Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([C:7]2[O:12][C:11](=[O:13])[C:10]3[CH:14]=[C:15]([Cl:19])[CH:16]=[C:17]([CH3:18])[C:9]=3[N:8]=2)[N:4]([C:20]2[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][N:21]=2)[N:3]=1.O.[NH2:28][NH2:29].O1CCCC1>O>[Br:1][C:2]1[CH:6]=[C:5]([C:7]([NH:8][C:9]2[C:17]([CH3:18])=[CH:16][C:15]([Cl:19])=[CH:14][C:10]=2[C:11]([NH:28][NH2:29])=[O:13])=[O:12])[N:4]([C:20]2[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][N:21]=2)[N:3]=1
Reactant: Cc1cc(Cl)cc2c(=O)oc(-c3cc(Br)nn3-c3ncccc3Cl)nc12
Reactant: NN
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(Cl)cc(C(=O)NN)c1NC(=O)c1cc(Br)nn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 0.40 g of 2-[3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-6-chloro-8-methyl-4H-3,1-benzoxazine-4-one, 0.08 ml of hydrazine monohydrate and 10 ml of tetrahydrofuran was stirred at room temperature for 3 hours. The reaction mixture was poured into water and then filtered. The resulting filter cake was washed with water and methyl tert-butyl ether. The filter cake was dissolved in ethyl acetate, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 0.35 g of 3-bromo-N-[4-chloro-2-(hydrazinocarbonyl)-6-methylphenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide of the formula:
Reaction SMILES: CS(O[CH2:6][CH:7]1[CH2:9][CH:8]1[CH2:10][C:11]1[N:19]2[C:14]([C:15]([NH2:20])=[N:16][CH:17]=[N:18]2)=[C:13]([C:21]2[CH:22]=[CH:23][C:24]3[C:28]([CH:29]=2)=[N:27][N:26]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:25]=3)[CH:12]=1)(=O)=O.[NH:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:30]([N:26]1[CH:25]=[C:24]2[C:28]([CH:29]=[C:21]([C:13]3[CH:12]=[C:11]([CH2:10][CH:8]4[CH2:9][CH:7]4[CH2:6][N:37]4[CH2:41][CH2:40][CH2:39][CH2:38]4)[N:19]4[C:14]=3[C:15]([NH2:20])=[N:16][CH:17]=[N:18]4)[CH:22]=[CH:23]2)=[N:27]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CS(=O)(=O)OCC1CC1Cc1cc(-c2ccc3cn(Cc4ccccc4)nc3c2)c2c(N)ncnn12
Reactant: C1CCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1ncnn2c(CC3CC3CN3CCCC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Temperature: 80 °C
Yield: 5.8 %

Procedure:
To a solution of (2-{[4-amino-5-(2-benzyl-2H-indazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]methyl}cyclopropyl)methyl methanesulfonate (0.2 g, 0.4 mmol) in DMF (2 mL) was added pyrrolidine (84 mg, 1.2 mmol) and DIEA (102 mg, 0.8 mmol), and the mixture was heated to 80° C. for 3 hours. The mixture was concentrated in vacuo and the residue was dissolved in methanol and purified by preparative HPLC to provide 11 mg (6%) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 8.60 (s, 1 H), 8.05 (d, 2 H), 8.0 (s, 1 H), 7.90 (d, 1 H), 7.70 (s, 1 H), 7.60-7.40 (m, 7 H), 7.25 (d, 1 H), 720 (s, 1 H), 5.70 (s, 2 H), 2.9-2.8 (m, 2 H), 2.4-2.2 (m, 6 H), 1.7 (m, 4 H), 1.1-0.9 (m, 2 H), 0.5-0.4 (m, 2 H); ES-MS m/z 478.2 [M+H]P, HPLC RT (min) 2.29.
Reaction SMILES: S(C)C.[CH:4]([Li])([CH3:6])[CH3:5].[C:8]([NH:27][C@@H:28]([CH2:31][CH3:32])[CH:29]=[O:30])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[NH4+].[Cl-]>CCOCC>[CH3:5][CH:4]([CH:29]([OH:30])[C@@H:28]([NH:27][C:8]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:31][CH3:32])[CH3:6]
Reactant: CC[C@@H](C=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: [Li]C(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CSC
Product: CC[C@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(O)C(C)C
Temperature: 25 °C

Procedure:
To a stirred suspension of CuBr.SMe2 (1.37 g, 2.2 eq, 6.66 mmol) in Et2O (100 mL) under an argon atmosphere at −78° C., was added isopropyllithium (0.7 M in pentane, 17.29 mL, 4 eq, 12.1 mmol) dropwise and the solution allowed to warm to room temperature. The mixture was recooled to −70° C., to which was added a solution of (S)-2-(trityl-amino)-butyraldehyde (1 g, 1 eq, 3.03 mmol) in Et2O (25 mL) dropwise with stirring. The reaction mixture was stirred at this temperature for 1 h, then allowed to warm to −55° C. and stirred at this temperature for 3 h. To the reaction mixture was added a saturated aqueous solution of NH4Cl (100 mL) and allowed to warm to room temperature over 16 h. The reaction mixture was extracted with Et2O (2×200 mL), and the combined organic phase washed with brine (50 mL), dried (MgSO4) and evaporated in vacuo. The residue was purified by silica gel column chromatography, eluted with hexane:ether (100:0→90:10) to afford the title compound as a colourless oil; Yield: 0.36 g (32%). (50% de 3R,4S: 50% de 3S,4S). 1H-NMR (d6-DMSO, 250 MHz): δ 0.44 (t, 3H, J=6.79 Hz, —NHCH(CH2CH3)CH(CH(CH3)2)OH), 0.52 & 0.76 (2×d, 6H, J=6.63 Hz, —NHCH(CH2CH3)CH(CH(CH3)2)OH), 0.80-1.15 (m, 2H, —NHCH(CH2CH3)CH(CH(CH3)2)OH), 1.70 (m, 1H, —NHCH(CH2CH3)CH(CH (CH3)2)OH), 2.10 (m, 1H, —NHCH(CH2CH3)CH(CH(CH3)2)OH), 2.76 (m, 1H, —NHCH(CH2CH3)CH(CH(CH3)2)OH), 2.99 (m, 1H, —NHCH(CH2CH3)CH(CH(CH3)2)OH), 4.55 (d, 1H, J=5.84 Hz, —NHCH(CH2CH3)CH(CH(CH3)2)OH), 7.17-7.46 (m, 15H, 3×Ph).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:10]([OH:12])=O)=[CH:8][CH:9]=1)=[O:4].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[F:43][C:44]([F:64])([F:63])[O:45][C:46]1[CH:62]=[CH:61][C:49]([CH2:50][O:51][C:52]2[CH:57]=[CH:56][C:55]([CH:58]([NH2:60])[CH3:59])=[CH:54][CH:53]=2)=[CH:48][CH:47]=1>ClCCl>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:10](=[O:12])[NH:60][CH:58]([C:55]2[CH:56]=[CH:57][C:52]([O:51][CH2:50][C:49]3[CH:61]=[CH:62][C:46]([O:45][C:44]([F:43])([F:63])[F:64])=[CH:47][CH:48]=3)=[CH:53][CH:54]=2)[CH3:59])=[CH:8][CH:9]=1)=[O:4]
Reactant: CC(N)c1ccc(OCc2ccc(OC(F)(F)F)cc2)cc1
Reactant: COC(=O)c1ccc(C(=O)O)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C(=O)NC(C)c2ccc(OCc3ccc(OC(F)(F)F)cc3)cc2)s1
Reaction time: 6.5 h
Yield: 60.4 %

Procedure:
To a solution of 160.0 mg (0.859 mmol) thiophene-2,5-dicarboxylic acid monomethyl ester in 25 ml dichloromethane were added 253.0 mg (1.293 mmol) N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride, 175 mg (1.295 mmol) 1-hydroxybenzotriazole hydrate and 130.7 g (1.291 mmol) triethylamine. After 30 min at room temperature 268.0 mg (0.861 mmol) 1-[4-(4-trifluoromethoxy-benzyloxy)-phenyl]-ethylamine were added. The reaction mixture was stirred for 6.5 h. The solvent was evaporated, to the residue was added ethyl acetate and the organic phase was extracted with saturated aqueous NaHCO3 solution and with water. The organic phase was dried over MgSO4 and the solvent was evaporated. The residue was triturated with diisopropyl to provide 249 mg (0.519 mmol) 5-{1-[4-(4-trifluoromethoxy-benzyloxy)-phenyl]-ethylcarbamoyl}-thiophene-2-carboxylic acid methyl ester.
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=[N:49][C:44]2[CH:45]=[CH:46][CH:47]=[N:48][C:43]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N1CCC[C@H](N)C1)(OC(C)(C)C)=O>>[CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:49][C@H:44]5[CH2:45][CH2:46][CH2:47][NH:48][CH2:43]5)=[O:29])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CC(C)(C)OC(=O)N1CCC[C@H](N)C1
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)N[C@H]2CCCNC2)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and (S)-1-Boc-3-aminopiperidine. The final compound was purified by reverse phase HPLC and basified to give the free base. Further, after washing with water (10 ml), t-butoxycarbonyl (Boc) protection group was removed using 40% TFA in dichloromethane (6 ml) and purified the product using preparative HPLC. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.08-1.95 (m., 14H) 2.40 (t, J=7.38 Hz, 2H) 2.80 (br. s., 1H) 2.96 (br. s., 1H) 3.33 (s, 3H) 3.81 (br. s., 1H) 3.94 (s, 3H) 4.06 (t, J=13.64 Hz, 2H) 4.45 (m, 1H) 7.34-7.55 (m, 2H) 7.90 (s, 1H) 8.03 (d, J=7.58 Hz, 1H) 8.21 (s, 1H) 8.26 (d, J=8.34 Hz, 1H). [M+H] calculated for C27H35F2N7O3, 544. found 544.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([F:9])[C:3]=1[C:10]1[N:11]=[N:12][NH:13][N:14]=1.[C:15]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([F:9])[C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[N:12][N:11]=1
Reactant: O=C([O-])[O-]
Reactant: Fc1cc(Cl)cc(Br)c1-c1nn[nH]n1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1nnnc1-c1c(F)cc(Cl)cc1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 34.4 %

Procedure:
A mixture of 5-(2-bromo-4-chloro-6-fluoro-phenyl)-2H-tetrazole (4.15 g, 14.95 mmol), K2CO3 (3.1 g, 22.43 mmol) and iodomethane (1.3 ml, 20.94 mmol) in DMF (30 ml) was stirred at 25° C. for 3 h. The mixture was partitioned between EtOAc (80 ml) and water (60 ml), the organic layer was separated, washed with water and brine, dried with Na2SO4 and concentrated. The remaining residue was purified by chromatography (silica gel; hexane/EtOAc 100:0-90:10) to obtain 5-(2-bromo-4-chloro-6-fluoro-phenyl)-1-methyl-1H-tetrazole as pale yellow solid (1.5 g, 35%) and the title compound (1.7 g, 39%) as reddish liquid. MS: 291.0 (MH+, 1Br).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([CH2:10][OH:11])[C:7]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]#[N:18])=[CH:6][C:5]=1[O:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]#[N:25])(=[O:3])[CH3:2].[H-].[Na+].[CH3:28]I>CN(C)C=O>[C:1]([C:4]1[CH:9]=[C:8]([CH2:10][O:11][CH3:28])[C:7]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]#[N:18])=[CH:6][C:5]=1[O:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]#[N:25])(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(CO)c(OCCCCC#N)cc1OCCCCC#N
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCc1cc(C(C)=O)c(OCCCCC#N)cc1OCCCCC#N
Reaction time: 8 h

Procedure:
A mixture of 688 mg of 5,5'-[(4-acetyl-6-hydroxymethyl-1,3-phenylene)bis(oxy)]bis pentanenitrile]in 15 ml of dimethylformamide was added to a suspension of 0.184 of a 50% oil dispersion of sodium hydride and 0.62 ml of methyl iodide in 45 ml of dimethylformamide at 0° C. The reaction was allowed to come to room temperature and stirred overnight. The reaction mixture was partitioned between ethyl acetate and dilute hydrochloric acid to which sodium chloride had been added. The organic layer was separated, dried over sodium sulfate, and concentrated in vacuo. The resulting residue was purified by high pressure liquid chromatography over silica gel eluting with a 0-70% ethyl acetate in hexane gradient to provide 110 mg of the desired title product. NMR, MS.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:33])[N:10]([C@@H:12]2[C@@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=3)[CH2:15][N:14]([C:25]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[O:26])[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1.Br[C:35]1[S:36][CH:37]=[N:38][N:39]=1.C(N(CC)C(C)C)(C)C>CN1CCCC1=O.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:33])[N:10]([C@@H:12]2[C@@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=3)[CH2:15][N:14]([C:25]([CH:27]3[CH2:32][CH2:31][N:30]([C:35]4[S:36][CH:37]=[N:38][N:39]=4)[CH2:29][CH2:28]3)=[O:26])[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1
Reactant: CN(C(=O)Oc1ccc(F)cc1)[C@H]1CN(C(=O)C2CCNCC2)C[C@@H]1c1ccc(Cl)c(Cl)c1
Reactant: Brc1nncs1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CN(C(=O)Oc1ccc(F)cc1)[C@H]1CN(C(=O)C2CCN(c3nncs3)CC2)C[C@@H]1c1ccc(Cl)c(Cl)c1
Yield: 32 %

Procedure:
To a solution of rac-[(3R,4S)-4-(3,4-dichloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester (100 mg, 0.20 mmol) in N-methylpyrrolidinone (1 mL) was added 2-bromo-1,3,4-thiadiazole (50 mg, 0.30 mmol) and N,N-diisopropyl ethyl amine (69 μl, 0.40 mmol). The solution was irradiated in the microwave for 35 min at 150° C. The reaction mixture was diluted with ethyl acetate (15 mL) and washed with an aqueous solution of sodium carbonate (1 M, 15 mL). The organic layer was separated and washed with brine (15 mL) and the aqueous layers were extracted with ethyl acetate (20 mL). The combined organic layers were dried over sodium sulfate and concentrated. Purification by chromatography (SiO2, ethyl acetate:methanol=100:0 to 80:20) afforded the title compound (37 mg, 32%) as an off-white foam. MS m/e: 578.1 [M]+.
Reaction SMILES: CO[C:3](=[O:28])[C:4]1[CH:13]=[C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Si:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][C:16]=2[F:25])[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[C:26]#[N:27].[BH4-].[Na+]>CO.C(Cl)Cl.O.O.O.O.O.O.[Co](Cl)Cl>[CH3:11][O:10][C:8]([C:7]1[CH:6]=[C:5]2[C:4](=[CH:13][C:12]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([Si:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][C:16]=1[F:25])[C:3](=[O:28])[NH:27][CH2:26]2)=[O:9]
Reactant: COC(=O)c1cc(Nc2ccc([Si](C)(C)C)cc2F)c(C(=O)OC)cc1C#N
Agent: Cl[Co]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1cc2c(cc1Nc1ccc([Si](C)(C)C)cc1F)C(=O)NC2
Temperature: 0 °C
Reaction time: 1 h
Yield: 49.4 %

Procedure:
To a solution of 2-cyano-5-(2-fluoro-4-trimethylsilanylphenylamino)-terephthalic acid dimethyl ester (300 mg, 0.75 mmol) in methanol (15 ml) and DCM (2 ml) at 0° C. was added silica (1 g) and cobalt (II) chloride hexahydrate (357 mg, 1.50 mmol) followed by sodium borohydride (285 mg, 7.50 mmol). During the addition of the sodium borohydride large amounts of effervescence were observed and the reaction turned black. The reaction mixture was stirred at 0° C. for 1 hour. The reaction was filtered and the filtrate concentrated in vacuo to provide a residu that was subjected to flash chromatography (SiO2, gradient 0-20% methanol in DCM) to yield the title compound as a brown solid (138 mg, 49%). LCMS (Method B): RT=4.18 min, 2M+H−=745 (100%), M+H+=373 (25%).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([OH:31])=[C:7]2[C:12](=[C:13]([C:15]#[N:16])[N:14]=1)[N:11]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:10](=[O:24])[C:9]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[CH:8]2)=O.[NH2:32][CH2:33][C:34]1[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=1.CC(O)=O.O>CCO>[N:37]1[CH:38]=[CH:39][C:34]([CH2:33][NH:32][C:3]([C:5]2[C:6]([OH:31])=[C:7]3[C:12](=[C:13]([C:15]#[N:16])[N:14]=2)[N:11]([CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:10](=[O:24])[C:9]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:8]3)=[O:2])=[CH:35][CH:36]=1
Reactant: COC(=O)c1nc(C#N)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Reactant: NCc1ccncc1
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: N#Cc1nc(C(=O)NCc2ccncc2)c(O)c2cc(-c3ccccc3)c(=O)n(Cc3ccccc3)c12
Yield: 43.4 %

Procedure:
A mixture of 1-benzyl-8-cyano-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (35 mg, 0.085 mmol) and 4-(aminomethyl)-pyridine (0.030 mL, 0.30 mmol) in 2 mL of EtOH was refluxed for 16 h. AcOH (0.1 mL) and water (4 mL) were added, and the resulting precipitate was isolated by filtration. The crude solid was purified by silica gel chromatography (0-45% EtOAc/CH2Cl2+1% AcOH) to give 18 mg of the title compound as an off-white solid. MS: (+) m/z 488.13 (M+1).
Reaction SMILES: FC1C=C(C[C@H](C2C([C:34]3[CH:35]=[CH:36][C:37]([F:43])=[C:38]([CH:42]=3)[C:39]([NH2:41])=[O:40])=CN=C(NCCOC)N=2)NC(=O)CN2C3CCCCC=3C(C(F)(F)F)=N2)C=C(F)C=1.Br[C:50]1[C:51]([C@@H:63]([NH:73][C:74](=[O:92])[CH2:75][N:76]2[C:84]3[C:83]([F:86])([F:85])[CH2:82][CH2:81][C:80]([F:88])([F:87])[C:79]=3[C:78]([CH:89]([F:91])[F:90])=[N:77]2)[CH2:64][C:65]2[CH:70]=[C:69]([F:71])[CH:68]=[C:67]([F:72])[CH:66]=2)=[N:52][C:53]([N:56]2[CH2:62][C:58]3([CH2:61][O:60][CH2:59]3)[CH2:57]2)=[N:54][CH:55]=1>>[F:90][CH:89]([F:91])[C:78]1[C:79]2[C:80]([F:88])([F:87])[CH2:81][CH2:82][C:83]([F:86])([F:85])[C:84]=2[N:76]([CH2:75][C:74]([NH:73][C@H:63]([C:51]2[C:50]([C:34]3[CH:35]=[CH:36][C:37]([F:43])=[C:38]([CH:42]=3)[C:39]([NH2:41])=[O:40])=[CH:55][N:54]=[C:53]([N:56]3[CH2:57][C:58]4([CH2:61][O:60][CH2:59]4)[CH2:62]3)[N:52]=2)[CH2:64][C:65]2[CH:70]=[C:69]([F:71])[CH:68]=[C:67]([F:72])[CH:66]=2)=[O:92])[N:77]=1
Reactant: COCCNc1ncc(-c2ccc(F)c(C(N)=O)c2)c([C@@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)(F)F)c3c2CCCC3)n1
Reactant: O=C(Cn1nc(C(F)F)c2c1C(F)(F)CCC2(F)F)N[C@@H](Cc1cc(F)cc(F)c1)c1nc(N2CC3(COC3)C2)ncc1Br
Product: NC(=O)c1cc(-c2cnc(N3CC4(COC4)C3)nc2[C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)F)c3c2C(F)(F)CCC3(F)F)ccc1F

Procedure:
The title compound (15B) was prepared according to the method presented for the synthesis of compound 11J of Example 11 utilizing 15A. 1H NMR (400 MHz, CD3OD) δ 8.69 (d, J=8.0 Hz, 1H), 8.09 (s, 1H), 7.45-7.31 (m, 2H), 7.21 (dd, J=10.7, 8.6 Hz, 1H), 7.03-6.63 (m, 2H), 6.42 (d, J=6.1 Hz, 2H), 5.23 (dd, J=15.1, 7.6 Hz, 1H), 5.05 (s, 2H), 4.88 (s, 4H), 4.39 (q, J=9.9 Hz, 4H), 3.00 (m, 2H), 2.50 (m, 4H). MS (m/z) 754.24 [M+H]+.
Reaction SMILES: [CH2:1]([O:4][C:5]([NH:7][CH2:8][C:9]([OH:11])=O)=[O:6])[CH:2]=[CH2:3].ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:37][CH2:38][C:39]1[N:40]2[CH:46]=[N:45][CH:44]=[C:41]2[S:42][CH:43]=1>CN(C=O)C.ClCCl>[CH2:1]([O:4][C:5]([NH:7][CH2:8][C:9]([NH:37][CH2:38][C:39]1[N:40]2[CH:46]=[N:45][CH:44]=[C:41]2[S:42][CH:43]=1)=[O:11])=[O:6])[CH:2]=[CH2:3]
Reactant: NCc1csc2cncn12
Reactant: C=CCOC(=O)NCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C=CCOC(=O)NCC(=O)NCc1csc2cncn12

Procedure:
A 5 ml portion of a dichloromethane solution containing 307 mg of N-allyloxycarbonyl glycine was cooled on ice, and 287 mg of 1-hydroxybenzotriazole and 438 mg of 1,3-dicyclohexylcarbodiimide were further added to the cooled mixture, followed by stirring under ice-cooling for 2 hours. Further, 5 ml of dichloromethane containing 3-aminomethylimidazo[5,1-b]thiazole and 10 ml of DMF were added thereto, and dichloromethane was then evaporated under reduced pressure, followed by stirring at room temperature for 1.5 hours. To the reaction solution, a saline solution was added, and extraction was then carried out three times with ethyl acetate. Afterward, the resulting organic layer was dried over anhydrous magnesium sulfate, and after the removal of the drying agent by filtration, the solvent was evaporated under reduced pressure. The resulting residue was purified by a silica gel column chromatograph to obtain 387 mg of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:15](=[CH:16][CH:17]=1)[O:14][C:7]1=[N:8][CH:9]=[C:10]([O:12][CH3:13])[CH:11]=[C:6]1[C:5]2=[O:18].[CH2:19]1COCC1.C[Mg]Cl>>[Br:1][C:2]1[CH:3]=[C:4]2[C:15](=[CH:16][CH:17]=1)[O:14][C:7]1=[N:8][CH:9]=[C:10]([O:12][CH3:13])[CH:11]=[C:6]1[C:5]2([CH3:19])[OH:18]
Reactant: C1CCOC1
Reactant: COc1cnc2oc3ccc(Br)cc3c(=O)c2c1
Agent: C[Mg]Cl
Product: COc1cnc2c(c1)C(C)(O)c1cc(Br)ccc1O2
Temperature: -30 °C

Procedure:
To a slurry of 7-bromo-3-methoxy-5H-chromeno[2,3-b]pyridin-5-one (23 g, 75 mmol) in THF (751 mL, 75 mmol) at −40° C. was added methylmagnesium chloride, 3.0 M solution in THF (88 mL, 263 mmol) over 2 minutes such that the temperature did not rise above −35° C. The resulting red slurry was maintained at −30° C. After 1 hour the reaction, which was now homogeneous, was quenched with 50 mL of ethyl acetate. The solution was then carefully quenched with 800 mL of 50% ammonium chloride. The mixture was poured into a separatory funnel containing ethyl acetate (100 mL). The layers were separated and the organics were washed with brined, dried over sodium sulfate, filtered and concentrated. The aqueous layer was extracted with ethyl acetate (3×500 mL). The combined organic layers were washed with water and then brine, dried over sodium sulfate, filtered, and combined with the above derived oil. This organic solution was washed with brined, dried over sodium sulfate, filtered and concentrated to provide 7-bromo-3-methoxy-5-methyl-5H-chromeno[2,3-b]pyridin-5-ol as a yellow solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6]([O:10][CH2:11][CH2:12][C:13]3[N:14]=[C:15]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[O:16][C:17]=3[CH3:18])=[CH:7][CH:8]=[CH:9][C:2]1=2.O1CC[CH2:28]OO1.[ClH:31]>ClCCl>[Cl:31][CH2:28][C:9]1[C:2]2[S:1][CH:5]=[CH:4][C:3]=2[C:6]([O:10][CH2:11][CH2:12][C:13]2[N:14]=[C:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:16][C:17]=2[CH3:18])=[CH:7][CH:8]=1
Reactant: Cl
Reactant: C1COOOC1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1cccc2sccc12
Solvent: ClCCl
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CCl)c2sccc12

Procedure:
A solution of 335 mg of 4-[2-(Benzo[b]thiophene-4-yloxy)-ethyl]-5-methyl-2-phenyl-oxazole (1 mmol) and 110 mg of Trioxane (3.6 mmol) in 15 ml dichloromethane was treated with 2 ml of 37% HCl solution and saturated for 10 min with HCl gas and reacted at 2° C. for 23 h. The resulting mixture was extracted wich 10% sodium carbonate solution and water and evaporated to dryness. Digestion with tert. butyl methylether at room temperature left a light brown residue (0.11 g) consisting of 4-[2-(7-Chloromethyl-benzo[b]thiophen-4-yloxy)-ethyl]-5-methyl-2-phenyl-oxazole with a m.p. of 144-145° C.
Reaction SMILES: [H-].[Na+].[F:3][CH:4]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]2[CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=[CH:20][C:7]=2[NH:6][C:5]1=[O:24].[CH3:25]I>O1CCCC1>[F:3][CH:4]1[N:10]=[C:9]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:8]2[CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=[CH:20][C:7]=2[N:6]([CH3:25])[C:5]1=[O:24]
Reactant: O=C1Nc2ccc([N+](=O)[O-])cc2C(c2ccccc2)=NC1F
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1C(=O)C(F)N=C(c2ccccc2)c2cc([N+](=O)[O-])ccc21
Temperature: 0 °C
Reaction time: 3 h
Yield: 60 %

Procedure:
A slurry of 0.20 g (0.08 mole) of sodium hydride in 10 ml of tetrahydrofuran was added to a solution of 1.74 g (0.0058 mole) of 3-fluoro-1,3-dihydro-7-nitro-5-phenyl-2H-1,4-benzodiazepin-2-one and 10 ml methyl iodide in 100 ml of tetrahydrofuran at 25°. The reaction mixture was stirred for 3 hr at 25°, and then poured into 300 ml of ice water. The aqueous mixture was extracted with methylene chloride, and the extracts were dried (MgSO4) and then evaporated to dryness under reduced pressure. The residue was dissolved in hot benzene and then fractionally precipitated by the addition of hexane. The first dark fractions of solid were discarded. The remaining fractions were collected on a filter and dried in vacuum to give 1.10 g (60%) of 3-fluoro-1,3-dihydro-1-methyl-7-nitro-5-phenyl-2H-1,4-benzodiazepin-2-one as a light tan amorphous solid with no distinct melting point: 1H nmr (CDCl3) δ 3.53 ppm (s, 3H), 5.59 ppm (d, J=57 Hz, 1H), 7.2-7.9 ppm (m, 6H) and 8.2-8.9 ppm (m, 2H); 19F nmr (CDCl3) δ -161.7 ppm (d, J=57 Hz).
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([C:21](=[O:24])[CH2:22]Cl)=[C:15]([CH:20]=1)[N:16]([CH3:19])[CH:17]=[O:18]>C(N(CC)CC)C.ClCCl>[C:1]([O:9][CH2:22][C:21]([C:14]1[CH:13]=[CH:12][C:11]([Cl:10])=[CH:20][C:15]=1[N:16]([CH3:19])[CH:17]=[O:18])=[O:24])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C=O)c1cc(Cl)ccc1C(=O)CCl
Reactant: O=C(O)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C=O)c1cc(Cl)ccc1C(=O)COC(=O)c1ccccc1

Procedure:
A solution of benzoic acid (18.8 g) in triethylamine (28.5 ml) and dichloromethane (110 ml) at 0° was added dropwise over 1 hour to the solution of 5'-chloro-2'-(2-chloroacetyl)-N-methylformanilide at 0° under nitrogen. The mixture was stirred for a further hour whilst maintaining the temperature at 0 to 5° and then heated under reflux overnight. After cooling, the reaction mixture was washed with water (2×100 ml), dried over magnesium sulphate, and the solvent removed by distillation to give the novel compound 2-[4-chloro-2-(N-methylformamido)phenyl]-2-oxoethyl benzoate in the form of a gum.