Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]([CH3:15])[CH2:3][C:4]1[O:9][C:8](=[O:10])[C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[N:5]=1.[NH:16]([CH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)[NH2:17].ClCC1C=NC=CC=1>C(O)C>[CH3:15][C:2]1[CH:3]=[C:4]([NH:5][C:6]2[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=2[C:8]([OH:9])=[O:10])[N:16]([CH2:18][C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[N:17]=1
Reactant: CC(=O)Cc1nc2ccccc2c(=O)o1
Reactant: NNCc1cccnc1
Agent: ClCc1cccnc1
Solvent: CCO
Product: Cc1cc(Nc2ccccc2C(=O)O)n(Cc2cccnc2)n1
Temperature: 25 °C
Yield: 66.5 %

Procedure:
A solution in ethanol (50 mL) of 2-(2-oxopropyl)-4H-3,1-benzoxazin-4-one (11.2 g, 55.1 mmol) and 3-hydrazinomethylpyridine (7.44 g, 60.4 mmol) which was prepared from 3-chloromethylpyridine following the method described in Reference Example 2-2, was heated under reflux for 1 hour. The solution was cooled to room temperature, and the resulting crude crystals were collected by filtration. The crystals were washed with ethanol and air dried to give the title compound (11.3 g, 67% yield). mp: 180-183° C. (recrystallized from ethanol).
Reaction SMILES: I.[N:2]1[NH:3][C:4](=[O:18])[CH2:5][CH2:6][C:7]=1[C:8]1[S:12][C:11]2[CH2:13][CH2:14][CH:15]([NH2:17])[CH2:16][C:10]=2[CH:9]=1.C(N(CC)CC)C.[C:26]1([S:32](Cl)(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN1CCN(C)C1=O>[N:2]1[NH:3][C:4](=[O:18])[CH2:5][CH2:6][C:7]=1[C:8]1[S:12][C:11]2[CH2:13][CH2:14][CH:15]([NH:17][S:32]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:34])=[O:33])[CH2:16][C:10]=2[CH:9]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: NC1CCc2sc(C3=NNC(=O)CC3)cc2C1
Agent: I
Solvent: CCN(CC)CC
Solvent: CN1CCN(C)C1=O
Product: O=C1CCC(c2cc3c(s2)CCC(NS(=O)(=O)c2ccccc2)C3)=NN1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.2 %

Procedure:
To 1.34 g of 2-[4,5-dihydropyridazin-3(2H)-on-6-yl]-5-amino-4,5,6,7-tetrahydrobenzo[b]thiophene.hydroiodide and 1.2 ml of triethylamine dissolved in 20 ml of 1,3-dimethyl-2-imidazolidinone was added 765 mg of benzenesulfonyl chloride, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into ice water and extracted with ethyl acetate. After the organic layer was washed and dried, the solvent was removed. The resulting crystals were recrystallized from nitromethane to obtain 1.22 g of 2-[4,5-dihydropyridazin-3(2H)-on-6-yl]-5-(phenylsulfonylamino)-4,5,6,7-tetrahydrobenzo[b]thiophene.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[N:10]([C:17]([C@H:19]1[CH2:24][CH2:23][C@H:22]([CH3:25])[CH2:21][CH2:20]1)=[O:18])[CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:4].[CH2:26]=O>ClCCCl>[CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[N:10]([C:17]([C@H:19]1[CH2:20][CH2:21][C@H:22]([CH3:25])[CH2:23][CH2:24]1)=[O:18])[CH:11]1[CH2:12][CH2:13][N:14]([CH3:26])[CH2:15][CH2:16]1)=[O:4]
Reactant: C=O
Reactant: COC(=O)c1sccc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCNCC1
Solvent: ClCCCl
Product: COC(=O)c1sccc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCN(C)CC1

Procedure:
To a stirred solution of 3-[(trans-4-methyl-cyclohexanecarbonyl)-piperidin-4-yl-amino]-thiophene-2-carboxylic acid methyl ester (1.0 g, 2.7 mmol), from step 3, in 1,2-dichloroethane (10 mL) was sequentially added aq. 37% HCHO solution (0.45 mL, 5.4 mmol) and NaBH(OAC)3 (2.86 g, 13.5 mmol) in one portion, stirred for over night, reaction was then quenched with aq. 10% NaOH solution, extracted with DCM. The combined organic extract was washed with brine, dried, and concentrated to obtain 3-[(trans-4-methyl-cyclohexanecarbonyl)-(1-methyl-piperidin-4-yl)-amino]-thiophene-2-carboxylic acid methyl ester (0.876 g, 85.5%) as a white solid. NMR 1H (CDCl3, 400 MHz): 7.54 (d, 1H), 6.86 (d, 1H), 4.7-4.6 (m, 1H), 3.85 (s, 3H), 2.9-2.7 (m, 2H), 2.22 (s, 3H), 2.15-1.1 (m, 14H), 0.8 (d, 3H), 0.75-0.5 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:36][CH3:37])=[CH:5][C:6]2[O:12][CH2:11][CH2:10][C:9]([C:13]([N:15]3[CH2:20][CH2:19][N:18]([C:21](=[O:34])[C:22]4[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[C:24]([O:32][CH3:33])[CH:23]=4)[CH2:17][CH2:16]3)=[O:14])=[CH:8][C:7]=2[CH:35]=1>[C].[Pd].CO>[CH3:1][O:2][C:3]1[C:4]([O:36][CH3:37])=[CH:5][C:6]2[O:12][CH2:11][CH2:10][CH:9]([C:13]([N:15]3[CH2:16][CH2:17][N:18]([C:21](=[O:34])[C:22]4[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[C:24]([O:32][CH3:33])[CH:23]=4)[CH2:19][CH2:20]3)=[O:14])[CH2:8][C:7]=2[CH:35]=1
Reactant: COc1cc2c(cc1OC)OCCC(C(=O)N1CCN(C(=O)c3cc(OC)c(OC)c(OC)c3)CC1)=C2
Agent: [Pd]
Solvent: CO
Product: COc1cc2c(cc1OC)OCCC(C(=O)N1CCN(C(=O)c3cc(OC)c(OC)c(OC)c3)CC1)C2

Procedure:
A mixture of 1-(7,8-dimethoxy-2,3-dihydro-1-benzoxepin4-ylcarbonyl)-4-(3,4,5-trimethoxybenzoyl)piperazine obtained in Working Example 26 (0.5 g) and methanol (20 ml) is stirred under a hydrogen stream in the presence of 10% palladium-carbon (0.3 g) under atmospheric pressure at room temperature for 10 hours. After filtration of the catalyst, the filtrate is concentrated under reduced pressure. The residue is dissolved in ethyl acetate. The resulting solution is washed with water, dried and concentrated in vacuo. The residue is tritutated with ethyl ether and the resulting powder is filtered off to give 1-(7,8-dimethoxy2,3,4,5-tetrahydro-1-benzoxepin-4-ylcarbonyl)-4-(3,4,5-trimethoxybenzoyl)piperazine as a colorless powder (0.4 g).
Reaction SMILES: C1(S([CH2:10][C:11]2[N:12]=[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[NH:14][N:15]=2)(=O)=O)C=CC=CC=1.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1/[CH:28]=[CH:29]\[C:30]#[N:31]>>[N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:13]1[N:12]=[C:11]2[CH:10]=[C:28]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=3)[CH:29]=[C:30]([NH2:31])[N:15]2[N:14]=1
Reactant: O=S(=O)(Cc1n[nH]c(-c2ccccn2)n1)c1ccccc1
Reactant: N#C/C=C\c1ccccn1
Product: Nc1cc(-c2ccccn2)cc2nc(-c3ccccn3)nn12

Procedure:
The title compound, MS m/e (%):289 (M+H+,100), was prepared in accordance with the general method of example 1 from 2-(5-benzenesulfonylmethyl-2H-[1,2,4]triazol-3-yl)-pyridine and (E)/(Z)-3-pyridin-2-yl-acrylonitrile.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11](=O)[CH2:12][CH2:13][C:14]([OH:16])=[O:15].[OH-].[K+].O.NN.Cl>C(O)COCCOCCO>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15]
Reactant: O=C(O)CCC(=O)c1ccc2ccccc2c1
Agent: Cl
Agent: NN
Agent: [K+]
Solvent: OCCOCCOCCO
Solvent: O
Product: O=C(O)CCCc1ccc2ccccc2c1
Temperature: 195 °C
Reaction time: 1.5 h
Yield: 94.7 %

Procedure:
To 300 ml of triethylene glycol contained in a 1-liter, 3-neck flask equipped with a magnetic stirrer, thermometer and take-off condenser was added 77.0 g (0.34 mole) of 4-(2-naphthyl)-4-oxobutyric acid, 61.2 g (1.09 moles) potassium hydroxide pellets and 45.44 ml of hydrazine monohydrate. The reaction mixture was heated up to 100°-110° C. with stirring and held there for 90 minutes. The temperature was gradually increased to 195° C. over 4 hours. Strong gas evolution commenced at about 130° C with some distillate coming over above 140° C. The reaction mixture was allowed to cool and then stirred at room temperature overnight. Next morning the reaction mixture was diluted with ice water and while cooling in ice was acidified with conc. hydrochloric acid. The white solids were collected by filtration, washed with warm water and air-dried to yield 69.0 g (94.9% by weight yield) of γ-(2-naphthyl) butyric acid. M.P. 96°- 99° C.; M/e 214; λmax 276 (5,580) ethanol.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:9][NH:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([NH:21][CH2:22][C:23]3[C:24]([NH:36][CH:37]4[CH2:42][CH2:41][O:40][CH2:39][CH2:38]4)=[C:25]4[CH:33]=[N:32][N:31]([CH2:34][CH3:35])[C:26]4=[N:27][C:28]=3[CH2:29][CH3:30])=[O:20])[N:14]=2)=[O:12])[CH:5]=[CH:6][C:7]=1[F:8].[CH3:43][N:44]1[CH2:49][CH2:48][CH:47]([CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[C:53](B3OC(C)(C)C(C)(C)O3)[CH:52]=2)[CH2:46][CH2:45]1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:34]([N:31]1[C:26]2=[N:27][C:28]([CH2:29][CH3:30])=[C:23]([CH2:22][NH:21][C:19]([C:15]3[CH:16]=[CH:17][CH:18]=[C:13]([C:11]([NH:10][CH2:9][C:4]4[CH:3]=[C:2]([C:55]5[CH:54]=[CH:53][CH:52]=[C:51]([CH2:50][CH:47]6[CH2:48][CH2:49][N:44]([CH3:43])[CH2:45][CH2:46]6)[CH:56]=5)[C:7]([F:8])=[CH:6][CH:5]=4)=[O:12])[N:14]=3)=[O:20])[C:24]([NH:36][CH:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)=[C:25]2[CH:33]=[N:32]1)[CH3:35]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(F)c(Br)c2)n1
Reactant: CN1CCC(Cc2cccc(B3OC(C)(C)C(C)(C)O3)c2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(F)c(-c3cccc(CC4CCN(C)CC4)c3)c2)n1
Temperature: 100 °C
Yield: 15.4 %

Procedure:
A mixture of N-[(3-bromo-4-fluorophenyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-2,6-pyridinedicarboxamide (50 mg, 0.078 mmol), 1-methyl-4-{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}piperidine (31.4 mg, 0.078 mmol), Na2CO3 (24.90 mg, 0.235 mmol) and PdCl2(dppf) (5.73 mg, 7.83 μmol) was diluted in a mixture of 1,4-dioxane (3 mL) and water (1 mL) in a 2-5 mL Biotage microwave reaction tube. The mixture was degassed by bubbling argon through it for 5 minutes and was then heated in a Biotage microwave at normal absorption for 10 minutes at 100° C. The crude mixture was filtered through a PL-Thiol MP SPE+ and was then washed with ethyl acetate and water. The organic layer was concentrated under vacuum to obtain a crude residue. It was purified with a Gilson HPLC (with 0.1% TFA in the solvents), eluting with 10 to 70% CH3CN in water at a flow rate of 20 mL/min. The product fractions were combined and converted to the free base with saturated 1 N NaOH, and the basified solution was extracted with ethyl acetate twice. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and then concentrated under vacuum to give N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-({6-fluoro-3′-[(1-methyl-4-piperidinyl)methyl]-3-biphenylyl}methyl)-2,6-pyridinedicarboxamide as a solid (9 mg, 15.4%). LC-MS m/z 747 (M+H)+, 0.79 min (ret time).
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([CH3:17])[CH2:5][C:6]([C:8]1[C:9]([C:13]([O:15][CH3:16])=[O:14])=[CH:10][NH:11][CH:12]=1)=[O:7].[C:18]1([CH2:28]Cl)[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1.Cl>CN(C)C=O.[I-].[K+]>[CH3:3][CH:4]([CH3:17])[CH2:5][C:6]([C:8]1[C:9]([C:13]([O:15][CH3:16])=[O:14])=[CH:10][N:11]([CH2:28][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][CH:19]=2)[CH:12]=1)=[O:7]
Reactant: COC(=O)c1c[nH]cc1C(=O)CC(C)C
Reactant: ClCc1cccc2ccccc12
Agent: Cl
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Product: COC(=O)c1cn(Cc2cccc3ccccc23)cc1C(=O)CC(C)C
Reaction time: 0.17 h
Yield: 71 %

Procedure:
To sodium hydride (0.42 g of a 60% oil dispersion, 0.0105 mol), freed from oil, stirred in dry dimethyl formamide (15 ml) under nitrogen was added methyl 4-(3-methyl-1-oxobutyl)-1H-pyrrole-3-carboxylate (2.2 g) prepared as described in b) above in portions over 20 minutes. After 10 minutes, potassium iodide (0.01 g) and (1-naphthalenyl)methyl chloride (1.85 g) in dimethyl formamide (20 ml) were added. The mixture was stirred for 4 hours and then poured into 0.5M hydrochloric acid and extracted with ethyl acetate. The organic layer was washed well with water and then brine, dried and evaporated to a gum, which was chromatographed with ethyl acetate-isohexane (1:3) to give an oil. The oil was crystallised from cyclohexane to yield the subtitle pyrrole (2.6 g).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[Se:16][C:17]([CH:20]=[CH2:21])=[CH:18][CH:19]=3)=[C:11]([F:22])[CH:10]=2)=[CH:5][CH:4]=1)[CH3:2]>C(OCC)(=O)C.[Pd]>[CH2:20]([C:17]1[Se:16][C:15]([C:12]2[CH:13]=[CH:14][C:9]([C:6]3[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=3)=[CH:10][C:11]=2[F:22])=[CH:19][CH:18]=1)[CH3:21]
Reactant: C=Cc1ccc(-c2ccc(-c3ccc(CC)cc3)cc2F)[se]1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCc1ccc(-c2ccc(-c3ccc(CC)[se]3)c(F)c2)cc1

Procedure:
3.10 g (8.73 mmol) of 2-(4′-ethyl-3-fluorobiphenyl-4-yl)-5-vinylselenophene are hydrogenated in 30 ml of ethyl acetate, in the presence of Pd/C (5% of Pd) at atmospheric pressure and RT. The reaction soln. is filtered and concentrated to dryness, and the crude product is purified by column chromatography (SiO2, n-heptane:toluene=9:1). The further purification is carried out by recrystallisation from ethanol and n-heptane. 2-Ethyl-5-(4′-ethyl-3-fluorobiphenyl-4-yl)selenophene is obtained as a colourless solid (m.p. 110° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:12][CH3:13])[C:10]=1[CH3:11])C=O.ClC1C=C(C=CC=1)[C:18]([O:20]O)=[O:19]>C(Cl)Cl>[CH:18]([O:20][C:5]1[CH:8]=[C:9]([O:12][CH3:13])[C:10]([CH3:11])=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:19]
Reactant: COc1cc(C=O)cc(OC)c1C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1cc(OC=O)cc(OC)c1C
Temperature: 25 °C
Reaction time: 19 h
Yield: 88 %

Procedure:
To a solution of 3,5-dimethoxy-4-methylbenzaldehyde (3.0 g, 16.8 mmol) in CH2Cl2 (35 mL) was added meta-chloroperoxybenzoic acid (77% purity; 5.8 g, 25.9 mmol). After stirring at room temperature for 19 hrs, additional meta-chloroperoxybenzoic acid (77% purity; 3.5 g, 15.6 mmol) was added. After heating for 4 hrs at 40° C. and cooling to room temperature, 10% aqueous Na2S2O5 was added and the mixture was stirred for 30 min. The mixture was diluted with CH2Cl2 and the layers separated. The organics were washed with 10% aqueous Na2S2O5, ˜5% aqueous NaHCO3 and brine then dried over MgSO4 and concentrated to give 3,5-dimethoxy-4-methylphenyl formate as a yellow solid (2.9 g, 88% yield).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[CH:5]=[C:4]([Cl:13])[N:3]=1.[NH2:14][C@H:15]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16]1.CCN(CC)CC>CN1C(=O)CCC1>[Cl:13][C:4]1[N:3]=[C:2]([NH:14][C@H:15]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16]2)[C:11]2[C:6]([CH:5]=1)=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2
Reactant: Fc1ccc2cc(Cl)nc(Cl)c2c1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(Cl)cc3ccc(F)cc23)C1
Temperature: 160 °C
Yield: 71.3 %

Procedure:
To a solution of 1,3-dichloro-7-fluoroisoquinoline (1 g, 4.6 mmol) in NMP (15 mL) was added (S)-tert-butyl 3-aminopyrrolidine-1-carboxylate (1.72 g, 9.3 mmol) and Et3N (1.4 g, 14 mmol). The reaction mixture was heated at 160° C. for 2 hours. The mixture was subsequently partition between H2O (20 mL) and EtOAc (20 mL). The aqueous phase was extracted with EtOAc (3×20 mL). The organic layers were combined, dried over Na2SO4, and concentrated. The crude product was purified by column chromatography eluting with petroleum ether and ethyl acetate (PE/EA=10:1-5:1 gradient) to give the title compound (1.2 g, 70%). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.26-8.23 (d, J=10.8 Hz, 1H), 7.82-7.80 (dd, J1=8.8 Hz, J2=5.2 Hz, 1H), 7.68-7.67 (d, J=5.6 Hz 1H), 7.63-7.60 (t, J=8.8 Hz, 1H), 7.10 (s, 1H), 4.63-4.53 (m, 1H), 3.70-3.66 (m, 1H), 3.48-3.45 (m, 1H), 3.29-3.26 (m, 1H), 2.23-2.18 (m, 1H), 2.03-1.97 (m, 1H), 1.40 (s, 9H).
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])[NH2:3].C(N(CC)CC)C.C[O:21][C:22](=O)[N:23]=[C:24](SC)[C:25]([C:39]1[CH:44]=[C:43]([O:45][CH3:46])[C:42]([O:47][CH3:48])=[CH:41][C:40]=1[F:49])=[N:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[N:37]=[C:36]([CH3:38])[O:35][N:34]=2)=[CH:29][CH:28]=1.Cl>CN(C)C=O>[F:49][C:40]1[CH:41]=[C:42]([O:47][CH3:48])[C:43]([O:45][CH3:46])=[CH:44][C:39]=1[C:25](=[N:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[N:37]=[C:36]([CH3:38])[O:35][N:34]=2)=[CH:29][CH:28]=1)[C:24]1[NH:23][C:22](=[O:21])[N:2]([C:4]2[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=2[C:6]([OH:8])=[O:7])[N:3]=1
Reactant: NNc1ccccc1C(=O)O
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)c(OC)cc1F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(F)c(C(=Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ccccc3C(=O)O)c(=O)[nH]2)cc1OC
Temperature: 85 °C
Reaction time: 21 h
Yield: 95.1 %

Procedure:
After adding 240 mg of 2-hydrazinobenzoic acid hydrochloride and 0.295 ml of triethylamine to a solution of 500 mg of [2-(2-fluoro-4,5-dimethoxyphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene]carbamic acid methyl ester in 10 ml of N,N-dimethylformamide (hereinafter, “DMF”), the mixture was stirred at 85° C. for 21 hours under a nitrogen atmosphere. After cooling the reaction mixture to room temperature, dilute hydrochloric acid (pH 3-4) was added and extraction was performed with ethyl acetate. The organic layer was then washed with dilute hydrochloric acid (pH 3-4) and saturated brine, and dried over anhydrous sodium sulfate. The desiccating agent was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give the title compound (548 mg) as a light yellow solid.
Reaction SMILES: [O:1]1[CH2:5][C:2]1([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)[C:3]#[CH:4].O>OS(O)(=O)=O.C(O)C>[F:12][C:9]1[CH:8]=[CH:7][C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[CH:11][CH:10]=1
Reactant: C#CC1(c2ccc(F)cc2)CO1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCO
Product: Fc1ccc(-c2ccco2)cc1
Temperature: 23 °C
Yield: 57.7 %

Procedure:
To a solution of 0.7 g HgSO4 in 40 mL of 2N H2SO4 was added 5.0 g (31 mmol) of the 3,4-epoxy-3-(4'-fluorophenyl)-1-butyne in 40 mL of absolute ethanol, dropwise. The reaction mixture was refluxed for 0.25 hour and cooled to 23° C. After addition to 50 mL of H2O, the aqueous phase was extracted twice with hexanes. The hexane layers were combined, dried (MgSO4) and concentrated under reduced pressure. Sublimation (90° C. at 0.2 mmHg) of the residue yielded 2.9 g (58%) of the 2-(4'-fluorophenyl)furan as a solid (m.p. 84°-86° C.) homogeneous by spectroscopic criteria; IR (film) 1571, 1505, 1223, 1152, 785 cm-1 ; 1HNMR (80 MHz, CDCl3) 7.5-7.0 (m, 6H), 6.65 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:14])[CH3:13])[C:5]([OH:7])=O.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.O[NH:30][C:31](=[NH:50])[C:32]1[CH:49]=[CH:48][C:35]2[CH2:36][CH2:37][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:39][CH2:40][C:34]=2[CH:33]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[O:7][N:30]=[C:31]([C:32]3[CH:49]=[CH:48][C:35]4[CH2:36][CH2:37][N:38]([C:41]([O:43][C:44]([CH3:45])([CH3:46])[CH3:47])=[O:42])[CH2:39][CH2:40][C:34]=4[CH:33]=3)[N:50]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(C(=N)NO)cc2CC1
Reactant: CC(C)Oc1ccc(C(=O)O)cc1Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(-c2nc(-c3ccc4c(c3)CCN(C(=O)OC(C)(C)C)CC4)no2)cc1Cl
Temperature: 80 °C
Yield: 28.5 %

Procedure:
To a solution of 3-chloro-4-[(1-methylethyl)oxy]benzoic acid (Preparation 6) (1.406 g, 6.55 mmol) in DMF was added HOBT (1.103 g, 7.20 mmol) and EDC (1.381 g, 7.20 mmol), the resultant solution was stirred under argon for 10 mins at room temp. 1,1-dimethylethyl 7-[(hydroxyamino)(imino)methyl]-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (Preparation 41)(2 g, 6.55 mmol) was then added to the reaction mixture and the solution heated at 80° C. overnight. The solvent was removed in vacuo and the residue dissolved in methanol for purification by Biotage Horizon, reverse phase cartridge, eluting 5-100% acetonitrile in water. The product containing fractions (last 5) were concentrated in vacuo to yield the title compound as a yellow oil (950 mg, 1.87 mmol, 29% yield). δH (d6DMSO, 400 MHz): 8.19 (1H, d), 8.11 (1H, dd), 7.83-7.89 (2H, m), 7.45 (1H, d), 7.37 (1H, d), 4.89 (1H, sept), 3.50 (4H, br.s), 2.96 (4H, br.s), 1.41 (9H, s), 1.36 (6H, d). MS (ES): C26H3035ClN3O4 requires 483; found 384 [M+H−100]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:34])=[C:5]([C:25]([O:32][CH3:33])=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[CH2:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([O:17]CC2C=CC=CC=2)[CH:8]=1.[H][H]>CO.[C].[Pd]>[CH3:1][O:2][C:3]1[C:4]([CH3:34])=[C:5]([C:25]([O:32][CH3:33])=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[CH2:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([OH:17])[CH:8]=1
Reactant: COC(=O)c1ccc(Cc2c(C)c(OC)c(OC)c(OC)c2OC)cc1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(Cc2c(C)c(OC)c(OC)c(OC)c2OC)cc1O
Yield: 96.8 %

Procedure:
Methyl 4-(3,4,5,6-tetramethoxy-2-methylbenzyl)-2-benzyloxybenzoate (530 mg, 1.1373 mmol) was dissolved in methanol (20 ml), added to a methanolic suspension (20 ml) of 10% palladium-carbon (100 mg) and stirred for 16 hours at room temperature in a hydrogen atmosphere. The reaction solution was filtered and the filtrate was concentrated under reduced pressure to give the title compound (414 mg, 1.101 mmol, 97%).
Reaction SMILES: [NH:1]([C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][N:4]=1)[NH2:2].[CH:15](OCC)(OCC)OCC>>[C:9]1([C:6]2[CH:7]=[N:8][C:3]3[N:4]([CH:15]=[N:2][N:1]=3)[CH:5]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCOC(OCC)OCC
Reactant: NNc1ncc(-c2ccccc2)cn1
Product: c1ccc(-c2cnc3nncn3c2)cc1

Procedure:
A mixture of 2.5 g. of 2-hydrazino-5-phenylpyrimidine and 25 ml. of triethyl orthoformate is heated for 16 hours under reflux. The material that separates is collected and crystallized from ethanol to give 1.5 g. of the product of the Example, m.p. 231° C.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]([NH:14][C@H:15]([C:19]([OH:21])=O)[CH:16]([CH3:18])[CH3:17])=[O:13].[B-](F)(F)(F)F.CN(C(ON1C(=O)C=CC=C1)=[N+](C)C)C.Cl.[CH2:43]([N:45]([C:48]1[CH:53]=[CH:52][C:51]([CH2:54][N:55]([NH2:80])[CH2:56][C@H:57]([OH:79])[C@@H:58]([NH:66][C:67](=[O:78])[C@H:68]([C:74]([CH3:77])([CH3:76])[CH3:75])[NH:69][C:70]([O:72][CH3:73])=[O:71])[CH2:59][C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)=[CH:50][CH:49]=1)[CH2:46][CH3:47])[CH3:44]>CN(C=O)C>[CH2:43]([N:45]([C:48]1[CH:53]=[CH:52][C:51]([CH2:54][N:55]([NH:80][C:19](=[O:21])[C@H:15]([CH:16]([CH3:17])[CH3:18])[NH:14][C:12]([O:11][CH3:10])=[O:13])[CH2:56][C@H:57]([OH:79])[C@@H:58]([NH:66][C:67](=[O:78])[C@H:68]([C:74]([CH3:76])([CH3:75])[CH3:77])[NH:69][C:70]([O:72][CH3:73])=[O:71])[CH2:59][C:60]2[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=2)=[CH:50][CH:49]=1)[CH2:46][CH3:47])[CH3:44]
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Reactant: CCN(CC)c1ccc(CN(N)C[C@H](O)[C@H](Cc2ccccc2)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)cc1
Agent: CN(C)C(On1ccccc1=O)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)c1ccc(CN(C[C@H](O)[C@H](Cc2ccccc2)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)NC(=O)[C@@H](NC(=O)OC)C(C)C)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
In analogy with Example 2, 0.42 ml of Hünig's base is added to 0.193 g (1.1 mmol) of N-methoxycarbonyl-(L)-valine and 0.327 g (1.1 mmol) of TPTU in 3 ml of DMF and the whole is stirred at RT for 10 min. After that, 0.63 g (1 mmol) of 1-[p-(N,N-diethylamino)-phenyl]-4(S)-hydroxy-2-amino-5(S)-[N-(N-methoxycarbonyl-(L)-tert-leucyl)amino]-6-phenyl-2-azahexane hydrochloride (Example 2f), dissolved in 2 ml of DMF, is added and the mixture is stirred at RT for 21 h. After working-up in the same way as described for Example 2, the residue is digested in DIPE and the title compound is filtered off. The suction filter residue is washed once again with DIPE and dried in a heated desiccator at 45° C. TLC: Rf0.50 (ethyl acetate). HPLC20-100: tret=10.93; FAB MS (M+H)+=685.