Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C@H:3]([C:7]([NH:9][C@H:10]([C:14]([N:16]([C@@H:18]([C@@H:57]([CH3:60])[CH2:58][CH3:59])[C@H:19]([O:55][CH3:56])[CH2:20][C:21]([N:23]1[CH2:27][CH2:26][CH2:25][C@H:24]1[C@H:28]([O:53][CH3:54])[C@@H:29]([CH3:52])[C:30]([NH:32][C@@H:33]([CH2:42][C:43]1[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[NH:45][CH:44]=1)[C:34]([N:36]1[CH2:41][CH2:40][CH2:39][CH2:38][O:37]1)=[O:35])=[O:31])=[O:22])[CH3:17])=[O:15])[CH:11]([CH3:13])[CH3:12])=[O:8])[CH:4]([CH3:6])[CH3:5].O=[CH:62][CH2:63][CH2:64][CH2:65][CH2:66][C:67]([OH:69])=[O:68].C(O)(=O)C>CO>[C:67]([CH2:66][CH2:65][CH2:64][CH2:63][CH2:62][N:2]([CH3:1])[C@H:3]([C:7]([NH:9][C@H:10]([C:14]([N:16]([C@@H:18]([C@@H:57]([CH3:60])[CH2:58][CH3:59])[C@H:19]([O:55][CH3:56])[CH2:20][C:21]([N:23]1[CH2:27][CH2:26][CH2:25][C@H:24]1[C@H:28]([O:53][CH3:54])[C@@H:29]([CH3:52])[C:30]([NH:32][C@@H:33]([CH2:42][C:43]1[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[NH:45][CH:44]=1)[C:34]([N:36]1[CH2:41][CH2:40][CH2:39][CH2:38][O:37]1)=[O:35])=[O:31])=[O:22])[CH3:17])=[O:15])[CH:11]([CH3:12])[CH3:13])=[O:8])[CH:4]([CH3:5])[CH3:6])([OH:69])=[O:68]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N1CCCCO1)OC)N(C)C(=O)[C@@H](NC(=O)[C@@H](NC)C(C)C)C(C)C
Reactant: O=CCCCCC(=O)O
Solvent: CO
Solvent: CC(=O)O
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N1CCCCO1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCCCC(=O)O)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.7 %

Procedure:
80 mg (0.08 mmol) of N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(2S)-3-(1H-indol-3-yl)-1-(1,2-oxazinan-2-yl)-1-oxopropan-2-yl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide (Intermediate 192) and 65.4 mg (0.5 mmol) of 6-oxohexanoic acid were combined in 9 ml of methanol and admixed with 10 μl of acetic acid and 37.4 mg (0.4 mmol) of borane-pyridine complex. The reaction mixture was stirred at RT overnight. This was followed by concentration under reduced pressure, and the residue was taken up in 1:1 acetonitrile/water and adjusted to pH 2 with trifluoroacetic acid. The reaction mixture was concentrated again and the residue was purified by means of preparative HPLC. After concentration of the corresponding fractions, 70 mg (86% of theory) of N-(5-carboxypentyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(2S)-3-(1H-indol-3-yl)-1-(1,2-oxazinan-2-yl)-1-oxopropan-2-yl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide were obtained as the trifluoroacetate.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:26]2[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[C:28](F)[CH:27]=2)[N:3]=1.CCO.CCN(C(C)C)C(C)C.[NH2:47][NH2:48]>O.CO>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:26]2[CH:27]=[C:28]3[C:29]([C:32]([NH2:33])=[N:47][NH:48]3)=[CH:30][CH:31]=2)[N:3]=1
Reactant: Cc1ccc(CNC(=O)[C@H]2CC[C@@H](C)N(c3cc(-c4ccc(C#N)c(F)c4)nc(N)n3)C2)cc1
Reactant: NN
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: Cc1ccc(CNC(=O)[C@H]2CC[C@@H](C)N(c3cc(-c4ccc5c(N)n[nH]c5c4)nc(N)n3)C2)cc1
Temperature: 110 °C
Yield: 42.2 %

Procedure:
Into a microwave tube, (3S,6R)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-6-methyl-N-[(4-methylphenyl)methyl]-3-piperidinecarboxamide (189.5 mg, 0.413 mmol), 5 mL of EtOH, Hunig's base (0.289 mL, 1.653 mmol), and hydrazine anhydrous (0.078 mL, 2.480 mmol) were added, and the yellow suspension mixture was heated overnight at 110° C. in an oil bath. LCMS showed mainly product. CH3OH (5 mL) was added to the solution. The black solid and the yellow solution were carefully separated due to the black solid is heavier than yellow solution. Water (20 mL) was added to the yellow solution, and a solid formed. The solid was filtered, washed by water, and dried in vacuum. The solid was recrystallized using CH3CN, and the solid in the solvent was filtered, washed by EtOAc and CH3CN, and dried in vacuum to afford the light yellow title compound (82 mg). LC-MS (ES) m/z=471 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.15 (d, J=6.6 Hz, 3H), 1.57-1.94 (m, 5H), 2.23-2.42 (m, 5H), 2.94 (m, 1H), 4.13-4.43 (m, 2H), 5.38 (s, 2H), 6.08 (s, 2H), 6.58 (s, 1H), 7.16 (m, 4H), 7.50-7.62 (m, 1H), 7.63-7.77 (m, 1H), 7.94 (s, 1H), 8.33-8.53 (m, 1H), 11.50 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[C:5]([C:7]2[O:12][C:11](=[O:13])[C:10]3[CH:14]=[C:15]([C:19]#[N:20])[CH:16]=[C:17]([CH3:18])[C:9]=3[N:8]=2)[N:4]([C:21]2[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][N:22]=2)[N:3]=1.[CH3:28][NH2:29]>O1CCCC1>[Cl:1][C:2]1[CH:6]=[C:5]([C:7]([NH:8][C:9]2[C:10]([C:11]([NH:29][CH3:28])=[O:13])=[CH:14][C:15]([C:19]#[N:20])=[CH:16][C:17]=2[CH3:18])=[O:12])[N:4]([C:21]2[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][N:22]=2)[N:3]=1
Reactant: CN
Reactant: Cc1cc(C#N)cc2c(=O)oc(-c3cc(Cl)nn3-c3ncccc3Cl)nc12
Solvent: C1CCOC1
Product: CNC(=O)c1cc(C#N)cc(C)c1NC(=O)c1cc(Cl)nn1-c1ncccc1Cl
Reaction time: 0.08 h

Procedure:
To a solution of 2-[3-chloro-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-6-cyano-8-methyl-4H-3,1-benzoxazin-4-one (e.g. the cyanobenzoxazinone product of Step F) (100 mg, 0.25 mmol) in tetrahydrofuran (5 mL) was added dropwise methylamine (2.0 M solution in MT, 0.5 mL, 1.0 mmol) and the reaction mixture was stirred for 5 minutes, at which point thin layer chromatography on silica gel confirmed completion of the reaction. The tetrahydrofuran solvent was evaporated under reduced pressure, and the residual solid was purified by chromatography on silica gel to afford the title compound, a compound of the present invention, as a white solid (52 mg), which decomposed in the melting apparatus above 140° C.
Reaction SMILES: [F:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[C:13]2[C:9]([CH2:10][C:11]3([CH2:20][CH2:19][CH:18]([O:21][CH3:22])[CH2:17][CH2:16]3)[C:12]2=[NH:15])=[CH:8][CH:7]=1.C(OC)(OC)OC.CC(O)C.O=[C:35]([CH3:39])[C:36](=[S:38])[NH2:37]>CO.CCCCCCC.CCOC(C)=O>[F:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[C:13]2[C:9]([CH2:10][C:11]3([C:12]42[NH:37][C:36](=[S:38])[C:35]([CH3:39])=[N:15]4)[CH2:16][CH2:17][CH:18]([O:21][CH3:22])[CH2:19][CH2:20]3)=[CH:8][CH:7]=1
Reactant: CC(=O)C(N)=S
Reactant: COC1CCC2(CC1)Cc1ccc(OCCCF)cc1C2=N
Solvent: CC(C)O
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: COC1CCC2(CC1)Cc1ccc(OCCCF)cc1C21N=C(C)C(=S)N1
Temperature: 60 °C
Reaction time: 8 h
Yield: 63.8 %

Procedure:
6′-(3-Fluoropropoxy)-4-methoxyspiro[cyclohexane-1,2′-inden]-1′(3′H)-imine (Example 20v, Step 2, 204 mg, 0.67 mmol), trimethyl orthoformate (0.193 mL, 1.76 mmol) and 2-propanol (5 mL) was added to a MW vial. The vial was sealed and the mixture was heated at 60° C. (oil bath). 2-Oxopropanethioamide (Intermediate 2, 138 mg, 1.34 mmol) in MeOH (15 mL) was added and the resulting mixture was stirred overnight at 60° C. and was then concentrated in vacuo. The product was isolated using flash chromatography (0-50% EtOAc in heptane) to give the title compound (167 mg, 64% yield): MS (ES+) m/z 391 [M+H]1.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3](=O)[CH2:4][C:5]#[N:6].[C:10]1([NH:16][NH2:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:10]1([N:16]2[C:5]([NH2:6])=[CH:4][C:3]([C:2]([F:9])([F:8])[F:1])=[N:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NNc1ccccc1
Reactant: N#CCC(=O)C(F)(F)F
Product: Nc1cc(C(F)(F)F)nn1-c1ccccc1

Procedure:
4,4,4-Trifluoro-3-oxo-butyronitrile and phenylhydrazine were combined by the procedure of Example B11 to provide 1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-amine. 1H-NMR (400 MHz, DMSO-d6) δ 7.59-7.50 (m, 4 H), 7.42 (m, 1 H), 5.78 (s, 1 H), 5.73 (br s, 2 H).
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.CO[CH:9]([O:28][CH3:29])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]([CH3:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)=[CH:13][CH:12]=1.B(F)(F)F.CCOCC>ClCCl>[CH3:29][O:28][CH:9]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH2:19][N:20]([CH3:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)=[CH:15][CH:16]=1)[C:5]#[N:6]
Reactant: COC(Cc1ccc(OCCN(C)c2ccccn2)cc1)OC
Reactant: C[Si](C)(C)C#N
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: COC(C#N)Cc1ccc(OCCN(C)c2ccccn2)cc1
Reaction time: 1.5 h

Procedure:
Trimethylsilyl cyanide (3.4 mL) was added dropwise to a solution of 1,1-dimethoxy-2-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]phenyl]ethane (2.64 g) in dichloromethane (70 mL) at room temperature. The mixture was stirred during the addition of boron trifluoride etherate (0.3 mL), and stirring continued at room temperature for 1.5 hrs. prior to the addition of a further portion of boron trifluoride etherate (1 mL). After a further 2 hours the mixture was diluted with dichloromethane (100 mL) and washed with saturated sodium bicarbonate solution (2×300 mL), water (2×300 mL) and brine (300 mL), dried (MgSO4) and evaporated. The residue was chromatographed on silica gel with 1% methanol in dichloromethane as eluent to afford the title compound, a gum, which was used without further purification.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([CH2:8][C:9]([OH:11])=O)=[O:7].[NH2:12][CH:13]1[C:27](=[O:28])[N:15]2[C:16]([C:24]([OH:26])=[O:25])=[C:17]([CH2:20][N:21]=[N+:22]=[N-:23])[CH2:18][S:19][C@H:14]12>>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([CH2:8][C:9]([NH:12][CH:13]1[C:27](=[O:28])[N:15]2[C:16]([C:24]([OH:26])=[O:25])=[C:17]([CH2:20][N:21]=[N+:22]=[N-:23])[CH2:18][S:19][C@H:14]12)=[O:11])=[O:7]
Reactant: [N-]=[N+]=NCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: O=C(O)CS(=O)c1ccco1
Product: [N-]=[N+]=NCC1=C(C(=O)O)N2C(=O)C(NC(=O)CS(=O)c3ccco3)[C@H]2SC1

Procedure:
348 mg. of 2-furylsulfinylacetic acid of the R form and 7-amino-3-azidomethyl-3-cephem-4-carboxylic acid were reacted in the same manner as described in Example 28 and 163 mg. of 7-(2-furylsulfinylacetamido)-3-azidomethyl-3-cephem-4-carboxylic acid of the R form were obtained.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[C:12](=O)[N:11]2[CH:6]([CH2:7][O:8][CH2:9][CH2:10]2)[C:5](=O)[NH:4]1.Cl>CO>[CH2:7]1[CH:6]2[CH2:5][NH:4][C@@H:3]([CH2:2][OH:1])[CH2:12][N:11]2[CH2:10][CH2:9][O:8]1
Reactant: O=C1N[C@@H](CO)C(=O)N2CCOCC12
Agent: Cl
Solvent: CO
Product: OC[C@H]1CN2CCOCC2CN1
Temperature: 0 °C
Yield: 96.8 %

Procedure:
(7S)-7-(hydroxymethyl)hexahydropyrazino[2,1-c][1,4]oxazine-6,9-dione (D130, 151 mg, 0.75 mmol) was suspended in 1M borane THF complex solution (7.5 mL) and heated at reflux for 24 hours. Checked by MS, which showed only the product at m/z=173 (M+1). The reaction was cooled to 0° C., MeOH (5 mL) added dropwise followed by conc.HCl solution (1 mL). The resulting mixture was heated at 50° C. for 4 hours. The solvent was removed and the residue loaded on a SCX column, washed with MeOH before eluting the compound with 1M NH3 in MeOH. Solvent evaporated under reduced pressure to afford the title compound as a colourless oil (125 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:10]([CH:13]1[CH2:22][CH2:21][C:16]2(OCC[O:17]2)[CH:15]=[C:14]1[C:23]([O:25][CH2:26][CH3:27])=[O:24])(=[O:12])=[O:11].Cl.O1CCCC1>>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:10]([CH:13]1[C:14]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:15][C:16](=[O:17])[CH2:21][CH2:22]1)(=[O:12])=[O:11]
Reactant: CCOC(=O)C1=CC2(CCC1S(=O)(=O)Nc1ccc(F)cc1Cl)OCCO2
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)C1=CC(=O)CCC1S(=O)(=O)Nc1ccc(F)cc1Cl
Temperature: 25 °C
Reaction time: 64 h
Yield: 96 %

Procedure:
To 2.55 g (6.07 mmol) of ethyl 8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate obtained in Example 1 was added 100 ml of a mixed solution of 1N hydrochloric acid-tetrahydrofuran (1:1), and the reaction solution was stirred at room temperature for 64 hours. Tetrahydrofuran was distilled off under reduced pressure, the residue was extracted by addition of ethyl acetate, and the organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; hexane:ethyl acetate=4:1), to give 2.19 g of the title compound as a pale brown powder (yield: 96%).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([CH3:14])=[C:6]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:7]=1.CC1(C)C(C)(C)OB([C:23]2[CH:32]=[CH:31][C:30]3[C:29]([CH3:34])([CH3:33])[CH2:28][CH2:27][C:26]([CH3:36])([CH3:35])[C:25]=3[CH:24]=2)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>C1COCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:14][C:5]1[CH:4]=[CH:3][C:2]([C:32]2[CH:23]=[CH:24][C:25]3[C:26]([CH3:36])([CH3:35])[CH2:27][CH2:28][C:29]([CH3:34])([CH3:33])[C:30]=3[CH:31]=2)=[CH:7][C:6]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1
Reactant: Cc1ccc(Cl)cc1N1CCNCC1
Reactant: CC1(C)CCC(C)(C)c2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1N1CCNCC1
Temperature: 120 °C
Reaction time: 4 h

Procedure:
100 mg (0.48 mmol) of 1-(5-chloro-2-methylphenyl)piperazine and 300 mg (0.95 mmol) and of 4,4,5,5-tetramethyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1,3,2-dioxaborolane are dissolved in 2 ml of THF, 302 mg (1.43 mmol) of potassium phosphate, 3 mg of palladium acetate and 11 mg of 2-dicylcohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl are added. The reaction mixture is degassed a number of times and stirred at 120° C. under nitrogen atmosphere for 4 h, subsequently diluted with water and extracted three times with ethyl acetate. The combined organic phases are dried over Na2SO4 and evaporated. The crude product is purified by means of preparative HPLC and converted into the hydrochloride using methanolic HCl.
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:31]=[CH:30][C:10]([C:11]([N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:23][CH2:22][C:20]3=[O:21])[CH2:15][CH2:14]2)=[O:12])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH:4]=[CH2:5].ClC1C=CC=C(C(OO)=[O:40])C=1.C(=O)([O-])O.[Na+]>ClCCl>[O:40]1[CH2:5][CH:4]1[CH2:3][CH2:2][CH2:1][O:6][C:7]1[CH:31]=[CH:30][C:10]([C:11]([N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:23][CH2:22][C:20]3=[O:21])[CH2:15][CH2:14]2)=[O:12])=[CH:9][CH:8]=1
Reactant: C=CCCCOc1ccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(c1ccc(OCCCC2CO2)cc1)N1CCC(N2C(=O)CCc3ccccc32)CC1
Reaction time: 8 h
Yield: 72.2 %

Procedure:
1-{1-[4-(4-Pentenyloxy)benzoyl]-4-piperidinyl}-3,4-dihydrocarbostyril (2 g) is dissolved in dichloromethane (50 ml) and thereto is added gradually m-chloroperbenzoic acid (1.6 g) at room temperature. The mixture is stirred under the same conditions overnight and the reaction mixture is poured into aqueous sodium hydrogen carbonate solution and the mixture is extracted with chloroform and dried with magnesium sulfate. The solvent is distilled off and the resulting residue is purified by silica gel column chromatography (solvent: n-hexane:ethyl acetate=1:1) to give 1-{1-[4-(3-oxiranylpropoxy)benzoyl]-4-piperidinyl}-3,4-dihydrocarbostyril (1.5 g).
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](Cl)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=1>>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([O:26][C:22]2[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=2)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1nc(Cl)c2ccccc2c1O
Reactant: Oc1cccnc1
Product: CCCCOC(=O)c1nc(Oc2cccnc2)c2ccccc2c1O

Procedure:
Synthesized from 1-chloro-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester and pyridin-3-ol in analogy to Example D-20 d); MS-(+)-ion: M+1=339.1.
Reaction SMILES: [C:1]([S:4][CH2:5][CH2:6][C:7](Cl)=[O:8])(=[O:3])[CH3:2].[CH2:10]([O:12][C:13]([CH:15]1[CH2:23][C:22]2[C:17](=[CH:18][C:19]([O:26][CH3:27])=[C:20]([O:24][CH3:25])[CH:21]=2)[NH:16]1)=[O:14])[CH3:11].C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[CH2:10]([O:12][C:13]([CH:15]1[CH2:23][C:22]2[C:17](=[CH:18][C:19]([O:26][CH3:27])=[C:20]([O:24][CH3:25])[CH:21]=2)[N:16]1[C:7](=[O:8])[CH2:6][CH2:5][S:4][C:1](=[O:3])[CH3:2])=[O:14])[CH3:11]
Reactant: CCOC(=O)C1Cc2cc(OC)c(OC)cc2N1
Reactant: CC(=O)SCCC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCOC(=O)C1Cc2cc(OC)c(OC)cc2N1C(=O)CCSC(C)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The solution of 3.6 g of 3-acetylthiopropanoyl chloride in 10 ml of methylene chloride is added dropwise while stirring under nitrogen to the suspension of 5.4 g of 5,6-dimethoxyindoline-2-carboxylic acid ethyl ester and 5.96 g of powdered potassium carbonate in 40 ml of methylene chloride. The mixture is stirred for 2 hours at room temperature, filtered and the filtrate washed successively with saturated aqueous sodium bicarbonate, water, 0.5N hydrochloric acid and water. The organic solution is dried, evaporated, the residue crystallized from petroleum ether and further purified by slurrying in diethyl ether for 2 hours, to yield the 1-(3-acetylthiopropanoyl)-5,6-dimethoxyindoline-2-carboxylic acid ethyl ester melting at 104°-106°.
Reaction SMILES: BrC1C=CC=CC=1.[Li].[NH2:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[C:12]#[N:13].[CH2:18]([N:20]([CH2:23][CH3:24])[C:21]#[N:22])[CH3:19]>O.C(OCC)C>[NH2:13][C:12]1[C:11]2[C:10](=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:9]=[C:21]([N:20]([CH2:23][CH3:24])[CH2:18][CH3:19])[N:22]=1
Reactant: CCN(C#N)CC
Reactant: N#Cc1ccccc1N
Agent: [Li]
Solvent: O
Solvent: CCOCC
Solvent: Brc1ccccc1
Product: CCN(CC)c1nc(N)c2ccccc2n1
Reaction time: 0.17 h

Procedure:
Under a nitrogen atmosphere 4.7 g. (0.03 mol) of bromobenzene dissolved in 35 ml. of anhydrous diethyl ether, are added to 0.42 g. (0.06 mol) of lithium. To the solution obtained, a solution of 0.03 mol o-aminobenzonitrile in 15 ml. of anhydrous diethyl ether is added dropwise at room temperature. After about 10 minutes, a solution of 0.03 mol diethylcyanamide in 10 ml. of anhydrous diethyl ether is added dropwise. The reaction mixture is then refluxed under the nitrogen atmosphere for 4 hours. The next day the mixture is decomposed by addition of water. The ethereal layer is separated off, washed with water, dried over sodium sulphate and concentrated by evaporation of solvent. Some petroleum ether (boiling range 28°-40°C.) is added to the residue, the solid is filtered off and crystallized from a mixture of methanol and water. 4-Amino-2-diethylaminoquinazoline, m.p. 125°-128°C., is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:37])[CH:5]=[C:6]([Cl:36])[C:7]=1[CH2:8][C@@H:9]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH:32]([F:34])[F:33])=[C:27]([OH:35])[CH:26]=1)[O:10][C:11](=[O:24])[CH2:12][N:13]1[C:21](=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]1=[O:23].C(=O)([O-])[O-].[K+].[K+].CC1C=CC(S(O[CH:55]2[CH2:59][CH2:58][O:57][CH2:56]2)(=O)=O)=CC=1.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:37])[CH:5]=[C:6]([Cl:36])[C:7]=1[CH2:8][C@@H:9]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH:32]([F:34])[F:33])=[C:27]([O:35][CH:55]2[CH2:59][CH2:58][O:57][CH2:56]2)[CH:26]=1)[O:10][C:11](=[O:24])[CH2:12][N:13]1[C:21](=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]1=[O:23]
Reactant: Cc1ccc(S(=O)(=O)OC2CCOC2)cc1
Reactant: O=C(CN1C(=O)c2ccccc2C1=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CN1C(=O)c2ccccc2C1=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OC2CCOC2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 9.7 %

Procedure:
To a solution of (S)-3,5-dichloro-4-(2-(4-(difluoromethoxy)-3-hydroxyphenyl)-2-(2-(1,3-dioxoisoindolin-2-yl)acetoxy)ethyl)pyridine 1-oxide (155 mg, 0.280 mmol) in DMF (3.8 ml), potassium carbonate (46.5 mg, 0.336 mmol) was added, and the mixture stirred at RT for 30 minutes. Tetrahydrofuran-3-yl 4-methylbenzenesulfonate (224 mg, 0.924 mmol) was added, and the mixture stirred at RT overnight. Water was added, and the aqueous phase extracted with AcOEt (2×). The organic phase was washed with brine, dried and evaporated under reduced pressure. The crude was purified through preparative HPLC (Method 2) to give 17 mg of title compound (yield 10%). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.45 (s, 2H), 7.92 (d, J=4.41 Hz, 4H), 7.18-7.27 (m, 1H), 7.05 (m, 2H), 6.98 (d, J=7.94 Hz, 1H), 6.02 (dd, J=8.38, 4.85 Hz, 1H), 5.12 (m, 1H), 4.30-4.58 (m, 2H), 3.62-4.06 (m, 4H), 3.14-3.43 (m, 2H), 2.20 (ddd, J=13.56, 6.73, 6.62 Hz, 1H), 1.86-2.05 (m, 1H). MS/ESI+ [M+H]+=622.7
Reaction SMILES: C([O:5][C:6]([C:8]1[C:12]2[CH2:13][C:14]([O:16]CC)=[CH:15][C:11]=2[N:10]([S:19]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[N:9]=1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[O:16]=[C:14]1[CH2:13][C:12]2[C:8]([C:6]([OH:7])=[O:5])=[N:9][N:10]([S:19]([C:22]3[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=3)(=[O:21])=[O:20])[C:11]=2[CH2:15]1
Reactant: CCOC1=Cc2c(c(C(=O)OC(C)(C)C)nn2S(=O)(=O)c2ccc(C)cc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2nc(C(=O)O)c3c2CC(=O)C3)cc1

Procedure:
To a solution of the intermediate from step B above, (414 mg, 1.02 mmol) in CH2Cl2 (2 mL) was added trifluoroacetic acid (2 mL). After stirring the reaction at room temperature for 1.5 hours it was concentrated in vacuo and azeotroped with toluene (2×). This material was used in the next step without any further purification.
Reaction SMILES: CC1(C)[N:6]2[C:7](=[O:12])[C@H:8]3[CH2:11][C@H:9]3[CH2:10][C@H:5]2[CH2:4][O:3]1.Cl>>[OH:3][CH2:4][C@@H:5]1[CH2:10][C@H:9]2[C@H:8]([CH2:11]2)[C:7](=[O:12])[NH:6]1
Reactant: CC1(C)OC[C@@H]2C[C@@H]3C[C@@H]3C(=O)N21
Agent: Cl
Product: O=C1N[C@H](CO)C[C@@H]2C[C@H]12
Temperature: 40 °C
Reaction time: 4 h

Procedure:
(5aS,6aS,7aS)-3,3-dimethylhexahydro-5H-cyclopropa[d][1,3]oxazolo[3,4-a]pyridin-5-one D25 (3.56 g) was dissolved in HCl (25 ml, 150 mmol) (6 M in water) into a 250 ml-round bottomed flask and the mixture was stirred at 40° C.: after 4 hours the reaction was complete. The solvent was evaporated at reduced pressure using a rotavapor (bath temperature: 40° C.). The oily residue was stripped with toluene and the residue dried under high vacuum for 3 hours, obtaining the title compound D26 as white solid (2.843 g). UPLC (Acid IPQC): rt=0.31 minutes, peak observed: 142 (M+1). C7H11NO2 requires 141. 1H NMR (500 MHz, DMSO-d6) d ppm 0.56-0.68 (m, 1 H) 0.93-1.05 (m, 1 H) 1.30-1.39 (m, 1 H) 1.39-1.48 (m, 1 H) 1.57-1.67 (m, 1 H) 1.98-2.09 (m, 1 H) 3.17-3.29 (m, 2 H) 3.31-3.40 (m, 1 H) 6.89-7.13 (m, 1 H)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:12])[C:9]=1[O:10]C)[CH2:5][Cl:6].B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:12][C:8]1[CH:7]=[C:4]([CH:3]=[C:2]([CH3:1])[C:9]=1[OH:10])[CH2:5][Cl:6]
Reactant: COc1c(C)cc(CCl)cc1C
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(CCl)cc(C)c1O

Procedure:
3,5-Dimethyl-4-methoxybenzyl chloride (I, PREPARATION 4, 1.8 g) is added to a solution of boron tribromide (1.5 m) in dichloromethane (70 ml) at 78°. The solution is allowed gradually to warm to 20°-25° overnight. The reaction is poured into an aqueous sodium bicarbonate solution, and the phases are separated. The dichloromethane phase is washed once with water and then with concentrated hydrochloric acid. The dried (sodium sulfate) organic phase is concentrated under reduced pressure to give the title compound.