Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[CH3:11][S:12]([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18](O)=O)(=[O:14])=[O:13].N>>[CH3:11][S:12]([C:15]1[CH:16]=[C:17]([C:18]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=3)[N:10]=2)[CH:21]=[CH:22][CH:23]=1)(=[O:13])=[O:14]
Reactant: NC(=NO)c1cccnc1
Reactant: CS(=O)(=O)c1cccc(C(=O)O)c1
Agent: N
Product: CS(=O)(=O)c1cccc(-c2nc(-c3cccnc3)no2)c1

Procedure:
The title compound was prepared according to the procedure of Example 8 using N′-hydroxynicotinimidamide (Aldrich) and 3-(methylsulfonyl)benzoic acid (Aldrich). 1H NMR (300 MHz, CD3OD) δ 3.24 (s, 3 H), 7.65 (ddd, J=8.0, 4.9, 1.0 Hz, 1 H), 7.89-7.96 (m, 1 H), 8.28 (ddd, J=8.0, 1.9, 1.0 Hz, 1 H), 8.55-8.61 (m, 2 H), 8.75 (dd, J=5.1, 1.7 Hz, 1 H), 8.78 (t, J=1.5 Hz, 1 H), 9.32 (dd, J=2.2, 0.8 Hz, 1 H) ppm; MS (DCI/NH3) m/z 302 (M+H)+.
Reaction SMILES: [C@@H:1]12[CH2:7][C@@H:4]([CH2:5][CH2:6]1)[CH2:3][C@@H:2]2[NH:8][C:9]1[S:10][CH:11]([CH2:15][CH2:16]Br)[C:12](=[O:14])[N:13]=1.[Li+].[CH3:19]C([N-]C(C)C)C.[CH3:26][C:27](C)=[O:28]>C1COCC1>[C@@H:1]12[CH2:7][C@@H:4]([CH2:5][CH2:6]1)[CH2:3][C@@H:2]2[NH:8][C:9]1[S:10][C:11]2([CH2:26][CH2:27][O:28][C:15]2([CH3:16])[CH3:19])[C:12](=[O:14])[N:13]=1
Reactant: O=C1N=C(N[C@H]2C[C@@H]3CC[C@H]2C3)SC1CCBr
Reactant: CC(C)=O
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1(C)OCCC12SC(N[C@H]1C[C@@H]3CC[C@H]1C3)=NC2=O
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2-((1S,2S,4R)-bicyclo[2.2.1]heptan-2-ylamino)-5-(2-bromoethyl)thiazol-4(5H)-one (134 mg, 0.5 mmol) in THF (1 mL) at −78° C. was added LDA (2.0 N, 1.25 ml). After 5 min, acetone (500 uL) was added, and the reaction mixture was stirred for 3 h at −78° C. The resulting reaction mixture was poured into a sat'd NaH2PO4 and extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The crude residue was purified through flash chromatography (4:1; Hexane:EtOAc) to give 2-((1S,2S,4R)-bicyclo[2.2.1]hept-2-ylamino)-6,6-dimethyl-7-oxa-1-thia-3-azaspiro[4.4]non-2-en-4-one as a white solid. (MS (ES+): 295 (M+H)+), and 5-((1S,2S,4R)-bicyclo[2.2.1]hept-2-ylamino)-4-thia-6-azaspiro[2.4]hept-5-en-7-one as a white solid. MS (ES+): 237 (M+H)+.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]1=[O:9].Cl[CH2:11][CH:12]=[CH:13][C:14]1[S:15][CH:16]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[N:18]=1>CN(C=O)C>[F:25][C:22]1[CH:21]=[CH:20][C:19]([C:17]2[N:18]=[C:14]([CH:13]=[CH:12][CH2:11][N:3]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]3=[O:9])[S:15][CH:16]=2)=[CH:24][CH:23]=1
Reactant: O=c1cccc[nH]1
Reactant: Fc1ccc(-c2csc(C=CCCl)n2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1ccccn1CC=Cc1nc(-c2ccc(F)cc2)cs1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
23.7 mg (0.54 mmol) of sodium hydride (55% in mineral oil) were added to 60.4 mg (0.54 mmol) of 1H-pyridin-2-one in 8 ml of DMF. The mixture was stirred at room temperature for 1 h, 92 mg (0.36 mmol) of 2-(3-chloropropenyl)-4-(4-fluorophenyl)thiazole were added, and the mixture was stirred at room temperature for another 4 h and subsequently at 50° C. for 2 h. After concentrating, water was added and the product was extracted with ethyl acetate. The organic phases were evaporated and the residue was purified by preparative HPLC (RP18, acetonitrile/water containing 0.1% TFA). Yield: 26 mg (23%).
Reaction SMILES: [NH2:1][C:2]1([CH2:8]O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.O=S(Cl)Cl.[CH3:14][C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1[N:24]=[C:25]=[S:26]>O1CCOCC1>[CH3:14][C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1[N:24]=[C:25]1[S:26][CH2:8][C:2]2([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)[NH:1]1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Reactant: NC1(CO)CCCCC1
Solvent: C1COCCO1
Solvent: O=S(Cl)Cl
Product: Cc1cc([N+](=O)[O-])ccc1N=C1NC2(CCCCC2)CS1
Yield: 20 %

Procedure:
1-Amino-1-(hydroxymethyl)cyclohexane (Method B1a) was dissolved in p-dioxane (80 mL) then treated with SOCl2 followed by 2-methyl-4-nitrophenyl isothiocyanate in a manner analogous to Method C2a to give 2-(2-methyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.5]decane (20%), which was reacted with isobutyl bromide in a manner analogous to Method D2a to yield 1-isobutyl-2-(2-methyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.5]decane (0.026 g, 2%): TLC (20% EtOAc/hex) Rf0.69.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[NH2:37][CH2:38][C:39]([NH:41][CH:42]([CH3:44])[CH3:43])=[O:40]>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([NH:37][CH2:38][C:39](=[O:40])[NH:41][CH:42]([CH3:44])[CH3:43])=[O:9]
Reactant: O=C(O)c1cc(F)ccc1[N+](=O)[O-]
Reactant: CC(C)NC(=O)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)NC(=O)CNC(=O)c1cc(F)ccc1[N+](=O)[O-]
Yield: 70 %

Procedure:
To a solution of 5-fluoro-2-nitrobenzoic acid (370 mg, 2.0 mmol) in anhydrous DMF (5 mL) was added 1-hydroxybenzotriazole hydrate (330 mg, 2.4 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (460 mg, 2.4 mmol) and 2-amino-N-isopropylacetamide (INTERMEDIATE I.1) (230 mg, 2.0 mmol). The resultant mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated in vacuo, the crude yellow residue dissolved in EtOAc (20 mL) and washed with dilute HCl (aq.) (3×5 mL), sat. NaHCO3 (aq.) (3×5 mL) and brine (1×5 mL). The organic layer was dried (Na2SO4), concentrated in vacuo and purified by chromatography on silica gel with MeOH:DCM (1:19, v/v) as eluent to afford 5-fluoro-N-(isopropylcarbamoylmethyl)-2-nitrobenzamide (INTERMEDIATE IV.1) (400 mg, 1.4 mmol, 70%) as yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([S:12](=[O:15])(=[O:14])[NH2:13])=[CH:4][C:3]=1[NH2:16].O.O.[C:19](O)(=[O:23])[C:20](O)=[O:21]>Cl>[OH:21][C:20]1[C:19]([OH:23])=[N:16][C:3]2[CH:4]=[C:5]([S:12](=[O:15])(=[O:14])[NH2:13])[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]=2[N:1]=1
Reactant: Nc1cc(S(N)(=O)=O)c2ccccc2c1N
Reactant: O=C(O)C(=O)O
Agent: Cl
Solvent: O
Product: NS(=O)(=O)c1cc2nc(O)c(O)nc2c2ccccc12
Temperature: 25 °C
Yield: 50 %

Procedure:
A mixture of 1.0 g (3.4 mmol) 1,2-diamino-4-sulphamoyl-naphtalene and 1.0 (7.9 mmol) oxalic acid dihydrate in 20 ml 2N HCl was refluxed for 2 hours. After cooling to room temperature the precipitate was filtered off and washed with water. The crude product was recrystallized from dimethylformamide/water to give 0.6 g (50%) of the title compound.
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][CH2:4][OH:5].[H-].[Na+].[CH2:9]([O:11][CH:12]([O:15][CH2:16][CH3:17])[CH2:13]Br)[CH3:10]>CN(C)C=O>[CH2:9]([O:11][CH:12]([O:15][CH2:16][CH3:17])[CH2:13][O:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:6])[CH3:10]
Reactant: OCCCCO
Reactant: CCOC(CBr)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(COCCCCO)OCC
Temperature: 0 °C
Reaction time: 8 h
Yield: 41.9 %

Procedure:
To a mixture of 56.3 g of 1,4-butanediol and 400 ml of N,N-dimethylformamide was slowly added 11.0 g of 60% sodium hydride (in oil) with stirring under ice cooling. After stirring at room temperature for 12 hours, 49.3 g of bromoacetaldehyde diethylacetal was added dropwise, and the stirring was further continued at 60° C. for 8 hours. The reaction mixture was poured into ice water, and extracted twice with ethyl acetate. The ethyl acetate layers were combined, washed with water, dried over anhydrous magnesium sulfate, and concentrated to give a crude product. This crude product was subjected to silica gel chromatography, which afforded 21.6 g (yield, 41%) of 4-(2,2-diethoxyethoxy)butanol.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8]([OH:10])=O)=[CH:4][CH:3]=1.[NH2:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][N:22]=1)[C:17]([NH2:19])=[O:18].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CO>CN(C1C=CN=CC=1)C.CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]([NH:13][C:14]2[CH:15]=[C:16]([CH:20]=[CH:21][N:22]=2)[C:17]([NH2:19])=[O:18])=[O:10])=[CH:11][CH:12]=1
Reactant: NC(=O)c1ccnc(N)c1
Reactant: O=C(O)COc1ccc(Br)cc1
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CO
Solvent: CN(C)C=O
Product: NC(=O)c1ccnc(NC(=O)COc2ccc(Br)cc2)c1
Temperature: 25 °C
Yield: 55.1 %

Procedure:
To solution of (4-bromo-phenoxy)-acetic acid (100 mg, 0.43 mmol), 2-amino isonicotinamide (89.39 mg, 0.65 mmol) and DMAP (106 mg, 0.86 mmol) in DMF 5 ml was added PyBOP (452 mg, 0.86 mmol), and stirred room temperature. Reaction mixture was poured onto ice cold water, diluted by methanol/MC mixture (10%). The organic phase was separated, sequentially washed with aqueous sodium bicarbonate, brine and water, dried over anhydrous MgSO4, and concentrated. The residue was purified by PLC (EtoAC:Hexane:MeOH=3:6:1˜2:4:1) to afford 2-[2-(4-bromo-phenoxy)-acetylamino]-isonicotinamide as a colorless solid (0.083 g, 55% yield).
Reaction SMILES: CS(Cl)(=O)=O.[C:6]([O:13][CH3:14])(=[O:12])/[CH:7]=[CH:8]\[C:9]([O-:11])=O.[Cl:15][C:16]1[CH:24]=[C:20]([C:21](O)=[O:22])[C:19]([NH2:25])=[CH:18][CH:17]=1>O.N1C=CC=CC=1.C(#N)C>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]2[N:25]=[C:9](/[CH:8]=[CH:7]/[C:6]([O:13][CH3:14])=[O:12])[O:11][C:21](=[O:22])[C:20]=2[CH:24]=1
Reactant: COC(=O)/C=C\C(=O)[O-]
Reactant: Nc1ccc(Cl)cc1C(=O)O
Agent: CS(=O)(=O)Cl
Solvent: CC#N
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)/C=C/c1nc2ccc(Cl)cc2c(=O)o1
Reaction time: 0.08 h
Yield: 68.3 %

Procedure:
A mixed solution comprising 1.49 g of methanesulfonyl chloride and 10 ml of acetonitrile was cooled with ice, and 10 ml of an acetonitrile solution comprising 1.3 g of monomethyl maleate and 1.34 g of pyridine was dropwise added thereto under cooling with ice over a period of 5 minutes, followed by stirring for 5 minutes at the same temperature. 10 ml of an acetonitrile solution comprising 1.72 g of 5-chloroanthranilic acid and 2.77 g of pyridine was added under cooling with ice over a period of 2 minutes, followed by rinsing with 5 ml of acetonitrile and stirring for 20 minutes at the same temperature. 1.49 g of methanesulfonyl chloride was added over a period of 2 minutes under cooling with ice, followed by rinsing with 2 ml of acetonitrile and stirring for 30 minutes, and then the temperature was returned to room temperature, followed by reaction for 4 hours. The reaction liquid was poured to 20 ml of water, followed by stirring for 30 minutes. The resulting crystals were collected by filtration, washed with water and a mixed liquid of acetonitrile:water (2:1), and dried to obtain 1.82 g of the brown desired product (melting point: 162 to 164° C.).
Reaction SMILES: [OH:1][C@:2]([CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)([CH:7]([CH3:9])[CH3:8])[CH2:3][C:4]([OH:6])=O.C1N=CN(C(N2C=NC=C2)=O)C=1.C1C[O:34][CH2:33][CH2:32]1>>[OH:6][C:4]1[CH2:3][C@@:2]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)([CH:7]([CH3:9])[CH3:8])[O:1][C:33](=[O:34])[CH:32]=1
Reactant: C1CCOC1
Reactant: CC(C)[C@](O)(CCc1ccc(O)cc1)CC(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Product: CC(C)[C@]1(CCc2ccc(O)cc2)CC(O)=CC(=O)O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The title compound was prepared using (S)-3-hydroxy-3-[2-(4-hydroxy-phenyl)-ethyl]-4-methyl-pentanoic acid (0.45 g, 1.78 mmol) from Example UUUU, THF (10 mL), and CDI (0.58 g, 3.58 mmol). The reaction was stirred overnight at room temperature then added to bis[3-ethoxy-3-oxopropanoato(1-)-O,O']-magnesate (1.5 g, 5.2 mmol) from Example VVVV and the reaction stirred for 3 days at room temperature. The reaction was concentrated and the residue partitioned between ethyl acetate and 1N HCl. The organic layer was washed with aqueous NaHCO3 and brine, dried (MgSO4) and concentrated.
Reaction SMILES: [CH2:1]([N:3]([C:31](=O)[C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[C:34]([F:39])[CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].Cl[CH2:42][C:43]([N:45]1[CH2:50][CH2:49][CH:48]([CH3:51])[CH2:47][CH2:46]1)=O>>[CH2:1]([N:3]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:42][CH2:43][N:45]2[CH2:50][CH2:49][CH:48]([CH3:51])[CH2:47][CH2:46]2)=[C:34]([F:39])[CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2]
Reactant: CCN(C(=O)c1ccc(O)c(F)c1)c1cc(OC)c(OC)cc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CC1CCN(C(=O)CCl)CC1
Product: CCN(Cc1ccc(OCCN2CCC(C)CC2)c(F)c1)c1cc(OC)c(OC)cc1C1CCc2cc(O)ccc2C1
Yield: 4 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(3-fluoro-4-hydroxybenzoyl)amino]-4,5-dimethoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (19 mg) and 2-chloro-1-(4-methylpiperidin-1-yl)ethanone (12 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (0.8 mg) was obtained.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[NH:7][CH2:6][C:5]=12.C(N(C(C)C)CC)(C)C.Cl.[N:25]1([C:30]2[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=2)[CH:29]=[CH:28][N:27]=[CH:26]1>CN(C)C1C=CN=CC=1.ClCCl>[N:25]1([C:30]2[CH:31]=[CH:32][C:33]([C:34]([N:7]3[C:8]4[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=4[CH2:10][N:4]4[CH:3]=[CH:2][CH:1]=[C:5]4[CH2:6]3)=[O:35])=[CH:37][CH:38]=2)[CH:29]=[CH:28][N:27]=[CH:26]1
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Reactant: O=C(Cl)c1ccc(-n2ccnc2)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(c1ccc(-n2ccnc2)cc1)N1Cc2cccn2Cc2ccccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]-benzodiazepine (0.75), diisopropylethylamine (1.20 g), and 4-dimethylaminopyridine (0.1 g) in dichloromethane (50 ml) was added 4-(imidazol-1-yl)benzoyl chloride hydrochloride (1.12 g). After stirring at room temperature for 18 hours, the reaction mixture was washed with water and saturated aqueous sodium bicarbonate. The dichloromethane solution was dried over anhydrous sodium sulfate, filtered through a short column of hydrous sodium magnesium silicate, and further eluted with several volumes of dichloromethane. The combined organic phase was concentrated on a hot plate with the gradual addition of hexane until crystallization occurred. After cooling, the crystals were collected by filtration to yield the title compound (0.57 g), m.p. 171-172° C.; MS, m/z: 354 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[N:15]=[C:14]([C:16]4[S:17][C:18]([C:27]([F:30])([F:29])[F:28])=[C:19]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)[CH:20]=4)[O:13][N:12]=3)[CH:9]=2)[NH:4][CH:3]=1.Br[CH2:32][CH2:33][C:34]([O-:36])=[O:35].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[N:15]=[C:14]([C:16]4[S:17][C:18]([C:27]([F:30])([F:28])[F:29])=[C:19]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)[CH:20]=4)[O:13][N:12]=3)[CH:9]=2)[N:4]([CH2:32][CH2:33][C:34]([OH:36])=[O:35])[CH:3]=1
Reactant: O=C([O-])CCBr
Reactant: FC(F)(F)c1sc(-c2nc(-c3ccc4[nH]cc(Cl)c4c3)no2)cc1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C(O)CCn1cc(Cl)c2cc(-c3noc(-c4cc(-c5ccccc5)c(C(F)(F)F)s4)n3)ccc21
Temperature: 131 °C
Reaction time: 1.5 h
Yield: 23 %

Procedure:
D8 (86 mg), 3-bromopropionate (52 mg), Cs2CO3 (126 mg) and DMF (1 ml) were placed in a microwave vial and stirred at 131° C. in the microwave reactor for 1.5 hours. The reaction mixture was then evaporated to dryness and treated with 2M aq. NaOH and EtOH (20 ml). This solution was stirred at 50° C. for 4 hours and then neutralised with HCl and evaporated to remove the EtOH. The aqueous solution was then extracted twice with EtOAc and the combined extracts evaporated. The residue was dissolved in DMSO, filtered, treated with MeCN causing precipitation of the product which was filtered and washed with MeCN to give the title compound (23 mg) as an off-white solid. δH (d6-DMSO, 400 MHz): 2.47-2.57 (solvent+2H) 4.37 (2H, t), 7.51-7.59 (5H, m), 7.72 (1H, s), 7.76 (1H, d), 7.89 (1H, d), 8.17 (1H, s), 8.25 (1H, s). MS (ES): C24H16ClF3N3O2S requires 517; found 516 (M−H+).
Reaction SMILES: C1C2C(COC([CH2:18][C:19]([N:21]3[CH2:25][C@H:24]([F:26])[CH2:23][C@@H:22]3[C:27]([O:29]C)=O)=[O:20])=O)C3C(=CC=CC=3)C=2C=CC=1.[NH:31]1CCCCC1>CO>[F:26][C@H:24]1[CH2:25][N:21]2[C:19](=[O:20])[CH2:18][NH:31][C:27](=[O:29])[CH:22]2[CH2:23]1
Reactant: COC(=O)[C@H]1C[C@@H](F)CN1C(=O)CC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: C1CCNCC1
Solvent: CO
Product: O=C1NCC(=O)N2C[C@H](F)CC12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A scintillation vial was charged with (2S,4R), (2R,4R)-methyl 1-(2-(((9H-fluoren-9-yl)methoxy)carbonyl)acetyl)-4-fluoropyrrolidine-2-carboxylate (815 mg, 1911 μmol), 19 mL MeOH and piperidine (946 μA 9556 μmol). The mixture was stirred at RT overnight The mixture was concentrated, dissolved in DCM/MeOH and purified by silica gel chromatography, 50-100% 90/10/1 DCM/MeOH/NH4OH in DCM. (7R)-7-fluoro-hexahydropyrrolo[1,2-a]pyrazine-1,4-dione was isolated as a white solid, and confirmed by 1H-NMR.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8](/[CH:11]=[C:12](/[C:15](=O)[CH3:16])\[C:13]#[N:14])[CH:9]=2)[NH:4][N:3]=1.O[C:19]1[C:23]([CH3:25])([CH3:24])[NH:22][C:21](=[O:26])[CH:20]=1.C([O-])(=O)C.[NH4+:31]>C(O)(=O)C>[CH3:16][C:15]1[NH:31][C:19]2[C:23]([CH3:25])([CH3:24])[NH:22][C:21](=[O:26])[C:20]=2[CH:11]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[NH:4][N:3]=[C:2]3[CH3:1])[C:12]=1[C:13]#[N:14]
Reactant: CC1(C)NC(=O)C=C1O
Reactant: CC(=O)/C(C#N)=C/c1ccc2[nH]nc(C)c2c1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: CC1=C(C#N)C(c2ccc3[nH]nc(C)c3c2)C2=C(N1)C(C)(C)NC2=O

Procedure:
A solution of 200 mg (0.888 mmol) (2E)-2-[(3-methyl-1H-indazol-5-yl)methylidene]-3-oxobutanenitrile (Example 2A), 226 mg (0.888 mmol, approx. 50% purity) 4-hydroxy-5,5-dimethyl-1,5-dihydro-2H-pyrrol-2-one [K. Matsuo et al., Chem. Pharm. Bull. 1984, 32, 3724-3729] and 102 mg (1.332 mmol) ammonium acetate in acetic acid (4 ml) was stirred at 100° C. for 15 min. The reaction mixture was concentrated under reduced pressure, and the residue was purified first by preparative RP-HPLC (acetonitrile/water+0.1% TFA gradient) and then by preparative TLC (eluent: dichloromethane/methanol 10:1) to give 33 mg (11% of th.) of the title compound.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH2:24]([O:26][CH2:27][C:28]1[C:29]([NH:43][CH2:44][CH3:45])=[N:30][CH:31]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:33]=1)[CH3:25]>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:32]5[CH:31]=[N:30][C:29]([NH:43][CH2:44][CH3:45])=[C:28]([CH2:27][O:26][CH2:24][CH3:25])[CH:33]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: CCNc1ncc(B2OC(C)(C)C(C)(C)O2)cc1COCC
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: CCNc1ncc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)cc1COCC

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and [3-ethoxymethyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-ethyl-amine (Stage 167.1.1) to give the title compound as a white solid. (HPLC: tR 2.30 min (Method A); M+H=472 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.90 (s, 1H), 8.19-8.16 (m, 1H), 8.12 (s, 1H), 8.05-8.01 (m, 1H), 7.87-7.83 (m, 1H), 7.44-7.41 (m, 2H), 6.07 (t, 1H), 4.39 (s, 2H), 3.92 (s, 3H), 3.56 (s, 3H), 3.51 (q, 2H), 3.46-3.37 (m, 2H), 1.95 (s, 3H), 1.19 (t, 3H), 1.15 (t, 3H))
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10](C(O)=O)=[CH:11][C:12]3[O:16][CH:15]=[N:14][C:13]=3[C:17]=2[F:18])=[C:4]([Cl:22])[CH:3]=1.C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:30])=CC=1.C([N:42]([CH2:45]C)CC)C>CC(O)(C)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:9]3[C:10](=[CH:11][C:12]4[O:16][CH:15]=[N:14][C:13]=4[C:17]=3[F:18])[NH:42][C:45]2=[O:30])=[C:4]([Cl:22])[CH:3]=1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: O=C(O)c1cc2ocnc2c(F)c1Nc1ccc(Br)cc1Cl
Reactant: CCN(CC)CC
Solvent: CC(C)(C)O
Product: O=c1[nH]c2cc3ocnc3c(F)c2n1-c1ccc(Br)cc1Cl
Temperature: 25 °C
Yield: 96.2 %

Procedure:
To a solution of 5-((4-bromo-2-chlorophenyl)amino)-4-fluorobenzo[d]oxazole-6-carboxylic acid (110 mg, 0.28 mmol) in t-BuOH (3 mL) was added DPPA (94 mg, 0.34 mmol) followed by triethylamine (58 mg, 0.57 mmol). The mixture was heated under reflux for 3 h and allowed to slowly warm to room temperature. The solvent was removed in vacuo and the resultant crude product was purified by column chromatography on silica gel (petroleum ether/ethyl acetate, 2:1, v/v). The corresponding product was obtained (white solid, 105 mg, 96.2% yield). 1H NMR (400 MHz, DMSO-d6): δ 11.78 (s, 1H), 8.69 (s, 1H), 7.99 (d, 1H), 7.77 (d, 1H), 7.51 (m, 1H), 7.41 (s, 1H).
Reaction SMILES: [OH:1][CH2:2][CH:3]([NH:12][CH:13]([CH:21]([CH3:23])[CH3:22])[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1.C(Cl)Cl.N1C=CC=CC=1.[S:33](Cl)(Cl)=[O:34].[OH2:37]>>[CH3:11][O:10][C:7]1[CH:6]=[CH:5][C:4]([CH:3]2[CH2:2][O:1][S:33](=[O:34])(=[O:37])[N:12]2[CH:13]([CH:21]([CH3:23])[CH3:22])[C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])=[CH:9][CH:8]=1
Reactant: O
Reactant: COc1ccc(C(CO)NC(C(=O)OC(C)(C)C)C(C)C)cc1
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(C2COS(=O)(=O)N2C(C(=O)OC(C)(C)C)C(C)C)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
t-Butyl 2-(2-hydroxy-1-(4-methoxyphenyl)ethylamino)-3-methylbutyrate (2.5 g; 7.73 mmol) was introduced into CH2Cl2 (200 ml), and the solution was cooled to −78° C. Addition of pyridine (3.12 ml; 38.65 mmol) was followed by slow dropwise addition of thionyl chloride (0.67 ml; 9.27 mmol). The reaction mixture was stirred for 1 h, during which the temperature was allowed to rise to 0° C. The reaction mixture was partitioned between aqueous 1% strength HCl/CH2Cl2 and extracted with CH2Cl2 (2×). The combined organic phases were washed with saturated NaHCO3 solution and dried over MgSO4, and the solvent was removed in a rotary evaporator. The residue was taken up in acetonitrile (20 ml) and cooled to 0° C. Then NaIO4 (1.82 g; 8.5 mmol), RuCl3.H2O (14.43 mg; 0.077 mmol) and water (20 ml) were added. The reaction mixture was stirred at 0° C. for 5 minutes and then at RT for a further 20 minutes. It was then partitioned between saturated NaHCO3 solution/CH2Cl2 and extracted with CH2Cl2 (2×). The combined organic phases were washed with saturated NaHCO3 and dried over MgSO4, and the solvent was removed in a rotary evaporator. Purification by chromatography resulted in t-butyl 2-(4-(4-methoxyphenyl)-2,2-dioxo-(1,2,3)oxathiazolidin-3-yl)-3-methylbutyrate (2.5 g; 6.48 mmol). MS: 403.15 (M+NH4+); Rt: 1.82 min (method: gradient 0 min 96% H2O (0.05% TFA) 2.0 min 95% acetonitrile, 95% acetonitrile to 2.4 min, 4% acetonitrile 2.45 min; flow rate 1 ml/min; column 0.4 μL (YMC J'sphere ODS H80 20X2 1.4μ); 30° C.).