Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Si:5]([CH3:19])([CH3:18])[O:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-])=O)([CH3:4])([CH3:3])[CH3:2].[CH:20]([Mg]Br)=[CH2:21].[Cl-].[NH4+]>C1COCC1.CCOC(C)=O>[C:1]([Si:5]([CH3:19])([CH3:18])[O:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:10]=1[NH:15][CH:21]=[CH:20]2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCc1ccccc1[N+](=O)[O-]
Reactant: C=C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCc1cccc2cc[nH]c12
Temperature: -45 °C
Reaction time: 0.25 h
Yield: 56 %

Procedure:
A solution of tert-butyl-dimethyl-[2-(2-nitro-phenyl)-ethoxy]-silane (85.6 g, 304 mmol) in THF (1 L) was cooled to −65° C. and a 1.0 M solution of vinyl magnesium bromide in THF (913 mL, 913 mmol) was introduced while maintaining a temperature below −60° C. The reaction was stirred for 15 minutes at −45° C., additional vinyl magnesium-bromide (152 mL, 152 mmol) was added and the reaction was stirred at −45° C. for 30 minutes. The cold reaction was poured into saturated aq ammonium chloride (800 mL) and diluted with EtOAc (500 mL). The two layers were separated and the aqueous layer was extracted with EtOAc(2×200 mL). The organic layers were combined, washed with brine (400 mL), dried (MgSO4), filtered and concentrated. Flash chromatography (95% hexane/EtOAc) gave the title compound (47.1 g, 56%) as a transparent brown oil. 1H NMR (400 MHz, DMSO-d6) −0.11 (s, 6H), 0.80 (s, 9H), 3.03 (t, J=6.8 Hz, 2H), 3.85 (t, J=6.8 Hz, 2H), 6.39 (dd, J=1.2, 3.2 Hz, 1H), 6.86–6.92 (m, 2H), 7.28 (dd, J=3, 3 Hz, 1H), 7.36 (dd, J=4.8, 4.8 Hz, 1H), 11.02 (br s, 1H). MS (electrospray, m/z) 276 (M++1).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].OS(O)(=O)=O.[CH3:17]O>>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([O:6][CH3:17])=[O:5]
Reactant: CO
Reactant: O=C(O)c1cc(F)ccc1Br
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(F)ccc1Br

Procedure:
To a solution of 2-bromo-5-fluorobenzoic acid (9) (21.90 g, 100 mmol) in methanol (100 mL) was added conc. H2SO4 (2 mL). The mixture was heated at reflux for 21 h. Most of the solvent was evaporated and diluted with water (200 mL). The mixture was extracted with EtOAc (150 mL×2). The combined extracts were washed with saturated NaHCO3 and brine, dried over MgSO4, and concentrated to give methyl 2-bromo-5-fluorobenzoate (10).
Reaction SMILES: [C:1]([O:14]CC)(=[O:13])[C:2]1[CH:12]=[CH:11][CH:10]=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:3]=1.C(O)C.[OH-].[K+]>O>[C:5]([O:7][CH2:8][CH3:9])(=[O:6])[C:4]1[CH:10]=[CH:11][CH:12]=[C:2]([C:1]([OH:14])=[O:13])[CH:3]=1
Reactant: CCOC(=O)c1cccc(C(=O)OCC)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cccc(C(=O)O)c1

Procedure:
A solution of 55 g. of this diethyl isophthalate in 140 ml. of ethanol was saponified by the addition of 15 g. of potassium hydroxide in 15 ml. of water. The resulting gel was refluxed 30 minutes, cooled and extracted with ether to remove unreacted diester. The water layer was acidified and the crude acid product precipitated. Ethyl hydrogen isophthalate having a melting point of 131° to 132° C. was obtained in a 16.5 g. yield after recrystallization from benzene.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([OH:13])[CH2:10][C@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.CN(C)C=O.[C:27]([Si:31](Cl)([CH3:33])[CH3:32])([CH3:30])([CH3:29])[CH3:28]>O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([O:13][Si:31]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:33])[CH3:32])[CH2:10][C@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)C[C@H]1C(=O)O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C(=O)O
Reaction time: 18 h

Procedure:
(2S,4S)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (5.31 g, 22.96 mmol) and imidazole (7.82 g, 115 mmol) were combined in dichlorormethane (106 mL) and dimethylformamide (22 mL) at ambient temperature and treated with portionwise addition of tert-butylchlorodimethylsilane (7.61 g, 50.5 mmol). The mixture was stirred for 18 hours then diluted with water and extracted into ethyl acetate and concentrated to provide the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[N:26]=[CH:25][CH:24]=[CH:23][N:22]=3)=[CH:17][CH:16]=2)[CH:7]=1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([S:35]([C:32]2[CH:33]=[CH:34][C:29]([Cl:28])=[CH:30][CH:31]=2)(=[O:37])=[O:36])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[N:26]=[CH:25][CH:24]=[CH:23][N:22]=3)=[CH:17][CH:16]=2)[CH:7]=1
Reactant: COC(=O)CCc1cccc(CNCc2ccc(-c3ncccn3)cc2)c1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Product: COC(=O)CCc1cccc(CN(Cc2ccc(-c3ncccn3)cc2)S(=O)(=O)c2ccc(Cl)cc2)c1

Procedure:
The title compound of Step A was prepared following the method described in Step B of Example 1 from 3-{3-[(4-pyrimidin-2-yl-benzylamino)-methyl]-phenyl}-propionic acid methyl ester, prepared in Step A of Example 11z, and 4-chlorobenzensulfonyl chloride using triethylamine in place of N,N-iisopropylethylamine. 1H NMR (400 MHz, CDCl3) δ 8.78 (m, 2H), 8.28 (d, 2H), 7.76 (d, 2H), 7.46 (d, 2H), 7.15 (m, 4H), 7.03 (d, 1H), 6.88 (d, 1H), 6.80 (s, 1H), 4.36 (s, 2H), 4.29 (s, 2H), 3.63 (s, 3H), 2.79 (t, 2H), 2.48 (t, 2H); MS 536 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH2:18])[CH:9]([NH2:17])[CH2:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:4][CH:3]=1.Cl.[CH2:20]([O:22][C:23]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:24]=1[C:25](=N)OCC)[CH3:21].ClC1C=CC(C2NC(C3C=CC(OC)=CC=3OCC)=NC2CC2CCCC2)=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[NH:18][C:25]([C:24]3[CH:30]=[CH:31][C:32]([O:34][CH3:35])=[CH:33][C:23]=3[O:22][CH2:20][CH3:21])=[N:17][CH:9]2[CH2:10][CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]2)=[CH:6][CH:7]=1
Reactant: NC(CC1CCCCC1)C(N)c1ccc(Cl)cc1
Reactant: CCOC(=N)c1ccc(OC)cc1OCC
Agent: CCOc1cc(OC)ccc1C1=NC(CC2CCCC2)C(c2ccc(Cl)cc2)N1
Agent: Cl
Product: CCOc1cc(OC)ccc1C1=NC(CC2CCCCC2)C(c2ccc(Cl)cc2)N1

Procedure:
5-(4-Chloro-phenyl)-4-cyclohexylmethyl-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro-1H-imidazole was prepared from 1-(4-chloro-phenyl)-3-cyclohexyl-propane-1,2-diamine and ethyl 2-ethoxy-4-methoxy-benzimidate hydrochloride in an analogous manner as described for the preparation of 5-(4-chloro-phenyl)-4-cyclopentylmethyl-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro-1H-imidazole (Example 9). HR-MS (ES, m/z) observed 427.2150, calculated for C25H32N2O2Cl [(M+H)+]427.2147.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[NH:16][CH2:15][N:14]([CH3:17])[C:13](=[N:18][C:19]3[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=3[CH3:27])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:28][N:29]=[C:30]=[O:31].O>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]([C:30](=[O:31])[NH:29][CH3:28])[CH2:15][N:14]([CH3:17])[C:13](=[N:18][C:19]3[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=3[CH3:27])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2=CC(=Nc3c(C)cc(C)cc3C)N(C)CN2)cc1OC
Reactant: CN=C=O
Solvent: c1ccncc1
Solvent: O
Product: CNC(=O)N1CN(C)C(=Nc2c(C)cc(C)cc2C)C=C1c1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 6-(3,4-dimethoxyphenyl)-3-methyl-1,2,3,4-tetrahydro-4-(2,4,6-trimethylphenylimino)pyrimidine (1.0 g) in pyridine (10 ml) was added methyl isocyanate (0.18 ml), and the mixture was stirred at ambient temperature for 3 hours. Then the mixture was poured into water (150 ml), and the resultant precipitates were collected. The precipitates were washed with water, and dried to give 6-(3,4-dimethoxyphenyl)-3-methyl-1-(N-methylcarbamoyl)-1,2,3,4-tetrahydro-4-(2,4,6-trimethylphenylimino)pyrimidine (0.99 g).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][NH:8][C:9]([NH:11][C:12]2[S:13][C:14]3[CH:20]=[C:19]([SH:21])[CH:18]=[CH:17][C:15]=3[N:16]=2)=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.P([O-])(O)(O)=O.[K+].SCC(C(CS)O)O.Cl[C:37]1[N:41]2[N:42]=[C:43]([O:46][CH3:47])[CH:44]=[CH:45][C:40]2=[N:39][N:38]=1>O.C(O)C>[CH3:47][O:46][C:43]1[CH:44]=[CH:45][C:40]2[N:41]([C:37]([S:21][C:19]3[CH:18]=[CH:17][C:15]4[N:16]=[C:12]([NH:11][C:9]([NH:8][CH2:7][CH2:6][N:1]5[CH2:2][CH2:3][CH2:4][CH2:5]5)=[O:10])[S:13][C:14]=4[CH:20]=3)=[N:38][N:39]=2)[N:42]=1
Reactant: O=C(NCCN1CCCC1)Nc1nc2ccc(S)cc2s1
Reactant: COc1ccc2nnc(Cl)n2n1
Agent: O=P([O-])(O)O
Agent: OC(CS)C(O)CS
Agent: [K+]
Solvent: O
Solvent: CCO
Product: COc1ccc2nnc(Sc3ccc4nc(NC(=O)NCCN5CCCC5)sc4c3)n2n1
Yield: 23.7 %

Procedure:
The 1-{6-[(6-methoxy[1,2,4]triazolo[4,3-b]pyridazin-3-yl)sulphanyl]-1,3-benzothiazol-2-yl}-3-[2-(pyrrolidin-1-yl)ethyl]urea was prepared according to the method described in Example 17a, but using 547 mg of 1-[2-(pyrrolidin-1-yl)ethyl]-3-(6-sulphanyl-1,3-benzothiazol-2-yl)urea, 25 cm3 of degassed ethanol, 8 mg of potassium dihydrogen phosphate in 0.2 cm3 of water, 787 mg of DL-dithiothreitol and 313 mg of 3-chloro-6-methoxy[1,2,4]-triazolo[4,3-b]pyridazine. 189 mg of 1-{6-[(6-methoxy[1,2,4]triazolo[4,3-b]pyridazin-3-yl)sulphanyl]-1,3-benzothiazol-2-yl}-3-[2-(pyrrolidin-1-yl)ethyl]urea are thus obtained in the form of a white powder, the characteristics of which are as follows:
Reaction SMILES: [I:1]I.N(OC(C)(C)C)=O.N[C:11]1[C:12]([Cl:21])=[C:13]([CH:17]=[C:18]([Cl:20])[CH:19]=1)[C:14]([OH:16])=[O:15].N(OCCCC)=O>CS(C)=O.O>[Cl:21][C:12]1[C:11]([I:1])=[CH:19][C:18]([Cl:20])=[CH:17][C:13]=1[C:14]([OH:16])=[O:15]
Reactant: Nc1cc(Cl)cc(C(=O)O)c1Cl
Reactant: II
Agent: CC(C)(C)ON=O
Agent: CCCCON=O
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)c1cc(Cl)cc(I)c1Cl
Temperature: 35 °C
Reaction time: 16 h
Yield: 84.8 %

Procedure:
In a flask 48.35 grams (0.191 mole) of iodine was dissolved in 90 mL of dimethyl sulfoxide. To this solution was added 29.47 grams (0.286 mole) of tertiary butyl nitrite. A solution of 39.25 grams (0.191 mole) of 3-amino-2,5-dichlorobenzoic acid in 130 mL of dimethyl sulfoxide was added dropwise to the solution of iodine and butyl nitrite. During this addition the temperature rose from 20° C. to 50° C., at which temperature the addition was stopped until the reaction mixture had cooled to 35° C. The addition was then completed. When the addition was complete, the reaction mixture was stirred for approximately 16 hours, then poured into water, and this mixture was extracted with ethyl acetate. The extracts were combined and washed with an aqueous solution of sodium hydrogen sulfite and finally with water. The combined extracts were dried over anhydrous sodium sulfate and filtered. The solvent was evaporated from the filtrate under reduced pressure, yielding 51.34 grams of 2,5-dichloro-3-iodobenzoic acid as a solid.
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].S(=O)(=O)(O)O.[Cl:14]Cl>>[Cl:14][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([OH:8])=[O:7]
Reactant: ClCl
Reactant: CCCCCC(=O)O
Agent: O=S(=O)(O)O
Product: O=C(O)CCCCCCl

Procedure:
155 parts by weight of the caproic acid were added to 1,000 parts by weight of 90% sulfuric acid saturated with chlorine and were reacted for 6 hours at 25° C. to obtain 100 parts by weight of 6-chlorocaproic acid.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:26])[C@@H:10]([CH2:24][OH:25])[NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(F)(F)F.[CH3:31]COCC.[N+](=C)=[N-]>ClCCl.C(=O)=O.CC(C)=O>[CH2:1]([O:8][C:9](=[O:26])[C@@H:10]([CH2:24][O:25][CH3:31])[NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(COC(=O)N[C@H](CO)C(=O)OCc2ccccc2)cc1
Reactant: CCOCC
Agent: C=[N+]=[N-]
Agent: FB(F)F
Agent: O=C=O
Solvent: CC(C)=O
Solvent: ClCCl
Product: COC[C@@H](NC(=O)OCc1ccc(OC)cc1)C(=O)OCc1ccccc1
Yield: 70 %

Procedure:
The N-p-methoxybenzyloxycarbonyl-D-serine benzyl ester (720 mg, 2.00 mmol) is dissolved in dry dichloromethane (20 ml) and the solution cooled in dry ice/acetone. Boron trifluoride etherate (100 μl) is added followed by the portionwise addition of diazomethane (30 mmol in 20 ml CH2Cl2) After about 30 minutes the solution is filtered and washed once with water (10 ml), then dried (MgSO4) and evaporated to dryness. The resulting residue is chromatographed on silica gel using chloroform as eluant to give the pure title compound as an oil (520 mg, 70%) which crystallises on standing to give a colourless solid of m.p. 68°-69° C.; [α]D20 --1.3° (c 4.0, CHCl3).
Reaction SMILES: C[Al](C)C.[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([NH2:12])=[N:10][CH:11]=1.[Si:13]([O:30][CH2:31][CH2:32][O:33][CH2:34][C@H:35]([OH:40])[C:36](OC)=[O:37])([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1.O>[Si:13]([O:30][CH2:31][CH2:32][O:33][CH2:34][C@H:35]([OH:40])[C:36]([NH:12][C:9]1[CH:8]=[CH:7][C:6]([Cl:5])=[CH:11][N:10]=1)=[O:37])([C:26]([CH3:29])([CH3:27])[CH3:28])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)[C@@H](O)COCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: Nc1ccc(Cl)cn1
Agent: C[Al](C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](OCCOC[C@H](O)C(=O)Nc1ccc(Cl)cn1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 61.3 %

Procedure:
Trimethylaluminium (2M in toluene) (4.97 mL, 9.94 mmol) was added carefully to 5-chloropyridin-2-amine (1.277 g, 9.94 mmol) in toluene (10 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 15 minutes. (S)-Methyl 3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-hydroxypropanoate (Intermediate AB3) (2 g, 4.97 mmol) in toluene (2 mL) was added. The reaction was heated to 120° C. for 2 hours in the microwave reactor. The reaction mixture was allowed to cool. The residue was neutralised with citric acid (1M, aq) and then diluted with water and extracted with EtOAc. The combined organics were dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 50% EtOAc in isohexane to afford the product (1.52 g, 61.3%). 1H NMR (400 MHz, CDCl3) δ 1.04 (9H, s), 3.63-3.68 (3H, m), 3.79-3.83 (2H, m), 3.85 (2H, d), 4.33 (1H, q), 7.34-7.46 (6H, m), 7.63-7.69 (5H, m), 8.18-8.25 (2H, m), 9.19 (1H, s); m/z (ES+) (M+H)+=499.55; HPLC tR=3.43 min.
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[NH:6][C:5](=[O:7])[CH2:4][CH2:3]1.[OH-].[Ba+2].[OH-].S(=O)(=O)(O)[OH:13].C(=O)([O-])[O-].[Ba+2]>O>[NH2:6][C:2]([CH3:8])([CH3:1])[CH2:3][CH2:4][C:5]([OH:13])=[O:7]
Reactant: CC1(C)CCC(=O)N1
Reactant: O=S(=O)(O)O
Agent: O=C([O-])[O-]
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Product: CC(C)(N)CCC(=O)O

Procedure:
For example, a mixture of 5,5-dimethyl-2-pyrrolidone, an excess amount of barium hydroxide and a sufficient amount of water is heated under reflux until the reaction is substantially complete. The cooled solution is made slightly acidic with sulfuric acid and neutralized with solid barium carbonate or other bases. After removal of solids by filtration, the filtrate is evaporated under reduced pressure to yield a crude product which after three recrystallizations from an inert solvent such as aqueous ethanol gives an analytically pure product of 4-amino-4,4-dimethyl butanoic acid (4-amino-4-methylvaleric acid). 4-amino-2,4-dimethylvaleric acid is prepared similarly from 3,5,5-trimethyl-2-pyrrolidone.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:9](=[O:11])[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(=O)([O-])[O-].[K+].[K+].Br[CH:19]1[CH2:23][CH2:22][NH:21][C:20]1=[O:24]>CC(C)=O>[NH:21]1[CH2:22][CH2:23][CH:19]([O:1]/[N:2]=[C:3](/[C:9](=[O:11])[CH3:10])\[C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:20]1=[O:24]
Reactant: CCOC(=O)C(=NO)C(C)=O
Reactant: O=C1NCCC1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)/C(=N\OC1CCNC1=O)C(C)=O
Temperature: 0 °C
Yield: 66.1 %

Procedure:
31.8 g of ethyl 2-hydroxyimino-3-oxo-n-butyrate are dissolved in 150 ml of acetone, and 83 g of anhydrous potassium carbonate are added thereto. 33 g of 3-bromo-2-pyrrolidone are added to the mixture at 20° to 25° C. with stirring, and the mixture is stirred at the same temperature for one hour. One liter of ice-water is added to said mixture, and the aqueous mixture is extracted with ethyl acetate. The extract is dried and concentrated under reduced pressure to remove solvent. The residue is crystallized with diisopropyl ether, and the crystals are collected by filtration. The crystals are recrystallized from ethyl acetate. 32 g of ethyl (Z)-2-[(2-pyrrolidon-3-yl)-oxyimino]-3-oxo-n-butyrate are obtained as colorless needles.
Reaction SMILES: O[CH2:2][C:3]1[C:4]([CH3:9])=[N:5][CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.CS([Cl:21])(=O)=O>C1C=CC=CC=1>[Cl:21][CH2:2][C:3]1[C:4]([CH3:9])=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ncccc1CO
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: Cc1ncccc1CCl
Reaction time: 8 h

Procedure:
To a solution of 3-hydroxymethy-2-methylpyridine (0.65 g, 5.3 mmol) in dry benzene (5 ml) was added triethylamine (1.0 ml, 7.4 mmol) followed by methanesulfonyl chloride (0.78 ml, 10.1 mmol) dropwise over 5 min. The heterogeneous dark gummy mixture was stirred at room temp. overnight. The reaction was filtered through Celite and washed with benzene (2×). The combined filtrates were washed with brine, dried (Na2SO4), and concentrated in vacuo to the crude product as a yellow oil which was used as is.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH2:13][C:10]2([O:12][CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][NH:16][CH3:17]>>[CH2:1]([N:8]1[CH2:14][CH2:13][C:10]([CH2:11][N:16]([CH3:17])[CH3:15])([OH:12])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(CN2CCC3(CO3)C2)cc1
Reactant: CNC
Product: CN(C)CC1(O)CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
9.6 g (50 mmol) of 5-benzyl-5-aza-1-oxaspiro[2,4]heptane are added dropwise to 50 ml of dimethylamine solution (50%) and the mixture is stirred overnight at room temperature. The batch is then concentrated and the residue is distilled.
Reaction SMILES: [CH3:1][NH:2][C:3]([NH2:5])=[O:4].C[O-].[Na+].C(O[C:12](=[O:27])[CH:13]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=1)[C:14]([O:16]CC)=O)C.O>CN(C)C=O>[Cl:26][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=1)[CH2:19][CH:13]1[C:12](=[O:27])[N:2]([CH3:1])[C:3](=[O:4])[NH:5][C:14]1=[O:16]
Reactant: CCOC(=O)C(Cc1cccc(Cl)c1)C(=O)OCC
Reactant: CNC(N)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1C(=O)NC(=O)C(Cc2cccc(Cl)c2)C1=O
Temperature: 130 °C

Procedure:
Methylurea (1.18 g, 16.0 mmol) and freshly prepared sodium methoxide (1.04 g, 19.2 mmol) were combined in dimethylformamide (15 mL) and a solution of 2-(3-chlorobenzyl)malonic acid diethyl ester (2.85 g, 10.0 mmol) in dimethylformamide (5 mL) was added. The reaction temperature was raised to 130° C. for 2 hours and then cooled to ambient temperature before water was added and the solution acidified with 2N HClaq. The resulting solid was filtered then washed with water and the dried to afford the product as a white solid, 840 mg. LC-MS: RT=2.87 mins, 267 (M+H)+ 265 (M−H)−.
Reaction SMILES: N#N.[Si:3]([O:10][CH2:11][C:12]1[N:13]=[C:14]([CH:17]=[O:18])[O:15][CH:16]=1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].[CH3:19][Al](C)C.[NH4+].[Cl-]>C(Cl)Cl.C1(C)C=CC=CC=1>[Si:3]([O:10][CH2:11][C:12]1[N:13]=[C:14]([CH:17]([OH:18])[CH3:19])[O:15][CH:16]=1)([C:6]([CH3:9])([CH3:7])[CH3:8])([CH3:5])[CH3:4]
Reactant: CC(C)(C)[Si](C)(C)OCc1coc(C=O)n1
Reactant: C[Al](C)C
Agent: N#N
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(O)c1nc(CO[Si](C)(C)C(C)(C)C)co1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 4-(((tert-butyldimethylsilyl)oxy)methyl)oxazole-2-carbaldehyde (268 mg, 1.11 mmol) in CH2Cl2 (9.2 mL) was treated dropwise at 0° C. with trimethylaluminium (1.11 mL of a 2.0 M solution in toluene, 2.22 mmol) and the resulting yellow solution was stirred for 45 min at 0° C. Sat. aq. NH4Cl was added to the reaction mixture which was extracted with CH2Cl2 (3×25 mL) and the combined org. layers were dried over Na2SO4, filtered and the solvent was removed under reduced pressure. Purification of the residue by FC (1:1 hept-EA) gave the title compound as a yellow oil: TLC: rf (1:1 hept-EA)=0.40. LC-MS-conditions 07: tR=0.85 min, [M]+=257.81.
Reaction SMILES: [C:1]([N:8]1[CH2:15][CH:14]([OH:16])[CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CC(C)([O-])C.[K+].Cl[C:24]1[C:33]2[C:28](=[CH:29][C:30]([O:34][CH3:35])=[CH:31][CH:32]=2)[CH:27]=[C:26]([CH3:36])[N:25]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CS(C)=O>[C:4]([O:3][C:1]([N:8]1[CH2:15][C@H:14]([O:16][C:24]2[C:33]3[C:28](=[CH:29][C:30]([O:34][CH3:35])=[CH:31][CH:32]=3)[CH:27]=[C:26]([CH3:36])[N:25]=2)[CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: COc1ccc2c(Cl)nc(C)cc2c1
Reactant: CC(C)(C)OC(=O)N1CC(O)C[C@H]1C(=O)O
Agent: CC(C)(C)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc2c(O[C@@H]3C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C3)nc(C)cc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-BOC-4-hydroxy-L-proline (A; 281 mg; 1.21 mmol) was dissolved in dimethylsulfoxide (3 mL) at room temperature then potassium t-butoxide (270 mg; 2.4 mmol) was added. The resulting solution was stirred at room temperature for 2 hours, then cooled to 0° C. A solution of 1-chloro-6-methoxy-3-methylisoquinoline in dimethylsulfoxide (3 mL) was then added dropwise to the cold solution, followed by t-BuOK, and the mixture was allowed to warn to room temperature. The solution was stirred for 16 hours. The reaction mixture was acidified to pH=4 with 5% aq. citric acid. The solution was extracted with ethyl acetate and the organic phase washed with water followed by brine. The organic phase was concentrated under reduced pressure to give (2S,4R)-1-(tert-butoxycarbonyl)-4-(6-methoxy-3-methylisoquinolin-1-yloxy)pyrrolidine-2-carboxylic acid.
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[N:10]=[CH:11][C:12]([CH2:14][CH2:15][O:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]4[O:27][C:26]([CH3:28])=[C:25]([C:29]([O:31]CC)=[O:30])[CH:24]=4)=[CH:19][CH:18]=3)=[CH:13][C:8]=2[C:7](=[O:34])[N:6]([CH3:35])[C:5]2[CH:36]=[CH:37][CH:38]=[N:39][C:4]1=2)[CH3:2].[OH-].[Na+]>CO.C1COCC1>[CH2:1]([N:3]1[C:9]2[N:10]=[CH:11][C:12]([CH2:14][CH2:15][O:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]4[O:27][C:26]([CH3:28])=[C:25]([C:29]([OH:31])=[O:30])[CH:24]=4)=[CH:19][CH:18]=3)=[CH:13][C:8]=2[C:7](=[O:34])[N:6]([CH3:35])[C:5]2[CH:36]=[CH:37][CH:38]=[N:39][C:4]1=2)[CH3:2]
Reactant: CCOC(=O)c1cc(-c2ccc(OCCc3cnc4c(c3)C(=O)N(C)c3cccnc3N4CC)cc2)oc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCN1c2ncc(CCOc3ccc(-c4cc(C(=O)O)c(C)o4)cc3)cc2C(=O)N(C)c2cccnc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.7 %

Procedure:
A mixture of ethyl 5-{4-[2-(11-ethyl-6,11-dihydro-5-methyl-6-oxo-5H-dipyrido[3,2-b:2′,3′-e][1,4]diazepin-8-yl)ethoxy]phenyl}-2-methyl-3-furanecarboxylate (64.0 mg, 0.12 mmol) and aqueous 1 N NaOH solution (2.00 mL, 2.00 mmol) in MeOH (2 mL) and THF (2 mL) was stirred at 25° C. for 3 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water and the resulting solution was washed with Et2O (3×). The aqueous layer was acidified with aqueous 1 N HCl solution (pH 3) and extracted with EtOAc. The organic layer was washed with water and brine, dried (MgSO4), filtered and concentrated under reduced pressure. The title compound (53 mg, 0.11 mmol) was suspended in water (5 mL) and treated with aqueous 0.1 N NaOH solution (1.06 mL, 0.11 mmol). The mixture was diluted with MeCN (2 mL) and the resulting solution was frozen and lyophilized to give the corresponding sodium salt of the title compound 1047 (50 mg, 79% yield) as a pale yellow solid.