Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.[OH:18][CH2:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>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.ClCCl.C(#N)C>[C:14]1([CH3:17])[CH:15]=[CH:16][C:11]([C:9]2[N:10]=[C:5]3[CH:4]=[CH:3][C:2]([C:24]4[CH:25]=[C:20]([CH2:19][OH:18])[CH:21]=[CH:22][CH:23]=4)=[CH:7][N:6]3[CH:8]=2)=[CH:12][CH:13]=1
Reactant: Cc1ccc(-c2cn3cc(Br)ccc3n2)cc1
Reactant: OCc1cccc(B(O)O)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: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CC#N
Product: Cc1ccc(-c2cn3cc(-c4cccc(CO)c4)ccc3n2)cc1
Yield: 45.7 %

Procedure:
Under a stream of nitrogen, 200 mg of 6-bromo-2-p-tolylimidazo[1,2-a]pyridine, 160 mg of 3-(hydroxymethyl)phenylboronic acid and 24 mg of tetrakis(triphenylphosphine)palladium are placed in a microwave tube containing 2 ml of toluene degassed beforehand under a stream of nitrogen, 2 ml of acetonitrile and 2 ml of a 2M solution of sodium carbonate. The tube is placed in a microwave apparatus and irradiated at 150° C. for 15 min. The organic phase is separated and dried and the filtrate is concentrated under reduced pressure. The residue obtained is taken up with 6 ml of dichloromethane. The precipitate is recovered by filtration, washed with dichloromethane and dried in a desiccator under reduced pressure. 100 mg of compound are obtained. Mp=171-173° C. 1H NMR (DMSO-d6, δ in ppm): 2.32 (s, 3H); 4.57 (d, J=5.6 Hz, 2H); 5.23 (t, J=5.7 Hz, 1H); from 7.19 to 7.67 (m, 8H); 7.84 (d, J=8 Hz, 2H); 8.32 (s, 1H); 8.82 (m, 1H). M+H=315.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:11]([O:13][C:14]([CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1)=[O:15])[CH3:12].[CH3:29]I>C1COCC1>[CH2:11]([O:13][C:14]([C:16]1([CH3:29])[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[CH2:18][CH2:17]1)=[O:15])[CH3:12]
Reactant: CI
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(C)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
A solution of NaHMDS (2M in THF, 148 mmol, 74 mL, diluted to 100 mL) is cooled at −78° C. and a solution of piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (25.74 g, 100 mmol) in THF (50 mL of solution) is added slowly. The mixture is stirred for 2 h at −78° C. Methyliodide (7.5 mL, 120 mmol) is dissolved in THF (60 mL) and the cold solution of enolate is added. The mixture is stirred at r.t. for 1 h and quenched with HCl (1M, 75 mL) and ether (200 mL). the phases are separated and the organic phase washed with HCl (1M, 2×50 mL) and NaOH (1M, 2×50 mL). The organic phase is dried (Na2SO4), filtered and evaporated to provide the crude title compound.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][CH2:16][CH:8]3[C:7](=[O:17])[NH:6][C:5]=2[CH:4]=1.[I-].C(C[P+](C)(C)C)#N.C(N(C(C)C)C(C)C)C.Cl.[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([N:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)=[CH:39][CH:38]=1>C(#N)CC.O>[Cl:36][C:37]1[CH:38]=[CH:39][C:40]([N:43]2[CH2:48][CH2:47][N:46]([CH2:2][C:3]3[CH:12]=[N:11][C:10]4[N:9]5[CH2:13][CH2:14][CH2:15][CH2:16][CH:8]5[C:7](=[O:17])[NH:6][C:5]=4[CH:4]=3)[CH2:45][CH2:44]2)=[CH:41][CH:42]=1
Reactant: Clc1ccc(N2CCNCC2)cc1
Reactant: O=C1Nc2cc(CO)cnc2N2CCCCC12
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CCC#N
Product: O=C1Nc2cc(CN3CCN(c4ccc(Cl)cc4)CC3)cnc2N2CCCCC12
Temperature: 90 °C
Reaction time: 2 h
Yield: 41.4 %

Procedure:
3-(hydroxymethyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one (100 mg, 0.43 mmol) was suspended in propionitrile (1 mL) and (cyanomethyl)trimethylphosphonium iodide (103 mg, 0.41 mmol) was added followed by N-ethyl-N-isopropylpropan-2-amine (180 ul, 1.03 mmol). To the stirred mixture was then added 1-(4-chlorophenyl)piperazine hydrochloride (94.0 mg, 0.41 mmol). The reaction was heated to 90° C. with stirring for 2 h. The reaction was then cooled to room temperature and diluted with water (3 mL) and filtered. The solids were collected and refluxed in ethanol (5 mL) for 1 h. The suspension was cooled back to room temperature and filtered. The solids were collected to afford the title compound (69.9 mg, 39%) as a white solid. 1H NMR (DMSO-d6) δ (ppm): 10.47 (s, 1H), 7.65 (d, J=1.8 Hz, 1H), 7.21 (d, J=9.1 Hz, 2H), 6.97 (d, J=1.8 Hz, 1H), 6.92 (d, J=9.1 Hz, 2H), 4.50 (d, J=12.9 Hz, 1H), 3.83 (dd, J=11.2, 2.7 Hz, 1H), 3.34 (d, J=5.6 Hz, 2H), 3.01-3.17 (m, 4H), 2.55-2.65 (m, 1H), 2.37-2.48 (m, 4H), 1.98-2.08 (m, 1H), 1.85 (d, J=12.4 Hz, 1H), 1.63 (d, J=12.6 Hz, 1H), 1.32-1.56 (m, 3H). [M+H] calc'd for C22H26ClN5O, 412; found, 412.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([OH:21])[CH2:9][N:10]([CH2:18][CH2:19]O)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:4][CH:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O>C1COCC1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]2[O:21][CH2:19][CH2:18][N:10]([C:11]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:17])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N(CCO)CC(O)c1ccc(Cl)nc1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCOC(c2ccc(Cl)nc2)C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 26.3 %

Procedure:
To a stirred solution of tert-butyl (RS)-2-(6-chloropyridin-3-yl)-2-hydroxyethyl(2-hydroxyethyl)carbamate (4.68 g) and triethylamine (3.5 ml) in THF (50 ml) at 0-5° C. was added dropwise methanesulfonyl chloride (1.84 ml). The reaction mixture was then stirred at room temperature for 2.5 hours to afford a yellow suspension. The reaction mixture was then filtered to remove triethylamine hydrochloride, washing the filter with THF (10 ml). The filtrate was cooled to 0-5° C. and potassium 2-methyl-2-butoxide (15.6 ml, 1.7 M solution in toluene) was added. The reaction mixture was stirred at room temperature for 15 min and then poured into EtOAc and washed sequentially with water and with saturated brine. The organic phase was dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel; gradient: 0% to 70% EtOAc in hexanes) to afford tert-butyl (RS)-2-(6-chloropyridin-3-yl)morpholine-4-carboxylate (1.16 g, 26%) as a yellow solid. MS (ISP): 301.2 ([{37Cl}M+H]+), 299.1 ([{35Cl}M+H]+), 245.2 ([{37Cl}M+H—C4H8]+), 243.2 ([{35Cl}M+H—C4H8]+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[NH2:16][C:17]([CH3:23])([CH2:20][CH2:21][CH3:22])[CH2:18][OH:19]>>[OH:19][CH2:18][C:17]([NH:16][C:8]([C:5]1[CH:4]=[C:3]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)[C:2]([Cl:1])=[CH:7][N:6]=1)=[O:10])([CH3:23])[CH2:20][CH2:21][CH3:22]
Reactant: O=C(O)c1cc(OCC2CC2)c(Cl)cn1
Reactant: CCCC(C)(N)CO
Product: CCCC(C)(CO)NC(=O)c1cc(OCC2CC2)c(Cl)cn1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-chloro-4-cyclopropylmethoxy-pyridine-2-carboxylic acid and 2-amino-2-methyl-1-pentanol (CAN 13893-61-3) as starting materials and isolated (21 mg, 71%) as colorless oil; MS (ESI, m/z): 327.2 (MH+).
Reaction SMILES: [BH4-].[Na+].[CH:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([NH2:16])(=[O:15])=[O:14])=[CH:9][C:8]=1[N+:17]([O-])=O)([CH3:5])[CH3:4].O>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[NH2:17][C:8]1[CH:9]=[C:10]([S:13]([NH2:16])(=[O:14])=[O:15])[CH:11]=[CH:12][C:7]=1[O:6][CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)Oc1ccc(S(N)(=O)=O)cc1[N+](=O)[O-]
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)Oc1ccc(S(N)(=O)=O)cc1N
Temperature: 23 °C
Reaction time: 0.5 h

Procedure:
Sodium borohydride (1.88 g, 49.6 mmol) was added slowly to a solution of nickel (II) chloride hexahydrate (3.93 g, 16.5 mmol) in methanol (60 mL) at 0° C. and the resulting black suspension was stirred for 30 min at 23° C. The mixture was cooled to 0° C. and 4-isopropoxy-3-nitro-benzenesulfonamide (8.6 g, 33.0 mmol, example 2, step c) was added followed by sodium borohydride (4.38 g, 115.6 mmol). The resulting black suspension was stirred for 30 min at 23° C. Water was added to the reaction mixture to quench excess NaBH4, followed by addition of saturated aqueous NaHCO3. The product was extracted with dichloromethane and the organic phase was washed with brine, dried with Na2SO4 and evaporated to give the title compound.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].Cl.[NH2:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]=1[OH:18].C(=O)([O-])[O-].[Ca+2]>O1CCOCC1>[Cl:1][CH2:2][C:3]([NH:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]=1[OH:18])=[O:4]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccc2ccccc2c1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: C1COCCO1
Product: O=C(CCl)Nc1ccc2ccccc2c1O
Temperature: 15 °C
Yield: 59.8 %

Procedure:
2 ml of chloroacetyl chloride (25.4 mmol) were added dropwise to a suspension of 5 g of 2-amino-1-naphthol hydrochloride (25.4 mmol) and 5.08 g of calcium carbonate in 200 ml of dioxane, with stirring and under an inert atmosphere. The reaction medium was stirred at 40° C. for 1 hour 30 minutes, cooled to 15° C., filtered on sintered glass and the inorganic salts were rinsed twice with ethyl acetate. The combined organic phases were concentrated until an insoluble product appeared. The concentrate was poured over 250 ml of ice-cold water. The precipitate formed was drained, washed with water and dried under vacuum to a constant weight to give 3.58 g of 2-chloro-N-(1-hydroxynaphthalen-2-yl)acetamide in the form of a beige powder with a yield of 60%.
Reaction SMILES: [CH3:1][O:2][P:3]([CH2:6][CH2:7][CH2:8][C:9]1([CH3:28])[CH2:18][CH2:17][C:16]2[C:11](=[C:12]3[CH:26]4[CH2:27][CH:23]([CH2:24][CH2:25]4)[C:13]3=[C:14]([O:19]COC)[CH:15]=2)[O:10]1)(=[O:5])[OH:4].[CH3:29]O>Cl>[CH3:29][O:4][P:3]([CH2:6][CH2:7][CH2:8][C:9]1([CH3:28])[CH2:18][CH2:17][C:16]2[C:11](=[C:12]3[CH:26]4[CH2:27][CH:23]([CH2:24][CH2:25]4)[C:13]3=[C:14]([OH:19])[CH:15]=2)[O:10]1)(=[O:5])[O:2][CH3:1]
Reactant: COCOc1cc2c(c3c1C1CCC3C1)OC(C)(CCCP(=O)(O)OC)CC2
Reactant: CO
Agent: Cl
Product: COP(=O)(CCCC1(C)CCc2cc(O)c3c(c2O1)C1CCC3C1)OC

Procedure:
190 mg of 6-methoxymethoxy-dimethyl phosphonate derivative from Step 3 was treated with a mixture of 20 mL of MeOH and 20 drops of concentrate HCl for overnight. After removal of most of the solvent, ethyl acetate was added and then washed with water, and dried over MgSO4. After the removal of solvents the residue was purified by flash column chromatography on silica gel (10% MeOH/DCM) to afford 90 mg of [3-(6-hydroxy-2-methyl-3,4,7,8,9,10-hexahydro-7,10-methano-2H-benzo[h]chromen-2-yl)-propyl]-phosphonic acid dimethyl ester. 1H-NMR (300 MHz, CDCl3) δ (ppm): 6.38 (s, 1H), 5.323 (s, 1H), 3.72-3.82 (m, 6H) 3.50-3.54 (m, 2H), 2.62-2.68 (m, 4H), 1.70-1.84 (m, 12H), 1.22-1.28 (s, 3H)
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]2[N:9]([C:10]3[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[CH3:18])[CH2:8][CH2:7][N:6]2[C:19]=1[C:20]([CH2:24][CH2:25][CH3:26])=[CH:21][CH2:22][CH3:23])[CH3:2].B.C1COCC1.C(O)(=O)C.CO>O1CCCC1>[CH2:1]([C:3]1[N:4]=[C:5]2[N:9]([C:10]3[C:11]([CH3:18])=[CH:12][C:13]([CH3:17])=[CH:14][C:15]=3[CH3:16])[CH2:8][CH2:7][N:6]2[C:19]=1[CH:20]([CH2:21][CH2:22][CH3:23])[CH2:24][CH2:25][CH3:26])[CH3:2]
Reactant: CCC=C(CCC)c1c(CC)nc2n1CCN2c1c(C)cc(C)cc1C
Agent: B
Solvent: CO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCCC(CCC)c1c(CC)nc2n1CCN2c1c(C)cc(C)cc1C
Temperature: 0 °C

Procedure:
6-Ethyl-5-(1-propyl-but-1-enyl)-1-(2,4,6-trimethyl-phenyl)-2,3-dihydro-1H-imidazo[1,2-a]imidazole (0.013 g, 0.000037 mol) in anhydrous tetrahydrofuran was treated with cold BH3-THF (0.15 mL 1.0M in tetrahydrofuran), and the mixture was heated at reflux for 1.5 h. The mixture was cooled to 0° C., treated with glacial acetic acid (0.25 mL), heated at reflux for 1.5 h, re-cooled to 0° C., treated with 1.5 mL methanol, and heated again at reflux for 1 h. Upon cooling to room temperature, the reaction mixture was concentrated under reduced pressure, and the residue was partitioned between 2.5 N NaOH and ether. The organic phase was washed with water and brine, and was then dried over anhydrous Na2SO4 and evaporated to give a pale yellow oil. The crude product was chromatographed on silica, eluting with 15% ethyl acetate /hexanes to give a glassy solid. LC/MS: tR=1.81 min., (MH+)=354.30.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:21])=[C:16](F)[C:17]=2[F:19])[C:12](=[O:22])[C:11]([C:23]([OH:25])=[O:24])=[CH:10]1.[CH2:26]([NH:28][CH2:29][CH2:30][CH:31]1[O:36][CH2:35][CH2:34][NH:33][CH2:32]1)[CH3:27]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:21])=[C:16]([N:33]3[CH2:34][CH2:35][O:36][CH:31]([CH2:30][CH2:29][NH:28][CH2:26][CH3:27])[CH2:32]3)[C:17]=2[F:19])[C:12](=[O:22])[C:11]([C:23]([OH:25])=[O:24])=[CH:10]1
Reactant: CCNCCC1CNCCO1
Reactant: O=C(O)c1cn(-c2ccc(F)cc2F)c2c(F)c(F)c(F)cc2c1=O
Product: CCNCCC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(-c4ccc(F)cc4F)c3c2F)CCO1

Procedure:
By the use of 1-(2,4-difluorophenyl)-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 2-(2ethylaminoethyl)morpholine, the reaction is similarly carried out as Example 26 to give 1-(2,4-difluorophenyl)-7-[2-(2ethylaminoethyl)morpholino]-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1)=O.[N:13]1[NH:14][C:15](=[O:19])[CH:16]=CC=1>>[O:19]=[C:15]1[NH:14][N:13]=[C:2]([C:4]2[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=2)[CH:1]=[CH:16]1
Reactant: O=c1cccn[nH]1
Reactant: CC(=O)c1ccc([N+](=O)[O-])cc1
Product: O=c1ccc(-c2ccc([N+](=O)[O-])cc2)n[nH]1

Procedure:
15 g of 4-nitroacetophenone are converted into the pyridazinone in accordance with with GWP 1.
Reaction SMILES: [CH3:1][N:2]1[N:6]=[N:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][N:14]3[CH2:19][CH2:18][C:17](=[O:20])[CH2:16][CH2:15]3)=[CH:9][CH:8]=2)=[N:3]1.[C-:21]#[N:22].[Na+].Cl.C(OCC)(=O)C>CCOCC.O>[OH:20][C:17]1([C:21]#[N:22])[CH2:18][CH2:19][N:14]([CH2:13][C:10]2[CH:9]=[CH:8][C:7]([C:4]3[N:5]=[N:6][N:2]([CH3:1])[N:3]=3)=[CH:12][CH:11]=2)[CH2:15][CH2:16]1
Reactant: Cn1nnc(-c2ccc(CN3CCC(=O)CC3)cc2)n1
Reactant: [C-]#N
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCOCC
Product: Cn1nnc(-c2ccc(CN3CCC(O)(C#N)CC3)cc2)n1
Temperature: 10 °C
Reaction time: 1.5 h
Yield: 100.6 %

Procedure:
A stirred solution of 8.62 grams (0.032 mole) of 1-{[4-(2-methyl-1,2,3,4-tetrazol-5-yl)phenyl]methyl}piperidin-4-one in 100 mL of ether and 150 mL of water was cooled to about 10° C. and 3.9 grams (2.5 equivalents) of sodium cyanide was added in one portion. To this was added 6.6 mL (2.5 equivalents) of hydrochloric acid (12 M) dropwise while maintaining the reaction mixture temperature at about 10° C. Upon completion of the addition, the reaction mixture was stirred for 1.5 hours while warming to ambient temperature. The reaction mixture was then poured into 200 mL of water, to which was then added 200 mL of ethyl acetate. The organic layer was separated and concentrated under reduced pressure to yield 9.6 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]2=[N:6][N:7]([C:9]3[CH:10]=[C:11]([CH:17]=[C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:19]=3[OH:20])[CH2:12][CH2:13][C:14]([OH:16])=[O:15])[N:8]=[C:4]2[CH:3]=1.[N+:27]([C:30]1[CH:47]=[C:46]([Cl:48])[CH:45]=[CH:44][C:31]=1[O:32][N:33]1[C:38]([CH3:40])([CH3:39])[CH2:37][CH:36](O)[CH2:35][C:34]1([CH3:43])[CH3:42])([O-:29])=[O:28]>>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]2=[N:6][N:7]([C:9]3[CH:10]=[C:11]([CH:17]=[C:18]([C:21]([CH3:22])([CH3:23])[CH3:24])[C:19]=3[OH:20])[CH2:12][CH2:13][C:14]([O:16][CH:36]3[CH2:35][C:34]([CH3:43])([CH3:42])[N:33]([O:32][C:31]4[CH:44]=[CH:45][C:46]([Cl:48])=[CH:47][C:30]=4[N+:27]([O-:29])=[O:28])[C:38]([CH3:40])([CH3:39])[CH2:37]3)=[O:15])[N:8]=[C:4]2[CH:3]=1
Reactant: CC1(C)CC(O)CC(C)(C)N1Oc1ccc(Cl)cc1[N+](=O)[O-]
Reactant: CC(C)(C)c1cc(CCC(=O)O)cc(-n2nc3ccc(Cl)cc3n2)c1O
Product: CC(C)(C)c1cc(CCC(=O)OC2CC(C)(C)N(Oc3ccc(Cl)cc3[N+](=O)[O-])C(C)(C)C2)cc(-n2nc3ccc(Cl)cc3n2)c1O

Procedure:
The title compound is prepared according to the procedure of Example 3 using 3-(5-chlorobenzotriazol-2-yl)-5-tert-butyl-4-hydroxyhydrocinnamic acid and 1-(2-nitro-4-chloro-phenoxy)-2,2,6,6-tetramethyl-4-hydroxypiperidine.
Reaction SMILES: C1N2CN3CN(C2)CN1C3.[C:11]([OH:14])(=O)[CH3:12].[NH:15]1[C:19]2=[N:20][CH:21]=[CH:22][CH:23]=[C:18]2C=[CH:16]1>O>[NH:15]1[C:19]2=[N:20][CH:21]=[CH:22][CH:23]=[C:18]2[C:12]([CH:11]=[O:14])=[CH:16]1
Reactant: c1cnc2[nH]ccc2c1
Reactant: CC(=O)O
Agent: C1N2CN3CN1CN(C2)C3
Solvent: O
Product: O=Cc1c[nH]c2ncccc12
Temperature: 120 °C
Reaction time: 3 h

Procedure:
Hexamethylenetetramine (9.63 g) and acetic acid (20 ml) were added to a suspension of 1H-pyrrolo[2,3-b]pyridine (5.91 g) in water (40 ml) and it was stirred at 120° C. for 3 hours. The reaction mixture was cooled to room temperature, water (120 ml) was added and the mixture was stirred at room temperature for an hour. The precipitated crystalline was collected to give 1H-pyrrolo[2,3-b]pyridin-3-carbaldehyde (4.85 g) as a colorless powder.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@@H:2]([C:10]([NH:12][C@H:13]([C:24]([OH:26])=[O:25])[CH2:14][S:15][CH2:16][C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O.C(OCC)C.[ClH:40]>C(O)(C(F)(F)F)=O.C(OCC)C>[NH2:1][C@@H:2]([C:10]([NH:12][C@H:13]([C:24]([OH:26])=[O:25])[CH2:14][S:15][CH2:16][C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1.[ClH:40]
Reactant: Cc1ccc(CSC[C@H](NC(=O)[C@@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)cc1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CCOCC
Product: Cc1ccc(CSC[C@H](NC(=O)[C@H](N)Cc2ccccc2)C(=O)O)cc1
Reaction time: 0.75 h

Procedure:
5 g BOC-(D)Phe-Cys(MBzl)-OH are dissolved in 80 ml TFA and 10 ml H2O and allowed to stand for 45 minutes at room-temperature. The solution is diluted with ethyl-ether and 20 ml ethyl-ether/HCl (~5 N) are added, and the precipitate is filtered off, washed with ethyl ether and dried to yield the title compound:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[CH:9](=[O:12])[CH2:10][CH3:11].N1C=CC=CC=1C(O)CCC>>[Br:8][C:4]1[N:3]=[C:2]([CH:9]([OH:12])[CH2:10][CH3:11])[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(Br)n1
Reactant: CCC=O
Agent: CCCC(O)c1ccccn1
Product: CCC(O)c1cccc(Br)n1

Procedure:
The title compound was prepared from 2,6-dibromopyridine (purchased from Sigma-Aldrich, St. Louis, Mo.) and propionaldehyde following a procedure similar to the one described above for the synthesis of 1-(pyridin-2-yl)butan-1-ol (Example 231, step A). Mass Spectrum (ESI) m/z=219.9 and 217.9 (M+1).
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C[C:25]([O-:28])(C)C.[K+].[Cl:30][C:31]1[CH:32]=[CH:33][C:34]([N+:39]([O-:41])=[O:40])=[C:35]([CH:38]=1)[CH:36]=O.Cl>O1CCCC1.CO.O1CCOCC1>[Cl:30][C:31]1[CH:32]=[CH:33][C:34]([N+:39]([O-:41])=[O:40])=[C:35]([CH2:36][CH:4]([O:28][CH3:25])[O:3][CH3:2])[CH:38]=1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)[O-]
Agent: Cl
Agent: [Cl-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: CO
Product: COC(Cc1cc(Cl)ccc1[N+](=O)[O-])OC
Temperature: 25 °C
Yield: 19.3 %

Procedure:
Slurry (methoxymethyl)triphenylphosphonium chloride (32.3 g, 93.7 mmol) in tetrahydrofuran (350 ml) and cool in an ice-water bath. Add 1.0M KOtBu (94 ml, 94 mmol) in tetrahydrofuran solution to the reaction dropwise via an addition funnel. Stir reaction for one hour, then add 5-chloro-2-nitrobenzaldehyde (14.5 g, 78.1 mmol) dropwise as a solution in 100 ml tetrahydrofuran. Continue to stir in the ice bath for 20 minutes, then let warm to ambient temperature. Quench with 0.1 N HCl, extract with ethyl acetate, wash organics with water and brine. Dry with sodium sulfate, filter, concentrate to a brown oil. Purify by flash chromatography (1% EtOAc:Hexanes) to give a crude mix of three spots. Dissolve the crude oil in methanol (200 ml), cool in an ice bath, add 4N HCl in dioxane (30 ml), stir overnight, warming to ambient temperature. Concentrate to brown oil. Purify by flash chromatography, elute with hexanes to 3% EtOAc:hexanes gradient. Yields the title compound (3.7 g, 15.1 mmol, 19%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH:11]2[NH:17][C:16](=[O:18])[C:15]3[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=3[N:13]3[C:23](=[O:31])[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=4[N:30]=[C:12]23)=[CH:2]1.C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[OH2:18].[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]([CH2:10][CH:11]2[NH:17][C:16](=[O:18])[C:15]3[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=3[N:13]3[C:23](=[O:31])[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=4[N:30]=[C:12]23)[CH2:2]1.[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]([CH2:10][CH:11]2[NH:17][C:16](=[O:18])[C:15]3[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=3[N:13]3[C:23](=[O:31])[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=4[N:30]=[C:12]23)[CH2:2]1
Reactant: O=C1NC(Cc2c[nH]c3ccccc23)c2nc3ccccc3c(=O)n2-c2ccccc21
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: O
Product: O=C1NC(CC2CNc3ccccc32)c2nc3ccccc3c(=O)n2-c2ccccc21
Reaction time: 1 h
Yield: 123.7 %

Procedure:
7-[(1H-Indol-3-yl)methyl]quinazolino(3,2-A)-1,4-benzodiazepin-5,13-(6H,7H)-dione (250 mg, 0.61 mmole) was dissolved in 2 ml of trifluoroacetic acid and treated in one portion with 106 μl (0.67 mmole) of triethylsilane under nitrogen. After 1 hour, 1 mmole more of triethylsilane was added and rapid stirring was continued overnight. Solvent and excess reagent were removed under reduced pressure and the residue partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic phase was washed with sodium bicarbonate solution and brine, then dried and concentrated. The resulting residue was purified by thick layer silica gel chromatography (9:1 ethyl acetate-hexane v/v) to give a white solid (yield 210 mg) as a mixture of diastereomers (approximately 58:42 HPLC). PMR (360 MHz, CD3OD): spectrum confirms structure assignment.
Reaction SMILES: [Cl:1][C:2]1[NH:7][C:6]([N:12]2[CH2:17][CH2:16][CH:15]([NH:18][C:19]([C:21]3[NH:22][C:23]([CH3:28])=[C:24]([Cl:27])[C:25]=3[Cl:26])=[O:20])[CH2:14][CH2:13]2)(C(OC)=O)[CH:5]=[CH:4][N:3]=1.[NH2:29]N.C[N:32]([CH:34]=[O:35])C>>[Cl:26][C:25]1[C:24]([Cl:27])=[C:23]([CH3:28])[NH:22][C:21]=1[C:19]([NH:18][CH:15]1[CH2:16][CH2:17][N:12]([C:6]2[CH:5]=[C:4]([C:34]([NH:32][NH2:29])=[O:35])[N:3]=[C:2]([Cl:1])[N:7]=2)[CH2:13][CH2:14]1)=[O:20]
Reactant: CN(C)C=O
Reactant: COC(=O)C1(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)C=CN=C(Cl)N1
Reactant: NN
Product: Cc1[nH]c(C(=O)NC2CCN(c3cc(C(=O)NN)nc(Cl)n3)CC2)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Methyl 2-chloro-6-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)pyrimidine-4-carboxylate (Example 6) (500 mg, 1.12 mmol), hydrazine (0.035 ml, 1.12 mmol), and TEA (0.16 ml, 1.12 mmol) were combined in DMF (3 ml) and stirred at room temperature. Within 1.5 h, a white precipitate had formed. The reaction was stirred for another 30 minutes, and then the precipitate was collected by suction filtration to give 377 mg of the title compound. 100 mg of the crude material was purified by preparatory HPLC, using a gradient of 40-70% acetonitrile/water (0.1% TFA) over 14 minutes to give 23 mg of the title compound.