent: [H-]
Agent: [Li+]
Product: CCCn1c(=Nc2ccc(OC)cc2)sc2ncccc2c1=O

Procedure:
The reaction procedure of Example 11 was followed except that 428 mg of 2-(4-methoxyanilino)-4H-pyrido[3,2-e]-1,3-thiazin-4-one, 14 mg of lithium hydride and 0.15 ml of propyl iodide were used. As a result, 227 mg of 2-[(4-methoxyphenyl)imino]-3-propyl-2,3-dihydro-4H-pyrido[3,2-e]-1,3-thiazin-4-one was obtained as a low polarity substance, and 78 mg of 2-[N-(4-methoxyphenyl)-N-propylamino]-4H-pyrido[3,2-e]-1,3-thiazin-4-one was obtained as a high polarity substance.
Reaction SMILES: [C:1]([NH:5][Si:6](Cl)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:20][C:21]([CH:23]=[C:24]([CH3:26])[CH3:25])=[CH-:22].[K+]>C1COCC1>[C:1]([NH:5][Si:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:25][C:24]([CH3:26])=[CH:23][C:21]([CH3:22])=[CH2:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: [CH-]=C(C)C=C(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: C=C(C)C=C(C)C[Si](NC(C)(C)C)(c1ccccc1)c1ccccc1
Reaction time: 8 h

Procedure:
To a solution of 0.3238 g (1.12 mmol) of (N-t-butylamino)(chloro)diphenylsilane in 50 mL of THF was added 1.500 g (1.12 mmol) of potassium 2,4-dimethylpentadienide. The reaction mixture was stirred overnight. The solvent was removed, the residue was extracted with pentane and filtered. The pentane was removed in vacuo to give the product as a pale yellow oil. The yield was 0.3633 g 93.0%. 1H NMR (C6D6) δ 7.79 (m, 4H), 7.22 (m, 6H), 5.65 (s, 1H), 5.08 (s, 1H), 4.98 (s, 1H), 2.44 (s, 2H), 1.84 (s, 3H), 1.57 (s, 3H), 1.30 (s, 1H), 1.09(s, 9H), (s, 6H). 13C NMR(C6D6)δ 142.7, 138.5, 136.0, 135.8, 129.6, 128.0, 126.5, 113.7, 50.2, 33.9, 27.9, 25.1, 24.5
Reaction SMILES: FC1C=CC([C:8](C2C=CC(F)=CC=2)=[C:9](C2N(C(C)C)N=NN=2)[CH:10]=[O:11])=CC=1.[F:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([C:46]2[CH:51]=[CH:50][C:49]([F:52])=[CH:48][CH:47]=2)=[C:35]([C:38]2[N:39]=[N:40][N:41]([CH:43]([CH3:45])[CH3:44])[N:42]=2)C=O)=[CH:30][CH:29]=1>>[F:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([C:46]2[CH:51]=[CH:50][C:49]([F:52])=[CH:48][CH:47]=2)=[C:35]([C:38]2[N:39]=[N:40][N:41]([CH:43]([CH3:44])[CH3:45])[N:42]=2)[CH:8]=[CH:9][CH:10]=[O:11])=[CH:30][CH:29]=1
Reactant: CC(C)n1nnnc1C(C=O)=C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CC(C)n1nnc(C(C=O)=C(c2ccc(F)cc2)c2ccc(F)cc2)n1
Product: CC(C)n1nnc(C(C=CC=O)=C(c2ccc(F)cc2)c2ccc(F)cc2)n1
Yield: 82 %

Procedure:
The general procedure of Example 23, Step A was repeated, except that the 3,3-bis(4-fluorophenyl)-2-[1-(1-methylethyl)-1H-tetrazol-5-yl]-2-propenal utilized therein was replaced by 3,3-bis(4-fluorophenyl)-2-[2-(1-methylethyl)-2H-tetrazol-5-yl]-2-propenal and there was thereby produced mostly 5,5-bis(4-fluorophenyl)-4-[2-(1-methylethyl)-2H-tetrazol-5-yl]-2,4-pentadienal in 82% yield; MS (CI): m/e=381 for (M+H)+. This product was then subjected to the general procedure of Example 23, Step B and there was thereby produced ethyl 9,9-bis(4-fluorophenyl)-5-hydroxy-8-[2-(1-methylethyl)-2H-tetrazol-5-yl]-3-oxo-6,8-nonadienoate containing some inseparable ethyl 7,7-bis(4-fluorophenyl)-5-hydroxy-6-[2-(2-(1-methylethyl)-2H-tetrazol-5-yl]-3-oxo-6-heptenoate in 69.7% yield.
Reaction SMILES: CC1(C)[O:6][C:5](=[O:7])[CH:4]([CH:8]([CH2:12][CH2:13][CH2:14][CH3:15])[C:9]([OH:11])=O)[O:3]1.[NH:17]1[CH2:21][CH2:20][CH2:19][CH:18]1[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1>>[OH:3][C@@H:4]([C@H:8]([C:9]([N:17]1[CH2:21][CH2:20][CH2:19][CH:18]1[C:22]1[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=1)=[O:11])[CH2:12][CH2:13][CH2:14][CH3:15])[C:5]([OH:6])=[O:7]
Reactant: CCCCC(C(=O)O)C1OC(C)(C)OC1=O
Reactant: c1cc(C2CCCN2)ccn1
Product: CCCC[C@@H](C(=O)N1CCCC1c1ccncc1)[C@H](O)C(=O)O

Procedure:
The title compound is prepared from 2-(2,2-dimethyl-4-oxo-1,3-dioxolan-5-yl)hexanoic acid B-5 and commercially available 4-pyrrolidin-2-yl-pyridine A-5 according to General Procedure B.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([CH3:13])[CH:12]=2)[CH:7]=1.O.O.O.O.O.O.C(O[O-])(=O)C1C(=CC=CC=1)C([O-])=[O:24].[Mg+2]>CC(O)C>[Br:1][C:2]1[CH:3]=[N+:4]([O-:24])[CH:5]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([CH3:13])[CH:12]=2)[CH:7]=1
Reactant: O=C([O-])c1ccccc1C(=O)O[O-]
Reactant: Cn1cc(-c2cncc(Br)c2)cn1
Agent: [Mg+2]
Solvent: O
Solvent: CC(C)O
Product: Cn1cc(-c2cc(Br)c[n+]([O-])c2)cn1

Procedure:
A slurry of 266 mg (1.12 mmol) 3-bromo-5-(1-methyl-1H-pyrazol-4-yl)-pyridine and 1.30 g (2.23 mmol) magnesium monoperoxyphthalate hexahydrate (85%) in 5 ml 2-propanol was stirred for 18 hours at room temperature. The reaction mixture was evaporated and the residue partitioned between saturated sodium bicarbonate solution and dichloromethane. The organic phase was dried over sodium sulfate and evaporated yielding 3-bromo-5-(1-methyl-1H-pyrazol-4-yl)-pyridine 1-oxide as slightly yellow solid; HPLC-MS: 1.34 min, [M+H] 254/256.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=1.[F:18][C:19]1[N:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[F:18][C:19]1[N:24]=[CH:23][C:22]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=2)=[CH:21][CH:20]=1
Reactant: OB(O)c1ccc(F)nc1
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCNC1=O
Product: N#Cc1cc(-c2ccc(F)nc2)c2c(c1)cc1n2CCNC1=O

Procedure:
The title compound, off-white solid (68 mg, 89%), MS (ISP) m/z=307.4 [(M+H)+], mp 268° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 15) (72.5 mg, 0.25 mmol) and commercially available 6-fluoro-pyridin-3-ylboronic acid (45.8 mg, 0.325 mmol).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][N:5]=1.Cl[CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19]>CN(C=O)C>[Cl:3][C:4]1[N:5]=[CH:6][C:7]2[CH:8]=[CH:9][N:10]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:11]=2[CH:12]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Clc1cc2[nH]ccc2cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1ccc2cnc(Cl)cc21
Reaction time: 1 h
Yield: 81.4 %

Procedure:
Sodium hydride (60%, 1.40 g, 35.0 mmol) was added in portions over 20 min to a solution of 6-chloro-5-aza-indole (4.45 g, 29.1 mmol) in DMF (17.2 mL) at 0° C. (ice bath). The mixture was stirred for 1 h. (2-Chloromethoxy-ethyl)-trimethyl-silane (5.83 g, 35.0 mmol) was then added over 15 min. After stirring for 1 h, the reaction was quenched with water (100 mL) and the mixture extracted with DCM (3×100 mL). The combined organic extracts were washed with brine (3×300 mL), dried over Na2SO4, filtered and concentrated. Chromatography on silica gel (gradient elution, 0-100%, EtOAc/petrol 40-60° C.), gave the title compound (6.7 g, 82%) as a yellow oil. 1H NMR (Me-d3-OD): 8.61 (1H, s), 7.63 (1H, s), 7.50 (1H, d), 6.71 (1H, d), 5.57 (2H, s), 3.53 (2H, t), 0.88 (2H, t), −0.04-0.16 (9H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[CH3:12][N:13]([CH3:16])[CH:14]=O>>[Cl:1][C:2]1[CH:7]=[C:6](/[CH:8]=[CH:12]/[N:13]([CH3:16])[CH3:14])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: CN(C)C=O
Reactant: Cc1cc(Cl)ncc1[N+](=O)[O-]
Product: CN(C)/C=C/c1cc(Cl)ncc1[N+](=O)[O-]
Yield: 70 %

Procedure:
A solution of 2-chloro-4-methyl-5-nitropyridine (1.0 equiv), 25.2 mL dimethylacetal dimethylformamide (2.2 equiv.) in dimethylformamide (0.8 M) was heated at 95° C. for 18 hours. Upon cooling the volatiles were removed in vacuo. The crude material was recrystallized from boiling methanol to yield (E)-2-(2-chloro-5-nitropyridin-4-yl)-N,N-dimethylethenamine (70%) as a red solid. 1H NMR (CDCl3): δ 8.80 (s, 1H), 7.32 (d, J=13.2, 1H), 7.25 (s, 1H), 5.95 (d, J=13.2, 1H), 3.02 (bs, 6H).
Reaction SMILES: [OH:1][CH:2]([CH2:16][NH:17][CH:18]([CH3:20])[CH3:19])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14]C)=[O:13])=[CH:7][CH:6]=1.[ClH:21]>>[ClH:21].[OH:1][CH:2]([CH2:16][NH:17][CH:18]([CH3:20])[CH3:19])[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][C:12]([OH:14])=[O:13])=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1ccc(OCC(O)CNC(C)C)cc1
Agent: Cl
Product: CC(C)NCC(O)COc1ccc(CC(=O)O)cc1

Procedure:
A solution of methyl 4-[2-hydroxy-3-[(1-methylethyl)amino]-propoxy]phenylacetate (563 mg, 2.00 mmol) in 6 M hydrochloric acid (15 ml) was heated at 100° C. for 4h. The reaction mixture was concentrated (rotavapor) and the residue was taken up in water and lyophilised. 1H and 13C NMR spectra were in accordance with the strucure and MALDI mass spectrometry gave a M+H at 268 as expected.