Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[NH:14][C:13](=[O:15])[C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:11][C:10]=1[C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1.[F:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][C:35]=1[F:36])[CH2:31]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[F:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][C:35]=1[F:36])[CH2:31][O:15][C:13]1[C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:11][C:10]([C:20]2[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=2)=[C:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[N:14]=1
Reactant: Fc1ccc(CBr)cc1F
Reactant: COC(=O)c1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)nc1OCc1ccc(F)c(F)c1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To a solution of methyl 6-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylate (300 mg, 0.73 mmol) from Example 51, Step A in DMF (3 mL) was added 3,4-difluorobenzyl bromide (0.122 mL, 0.95 mmol) and then cesium carbonate (310 mg, 0.95 mmol). The reaction was stirred at 50° C. for 3 h and was then diluted with water and extracted three times with methylene chloride. The organic layers were washed with a portion of brine and the combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude products. The products were separated by preparative TLC (3×1 mm) eluted with 25% ethyl acetate in hexanes to yield faster eluting O-alkylation title product. HPLC/MS: 534 (M+1), 536 (M+3); Rt=5.17 min. 1HNMR (CDCl3): δ 3.981 (s, 3H), 5.489 (s, 2H), 7.04 (br d, J=8.4 Hz, 2H), 7.11 (d, J=8.2 Hz, 1H), 7.2-7.6 (m, 3H), 7.38 (d, J=2.0 Hz, 1H), 8.285 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5](O)=O.[NH2:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:18]=1[NH2:19]>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[NH:19][C:18]3[CH:17]=[CH:16][N:15]=[CH:14][C:13]=3[N:12]=2)[CH:8]=[C:9]([Cl:11])[CH:10]=1
Reactant: O=C(O)c1cc(Cl)cc(Cl)c1
Reactant: Nc1ccncc1N
Product: Cl
Product: Clc1cc(Cl)cc(-c2nc3cnccc3[nH]2)c1

Procedure:
When 3,5-dichlorobenzoic acid and 3,4-diaminopyridine were reacted according to the procedure in Example 1, the title compound (base) was obtained. Upon converting to the hydrochloride salt and crystallization from ethanol/dimethylformamide/water, a 61% yield of pure 2-(3,5-dichlorophenyl)imidazo[4,5-c]pyridine hydrochloride was obtained as cream-colored needles, m.p. >320° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[C:18]([Cl:19])=[CH:17][C:16]([O:20][CH2:21][CH:22]=[C:23]([Cl:25])[Cl:24])=[CH:15][C:14]=2[Cl:26])=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:35])C=1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:9][CH2:10][CH2:11][O:12][C:13]2[C:18]([Cl:19])=[CH:17][C:16]([O:20][CH2:21][CH:22]=[C:23]([Cl:24])[Cl:25])=[CH:15][C:14]=2[Cl:26])=[O:35])=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: ClC(Cl)=CCOc1cc(Cl)c(OCCCSc2ccc(Cl)cc2)c(Cl)c1
Solvent: ClCCl
Product: O=S(CCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl)c1ccc(Cl)cc1
Temperature: 0 °C
Yield: 73.5 %

Procedure:
A mixture of 0.50 g of 1-(3-(4-chlorophenylthio)propyloxy)-2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)benzene and 20 ml of methylene chloride was stirred under cooling with ice-water, to which 0.26 g of m-chloroperbenzoic acid was added. After stirring at room temperature for 24 hours, the methylene chloride layer was separated, washed successively with saturated aqueous sodium sulfite solution, saturated aqueous sodium hydrogencarbonate solution and saturated saline solution, dried with magnesium sulfate, and concentrated to obtain a crude product. The crude product was subjected to silica gel chromatography, which afforded 0.38 g of 1-(3-(4-chlorophenylsulfinyl)propyloxy)-2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)benzene (73% yield), nD24.5 1.5962.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[CH:18]=[C:19]([CH:21]=[CH:22][C:23]=2[F:24])[NH2:20])[CH:5]=[CH:4][N:3]=1.N1C=CC=CC=1.[F:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:33]=1[S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[CH:18]=[C:19]([NH:20][S:39]([C:33]3[C:34]([F:38])=[CH:35][CH:36]=[CH:37][C:32]=3[F:31])(=[O:41])=[O:40])[CH:21]=[CH:22][C:23]=2[F:24])[CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(Cl)c1c(F)cccc1F
Reactant: CC(C)(C)c1nc(-c2cc(N)ccc2F)c(-c2ccnc(Cl)n2)s1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)c1nc(-c2cc(NS(=O)(=O)c3c(F)cccc3F)ccc2F)c(-c2ccnc(Cl)n2)s1
Temperature: 0 °C
Reaction time: 8 h
Yield: 20.9 %

Procedure:
To a solution of 3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-4-fluoroaniline (7.4 g, 20.4 mmol) in DCM (200 mL) was added pyridine (4.85 g, 61.3 mmol) and cooled to 0° C. 2,6-Difluorobenzene-1-sulfonyl chloride (4.76 g, 22.5 mmol) in DCM (10 mL) was added dropwise to the mixture. The reaction was stirred at rt overnight. Then the reaction was washed with water (200 mL), and extracted with DCM (2×100 mL). The organic layer was washed with brine, dried over anhydrous Na2SO4, filtrated and concentrated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (petroleum ether:EtOAc 5:1) to afford the title compound of Step E (2.3 g, 7.2% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.56 (d, J=5.3 Hz, 1H), 7.62-7.75 (m, 1H), 7.20-7.32 (m, 5H), 6.92 (d, J=5.3 Hz, 1H), 1.40 (s, 9H). m/z (ES+): 539 [M+H]+.
Reaction SMILES: C1C2C(=CC=CC=2)CCC1.[CH:11]1([C:21]([OH:23])=O)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][CH2:12]1.S(Cl)([Cl:26])=O>>[C@@H:11]1([C:21]([Cl:26])=[O:23])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][CH2:12]1
Reactant: O=C(O)C1CCCc2ccccc21
Reactant: O=S(Cl)Cl
Solvent: c1ccc2c(c1)CCCC2
Product: O=C(Cl)[C@H]1CCCc2ccccc21

Procedure:
According to Route A, 1,2,3,4-tetrahydronaphthalene (Compound VI) is converted into 1,2,3,4-tetrahydro-1-naphthoic acid (Compound VII), which is optically resolved to obtain the S-enantiomer (Compound VIIA). The optically enriched acid then is reacted with thionyl chloride to afford (S)-1,2,3,4-tetrahydro-1-naphthoyl chloride (Compound VIIIA). This acid chloride is reacted with Compound III to afford N-(1-azabicyclo[2.2.2]oct-3S-yl)-(1,2,3,4-tetrahydronaphthalen-1S-ylmethyl)amine (Compound IXA), which subsequently is converted to palonosetron hydrochloride over several steps.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1NC.C[CH2:10][N:11](C(C)C)C(C)C.[CH3:18][O:19][C:20]([C:22]1[S:23][C:24]([S:40][CH3:41])=[C:25]([S:27]([C:30]2[CH:35]=[CH:34][C:33](Br)=[C:32]([N+:37]([O-:39])=[O:38])[CH:31]=2)(=[O:29])=[O:28])[CH:26]=1)=[O:21]>C1COCC1>[CH3:18][O:19][C:20]([C:22]1[S:23][C:24]([S:40][CH3:41])=[C:25]([S:27]([C:30]2[CH:35]=[CH:34][C:33]([NH:11][CH2:10][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[C:32]([N+:37]([O-:39])=[O:38])[CH:31]=2)(=[O:29])=[O:28])[CH:26]=1)=[O:21]
Reactant: COC(=O)c1cc(S(=O)(=O)c2ccc(Br)c([N+](=O)[O-])c2)c(SC)s1
Reactant: CCN(C(C)C)C(C)C
Reactant: CNc1ccccn1
Solvent: C1CCOC1
Product: COC(=O)c1cc(S(=O)(=O)c2ccc(NCc3ccccn3)c([N+](=O)[O-])c2)c(SC)s1
Yield: 69 %

Procedure:
Pyridin-2-yl-methylamine (60 μL), DIEA (175 μL, 1 mmol), and 4-(4-bromo-3-nitro-benzenesulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester ((Example 264: step b) 56 mg, 0.12 mmol) were heated at 60° C. in THF (3 mL) for 30 min. The solvent was removed in vacuo and the residue was purified by SiO2 flash column chromatography to yield the title compound (41 mg, 69%). 1H-NMR (CDCl3): δ 9.46 (m, 1H), 8.90 (m, 1H), 8.64 (m, 1H), 8.01 (d, 1H, J=2.6 Hz), 7.94 (m, 1H), 8.03 (m, 2H), 7.71 (dt, 1H, J=1.9, 7.7 Hz), 7.28 (m, 2H), 6.95 (d, 1H, J=9.0 Hz), 4.67 (d, 1H, J=5.1 Hz), 3.87 (s, 3H), 2.60 (s, 3).
Reaction SMILES: C(B(CC)[C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)C.Br[C:13]1[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.O.C(O)C.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>[N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([C:13]2[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=2)[CH:5]=1
Reactant: CCB(CC)c1cccnc1
Reactant: Oc1cccc(Br)c1
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: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: Oc1cccc(-c2cccnc2)c1
Reaction time: 0.25 h
Yield: 92 %

Procedure:
A mixture of diethyl(3-pyridyl)borane (11.80 g, 80.0 mmol), 3-bromophenol (16.60 g, 96.0 mmol), Pd(PPh3)4 (0.92 g, 0.80 mmol), and Na2CO3 (17.0 g, 160.0 mmol) in toluene/water/ethanol (160/80/40 mL) was purged with nitrogen for 5 min and then heated at reflux under nitrogen for 2 h. After solvent removal, the aqueous residue was partitioned between ethyl acetate/brine (400/250 mL). The separated organic layer was washed with brine, filtered, and concentrated. The solid residue was taken up in 130 mL of 3 M HCl, stirred for 15 min, diluted with brine (150 mL), and extracted with ethyl acetate (2×250 mL). The separated aqueous layer was cooled in ice/water bath, adjusted to pH 10 with solid NaOH and Na2CO3, and extracted with ethyl acetate (2×300 mL). The organic extract was dried over sodium sulfate and concentrated to give 12.60 g (92%) of 3-pyridin-3-yl-phenol as a light yellow solid: 1H NMR (CDCl3) δ 6.99 (m, 1H), 7.08 (m, 1H), 7.22 (m, 1H), 7.36 (m, 1H), 7.43 (m, 1H), 8.00 (dd, 1H), 8.60 (d, 1H), 9.00 (s, 1H); MS m/z (relative intensity) 171 (M+, 100), 142 (17), 115 (21).
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1.[OH:25][CH2:26][C:27]([NH:30][S:31]([C:34]1[S:35][C:36](Cl)=[CH:37][CH:38]=1)(=[O:33])=[O:32])([CH3:29])[CH3:28]>>[OH:25][CH2:26][C:27]([NH:30][S:31]([C:34]1[S:35][C:36]([C:13]#[C:12][C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:1])[F:24])=[CH:4][C:5]([C:14]4[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=4)=[N:6][C:7]=23)=[CH:37][CH:38]=1)(=[O:33])=[O:32])([CH3:29])[CH3:28]
Reactant: CC(C)(CO)NS(=O)(=O)c1ccc(Cl)s1
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: CC(C)(CO)NS(=O)(=O)c1ccc(C#Cc2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)s1

Procedure:
The title compound was prepared from 7-difluoromethyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.2) (169 mg, 0.5 mmol) and 5-chloro-thiophene-2-sulfonic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (example B.22) (135 mg, 1.0 mmol) according to general procedure II. Obtained as a light brown orange solid (66 mg, 23%). MS (ISP) 571.3 [(M+H)+]; mp 157° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13](Cl)[CH:12]=2)=[CH:4][C:5]([F:9])=[C:6]([CH:8]=1)[NH2:7].[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH3:26][N:27]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[N:28]1>CN(C=O)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>[Br:1][C:2]1[C:3]([O:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([C:30]3[CH:29]=[N:28][N:27]([CH3:26])[CH:31]=3)[CH:12]=2)=[CH:4][C:5]([F:9])=[C:6]([CH:8]=1)[NH2:7]
Reactant: Nc1cc(Br)c(Oc2ccnc(Cl)c2)cc1F
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc(-c2cc(Oc3cc(F)c(N)cc3Br)ccn2)cn1
Temperature: 90 °C
Yield: 52.3 %

Procedure:
A mixture of 5-bromo-4-((2-chloropyridin-4-yl)oxy)-2-fluoroaniline (994 mg, 3.13 mmol), K3PO4 (1.993 g, 9.39 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (716 mg, 3.44 mmol) in DMF (10 mL) and water (1.5 mL) was sparged with Ar, treated with Pd(PPh3)4 (362 mg, 0.313 mmol) and heated at 90° C. overnight. The mixture was cooled to RT, diluted with water, extracted with EtOAc (2×) and the combined organics were washed with brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (EtOAc/Hex) to afford 5-bromo-2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)aniline (594 mg, 52%). MS (ESI) m/z: (M+H+): 363.0.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:11][C:12]([OH:14])=O.S(Cl)(Cl)=O.CC1C([N+]([O-])=O)=CC=CC=1CC(Cl)=O.[CH2:33]([NH:36][CH2:37][CH2:38][CH3:39])[CH2:34][CH3:35]>>[CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:11][C:12]([N:36]([CH2:37][CH2:38][CH3:39])[CH2:33][CH2:34][CH3:35])=[O:14]
Reactant: CCCNCCC
Reactant: Cc1c(CC(=O)O)cccc1[N+](=O)[O-]
Agent: Cc1c(CC(=O)Cl)cccc1[N+](=O)[O-]
Solvent: O=S(Cl)Cl
Product: CCCN(CCC)C(=O)Cc1cccc([N+](=O)[O-])c1C

Procedure:
The process as shown above comprises conversion of 2-methyl-3-nitro phenyl acetic acid (II) with thionyl chloride to 2-Methyl-3-nitro-phenylacetyl chloride (III), which upon reaction with Di-n-propyl amine (DPA) gives 2-Methyl-3-nitro phenyl-N,N-di-n-propyl acetamide (IV) in syrup form. This intermediate (IV) is further reduced with Borane/THF and subsequent treatment with HCl/NaOH to give 2-Methyl-3-nitro phenyl ethyl-N,N-di-n-propyl amine (V). Further, compound (V) is treated with Na metal, Ethanol and diethyl oxalate to obtain Ethyl 6-(2-di-n-propylaminoethyl)-2-nitrophenyl pyruvate (VI), which is further treated with hydrogen peroxide , NaOH and HCl and converted to 6-(2-Di-n-propylaminoethyl)-2-nitro phenyl acetic acid hydrochloride (VII). This intermediate is reduced with palladium/carbon to give Ropinirole hydrochloride (Ia).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][OH:10].CN(C=O)C.N1([C:21]([CH:23]2[C:36](=[O:37])[C:35]3[C:26](=[C:27]4[C:32](=[CH:33][CH:34]=3)[CH:31]=[CH:30][CH:29]=[N:28]4)[N:25]=[CH:24]2)=[O:22])C=CN=C1>C(O)(=O)C>[CH3:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][C:21]([CH:23]1[C:36](=[O:37])[C:35]2[C:26](=[C:27]3[C:32](=[CH:33][CH:34]=2)[CH:31]=[CH:30][CH:29]=[N:28]3)[N:25]=[CH:24]1)=[O:22]
Reactant: COCCOCCO
Reactant: O=C1c2ccc3cccnc3c2N=CC1C(=O)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COCCOCCOC(=O)C1C=Nc2c(ccc3cccnc23)C1=O
Reaction time: 0.5 h

Procedure:
Sodium hydride (3.15 g, 60%) was added in portions to a mixture of 2-(2-methoxyethoxy)ethanol (15 ml) and DMF (200 ml). The mixture was stirred for approximately 30 minutes until effervescence ceased. 3-(Imidazol-1-ylcarbonyl)-4-oxo-3,4-dihydro-1,10-phenanthroline (21.05 g) was added and the mixture stirred for 18 hours. The mixture was acidified to pH 5-6 with acetic acid, and evaporated to dryness under reduced pressure. Water (50 ml) was added and the mixture extracted with dichloromethane. The organic layer was washed with brine, dried (MgSO4) and evaporated to dryness under reduced pressure. The residue was purified by flash chromatography on silica using dichloromethane, followed by a 24:1:0.1 mixture of dichloromethane methanol : triethylamine as eluant. The product so obtained was triturated with ethyl acetate to give 3-[2-(2-methoxyethoxy)ethoxycarbonyl]-4-oxo-3,4-dihydro-1,10-phenanthroline in 68% overall yield, mp 164-165° C.
Reaction SMILES: [N:1]1([C:7]([NH:9][CH:10]([CH2:14][S:15]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:17])=[O:16])[C:11]([OH:13])=O)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH2:25][CH:26]1[C:29](=[O:30])[NH:28][CH:27]1[O:31][C:32](=[O:34])[CH3:33].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>ClCCl>[N:1]1([C:7]([NH:9][CH:10]([CH2:14][S:15]([CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)(=[O:16])=[O:17])[C:11]([NH:25][CH:26]2[C:29](=[O:30])[NH:28][CH:27]2[O:31][C:32](=[O:34])[CH3:33])=[O:13])=[O:8])[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: O=C(O)C(CS(=O)(=O)Cc1ccccc1)NC(=O)N1CCOCC1
Reactant: CC(=O)OC1NC(=O)C1N
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(=O)OC1NC(=O)C1NC(=O)C(CS(=O)(=O)Cc1ccccc1)NC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 12.5 %

Procedure:
2-[(Morpholine-4-carbonyl)-amino]-3-phenylmethanesulfonyl-propionic acid (100 mg, 0.28 mmol), acetic acid 3-amino-4-oxo-azetidin-2-yl ester (52 mg, 0.36 mmol), EDC (100 mg, 0.52 mmol), and HOBt (100 mg, 0.64 mmol) were combined. Dichloromethane (2 mL) was added and then 4-methylmorpholine (0.2 mL). The mixture was stirred at ambient temperature for 2 h. After dilution with ethyl acetate (100 mL) the solution was washed with 1N aqu. HCl (30 mL), sat. aqu. NaHCO3 (30 mL) and brine (30 mL), dried with MgSO4 and evaporated under vacuum. The residue was subjected to flash chromatography on silica gel (ethyl acetate) to give acetic acid 3-{2-[(morpholine-4-carbonyl)-amino]-3-phenylmethanesulfonyl-propionylamino}-4-oxo-azetidin-2-yl ester (17 mg, 0.035 mmol). 1H NMR: (DMSO) 9.18 (s, 1H), 8.72 (d, J=6.4 Hz, 1H), 7.41–7.30 (m, 5H), 7.08 (m, 1H), 5.76 (s, 1H), 4.80–4.61 (m, 2H), 4.49 (s, 2H), 3.63–3.22 (m, 10H), 2.08 (s, 3H). MS: (M+H)+ 483.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]3[CH2:21][CH2:20][CH2:19]3)[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1>>[CH:18]1([N:13]2[C:12]([C:34]3[CH:35]=[CH:36][C:31]([CH3:30])=[CH:32][CH:33]=3)=[C:11]3[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]3)=[N:14]2)[CH2:19][CH2:20][CH2:21]1
Reactant: CC(C)(C)OC(=O)N1CCc2nn(C3CCC3)c(OS(=O)(=O)C(F)(F)F)c2CC1
Reactant: Cc1ccc(B(O)O)cc1
Product: Cc1ccc(-c2c3c(nn2C2CCC2)CCNCC3)cc1
Yield: 95.2 %

Procedure:
The title compound (117 mg) was prepared according to Example 263 using 192 mg of 2-cyclobutyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 276, Step A) and 83 mg of 4-methylphenylboronic acid. MS (ESI): exact mass calculated for C18H23N3, 281.19; found, m/z 282.5 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.41-7.32 (m, 2H), 7.23-7.13 (m, 2H), 4.71-4.65 (m, 2H), 4.00-3.41 (m, 2H), 3.32-3.05 (m, 3H), 2.95-2.79 (m, 2H), 2.67-2.58 (m, 2H), 2.43 (s, 3H), 2.28-2.23 (m, 2H), 1.84-1.71 (m, 2H).
Reaction SMILES: CC1(C)[O:9][C:8](=[O:10])[C:5]2([CH2:7][CH2:6]2)[C:4](=[O:11])O1.[CH2:13]1[C:21]2[C:16](=[CH:17][C:18]([NH2:22])=[CH:19][CH:20]=2)[CH2:15][O:14]1>C(O)C>[CH2:13]1[C:21]2[C:16](=[CH:17][C:18]([N:22]3[CH2:6][CH2:7][CH:5]([C:8]([OH:9])=[O:10])[C:4]3=[O:11])=[CH:19][CH:20]=2)[CH2:15][O:14]1
Reactant: Nc1ccc2c(c1)COC2
Reactant: CC1(C)OC(=O)C2(CC2)C(=O)O1
Solvent: CCO
Product: O=C(O)C1CCN(c2ccc3c(c2)COC3)C1=O
Yield: 83.7 %

Procedure:
This compound was prepared according to general method 1 starting from 6,6-dimethyl-5,7-dioxaspiro[2.5]octane-4,8-dione (0.250 g; 1.45 mmol) and 1,3-dihydroisobenzofuran-5-amine (0.608 g; 4.36 mmol) in ethanol (3 mL). 1-(1,3-dihydroisobenzofuran-5-yl)-2-oxopyrrolidine-3-carboxylic acid 0.300 g (84%) was obtained as a white solid.
Reaction SMILES: [N:1](=[C:3]1[C:7](=[N:8][OH:9])[CH2:6][O:5][C:4]1=[O:10])[OH:2].[CH:11]([NH2:14])([CH3:13])[CH3:12]>CO>[OH:5][CH2:6][C:7](=[N:8][OH:9])[C:3](=[N:1][OH:2])[C:4]([NH:14][CH:11]([CH3:13])[CH3:12])=[O:10]
Reactant: O=C1OCC(=NO)C1=NO
Reactant: CC(C)N
Solvent: CO
Product: CC(C)NC(=O)C(=NO)C(CO)=NO
Reaction time: 3 h

Procedure:
9.4 g of 3,4-dioximino-2-oxotetrahydrofuran are suspended in 50 ml of methanol, and 4.2 g of isopropylamine are added. The mixture is stirred for 3 h and then cooled in an ice bath. The solid material is filtered off with suction and recrystallized from methanol.
Reaction SMILES: [F:1][C@H:2]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10]1[CH:15]=[CH:14][N:13]=[C:12](F)[N:11]=1)[CH3:3].[F:17][C:18]1[C:23]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:21]=[CH:20][C:19]=1[C:28]1[CH:29]=[N:30][C:31]([C@@H:34]([NH2:36])[CH3:35])=[N:32][CH:33]=1.CCN(C(C)C)C(C)C.O>CS(C)=O>[F:17][C:18]1[C:23]([C:24]([F:26])([F:25])[F:27])=[CH:22][CH:21]=[CH:20][C:19]=1[C:28]1[CH:33]=[N:32][C:31]([C@@H:34]([NH:36][C:12]2[N:11]=[C:10]([N:5]3[C@@H:4]([C@@H:2]([F:1])[CH3:3])[CH2:8][O:7][C:6]3=[O:9])[CH:15]=[CH:14][N:13]=2)[CH3:35])=[N:30][CH:29]=1
Reactant: C[C@H](F)[C@H]1COC(=O)N1c1ccnc(F)n1
Reactant: C[C@H](N)c1ncc(-c2cccc(C(F)(F)F)c2F)cn1
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1nccc(N2C(=O)OC[C@@H]2[C@H](C)F)n1)c1ncc(-c2cccc(C(F)(F)F)c2F)cn1
Yield: 76.1 %

Procedure:
(R)-4-((S)-1-fluoroethyl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one (50 mg, 0.218 mmol) and (S)-1-(5-(2-fluoro-3-(trifluoromethyl)phenyl)pyrimidin-2-yl)ethanamine (75 mg, 0.262 mmol) were taken up in 3 mL DMSO. Hunig's base (57 uL, 0.327 mmol) was added. The mixture was heated to 110 C for 1.5 h. The reaction mixture was poured into 30 mL water, and extracted with EtOAc (2×30 mL). Organics were washed with 20 mL each water, and brine. Combined organics were dried over Na2SO4, filtered and concentrated on silica gel. Column chromatography (25-100% EtOAc/heptane) gave 82 mg white solid. 1H NMR (400 MHz, CDCl3) δ 8.91 (d, J=1.4 Hz, 2H), 8.25 (d, J=5.7 Hz, 1H), 7.79-7.61 (m, 2H), 7.52 (d, J=5.7 Hz, 1H), 7.44 (tt, J=7.7, 0.8 Hz, 1H), 6.12 (s, 1H), 5.32 (s, 1H), 5.08 (br s, 1H), 4.80 (dddd, J=26.5, 9.1, 3.4, 1.5 Hz, 1H), 4.58 (dd, J=8.8, 3.4 Hz, 1H), 4.44 (td, J=9.0, 1.3 Hz, 1H), 1.68 (d, J=8.8 Hz, 3H), 1.43-1.24 (m, 3H). HRMS (A) m/z 495.1611 (M+H)+. Anal. RP-HPLC tR=3.68 min. Purity 96%/100%.
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[C:34]([CH2:38][C:39](Cl)=[O:40])([CH3:37])([CH3:36])[CH3:35]>C(#N)C>[O:32]=[C:26]1[CH:25]([N:18]2[C:17](=[O:33])[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:39](=[O:40])[CH2:38][C:34]([CH3:37])([CH3:36])[CH3:35])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: CC(C)(C)CC(=O)Cl
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC(C)(C)CC(=O)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.33 h

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.62 g, 4 mmol) was added to a stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione hydrochloride (0.6 g, 1.9 mmol) in acetonitrile (50 ml). After stirring for 20 min, t-butylacetyl chloride (0.25 g, 1.9 mmol) was added. The mixture was stirred at room temperature for 17 hours. Solvent was removed in vacuo and the residue was dissolved in dichloromethane (90 ml) and washed with 0.1N HCl (30 ml), water (30 ml), brine (30 ml) and then dried. Solvent was removed in vacuo and the solid residue was slurried in ethanol (10 ml) to give after filtration 0.55 g (77%) of the product: mp 145-147° C.; 1H NMR (DMSO-d6) δ 11.14 (s, 1H), 8.39 (t, J=5.7 Hz, 1H), 7.87-7.69 (m, 3H), 5.19-5.12 (dd, J=5.3 and 12.4 Hz, 1H), 4.72 (d, J=5.8 Hz, 2H), 2.92-2.83 (m, 1H), 2.63-2.51 (m, 2H), 2.08 (s, 2H), 2.08-2.04 (m, 1H), 0.97 (s, 9H); 13C NMR (DMSO-d6) δ 172.69, 171.35, 169.74, 167.51, 166.96, 139.61, 134.69, 133.41, 131.52, 127.11, 121.87, 48.86, 48.62, 37.53, 30.93, 30.52, 29.71, 22.00; Anal. Calcd. For C20H23N3O5+0.28 water: C, 61.52; H, 6.08; N, 10.76. Found: C, 61.23; H, 6.18; N, 10.57.