Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([C:10]1[CH:18]=[CH:17][C:13]([C:14]([NH2:16])=[NH:15])=[CH:12][CH:11]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[CH3:19][O:20][CH:21]([C:26](OC)=[O:27])[C:22](OC)=[O:23]>C(O)(=O)C>[OH:23][C:22]1[C:21]([O:20][CH3:19])=[C:26]([OH:27])[N:16]=[C:14]([C:13]2[CH:12]=[CH:11][C:10]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])=[CH:18][CH:17]=2)[N:15]=1
Reactant: COC(=O)C(OC)C(=O)OC
Reactant: CCCCCCCCc1ccc(C(=N)N)cc1
Agent: Cl
Solvent: CC(=O)O
Product: CCCCCCCCc1ccc(-c2nc(O)c(OC)c(O)n2)cc1
Yield: 89.3 %

Procedure:
Metal sodium (23.4 g, 1.02 mol) was added to methanol (500 ml) to obtain sodium methoxide, followed by adding thereto 4-octylbenzamidine hydrochloride (84 g, 0.31 mol) and dimethyl methoxymalonate (55 g, 0.31 mol), refluxing the mixture for 8 hours, pouring the reaction mixture in acetic acid (500 ml), filtering off deposited crystals, washing them with water and drying to obtain 4,6-dihydroxy-5-methoxy-2-(4-octylphenyl)pyrimidine (91.5 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:11]=[C:10]([C:12]([O:14]CC)=O)[O:9][N:8]=1.O/[N:18]=[C:19](\[NH2:27])/[C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1.[H-].[Na+]>CN(C)C=O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:11]=[C:10]([C:12]2[O:14][N:27]=[C:19]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)[N:18]=2)[O:9][N:8]=1
Reactant: Cc1ccc(/C(N)=N/O)cc1
Reactant: CCOC(=O)c1cc(-c2ccccn2)no1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2noc(-c3cc(-c4ccccn4)no3)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.6 %

Procedure:
To a solution of ethyl 3-(pyridin-2-yl)isoxazole-5-carboxylate (13.6 g, 62.5 mmol) and (Z)—N′-hydroxy-4-methylbenzimidamide (9.68 g, 62.5 mmol) in N,N-dimethylformamide (210 mL) cooled in an ice-bath was added 60% sodium hydride (6.25 g, 156 mmol) portion-wise. After the addition, the reaction mixture was warmed to room temperature and stirred for 1 h. The reaction mixture was concentrated, water (500 mL) was added, and the mixture was stirred at room temperature for 30 minutes. The solid was collected vacuum filtration, triturated with methanol, and re-collected to give 5-(3-(pyridin-2-yl)isoxazol-5-yl)-3-p-tolyl-1,2,4-oxadiazole (17.8 g, 93% yield) as a solid. The compound had an HPLC retention time=3.86 minutes (YMC-Combi 4.6×50 mm S-5 ODS column) eluting with 10-90% aqueous methanol+0.2% phosphoric acid over a 4 minute gradient. MS: (M+H)=305+. 1H NMR (400 MHz, CDCl3) δ ppm 2.46 (s, 3H), 7.35 (d, J=8.28 Hz, 2H), 7.41-7.47 (m, 1H), 7.83-7.91 (m, 2H), 8.09 (d, J=8.28 Hz, 2H), 8.20 (d, J=8.03 Hz, 1H), and 8.76 (d, J=5.02 Hz, 1H).
Reaction SMILES: C([CH2:3][C:4]1[N:8]2[CH2:9][CH2:10][O:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:20]([OH:23])([CH3:22])[CH3:21])=[CH:14][C:13]=3[C:7]2=[N:6][C:5]=1[C:24]([NH2:26])=[O:25])#N.BrC1C=CC2OCCN3C(CCl)=C(C([O-])=O)N=C3C=2C=1.[Cl:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=1[OH:54]>>[Cl:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=1[O:54][CH2:3][C:4]1[N:8]2[CH2:9][CH2:10][O:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:20]([OH:23])([CH3:22])[CH3:21])=[CH:14][C:13]=3[C:7]2=[N:6][C:5]=1[C:24]([NH2:26])=[O:25]
Reactant: CC(C)(O)C#Cc1ccc2c(c1)-c1nc(C(N)=O)c(CC#N)n1CCO2
Reactant: Oc1ccccc1Cl
Agent: O=C([O-])c1nc2n(c1CCl)CCOc1ccc(Br)cc1-2
Product: CC(C)(O)C#Cc1ccc2c(c1)-c1nc(C(N)=O)c(COc3ccccc3Cl)n1CCO2
Yield: 6 %

Procedure:
Prepared similarly to as described in the synthesis of 3-(cyanomethyl)-10-(3-hydroxy-3-methylbut-1-yn-1-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide starting from 10-bromo-3-(chloromethyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxylate replacing sodium cyanide with 2-chlorophenol to give the titled compound as an off-white solid (7 mg, 6%).
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].[OH:19][C@H:20]1[CH2:24][CH2:23][C@H:22]([NH:25]C2C3N(C=CC=3)N=CC=2C(N)=O)[C:21]1([CH3:39])[CH3:38].C(=O)(O)[O-].[Na+]>ClCCl>[OH:19][C@@H:20]1[CH2:24][CH2:23][C@H:22]([NH:25][C:9](=[O:10])[O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:21]1([CH3:39])[CH3:38]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC1(C)[C@@H](Nc2c(C(N)=O)cnn3cccc23)CC[C@@H]1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)[C@H](O)CC[C@@H]1NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 10.1 %

Procedure:
Triethylamine (6.69 mL, 48.0 mmol) and benzyl chloroformate (4.22 g, 24.71 mmol) were added to a solution of 3-amino-2,2-dimethylcyclopentanol (3.10 g, 23.99 mmol, from Step 3 of Intermediates 15 and 16) in dichloromethane (100 mL) at 0° C. The resulting mixture was stirred at room temperature for 15 h, treated with saturated sodium bicarbonate (50 mL) and extracted with dichloromethane (3×150 mL). The combined organic extracts were washed with water (50 mL), brine (50 mL), dried (MgSO4), filtered and concentrated. Silica gel chromatography, eluting with 0 to 40% ethyl acetate in hexanes, gave separation of the two major components. The first eluted product was found to be benzyl cis-3-hydroxy-2,2-dimethylcyclopentylcarbamate (cis-isomer B, 640 mg, 10% yield). 1H NMR (400 MHz, methanol-d4) δ ppm 7.13-7.53 (5 H, m), 5.06 (2 H, s), 3.53-3.86 (2 H, m), 1.81-2.05 (2 H, m), 1.36-1.71 (2 H, m), 0.86-1.07 (3 H, m), 0.78 (3 H, s); MS (ES+) m/z: 264.2 (M+H); HPLC retention time: 2.32 min (analytical HPLC Method A). The second eluted product was benzyl trans-3-hydroxy-2,2-dimethylcyclopentylcarbamate (trans-isomer A, 1.77 g, 28% yield). 1H NMR (400 MHz, methanol-d4) δ ppm 7.21-7.51 (5 H, m), 5.06 (2 H, s), 3.91 (1 H, t, J=8.25 Hz), 3.64-3.79 (1 H, m), 1.99-2.20 (2 H, m), 1.33-1.62 (2 H, m), 0.94 (3 H, s), 0.79 (3 H, s); MS (ES+) m/z: 264.3 (M+H); HPLC retention time: 2.29 min (analytical HPLC Method A).
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].[F:4][C:5]1[CH:10]=[CH:9][C:8]([P:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)Cl)=[CH:7][CH:6]=1.N>>[F:19][C:16]1[CH:17]=[CH:18][C:13]([P:11]([C:8]2[CH:9]=[CH:10][C:5]([F:4])=[CH:6][CH:7]=2)[O:3][CH2:1][CH3:2])=[CH:14][CH:15]=1
Reactant: Fc1ccc(P(Cl)c2ccc(F)cc2)cc1
Reactant: CCO
Agent: N
Product: CCOP(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Yield: 83.8 %

Procedure:
87 g (1.90 mol) of absolute ethanol are cooled to -15° C. under a nitrogen atmosphere. 67 g (0.26 mol) of bis-(4-fluorophenyl)chlorophosphine are then added dropwise at this temperature in 50 minutes with vigorous stirring. 5.2 g (0.31 mol) of ammonia gas are then introduced at this temperature. The mixture is then further stirred until room temperature is reached and stirred for a further 16 hours. The mixture is then filtered by suction and rinsed out with ethanol. The filtrate is freed from ethanol and excess ammonia in vacuo. The remaining residue is distilled at 0.45 mbar at an overhead temperature of 102° C. 58 g of ethyl bis-(4-fluorophenyl)-phosphinite are obtained. This corresponds to a yield of 84% of theory.
Reaction SMILES: [F:1][CH:2]([F:21])[O:3][C:4]1[CH:20]=[CH:19][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15](=[N:17]O)[CH3:16])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1.[H][H]>N.[Ni]>[F:1][CH:2]([F:21])[O:3][C:4]1[CH:20]=[CH:19][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]([NH2:17])[CH3:16])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: CC(=NO)c1ccc(Oc2ccc(OC(F)F)cc2)cc1
Agent: [Ni]
Agent: N
Product: CC(N)c1ccc(Oc2ccc(OC(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.35 g (4.60 mmol) of 1-[4-(4-difluoromethoxy-phenoxy)-phenyl]-ethanone-oxime were dissolved in 50 ml of 7M methanolic ammonia, then combined with 100 mg Raney nickel. The mixture was shaken overnight at RT and 50 psi hydrogen pressure. The catalyst was removed by suction filtering and the filtrate was evaporated down.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:12]([NH2:14])[CH3:13]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:14][CH2:12][CH3:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: CCN
Product: CCNS(=O)(=O)c1ccc(Br)cc1
Reaction time: 16 h
Yield: 26.7 %

Procedure:
Following general procedure A, 4-Bromobenzene sulfonyl chloride (0.40 g, 1.56 mmol) and ethylamine (5 mL, [2.0M], 10 mmol) were stirred together for 16 hours. 4-bromo-N-ethylbenzenesulfonamide (0.11 g) was provided after purification. MS (ESI) m/z 264. HPLC purity 100.0% at 210-370 nm, 8.1 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:34])[N:10]([CH2:15][CH:16]([OH:33])[CH:17]([NH:25]C(OC(C)(C)C)=O)[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:11][CH:12]([CH3:14])[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(N(CC)C(C)C)(C)C.[O:45]1[CH:49]2[O:50][CH2:51][CH2:52][CH:48]2[CH:47]([O:53][C:54](=[O:63])ON2C(=O)CCC2=O)[CH2:46]1>O1CCOCC1>[CH2:1]([O:8][C:9](=[O:34])[N:10]([CH2:15][CH:16]([OH:33])[CH:17]([NH:25][C:54]([O:53][CH:47]1[CH:48]2[CH:49]([O:50][CH2:51][CH2:52]2)[O:45][CH2:46]1)=[O:63])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:11][CH:12]([CH3:13])[CH3:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OC1COC2OCCC12)ON1C(=O)CCC1=O
Reactant: CC(C)CN(CC(O)C(Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CN(CC(O)C(Cc1ccccc1)NC(=O)OC1COC2OCCC12)C(=O)OCc1ccccc1
Reaction time: 8 h
Yield: 73.4 %

Procedure:
(3-tert-Butoxycarbonylamino-2-hydroxy-4-phenyl-butyl)-isobutyl-carbamic acid benzyl ester 16 (7.54 g, 15 mmol) and 35 ml of 4M HCl in dioxane were stirred 30 min under an argon atmosphere. The mixture was concentrated in vacuo, and co-evaporated twice with dichloromethane. The residue was dissolved in dichloromethane (50ml) and N,N-diisopropylethylamine (6.1 ml, 35 mmol), and carbonic acid 2,5-dioxo-pyrrolidin-1-yl ester hexahydro-furo[2,3-b]furan-3-yl ester 17 (4.88g, 18 mmol) was added. The reaction mixture was stirred overnight, and then concentrated in vacuo. The residue was diluted with dichloromethane, and sequentially washed with brine, 10% KHSO4, brine, saturated NaHCO3, and brine, then dried over MgSO4, and concentrated in vacuo. The oily residue was purified by flash chromatography using 70:30 ethyl acetate hexane as eluant, to give [3-(Hexahydro-furo[2,3-b]furan-3-yloxycarbonylamino)-2-hydroxy-4-phenyl-butyl]-isobutyl-carbamic acid benzyl ester 18 (5.8 g, 73%) as a white solid. TLC: Rf 0.56 (7:3 ethyl acetate: hexane). MS m/z 527 (MH)+.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][N:11]=[C:12]([C:15]#[N:16])[C:13]#[N:14])([CH3:3])[CH3:2].C(C1C=CC=CC=1N)(C)C.C(#N)CC#N.O.[NH2:33][NH2:34]>>[NH2:14][C:13]1[C:12](=[N:11][NH:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:1]([CH3:2])[CH3:3])[C:15]([NH2:16])=[N:34][N:33]=1
Reactant: CC(C)c1ccccc1NN=C(C#N)C#N
Reactant: NN
Agent: CC(C)c1ccccc1N
Solvent: O
Solvent: N#CCC#N
Product: CC(C)c1ccccc1NN=C1C(N)=NN=C1N
Yield: 73 %

Procedure:
This compound was prepared using 106 mg (0.5 mmol) of 2-[(2-isopropylphenyl)-hydrazono]malononitrile, which was derived from 2-isopropylaniline (142 μL, 1.0 mmol) and malononitrile (1.5 mmol) as described in Example 8, and hydrazine hydrate. Precipitate formed in the reaction tube approximately 5 min after the addition of hydrazine hydrate. The resulting solid was isolated by filtration, washed with ethanol, and dried to yield 90 mg (73%) of the title compound as a greenish yellow solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10](=[NH:14])OCC.[NH2:15][C:16]1[C:21]([O:22][CH2:23][C:24]2[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:31])=[CH:20][CH:19]=[CH:18][N:17]=1>C(O)C>[ClH:2].[Cl:31][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]([F:30])[C:24]=1[CH2:23][O:22][C:21]1[C:16]([NH:15][C:10](=[NH:14])[CH2:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[Cl:2])=[N:17][CH:18]=[CH:19][CH:20]=1
Reactant: Nc1ncccc1OCc1c(F)cccc1Cl
Reactant: CCOC(=N)Cc1ccccc1Cl
Agent: Cl
Solvent: CCO
Product: N=C(Cc1ccccc1Cl)Nc1ncccc1OCc1c(F)cccc1Cl

Procedure:
A mixture of ethyl 2-chlorophenylacetimidate hydrochloride (5.07 g, 0.0216 mol), 2-amino-3-(2-chloro-6-fluorobenzyloxy)pyridine (4.95 g, 0.0196 mol)and ethanol (150 ml) was heated under reflux for 2 hours. The solvent was evaporated off and the resultant oil was purified by chromatography (silica gel, 1% methanol/dichloromethane) and trituration with ether. Yield 0.7 g (8%), m.p. 156°-158 ° C.
Reaction SMILES: [CH2:1]([C:16]1[CH:17]=[C:18]([OH:22])[CH:19]=[CH:20][CH:21]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[CH2:23](O)[C:24]#[CH:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O.CCCCCC>[CH2:1]([C:16]1[CH:17]=[C:18]([O:22][CH2:25][C:24]#[CH:23])[CH:19]=[CH:20][CH:21]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: C#CCO
Reactant: CCCCCCCCCCCCCCCc1cccc(O)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: O
Product: C#CCOc1cccc(CCCCCCCCCCCCCCC)c1
Reaction time: 4.5 h

Procedure:
To a solution of 24.4 g (80 mmol) of 3-pentadecylphenol, 4.93 g (88 mmol) of propargyl alcohol and 23.1 g (88 mmol) of triphenylphosphine cooled to 15° C. is added dropwise 15.3 g (13.9 ml, 88 mmol) of diethyl azodicarboxylate. The mixture is stirred for 4.5 hours and then is diluted with water and extracted with hexane (3 times). The hexane extracts are combined, washed with 1N sodium hydroxide and are dried over magnesium sulfate overnight. Filtration and evaporation gives crude oil which is subjected to flash chromatography using hexane as eluting solvent. The appropriate fractions are combined to give the title compound as an oil which solidifies upon standing: mp. 26°-27° C. The product is used without further characterization.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[CH2:15][CH:14]([N:17]([CH2:21][CH2:22][CH3:23])[CH2:18][CH2:19][CH3:20])[CH2:13][CH2:12]2.[CH3:24][Sn:25](Cl)([CH3:27])[CH3:26].O>C1COCC1>[CH2:18]([N:17]([CH2:21][CH2:22][CH3:23])[CH:14]1[CH2:13][CH2:12][C:11]2[C:16](=[C:7]([Sn:25]([CH3:27])([CH3:26])[CH3:24])[CH:8]=[CH:9][CH:10]=2)[CH2:15]1)[CH2:19][CH3:20]
Reactant: CCCN(CCC)C1CCc2cccc(Br)c2C1
Reactant: C[Sn](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CCCN(CCC)C1CCc2cccc([Sn](C)(C)C)c2C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 152.2 %

Procedure:
Butyllithium (1.2M in hexane; 2.8 ml; 3.4 mmol) was added to a solution of 8-bromo-2-di-n-propylamino-1,2,3,4-tetrahydronaphthalene (1 g; 3.22 mmol) in THF (50 ml) at -78° C. After 1.5 hr., a solution of trimethyltin chloride (1.3 g, 2.0 mmol) in THF (20 ml) was added. The reaction mixture was allowed to warm to room temperature, stirred overnight at room temperature, poured into water, and extracted with methylene chloride. The extract was dried (Na2SO4) and concentrated to give the crude product. Purification by chromatography using 1:10 methanol:methylene chloride gave 1.2 g of the desired product which was used directly in the next step.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[N:19][C:20]([N:22]5[CH2:27][CH2:26][N:25]([CH2:28][C:29](O)=[O:30])[CH2:24][CH2:23]5)=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:32]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[CH3:33][N:34](C)[CH:35]=O.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1>>[CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[N:19][C:20]([N:22]5[CH2:27][CH2:26][N:25]([CH2:28][C:29]([N:34]([CH3:35])[CH3:33])=[O:30])[CH2:24][CH2:23]5)=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:32]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(N3CCN(CC(=O)O)CC3)cc1OCC2
Reactant: CN(C)C=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(N3CCN(CC(=O)N(C)C)CC3)cc1OCC2
Temperature: 25 °C

Procedure:
2-(4-(2-(1-Isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-yl)piperazin-1-yl)acetic acid (0.050 g, 0.00011 mol) dissolved in N,N-Dimethylformamide (1.79 mL, 0.0231 mol) and treated sequentially with N,N-Diisopropylethylamine (0.119 mL, 0.000686 mol) Dimethylamine hydrochloride (0.0373 g, 0.000457 mol) then N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium Hexafluorophosphate (0.0521 g, 0.000137 mol). Stir at r.t. 2 h. Add sat. sodium bicarbonate, extract with ethyl acetate. Dry organics over sodium sulfate and concentrate to give 331, analyzed by rHPLC. MS: (ESI+)=466.2. 1H NMR (400 MHz, DMSO) δ 9.10 (s, 1H), 7.89 (s, 1H), 7.84 (s, 1H), 6.34 (s, 1H), 6.01-5.79 (m, 1H), 4.50 (d, J=10.0 Hz, 4H), 3.53 (s, 4H), 3.18 (s, 2H), 3.03 (s, 3H), 2.82 (s, 3H), 1.47 (d, J=6.5 Hz, 6H).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([NH:11][CH2:12][C:13]([OH:15])=O)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C)C=O.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[NH2:26]>ClCCl>[CH3:21][O:22][C:23]1[CH:24]=[C:25]([NH:26][C:13](=[O:15])[CH2:12][NH:11][C:9](=[O:10])[O:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:27]=[CH:28][C:29]=1[O:30][CH3:31]
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: COc1ccc(N)cc1OC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(NC(=O)CNC(=O)OCc2ccccc2)cc1OC
Temperature: 25 °C

Procedure:
To a suspension of 25.9 g (124 mmol) of N-(phenylmethoxycarbonyl)glycine in 370 ml of dichloromethane, were added at 0° C., 0.74 ml of dimethylformamide and 18.8 g (148 mmol) of oxyalylchloride. The mixture was allowed to warm to room temperature and was then added dropwise to a mixture of 19.0 g (124 mmol) of 3,4-dimethoxyaniline (sublimed) and washed with 10% hydrochloric acid solution and twice with water, and dried over sodium sulfate. After the evaporation of the solvent, the residue was triturated with ether and dried in vacuo; yield: 26.3 g.
Reaction SMILES: [CH:1]([Si:4]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[O:5][CH2:6][C:7]1[S:8][C:9](B2OC(C)(C)C(C)(C)O2)=[CH:10][C:11]=1[CH3:12])([CH3:3])[CH3:2].Br[C:29]1[CH:34]=[CH:33][C:32]([O:35][C:36]([F:39])([F:38])[F:37])=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[CH:1]([Si:4]([CH:22]([CH3:24])[CH3:23])([CH:25]([CH3:27])[CH3:26])[O:5][CH2:6][C:7]1[S:8][C:9]([C:29]2[CH:30]=[CH:31][C:32]([O:35][C:36]([F:37])([F:38])[F:39])=[CH:33][CH:34]=2)=[CH:10][C:11]=1[CH3:12])([CH3:2])[CH3:3]
Reactant: FC(F)(F)Oc1ccc(Br)cc1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)sc1CO[Si](C(C)C)(C(C)C)C(C)C
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: COCCOC
Solvent: O
Product: Cc1cc(-c2ccc(OC(F)(F)F)cc2)sc1CO[Si](C(C)C)(C(C)C)C(C)C

Procedure:
A mixture of triisopropyl{[3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thien-2-yl]methoxy}silane (intermediate 116, 0.40 g) in 1,2-dimethoxyethane (12 ml) and water (6 ml) was treated with 4-bromo-trifluoromethoxybenzene (0.26 g), sodium carbonate (0.26 g) and tetrakis(triphenylphosphine)palladium (0) (0.120 g). The reaction mixture was stirred at reflux for 2 hours and then partitioned between water and ethyl acetate. The aqueous layer was separated and extracted with further ethyl acetate and then the organic solutions combined and dried over magnesium sulfate. The crude product was purified by Si SPE using dichloromethane as eluent to give the title compound as a yellow gum.
Reaction SMILES: [ClH:1].Cl.[CH2:3]([C:7]1[N:12]=[N:11][C:10]([O:13][CH2:14][CH:15]2[O:20][CH2:19][CH2:18][NH:17][CH2:16]2)=[CH:9][C:8]=1[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:23][CH:22]=1)[CH2:4][CH2:5][CH3:6].Cl.[CH2:35](OCC)C>C(Cl)Cl>[ClH:1].[ClH:1].[CH2:3]([C:7]1[N:12]=[N:11][C:10]([O:13][CH2:14][CH:15]2[O:20][CH2:19][CH2:18][N:17]([CH3:35])[CH2:16]2)=[CH:9][C:8]=1[C:21]1[CH:22]=[CH:23][C:24]([O:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:25][CH:26]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCc1nnc(OCC2CNCCO2)cc1-c1ccc(OC2CCCCC2)cc1
Reactant: CCOCC
Agent: Cl
Solvent: ClCCl
Product: CCCCc1nnc(OCC2CN(C)CCO2)cc1-c1ccc(OC2CCCCC2)cc1

Procedure:
To a solution of 2-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxymethyl]-morpholine dihydrochloride (0.067 mmol, 0.031 g) and aqueous formaldehyde (37%, 0.304 mmol, 0.025 mL) in dry DCM (2 mL) was added macroporous resin-bound triacetoxyborohydride (loading 2.36 mmol/gram, 0.364 mmol, 0.154 g). The mixture was shaken for 12 hours. The reaction was filtered and the resin was washed with DCM (5 mL). The solvent was removed under reduced pressure. The crude product was purified on a 4 g SiO2 cartridge with 4-6% (2N NH3 in MeOH) in DCM to give 2-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxymethyl]-4-methyl-morpholine. The neutral amine was treated with 2N HCl in diethyl ether (1 mL) and DCM (1 mL). The volatiles were removed under reduced pressure and the salt was triturated with diethyl ether and filtered to provide the title compound (0.022 g). LCMS: m/z 441 [M+1]. 1H NMR (400 MHz, CD3OD) δ 7.35-7.46 (3H, m), 7.09 (2H, d), 4.56-4.68 (2H, m), 4.38-4.47 (1H, m), 4.13-4.29 (2H, m), 3.91 (1H, t), 3.68 (1H, d), 3.49 (1H, d), 3.12-3.26 (2H, m), 3.00-3.09 (2H, m), 2.97 (3H, s), 1.99-2.02 (2H, m), 1.80-1.82 (2H, m), 1.19-1.66 (10H, m), 0.81 (3H, t).
Reaction SMILES: O=C1C=CC(=O)[N:3]1[CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12].[NH2:14][CH2:15][C:16]([NH:18][CH2:19][C:20]([NH:22][CH2:23][C:24]([NH:26][CH2:27][CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:25])=[O:21])=[O:17].Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[CH2:9]([CH2:8][NH2:3])[CH2:10][C:11]([OH:13])=[O:12].[NH2:14][CH2:15][C:16]([NH:18][CH2:19][C:20]([NH:22][CH2:23][C:24]([NH:26][CH2:27][CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:25])=[O:21])=[O:17]
Reactant: O=C(O)CCCN1C(=O)C=CC1=O
Agent: CC(C)(C)OC(=O)CCNC(=O)CNC(=O)CNC(=O)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: NCCCC(=O)O
Reaction time: 3 h

Procedure:
513 mg (2.8 mmol) of 4-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)butanoic acid, 800 mg (0.2.8 mmol) tert-butyl 3-(2-(2-(2-aminoacetamido)acetamido)acetamido)propanoate and 583 mg (3.0 mmol) N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride were disolved in 12 mL of dimethyl formamide and stirred for 3 hours. The reaction mixture was purified in four equal portions by reverse phase HPLC using a 5.0 cm×25 cm C18 column. The column was eluted at 100 mL/min with deionized water containing 0.3% formic acid and 5% acetonitrile for 10 min followed by a 13 min linear gradient from 5% acetonitrile to 33% acetonitrile. Product fractions (retention time of 21 min) were combined and solvent was removed by rotary evaporation under vacuum to give 832 mg (62%) of the title compound. 1H NMR (d6-DMSO) 8.10-8.16 (m, 2H), 8.07 (t, J=4.8 Hz, 1H), 7.0-7.15 (m, 1H), 3.747 (t, J=6.0 Hz, 3H), 3.64 (d, J=5.6 Hz, 2H), 3.41 (t, J=6.8, 2H), 3.1-3.33 (m, 1H), 3.19-3.26 (m, 2H), 2.348 (t, J=6.8, 2H), 2.132 (t, J=7.2 Hz, 2H), 1.67-1.76 (m, 2H), 1.39 (s, 9H). 13C NMR (d6-DMSO) 171.80, 170.98, 170.39, 169.48, 168.96, 168.56, 134.37, 79.83, 42.05, 41.83, 37.38, 34.82, 34.71, 32.26, 27.83, 23.95. HRMS (M+Na+) Calc. 504.2070 found 504.2046
Reaction SMILES: CS([C:5]1[N:14]2[C:8]([CH2:9][C:10]3[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=3[CH:12]=[CH:13]2)=[N:7][N:6]=1)(=O)=O.[O-:19][CH2:20][CH3:21].[Na+].C(O)C.C[O-].[Na+].CO>>[CH2:20]([O:19][C:5]1[N:14]2[C:8]([CH2:9][C:10]3[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=3[CH:12]=[CH:13]2)=[N:7][N:6]=1)[CH3:21]
Reactant: CS(=O)(=O)c1nnc2n1C=Cc1ccccc1C2
Reactant: CC[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: CCOc1nnc2n1C=Cc1ccccc1C2

Procedure:
By a procedure similar to that described in Example 34, 3-methylsulfonyl-11H-s-triazolo[3,4-b][3] benzazepine was reacted with sodium ethoxide/ethanol, in lieu of sodium methoxide/methanol, to obtain 3-ethoxy-11H-s-triazolo[3,4-b][3]benzazepine as crystals. Recrystallization from acetone yielded colorless needles, melting point: 143°-144° C.