Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)=[O:4].[NH2:14][C:15]1[CH2:16][C:17]([C:27]([N:29]([CH2:33][CH2:34][CH3:35])[CH2:30][CH2:31][CH3:32])=[O:28])=[CH:18][C:19]2[CH:25]=[CH:24][C:23](Br)=[CH:22][C:20]=2[N:21]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.CCOC(C)=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>[NH2:14][C:15]1[CH2:16][C:17]([C:27]([N:29]([CH2:33][CH2:34][CH3:35])[CH2:30][CH2:31][CH3:32])=[O:28])=[CH:18][C:19]2[CH:25]=[CH:24][C:23]([C:8]3[CH:7]=[C:6]4[C:5](=[CH:10][CH:9]=3)[C:3](=[O:4])[O:2][CH2:1]4)=[CH:22][C:20]=2[N:21]=1
Reactant: CCCN(CCC)C(=O)C1=Cc2ccc(Br)cc2N=C(N)C1
Reactant: COC(=O)c1ccc(B(O)O)cc1
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: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCCN(CCC)C(=O)C1=Cc2ccc(-c3ccc4c(c3)COC4=O)cc2N=C(N)C1
Temperature: 100 °C

Procedure:
(1E,4E)-2-Amino-8-(1-oxo-1,3-dihydroisobenzofuran-5-yl)-N,N-dipropyl-3H-benzo[b]azepine-4-carboxamide was prepared as follows, substituting 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isobenzofuran-1(3H)-one for 4-(methoxycarbonyl)phenylboronic acid. (1E,4E)-2-amino-8-bromo-N,N-dipropyl-3H-benzo[b]azepine-4-carboxamide (75.0 mgs, 0.206 mmol), 4-(methoxycarbonyl)phenylboronic acid (55.6 mgs, 0.309 mmol, tetrakis(triphenylphosphine)palladium(0) (23.8 mgs, 0.021 mmol), 2M aqueous potassium carbonate (0.309 ml, 0.618 mmol) were combined in 2 mls of acetonitrile in a microwave reaction vial. This mixture was heated in a microwave to 100° C. for 30 minutes. The mixture was then diluted with EtOAc, washed twice with brine, dried over sodium sulfate, and concentrated under reduced pressure. Preparative thin layer chromatography (2×0.5 mm plates, 7% MeOH/DCM) was then used. 1H NMR (400 MHz, CDCl3) δ 7.96-8.00 (m, 1H), 7.78-7.82 (m, 1H), 7.72-7.74 (m, 1H), 7.52-7.55 (m, 1H), 7.38-7.42 (m, 1H), 7.30-7.35 (m, 1H), 6.85 (s, 1H), 5.37 (s, 2H), 3.60-3.71 (m, 2H), 3.39-3.53 (m, 4H), 2.85 (m, 2H), 1.59-1.75 (m, 4H), 0.90-0.99 (m, 6H); m/z (APCI-pos) M+1=418.2.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[C:16](Cl)[CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:9]=2[C:8]1=[O:27].[N:37]1([CH:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1>>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[C:16]([N:46]3[CH2:47][CH2:48][CH:43]([N:37]4[CH2:42][CH2:41][O:40][CH2:39][CH2:38]4)[CH2:44][CH2:45]3)[CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:9]=2[C:8]1=[O:27]
Reactant: O=C1c2c(-c3ccc(F)cc3)cc(Cl)nc2OCCCN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: C1CC(N2CCOCC2)CCN1
Product: O=C1c2c(-c3ccc(F)cc3)cc(N3CCC(N4CCOCC4)CC3)nc2OCCCN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 39.3 %

Procedure:
In a similar manner to Example 1, 5-[3,5-bis(trifluoromethyl)benzyl]-9-chloro-7-(4-fluorophenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (53.3 mg) was reacted with 4-(morpholine-4-yl)piperidine (20.4 mg) to obtain 5-[3,5-bis(trifluoromethyl)benzyl]-7-(4-fluorophenyl)-9-[4-(morpholine-4-yl)piperidine-1-yl]-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (26.2 mg, 39%).
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[NH2:20][CH2:21][CH2:22][OH:23]>>[OH:23][CH2:22][CH2:21][NH:20][S:16]([C:14]1[S:15][C:11]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=2[CH3:10])=[CH:12][CH:13]=1)(=[O:18])=[O:17]
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)s2)c(C)[nH]c1=O
Reactant: NCCO
Product: CCc1cc(-c2ccc(S(=O)(=O)NCCO)s2)c(C)[nH]c1=O
Yield: 38 %

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonyl chloride is reacted with 2-aminoethanol as described in Step 5, Example 24 to give the title compound as a yellow solid (38% yield). LC/MS: RT 2.20 min; m/e 343 (M+H); 1H NMR (δ, ppm): 11.80 (1H, br), 7.80 (1H, s), 7.53 (1H, d), 7.32 (1H, s), 7.13 (1H, d), 4.72 (1H, t), 3.26-3.42 (2H, m), 2.90 (2H, t), 2.30-2.60 (3H, s), 2.4 (2H, q), 1.10 (3H, t).
Reaction SMILES: [NH2:1]/[C:2](/[CH3:8])=[CH:3]\[C:4]([O:6][CH3:7])=[O:5].[ClH:9].[H][H]>CO.[Pt]>[ClH:9].[NH2:1][CH:2]([CH3:8])[CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: [H][H]
Reactant: COC(=O)/C=C(/C)N
Agent: [Pt]
Agent: Cl
Solvent: CO
Product: COC(=O)CC(C)N
Yield: 96 %

Procedure:
5.0 g (43.4 mmol) of methyl 3-aminocrotonate, 70 ml of a 9.3% strength solution of 17 g (43 mmol) of HCl gas in anhydrous methanol and 0.22 g of Pt/C catalyst (Heraeus K0129) were introduced into a 160 ml Parr autoclave. The hydrogenation was carried out for 3 hours at 21-25° C. under 5-10 bar of hydrogen. The catalyst was then filtered off and the solvent was completely removed by distillation on a rotary evaporator. 6.34 g of pure methyl (RS)-3-amino-butyrate hydrochloride were obtained as an oil.
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9](/[CH:12]=[CH:13]/[CH2:14][CH2:15][C:16]2[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].CC(C)=[O:26].OS(O)(=O)=O.O=[Cr](=O)=O.O>CC(C)=O>[CH2:1]([C@H:6]1[CH2:7][CH2:8][C@H:9](/[CH:12]=[CH:13]/[CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:20]([OH:26])=[O:21])=[CH:22][CH:23]=2)[CH2:10][CH2:11]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CC(C)=O
Reactant: CCCCC[C@H]1CC[C@H](/C=C/CCc2ccc(C=O)cc2)CC1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: CCCCC[C@H]1CC[C@H](/C=C/CCc2ccc(C(=O)O)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4 g of 4-[4E-(trans-4-pentylcyclohexyl)-3-butenyl]benzaldehyde (prepared according to Example 5) in 100 ml of acetone was treated dropwise with 10 ml of Jones' reagent. The mixture was stirred at room temperature for 1 hour and then poured into 100 ml of water. The precipitate which thereby resulted was filtered off, washed portionwise with water and dried in a vacuum. The crude product was recrystallized from ethanol and gave 2.5 g of pure 4-[4E-(trans-4-pentylcyclohexyl)-3-butenyl]benzoic acid.
Reaction SMILES: O[N:2]1[C:6]2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.CN.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]([C:56]2[CH:61]=[CH:60][C:59]([Cl:62])=[CH:58][CH:57]=2)[N:33]2[CH2:36][CH:35]([CH2:37][S:38]([NH:41][C:42]3[CH:43]=[C:44]([CH:53]=[CH:54][CH:55]=3)[C:45]([NH:47][C@@H:48]([CH3:52])[C:49](O)=[O:50])=[O:46])(=[O:40])=[O:39])[CH2:34]2)=[CH:28][CH:27]=1>O1CCCC1.C(N(CC)CC)C>[Cl:62][C:59]1[CH:58]=[CH:57][C:56]([CH:32]([C:29]2[CH:28]=[CH:27][C:26]([Cl:25])=[CH:31][CH:30]=2)[N:33]2[CH2:36][CH:35]([CH2:37][S:38]([NH:41][C:42]3[CH:43]=[C:44]([CH:53]=[CH:54][CH:55]=3)[C:45]([NH:47][C@H:48]([C:49](=[O:50])[NH:2][CH3:6])[CH3:52])=[O:46])(=[O:40])=[O:39])[CH2:34]2)=[CH:61][CH:60]=1
Reactant: On1nnc2ccccc21
Reactant: C[C@H](NC(=O)c1cccc(NS(=O)(=O)CC2CN(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)C2)c1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CNC(=O)[C@H](C)NC(=O)c1cccc(NS(=O)(=O)CC2CN(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)C2)c1
Temperature: 20 °C
Yield: 111.9 %

Procedure:
60 mg of 1-hydroxybenzotriazole, 200 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 0.700 cm3 of a 2M solution of methylamine in tetrahydrofuran, 0.370 cm3 of triethylamine and 8 cm3 of tetrahydrofuran are added successively to a solution of 0.5 g of (S)-2-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}methanesulphonylamino)benzoyl-amino]propionic acid in 15 cm3 of tetrahydrofuran, stirred at a temperature in the region of 20° C. under an inert atmosphere. The reaction medium is stirred at a temperature in the region of 20° C. for 18 hours. After concentration to dryness under reduced pressure, the residue is dissolved in a mixture consisting of 30/15 cm3 of dichloromethane/water. After separation by settling out, the aqueous phase is extracted twice with 15 cm3 of dichloromethane. The organic phases are combined, washed with 15 cm3 of a saturated aqueous solution of sodium chloride, dried over magnesium sulphate, filtered and then concentrated to dryness, to give 0.415 g of a crude product which is purified by flash chromatography on a Merck 25 g silica cartridge (particle size: 15-40 μm; eluent: 100 ethyl acetate). After concentration of the fractions under reduced pressure, 0.293 g of a product is obtained which is triturated in a minimum amount of pentane. After filtration, concentration to dryness under reduced pressure and drying, 0.247 g of a solid cream is obtained. 147 mg of this solid cream are injected onto a column 6 cm in diameter containing 700 g of Chiralpak IA 20 μM chiral stationary phase. The elution is carried out at 80 cm3 per minute with a mobile phase composed of 95% acetonitrile and 5% dichloromethane. The dextrorotatory enantiomer is eluted in the second position. After concentration of the mobile phase, 105 mg of 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}methanesulphonylamino)-N—((S)-1-methyl-carbamoylethyl)benzamide are obtained in the form of an amorphous white powder.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[C:7]([C:9]([OH:11])=[O:10])[CH:6]=[CH:5][N:4]=1)[NH2:2].[CH:12]1([C:15](=O)[CH2:16][C:17](OCC)=[O:18])[CH2:14][CH2:13]1>>[CH:12]1([C:15]2[CH:16]=[C:17]([OH:18])[N:1]([C:3]3[CH:8]=[C:7]([CH:6]=[CH:5][N:4]=3)[C:9]([OH:11])=[O:10])[N:2]=2)[CH2:14][CH2:13]1
Reactant: NNc1cc(C(=O)O)ccn1
Reactant: CCOC(=O)CC(=O)C1CC1
Product: O=C(O)c1ccnc(-n2nc(C3CC3)cc2O)c1
Yield: 24 %

Procedure:
The title compound was prepared in 24% yield from 2-hydrazinylpyridine-4-carboxylic acid and ethyl 3-cyclopropyl-3-oxopropanoate according to the procedure for the preparation of Example 1. 1H NMR (400 MHz, CD3OD): δ 0.83-0.88 (2H, m), 1.05-1.09 (2H, m), 1.88-1.91 (1H, m), 4.86 (1H, s), 7.70 (1H, dd, J=5.2, 1.2 Hz), 8.54 (1H, d, J=5.2 Hz), 8.75 (1H, s). [M+H] Calc'd for C12H11N3O3, 246; Found, 246.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15]([C:17]2[NH:18][C:19]([CH3:24])=[C:20]([Cl:23])[C:21]=2[Cl:22])=[O:16])[C@H:10]([CH2:25][OH:26])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[S:27](Cl)([C:30]1[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=1)(=[O:29])=[O:28]>N1C=CC=CC=1.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15]([C:17]2[NH:18][C:19]([CH3:24])=[C:20]([Cl:23])[C:21]=2[Cl:22])=[O:16])[C@H:10]([CH2:25][O:26][S:27]([C:30]2[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=2)(=[O:29])=[O:28])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1[nH]c(C(=O)N[C@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2CO)c(Cl)c1Cl
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2NC(=O)c2[nH]c(C)c(Cl)c2Cl)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 78.4 %

Procedure:
Cis(±)tert-butyl-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-(hydroxymethyl)piperidine-1-carboxylate (Intermediate 71; 1.46 g) was dissolved in dry pyridine (20 ml) and cooled to 0° C. Tosylchloride (822 mg) was added in a single portion. The reaction was allowed to slowly warm to room temperature and stirred overnight. The mixture was diluted with EtOAc and washed with water, dried over Na2SO4, filtered and concentrated in vacuo. The foam was purified by flash column chromatography eluting with (40% EtOAc/60% hexanes) to give title compound (1.58 g). MS (ES)(MH+): 560 for C24H31Cl2N3O6S; NMR (CDCl3): 1.46 (brs, 11H), 1.89 (m, 1H), 1.98 (m, 1H), 2.31 (s, 3H), 2.35 (s, 3H), 2.8 (m, 2H), 3.96-4.23 (m, 4H), 6.4 (d, 1H), 7.19 (d, 2H), 7.68 (d, 2H), 10.3 (brs, 1H).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.CC(C)([O-])C.[K+].F[C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[C:24]([O:31][CH3:32])[CH:23]=1>O1CCCC1>[CH3:32][O:31][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][C:25]=1[N+:28]([O-:30])=[O:29])[O:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 43.6 %

Procedure:
To a mixture of tert-butyl 4-hydroxypiperidine-1-carboxylate (1.49 g) and tetrahydrofuran (30 mL), potassium tert-butoxide (830 mg) was added under ice cooling and stirred for 30 minutes, followed by addition of a mixture of 4-fluoro-2-methoxy-1-nitrobenzene (1.00 g) and tetrahydrofuran (20 mL). After stirring at room temperature for 3 hours, the reaction mixture was extracted by addition of water and ethyl acetate, washed with saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; n-hexane:diethyl ether=4:1) to give tert-butyl 4-(3-methoxy-4-nitrophenoxy)piperidine-1-carboxylate (898 mg).
Reaction SMILES: [CH2:1]([N:8]1[CH2:15][CH:14]2[CH:10]([C:11](=[O:20])[C:12]3[C:18](Br)=[CH:17][S:16][C:13]=32)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][Zn]C.C1(C)C=CC=CC=1>O1CCOCC1.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]>[CH2:1]([N:8]1[CH2:15][CH:14]2[CH:10]([C:11](=[O:20])[C:12]3[C:18]([CH3:21])=[CH:17][S:16][C:13]=32)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Zn]C
Reactant: O=C1c2c(Br)csc2C2CN(Cc3ccccc3)CC12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: Cc1csc2c1C(=O)C1CN(Cc3ccccc3)CC21
Temperature: 22 °C
Yield: 97 %

Procedure:
A solution of the product from step e) (2.4 g, 6.89 mmol) in dioxane (34.5 ml) was treated with Pd(dppf)2Cl2 (337 mg, 0.41 mmol) and a 2M solution of dimethylzinc in toluene (6.89 ml, 13.78 mmol) at 102° C. for 1 hour. The reaction was cooled to 22° C. and carefully quenched with sat. NH4Cl (20 ml). After the effervescence subsided, the reaction was extracted with EtOAc (3×50 ml). The combined organic layers were dried (MgSO4) and passed through a plug of silica-gel using 50:50 hexanes:EtOAc to give the subtitle compound (1.9 g, 97%). MS calculated for C17H17NOS+H 284, observed 284.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=[O:23])[CH2:9][C:10]2[CH:11]=[C:12]([CH:20]=[CH:21][CH:22]=2)[O:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:5]=[CH:6][CH:7]=1.Cl[CH2:25][C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:34]=[CH:35][C:26]=1[CH2:25][O:1][C:2]1[CH:3]=[C:4]([C:8](=[O:23])[CH2:9][C:10]2[CH:11]=[C:12]([CH:20]=[CH:21][CH:22]=2)[O:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:5]=[CH:6][CH:7]=1
Reactant: ClCc1ccc2ccccc2n1
Reactant: CCOC(=O)COc1cccc(CC(=O)c2cccc(O)c2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cccc(CC(=O)c2cccc(OCc3ccc4ccccc4n3)c2)c1
Temperature: 60 °C

Procedure:
A mixture of ethyl 2-(3-(2-(3-hydroxyphenyl)2-oxoethyl)phenoxy)acetate (0.01 mol), 2-chloromethylquinoline (0.01 mol), and K2CO3 (0.01 mol) in 20 mL of DMF are heated at 60° C. overnight. After work-up, the crude product is purified by flash chromatography to give ethyl 2-(3-(2-(3-(2-quinolinylmethyloxy)phenyl)-2-oxoethyl)phenoxy)acetate.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH:19]([OH:24])[C:20]([O:22][CH3:23])=[O:21])=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:25][C:26]1[CH:31]=[CH:30][C:29](O)=[CH:28][CH:27]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][CH:19]([O:24][C:29]2[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=2)[C:20]([O:22][CH3:23])=[O:21])=[CH:16][CH:17]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)C(O)Cc1ccc(OCCNC(=O)OC(C)(C)C)cc1
Reactant: Oc1ccc(F)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)C(Cc1ccc(OCCNC(=O)OC(C)(C)C)cc1)Oc1ccc(F)cc1
Yield: 58.5 %

Procedure:
In a similar manner to that described in Example 122, a reaction was carried out using methyl 3-[4-(2-t-butoxycarbonylaminoethoxy)phenyl]-2-hydroxypropionate (420 mg), which is obtained in a similar manner to that described in Reference example 39(a), 4-fluorophenol (284 mg), triphenylphosphine (666 mg) and solution of diethylazodicarboxylate in toluene (40%, 1.10 ml) and the reaction mixture was treated to afford the desired compound (314 mg) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]#[N:25])=[N:15][CH:14]=[N:13][C:12]=3[O:11][C:10]=2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:5][CH:4]=1.C[Si]([N:36]=[N+:37]=[N-:38])(C)C.C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:17]3[C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]4[NH:38][N:37]=[N:36][N:25]=4)=[N:15][CH:14]=[N:13][C:12]=3[O:11][C:10]=2[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:7][CH:8]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(NCCCCCC#N)c23)cc1
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(NCCCCCc4nnn[nH]4)c23)cc1

Procedure:
Stir 1.00 g (2.4 mmol) 6-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]amino}hexanenitrile, 4.19 g (26.3 mmol) trimethylsilylazide and 0.91 g (3.6 mmol) di-n-butyltin oxide in 50 ml toluene overnight at 80° C. After concentrating by evaporation, take up the residue in water, acidify with dilute hydrochloric acid and extract with methylene chloride. Wash the organic phase with sodium chloride solution, dry over magnesium sulphate and concentrate by evaporation. Purify the raw product by RP-HPLC (column: Gromsil 250 mm×40 mm, 10 μm; acetonitrile/water gradient: 0-3 min 10% acetonitrile, 3-50 min 10%→98% acetonitrile, 50-55 min 98% acetonitrile). Crystallize the combined product fractions from diethyl ether and dry overnight at 50° C. in a vacuum drying cabinet. 598 mg (54% of theor.) of the title compound is obtained as almost white crystals.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]=[C:5]([CH3:7])[CH3:6].[N+:8]([C:11]1[NH:12][CH:13]=[CH:14][N:15]=1)([O-:10])=[O:9]>CN(C)C=O.C(OCC)C>[CH3:6][C:5]([CH3:7])=[CH:4][CH2:3][CH2:2][N:12]1[CH:13]=[CH:14][N:15]=[C:11]1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ncc[nH]1
Reactant: CC(C)=CCCBr
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)=CCCn1ccnc1[N+](=O)[O-]
Temperature: 75 °C
Reaction time: 48 h

Procedure:
5-Bromo-2-methyl-2-pentene (25 g, 0.154 mol) was dissolved in dry dimethylformamide (DMF) (200 mL). To the solution was added K2 CO3 (21.3 g, 0.154 mol) and 2-nitroimidazole (17.4 g, 0.154 mol). The mixture was stirred under N2 atmosphere at 75° C. for 48 hours. DMF was evaporated on a rotary evaporator. The yellow gummy residue was stirred with water (150 mL) to give yellow solid, which was dissolved in diethyl ether (150 mL), dried over Na2SO4 and evaporated on a rotary evaporator to yield the title product. Yield 27.8 g (92%). mp: 49°-51° C. MS: (M+H)+ =196, M+ =195. 1H NMR (CDCl3) δ 1.45 and 1.68 (s, 6H, gem-di-CH3), 2.52 (q, 2H, CH2CH=), 4.43 [t, 2H, CH2 -(2-nitroimidazolyl)], 5.08 (t, 1H, CH2CH=), 7.05 and 7.14 (s, 2H, 2-nitroimidazolyl-H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([C:19]([F:22])([F:21])[F:20])=[CH:4][N:3]=1.[NH2:23][C:24]1[CH:38]=[CH:37][C:27]([CH2:28][P:29](=[O:36])([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32])=[CH:26][C:25]=1[Cl:39]>>[Cl:39][C:25]1[CH:26]=[C:27]([CH:37]=[CH:38][C:24]=1[NH:23][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11](=[O:12])[NH:13][CH3:14])[C:5]([C:19]([F:22])([F:21])[F:20])=[CH:4][N:3]=1)[CH2:28][P:29](=[O:36])([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32]
Reactant: CCOP(=O)(Cc1ccc(N)c(Cl)c1)OCC
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1C(F)(F)F
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccccc3C(=O)NC)n2)c(Cl)c1)OCC

Procedure:
The title compound was prepared using the procedure from Example 102 with 2-{[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]amino}-N-methylbenzamide (0.060 g, 0.18 mmol) and diethyl (4-amino-3-chlorobenzyl)phosphonate (Compound 104A, 0.101 g, 0.363 mmol). 1H NMR (400 MHz, DMSO-d6) δ11.56 (s, 1H), 9.40 (s, 1H), 8.70 (d, J=4.55 Hz, 1H), 8.38 (s, 1H), 7.66 (dd, J=1.39, 7.96 Hz, 1H), 7.50 (d, J=8.08 Hz, 1H), 7.46 (t, J=2.27 Hz, 1H), 7.29-7.34 (m, 1H), 7.24-7.29 (m, 2H), 7.04 (t, J=7.20 Hz, 1H), 3.94-4.05 (m, 4H), 2.77 (d, J=4.55 Hz, 3H), 1.19 (t, J=6.95 Hz, 6H); MS (ES+): m/z: 572.08 [MH+]. HPLC: tR=3.42 min (Micromass ZQ3: polar—5 min).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:4]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:37]=[CH:38][CH:39]=1)[CH2:26][N:27]1[CH:32]=[CH:31][C:30]([C:33](O)=[O:34])=[CH:29][C:28]1=[O:36]>>[Cl:14][C:8]1[CH:7]=[C:6]2[C:11]([C:12](=[O:13])[C:3]([CH2:2][NH:1][C:33]([C:30]3[CH:31]=[CH:32][N:27]([CH2:26][C:25]4[CH:37]=[CH:38][CH:39]=[C:23]([O:22][CH3:21])[CH:24]=4)[C:28](=[O:36])[CH:29]=3)=[O:34])=[CH:4][N:5]2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:10][CH:9]=1
Reactant: NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O
Reactant: COc1cccc(Cn2ccc(C(=O)O)cc2=O)c1
Product: COc1cccc(Cn2ccc(C(=O)NCc3cn(-c4ccccc4)c4cc(Cl)ccc4c3=O)cc2=O)c1

Procedure:
1-(3-Methoxy-benzyl)-2-oxo-1,2-dihydro-pyridine-4-carboxylic acid (7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-amide was prepared starting from intermediate D and 1-(3-methoxy-benzyl)-2-oxo-1,2-dihydro-pyridine-4-carboxylic acid. MS calcd. for C30H25ClN3O4 [(M+H)+] 526.2, obsd. 526.0.
Reaction SMILES: Cl.[F:2][C:3]([F:21])([F:20])[O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:18][CH:17]3[CH:13]([CH2:14][NH:15][CH2:16]3)[C:12]2=[O:19])=[CH:7][CH:6]=1.[N:22]([C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=1)=[C:23]=[O:24].CCN(CC)CC>ClCCl>[F:33][C:32]([F:34])([F:35])[O:31][C:28]1[CH:27]=[CH:26][C:25]([NH:22][C:23]([N:15]2[CH2:14][CH:13]3[CH:17]([CH2:18][N:11]([C:8]4[CH:9]=[CH:10][C:5]([O:4][C:3]([F:2])([F:20])[F:21])=[CH:6][CH:7]=4)[C:12]3=[O:19])[CH2:16]2)=[O:24])=[CH:30][CH:29]=1
Reactant: O=C1C2CNCC2CN1c1ccc(OC(F)(F)F)cc1
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)N1CC2CN(c3ccc(OC(F)(F)F)cc3)C(=O)C2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.4 %

Procedure:
2-(4-Trifluoromethoxy-phenyl)-hexahydro-pyrrolo[3,4-c]pyrrol-1-one, hydrochloride (0.11 g, 0.36 mmol), 1-isocyanato-4-(trifluoromethoxy)benzene (0.15 g, 0.72 mmol) and Et3N (0.15 g, 1.44 mmol) were added to dichloromethane (2 mL), the mixture was stirred at ambient temperature overnight. The mixture was concentrated under reduced pressure, purified by prep-HPLC to yield the title compound (50 mg, 28%) as white solid. 1H NMR (300 MHz, CDCl3): δ 7.68-7.65 (m, 2H), 7.42-7.40 (m, 2H), 7.39-7.13 (m, 4H), 4.18-4.03 (m, 3H), 3.79-3.69 (m, 2H), 3.45-3.38 (m, 2H), 3.22-3.20 (m, 1H); LC-MS: 489.8 [M+1]+.