Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC([O-])(C)C.[K+].Br[CH:8]([C:11]1([CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:16][CH2:15][CH:14]([CH:17]2[CH2:22][CH2:21][CH:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:19][CH2:18]2)[CH2:13][CH2:12]1)[CH2:9]Br.O.Cl>C(O)(C)(C)C>[C:8]([C:11]1([CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:12][CH2:13][CH:14]([CH:17]2[CH2:22][CH2:21][CH:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:19][CH2:18]2)[CH2:15][CH2:16]1)#[CH:9]
Reactant: CCCCCC1CCC(C2CCC(CCCCC)(C(Br)CBr)CC2)CC1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: C#CC1(CCCCC)CCC(C2CCC(CCCCC)CC2)CC1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
32.48 g of KOtBu are added at RT to 47.50 g of 4-(1,2-dibromoethyl)-4,4′-dipentylbicyclohexyl in 150 ml of tert-butanol. The mixture is heated to 60° C. and stirred at this temperature overnight. Water is subsequently added to the reaction mixture, which is acidified with dilute hydrochloric acid and subjected to conventional work-up, giving 4-ethynyl-4,4′-dipentylbicyclohexyl.
Reaction SMILES: [C:1]1([CH:7]2[O:12][C:11]3[CH:13]=[CH:14][C:15]([O:17][C:18]4[CH:23]=[CH:22][C:21]([N+]([O-])=O)=[CH:20][N:19]=4)=[CH:16][C:10]=3[O:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C2OC3C=CC(O)=CC=3OC2)C=CC=CC=1.ClC1C=CC([C:51]([F:54])([F:53])[F:52])=CN=1>>[C:1]1([CH:7]2[O:12][C:11]3[CH:13]=[CH:14][C:15]([O:17][C:18]4[CH:23]=[CH:22][C:21]([C:51]([F:54])([F:53])[F:52])=[CH:20][N:19]=4)=[CH:16][C:10]=3[O:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)OCC(c2ccccc2)O3)nc1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: Oc1ccc2c(c1)OCC(c1ccccc1)O2
Product: FC(F)(F)c1ccc(Oc2ccc3c(c2)OCC(c2ccccc2)O3)nc1

Procedure:
2-(2,3-Dihydro-2-phenyl-benzo[1,4]dioxin-6-yloxy)5-trifluoromethylpyridine was prepared in the same way as 2-(2,3-dihydro-2-phenyl-benzo[1,4]dioxin-6-yloxy)-5-nitropyridine above from 2,3-dihydro-2-phenyl-benzo[1,4]dioxin-6-ol (80 mg) and 2-chloro-5-(trifluoromethyl)pyridine (64 mg). Yield is 50 mg and mp 104-110° C. 1H NMR (DMSO-d6) δ=4.15 (dd, J=8.3, 11.4Hz, 1H), 4.46 (dd, J=2.3, 11.4 Hz, 1H), 5.27 (dd, J=2.3, 8.3 Hz, 1H), 6.72 (dd, J=2.8, 8.8 Hz, 1H), 6.84 (d, J=2.8 Hz, 1H), 7.03 (d, J=8.8 Hz, 1H), 7.19 (d, J=8.8 Hz, 1H), 7.39-7.52 (m, 5H), 8.20 (dd, J=8.8, 2.6 Hz, 1H), 8.58 (d, J=2.6 Hz, 1H).
Reaction SMILES: [C:1](=O)([O:3]C(C)(C)C)N.[NH2:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:15]=1[C:16]#[N:17].[F:18][C:19]1[CH:28]=[CH:27][CH:26]=[CH:25][C:20]=1[C:21]([NH:23][NH2:24])=O>>[F:18][C:19]1[CH:28]=[CH:27][CH:26]=[CH:25][C:20]=1[C:21]1[N:17]=[C:16]2[N:24]([C:1](=[O:3])[NH:9][C:10]3[CH:11]=[N:12][CH:13]=[CH:14][C:15]=32)[N:23]=1
Reactant: CC(C)(C)OC(N)=O
Reactant: N#Cc1ccncc1N
Reactant: NNC(=O)c1ccccc1F
Product: O=c1[nH]c2cnccc2c2nc(-c3ccccc3F)nn12
Yield: 78 %

Procedure:
When the tert-butyl carbamate of 3-amino-4-cyanopyridine replaces the urethane described in Example 37 and o-fluorobenzhydrazide replaces 2-furoylhydrazine in the same example, 2-(2-fluorophenyl)-pyrido[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)one is obtained in 78% yield, m.p. 324°-326°. It is purified as the membrane sulphonate salt, m.p. 285° to 287°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:11]2([CH2:14][CH:13]([OH:15])[CH2:12]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:18][S:19](Cl)(=[O:21])=[O:20]>O1CCCC1.C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]2([CH2:12][CH:13]([O:15][S:19]([CH3:18])(=[O:21])=[O:20])[CH2:14]2)[CH2:16][CH2:17]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(O)C2
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(OS(C)(=O)=O)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
After dissolving 106 mg of 7-(tert-butoxycarbonyl)-2-hydroxy-7-azaspiro[3.5]nonane in 10 ml of tetrahydrofuran, 0.04 ml of methanesulfonyl chloride and 0.07 ml of triethylamine were added and the mixture was stirred overnight at room temperature. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. After adding water to the residue, extraction was performed with ethyl acetate. The organic layer was washed with water and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (148 mg, 100% yield).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:15])[N:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]([CH3:8])[C:6]=1[CH3:7].[Cl:16][C:17]1[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=1.N>O.CC(O)C.[Fe-3](C#N)(C#N)(C#N)(C#N)(C#N)C#N.[K+].[K+].[K+]>[Cl:16][C:17]1/[C:22](=[N:1]/[C:2]2[C:3](=[O:15])[N:4]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:5]([CH3:8])[C:6]=2[CH3:7])/[CH:21]=[CH:20][C:19](=[O:23])[CH:18]=1
Reactant: Oc1cccc(Cl)c1
Reactant: Cc1c(N)c(=O)n(-c2ccccc2)n1C
Agent: N#C[Fe-3](C#N)(C#N)(C#N)(C#N)C#N
Agent: N
Agent: [K+]
Solvent: O
Solvent: CC(C)O
Product: Cc1c(/N=C2\C=CC(=O)C=C2Cl)c(=O)n(-c2ccccc2)n1C

Procedure:
10 mmol of 4-amino-1,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one was dissolved in 30 ml of water. This solution was admixed with 10 mmol of 3-chlorophenol in solution in 30 ml of 2-propanol, 3 ml of 20% aqueous ammonia and 22 mmol of potassium ferricyanide at a temperature ranging from 5 to 10° C.
Reaction SMILES: C([O:5][C:6](=[O:29])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[S:19](=[O:27])(=[O:26])[NH:18]2)=[C:9]1[CH3:28])(C)(C)C.Cl[CH2:31][C:32]1[C:33]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[N:34][O:35][C:36]=1[CH3:37]>>[CH3:28][C:9]1[N:8]([CH2:7][C:6]([OH:5])=[O:29])[C:16]2[C:11]([C:10]=1[CH:17]1[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[S:19](=[O:27])(=[O:26])[N:18]1[CH2:31][C:32]1[C:33]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[N:34][O:35][C:36]=1[CH3:37])=[CH:12][CH:13]=[CH:14][CH:15]=2
Reactant: Cc1c(C2NS(=O)(=O)c3ccccc32)c2ccccc2n1CC(=O)OC(C)(C)C
Reactant: Cc1onc(-c2ccccc2)c1CCl
Product: Cc1onc(-c2ccccc2)c1CN1C(c2c(C)n(CC(=O)O)c3ccccc23)c2ccccc2S1(=O)=O

Procedure:
The title compound was prepared by the method described for example 14 using the product from example 3, step c) and 4-chloromethyl-5-methyl-3-phenyl-isoxazole. MS: ESI (negative): 526 (M−H).
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH:13][S:14]([C:17]2[CH:29]=[CH:28][C:20]([C:21]([NH:23][CH2:24][C:25](O)=[O:26])=[O:22])=[CH:19][CH:18]=2)(=[O:16])=[O:15])=[CH:4][CH:3]=1.[OH:32][CH:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>>[F:1][C:2]1[CH:31]=[CH:30][C:5]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH:13][S:14]([C:17]2[CH:18]=[CH:19][C:20]([C:21]([NH:23][CH2:24][C:25]([N:36]3[CH2:37][CH2:38][CH:33]([OH:32])[CH2:34][CH2:35]3)=[O:26])=[O:22])=[CH:28][CH:29]=2)(=[O:15])=[O:16])=[CH:4][CH:3]=1
Reactant: O=C(O)CNC(=O)c1ccc(S(=O)(=O)Nc2ccccc2Oc2ccc(F)cc2)cc1
Reactant: OC1CCNCC1
Product: O=C(NCC(=O)N1CCC(O)CC1)c1ccc(S(=O)(=O)Nc2ccccc2Oc2ccc(F)cc2)cc1

Procedure:
The title compound was prepared from {4-[2-(4-fluoro-phenoxy)-phenylsulfamoyl]-benzoylamino}-acetic acid and 4-hydroxypiperidine according to the method described in Example 1.1/f. MS (EI) 528.4 (MH+).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[NH:24][CH2:23][CH2:22][C:21]([C:25]([NH:27][C:28]4[CH:33]=[CH:32][C:31]([C@H:34]([OH:42])[C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][N+:36]=5[O-:41])=[CH:30][CH:29]=4)=[O:26])=[CH:20][C:19]=3[CH:43]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[CH:44]([C:46]1[S:47][CH:48]=[CH:49][N:50]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl.O>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:44][C:46]4[S:47][CH:48]=[CH:49][N:50]=4)[CH2:23][CH2:22][C:21]([C:25]([NH:27][C:28]4[CH:29]=[CH:30][C:31]([C@H:34]([OH:42])[C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][N+:36]=5[O-:41])=[CH:32][CH:33]=4)=[O:26])=[CH:20][C:19]=3[CH:43]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=Cc1nccs1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc([C@H](O)c4cccc[n+]4[O-])cc2)CCN3)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc([C@H](O)c4cccc[n+]4[O-])cc2)CCN3Cc2nccs2)cc1
Reaction time: 96 h
Yield: 48.6 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[(S)-hydroxy(1-oxidopyridin-2-yl)methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (200 mg) and 2-formylthiazole (0.24 g) in 1,2-dichloroethane (10 ml) was added sodium triacetoxyborohydride (0.22 g) at room temperature and the mixture was stirred for 4 days. To the reaction solution were added 2-formylthiazole (0.24 g), sodium triacetoxyborohydride (0.22 g) and acetic acid (1 droplet), and the mixture was further stirred for 24 hours. To the reaction solution was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography (ethanol:ethyl acetate 1:4→1:3), which was recrystallized from ethyl acetate, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[(S)-hydroxy(1-oxidopyridin-2-yl)methyl]phenyl]-1-(thiazol-2-ylmethyl)-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 86) (113.6 mg) as yellow crystals.
Reaction SMILES: [Se](=O)=O.[OH2:4].[CH3:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][C:10]([O:20][CH3:21])=[C:11]([O:18][CH3:19])[C:12]=2[O:16][CH3:17])[N:7]=1>O1CCOCC1>[CH3:17][O:16][C:12]1[C:11]([O:18][CH3:19])=[C:10]([O:20][CH3:21])[CH:9]=[C:8]2[C:13]=1[CH:14]=[CH:15][C:6]([CH:5]=[O:4])=[N:7]2
Reactant: O
Reactant: COc1cc2nc(C)ccc2c(OC)c1OC
Agent: O=[Se]=O
Solvent: C1COCCO1
Product: COc1cc2nc(C=O)ccc2c(OC)c1OC
Temperature: 45 °C
Reaction time: 1.5 h

Procedure:
Selenium dioxide (980 mg) was suspended in a mixed solvent of dioxane (12 mL) and water (0.5 mL), and the suspension was heated to 45° C. A solution of 2-methyl-5,6,7-trimethoxyquinoline (1.97 g) in dioxane (3 mL) was slowly added dropwise thereto, and the mixture was heated to 105° C. and stirred for 1.5 hours. After allowing the reaction mixture to room temperature, selenium dioxide was filtered, and the filtrate was concentrated and purified by column chromatography on silica gel (ethyl acetate:hexane=1:4) to obtain the title compound.
Reaction SMILES: C([Si]([C:8]1[C:13]([F:14])=[C:12]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[N:21][CH:22]=3)[NH:17][N:16]=2)[N:11]=[C:10]([N:24]2[CH2:29][CH2:28][NH:27][C@H:26]([C@:30]([CH3:39])([O:34][Si](C)(C)C)[CH:31]([CH3:33])[CH3:32])[CH2:25]2)[C:9]=1[F:40])(C)C)(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CCOC(C)=O>[F:40][C:9]1[C:10]([N:24]2[CH2:29][CH2:28][NH:27][C@H:26]([C@:30]([OH:34])([CH:31]([CH3:32])[CH3:33])[CH3:39])[CH2:25]2)=[N:11][C:12]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[N:21][CH:22]=3)[NH:17][N:16]=2)=[C:13]([F:14])[CH:8]=1
Reactant: CC(C)[C@@](C)(O[Si](C)(C)C)[C@@H]1CN(c2nc(-c3n[nH]c4ncncc34)c(F)c([Si](C)(C)C(C)(C)C)c2F)CCN1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)[C@@](C)(O)[C@@H]1CN(c2nc(-c3n[nH]c4ncncc34)c(F)cc2F)CCN1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41 %

Procedure:
To a solution of tert-butyl-[2-[(3S)-3-[(1R)-1,2-dimethyl-1-trimethylsilyloxy-propyl]piperazin-1-yl]-3,5-difluoro-6-(1H-pyrazolo[3,4-d]pyrimidin-3-yl)-4-pyridyl]-dimethyl-silane (134 mg, 0.23 mmol) in THF (3 mL) was added TBAF (1M in THF) (499.8 μL of 1 M, 0.50 mmol) and stirred at ambient temperature for 1 hour. After this time, the reaction mixture was diluted with EtOAc and the organics were washed with water (×3), brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by reverse phase preparative HPLC [Waters Sunfire C18, 5 mM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min] The fractions were isolated and TFA was removed using PS-carbonate cartridge and freeze-dried to give the title compound as an off-white solid (38 mg, 40.2% Yield). H1 NMR (400.0 MHz, DMSO) δ 9.74 (s, 1H), 9.05 (s, 1H), 7.96 (dd, 1H), 4.15 (br s, 1H), 4.01 (d, 1H), 3.76 (d, 1H), 3.11 (d, 1H), 2.85 (d, 2H), 2.77-2.70 (m, 2H), 1.80 (quintet, 1H), 1.05 (s, 3H), 0.89 (d, 3H) and 0.84 (d, 3H) ppm; MS (ES+) 404.2.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:14]1[N:19]=[CH:18][N:17]=[C:16]([N:20]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[CH3:21])[CH:15]=1)[CH2:9][CH2:8]2)(=[O:4])=[O:3].C(N(CC)CC)C.Cl[C:36]([O:38][CH:39]([CH3:41])[CH3:40])=[O:37]>C(Cl)Cl.C1(C)C=CC=CC=1>[CH:39]([O:38][C:36]([N:25]1[CH2:26][CH2:27][CH:22]([N:20]([C:16]2[CH:15]=[C:14]([N:10]3[C:11]4[C:7](=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:13][CH:12]=4)[CH2:8][CH2:9]3)[N:19]=[CH:18][N:17]=2)[CH3:21])[CH2:23][CH2:24]1)=[O:37])([CH3:41])[CH3:40]
Reactant: CN(c1cc(N2CCc3cc(S(C)(=O)=O)ccc32)ncn1)C1CCNCC1
Reactant: CC(C)OC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(C)OC(=O)N1CCC(N(C)c2cc(N3CCc4cc(S(C)(=O)=O)ccc43)ncn2)CC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
7d was dissolved in DCM (1 mL) and triethylamine (0.1 mL, 14 eq) was added. Isopropyl chloroformate (0.1 mL of a 1 M solution in toluene, 2 eq) was added and the reaction mixture was stirred at room temperature for 17 h. The solution was evaporated and purified by preparative HPLC to give 7-1; LC-MS 474.0 (MH+), tR=5.21 (Method 5). EC50: 69 nM.
Reaction SMILES: C(O[C:4](=[O:20])[C:5](=[CH:11][NH:12][C:13]1[N:17]([CH2:18][CH3:19])[N:16]=[CH:15][CH:14]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.C1(OC2C=CC=CC=2)C=CC=CC=1>C(O)C>[CH2:9]([O:8][C:6]([C:5]1[C:4]([OH:20])=[C:14]2[CH:15]=[N:16][N:17]([CH2:18][CH3:19])[C:13]2=[N:12][CH:11]=1)=[O:7])[CH3:10]
Reactant: CCOC(=O)C(=CNc1ccnn1CC)C(=O)OCC
Solvent: CCO
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cnc2c(cnn2CC)c1O

Procedure:
253 g. [[(1-Ethyl-5-pyrazolyl)amino]methylene]malonic acid diethyl ester (0.09 mol.) are dissolved in 770 g. of diphenyl ether. The reaction mixture is heated to 235°-250° (bath temperature) and allowed to react at this temperature for 1-2 hours while the resulting ethanol is continuously distilled off. The last amount of alcohol is removed by means of a water aspirator. The diphenyl ether is separated by distillation with a fractionating column in vacuo. The 1-ethyl-4-hydroxy-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester is obtained at b.p. 0.05 115°-120°, yield 195 g. (92%), m.p. 85°-87°. The compound is recrystallized from ligroin (90°-100°), m.p. 87°-89°. Hydrolysis of this product with aqueous sodium hydroxide yields 1-ethyl-4-hydroxy-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid, m.p. 201°-202°.
Reaction SMILES: [NH:1]([C:24]([O:26]C(C)(C)C)=O)[C@H:2]([C:7]([NH:9][C@H:10]([C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C@@H:11]([CH3:13])[OH:12])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5].[NH:31]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[C@H:32](C(O)=O)[CH2:33][CH2:34][CH2:35][CH3:36].C1C2C3C(=O)N(O)C(=O)C3C1C=C2.C1CCC(N=C=NC2CCCCC2)CC1>C(O)(C(F)(F)F)=O.CN(C=O)C>[NH:31]([C:40]([O:42][C:43]([CH3:44])([CH3:46])[CH3:45])=[O:41])[C@H:32]([C:24]([NH:1][C@H:2]([C:7]([NH:9][C@H:10]([C:14]([O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:15])[C@@H:11]([CH3:13])[OH:12])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5])=[O:26])[CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: C[C@@H](O)[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1C2C3C=CC(C3)C2C(=O)N1O
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(=O)OCc1ccccc1)[C@@H](C)O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Boc-Asn-Thr-OBzl (3.1 g) was dissolved in TFA (30 ml), and the solution was allowed to stand at room temperature for 10 minutes, and the solvent was evaporated. The residue was triturated with ether to give powders, which were dissolved in DMF (30 ml) together with TEA (1.5 ml) and to this was added Boc-Nle-ONB which was prepared from Boc-Nle-OH (1.69 g), HONB (1.50 g) and DCC (1.73 g). The mixture was stirred at room temperature for 15 hours and the solvent was evaporated. The residue was triturated with water (50 ml) to give powders, which were collected by filtration and washed with ether. Yield 3.8 g (96.7%); m.p. 160°-163° C. [α]D21.5 -13.6° (c=0.8, DMF); Rf1 0.58
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][C:15]([CH3:17])=C)[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:18]1CCOCC1.N1C(C)=CC=CC=1C.I([O-])(=O)(=O)=O.[Na+]>C(OCC)(=O)C.[Os](=O)(=O)(=O)=O.O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][C:15](=[O:18])[CH3:17])[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1COCCO1
Reactant: C=C(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)OC
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1cccc(C)n1
Product: COC(=O)[C@H](CC(C)=O)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of (S)-methyl 2-((tert-butoxycarbonyl)amino)-4-methylpent-4-enoate (500 mg, 2.055 mmol) in a solvent mixture of 1,4-dioxane (10 mL) and water (2.5 mL) at 0° C., was added 2,6-lutidine (0.479 mL, 4.11 mmol) and osmium tetroxide (2.5% in 2-methyl-2-propanol) (0.516 mL, 0.041 mmol), followed by sodium metaperiodate (1.758 g, 8.22 mmol). The reaction mixture was stirred at 0° C. for 15 min and warmed to room temperature and stirred for an additional 3 h. The mixture was diluted with ethyl acetate (150 mL) and washed with 10% aqueous NaHCO3. The organic layer was separated, dried over sodium sulphate and concentrated under reduced pressure to afford (S)-methyl 2-((tert-butoxycarbonyl)amino)-4-oxopentanoate (500 mg, 2.040 mmol, 100% crude yield) as a yellow liquid. The material was carried on without further purification. 1H NMR (400 MHz, CDCl3): δ ppm 5.48 (s, 1H), 4.51 (t, J=8.00 Hz, 1H), 3.75 (s, 3H), 3.23 (d, J=4.00 Hz, 1H), 3.17 (d, J=4.00 Hz, 1H), 2.18 (s, 3H), 1.46 (s, 9H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:15]=[CH:14][C:13]3[N:12]=[C:11]([NH:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[NH:10][C:9](=[O:23])[C:8]=3[C:7]=2[CH:24]=1.[CH2:25]([O:27][C:28](=[O:47])[C@H:29]([CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])[NH:30][C:31](=[O:39])[C:32]1[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=1)[CH3:26].C(N(CC)CC)C>CN(C=O)C>[O:23]=[C:9]1[C:8]2[C:7]3[CH:24]=[C:3]([CH2:2][NH:38][C:35]4[CH:36]=[CH:37][C:32]([C:31]([NH:30][C@H:29]([C:28]([O:27][CH2:25][CH3:26])=[O:47])[CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])=[O:39])=[CH:33][CH:34]=4)[CH:4]=[CH:5][C:6]=3[CH:15]=[CH:14][C:13]=2[N:12]=[C:11]([NH:16][C:17](=[O:22])[C:18]([CH3:20])([CH3:19])[CH3:21])[NH:10]1
Reactant: CC(C)(C)C(=O)Nc1nc2ccc3ccc(CBr)cc3c2c(=O)[nH]1
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(N)cc1)C(=O)OCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(NCc2ccc3ccc4nc(NC(=O)C(C)(C)C)[nH]c(=O)c4c3c2)cc1)C(=O)OCC

Procedure:
To a hot solution of N-(1,2-dihydro-9-methyl-1-oxobenzo[f]quinazolin-3-yl)pivalamide (0.94 g, 3.0 mmol) in benzene (250 ml) under nitrogen were added N-bromosuccinimide (0.57 g, 3.2 mmol) (Kodak) and 2,2'-azobisisobutyronitrile (AIBN) (35 mg, 0.21 mmol) (Kodak). The solution was stirred at reflux for 1.5 hours and then concentrated in vacuo to give crude N-(9-bromomethyl-1,2-dihydro-1-oxobenzo[f]quinazolin-3-yl)pivalamide. The pivalamide and N-(4-aminobenzoyl)-L-glutamic acid diethyl ester (2.5 g, 7.8 mmol)(Aldrich) in DMF (10 ml) were stirred under nitrogen at 105°-110° C. for 5 minutes and then allowed to cool. Triethylamine (0.5 ml, 3.6 mmol) was added and the solution was concentrated under high vacuum. The residue was purified by chromatography on silica gel (130 g) eluting with ethyl acetate:methylene chloride (1:19->2:3), followed by recrystallization of the solid from ethanol/diethyl ether. This was filtered and dried under high vacuum to give diethyl N-(4-(((1,2-dihydro-1-oxo-3-pivalamido-benzo[f]quinazolin-9-yl)methyl)amino)benzoyl)-L-glutamate (0.32 g) as a white solid. The filtrate was concentrated and the residue purified by chromatography and crystallization to give an additional 0.243 g. 1H NMR (DMSO-d6, 300 MHz) δ: 1.15 (t, J=7 Hz, 3H, ester CH3), 1.16 (t, J=7 Hz, 3H, ester CH3), 1.28 (s, 9H, t-butyl), 1.87-2.13 (m, 2H, glu CH2), 2.39 (t, J=7 Hz, 2H, glu CH2), 4.03 (q, J=7 Hz, 2H, ester CH2), 4.07 (q, J=7 Hz, 2H, ester CH2), 4.30-4.40 (m, 1H, glu CH), 4.57 (d, J=6 Hz, 2H, C9 -CH2), 6.63 (d, J=9 Hz, 2H, Ar), 7.04 (t, J=6 Hz, 1H, ArNH), 7.53 (d, J=9 Hz, 1H, Ar), 7.61 (dd, J=8,2 Hz, 1H, Ar), 7.62 (d, J=9 Hz, 2H, Ar), 7.99 (d, J=8 Hz, 1H, Ar) 8.21 (d, J=8 Hz, 1H, glu NH), 8.22 (d, J=9 Hz, 1H, Ar), 9.75 (s, 1H, Ar), 11.25 (s, 1H, N2H), 12.30 (br s, 1H, NH). Mass spectrum (CI-CH4) 630 (M+1, 6.5%), 243 (100%). Anal. Calculated for C34H39N5O7 : C, 64.85; H, 6.24; N, 11.12. Found: C, 64.74; N, 6.25; N, 11.10.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:10][CH:11]1[CH2:13][CH2:12]1.[Li]CCCC.C([O:22][B:23]1OC(C)(C)C(C)(C)[O:24]1)(C)C>O1CCCC1>[CH:11]1([CH2:10][O:9][C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[B:23]([OH:24])[OH:22])[CH2:13][CH2:12]1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: Fc1ccc(OCC2CC2)c(Br)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1cc(F)ccc1OCC1CC1
Temperature: -40 °C
Reaction time: 2 h
Yield: 26.8 %

Procedure:
To a solution of Example 274a (0.1 g, 0.408 mmol) in tetrahydrofuran (2 mL) at −20° C. was added nBuLi (0.180 mL of a 2.5 M solution in hexanes, 0.449 mmol). The reaction mixture was stirred for 2 hours, then cooled to −40° C. 2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.092 mL, 0.449 mmol) was added dropwise. The reaction mixture was stirred for 30 minutes. The reaction mixture was quenched with 1M citric acid at 0° C. The mixture was stirred at ambient temperature for 1 hour and then extracted with ethyl acetate. The layers were separated, and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified by flash chromatography (silica gel, 10-33% ethyl acetate/hexanes gradient) to provide the title compound (23 mg, 20% yield).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Cl:12][C:13]1[C:14](=[O:21])[NH:15][N:16]=[C:17]([OH:20])[C:18]=1[Cl:19].C(N(CC)CC)C>CN(C)C=O>[Cl:12][C:13]1[C:14](=[O:21])[NH:15][N:16]=[C:17]([O:20][CH2:2][CH2:3][CH2:4][S:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:18]=1[Cl:19]
Reactant: O=c1[nH]nc(O)c(Cl)c1Cl
Reactant: BrCCCSc1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=c1[nH]nc(OCCCSc2ccccc2)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 66.7 %

Procedure:
After 1.57 g of 1-bromo-3-phenylthiopropane, 2 g of 4,5-dichloro-6-hydroxy-3(2H)-pyridazinone and 1.3 g of triethylamine were dissolved in dimethylformamide, the mixture was stirred at room temperature for 24 hours. The reaction mixture was poured onto water. The formed crystals were taken by filtration and thoroughly washed with water. The crystals were recrystallized from ethanol to give 1.5 g of the objective compound. Yield, 52%, Melting point, 187°-188° C.