Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.[NH2:12][CH:13]([CH2:21][CH3:22])[C:14]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[O:15]>>[CH2:17]([O:16][C:14](=[O:15])[CH:13]([NH:12][C:9](=[O:11])[CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1])[CH2:21][CH3:22])[CH:18]([CH3:19])[CH3:20]
Reactant: CCC(N)C(=O)OCC(C)C
Reactant: Cc1ccccc1CC(=O)O
Product: CCC(NC(=O)Cc1ccccc1C)C(=O)OCC(C)C

Procedure:
Following General Procedure I′ above and using 2-methylphenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure J′ above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([O:20][CH3:21])=[CH:8][C:9]2[O:14][C:13](=[O:15])[C:12]3[CH2:16][CH2:17][CH2:18][C:11]=3[C:10]=2[CH:19]=1.[N+:22]([C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:27][CH:26]=1)([O-:24])=[O:23].C([O-])(=O)/C=C/C([O-])=O>CC(C)=O>[CH3:21][O:20][C:7]1[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:34]2[CH2:35][CH2:36][N:31]([C:28]3[CH:27]=[CH:26][C:25]([N+:22]([O-:24])=[O:23])=[CH:30][CH:29]=3)[CH2:32][CH2:33]2)=[CH:19][C:10]2[C:11]3[CH2:18][CH2:17][CH2:16][C:12]=3[C:13](=[O:15])[O:14][C:9]=2[CH:8]=1
Reactant: COc1cc2oc(=O)c3c(c2cc1OCCCCl)CCC3
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Agent: O=C([O-])/C=C/C(=O)[O-]
Solvent: CC(C)=O
Product: COc1cc2oc(=O)c3c(c2cc1OCCCN1CCN(c2ccc([N+](=O)[O-])cc2)CC1)CCC3
Yield: 43 %

Procedure:
Method B (60 h at 50° C.); starting materials: 8-(3-chloropropoxy)-2,3-dihydro-7-methoxy-cyclopenta[c][1]benzopyran-4(1H)-one (example 83) and 1-(4-nitrophenyl)piperazine; yield 43%; fusion point 226°-228° C. (decomposes; from acetone). Fumarate: method E; yield 92%; fusion point 216° C. (decomposes; from acetone).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:11][CH3:12])=[CH:5][C:6]=1[C:7]([O:9]C)=O.Cl[C:14](Cl)([O:16]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.[N:32]1([CH2:38][CH2:39][NH2:40])[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>C(Cl)Cl>[CH2:11]([C:4]1[S:3][C:2]2[NH:1][C:14](=[O:16])[N:40]([CH2:39][CH2:38][N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[C:7](=[O:9])[C:6]=2[CH:5]=1)[CH3:12]
Reactant: CCc1cc(C(=O)OC)c(N)s1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: NCCN1CCOCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1cc2c(=O)n(CCN3CCOCC3)c(=O)[nH]c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
To a solution (40 mL) of methyl 2-amino-5-ethylthiophene-3-carboxylate (0.5 g) in methylene chloride were added triphosgene (0.32 g) and triethylamine (0.59 mL), and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added 2-morpholin-4-ylethanamine (1.06 mL), and the mixture was further stirred at room temperature for 1 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in methanol (20 mL), sodium methoxide (28% methanol solution, 1.3 g) was added, and-the mixture was stirred at 60° C. for 2 hr. The reaction mixture was neutralized with hydrochloric acid (10% methanol solution), insoluble material was filtered off, and the solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as a colorless solid (0.56 g, 67%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[C:16]([CH3:23])[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.[H][H]>C1COCC1.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([CH3:23])[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1N
Reaction time: 7 h
Yield: 99 %

Procedure:
Mix a slurry of 4-(6-methyl-5-nitro-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (46.00 g, 142.7 mmol) in THF (750 mL) at room temperature with Pd/C (5% Aldrich, 3.04 g, 1.43 mmol) then place under a hydrogen atmosphere (Parr shaker, 40-45 psi) for 6 hours. Add MeOH (250 mL), and subject the slurry to an atmosphere of hydrogen for 4 hours at room temperature. Add additional catalyst (3.04 g), then place the mixture under hydrogen for 7 hours. Filter the mixture through a pad of Celite 521®, washing with THF and MeOH then concentrate under reduced pressure to provide the title compound a pale pink solid. (41.58 g, 99% yield, MS(ES+): m/z=293 [M+H]).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](OC1C=CC=CC=1)=[N:8][CH:7]=[CH:6]2.C([O-])(=O)C.[NH4+:24]>[OH-].[Na+]>[NH2:24][C:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2)[CH:6]=[CH:7][N:8]=1
Reactant: [NH4+]
Reactant: COc1ccc2c(Oc3ccccc3)nccc2c1
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc2c(N)nccc2c1
Temperature: 150 °C
Reaction time: 8 h
Yield: 74.3 %

Procedure:
A mixture of 6-methoxy-1-phenoxyisoquinoline (21.3 g, 85 mmol) and ammonium acetate (55 g) was heated, under a nitrogen atmosphere, to 150° C. and stirred overnight. The mixture was allowed to cool to ambient temperature, after which 3 N sodium hydroxide (280 ml) was added with stirring. The thus obtained solution was extracted with ethyl acetate (2×300 ml) and the combined organic layers were extracted with 2N hydrochloric acid (100 ml). Subsequently, the pH of the aqueous layer was adjusted to 12 with 2 N sodium hydroxide. Extraction with ethyl acetate (300 ml) then afforded an organic layer, which was washed with brine (100 ml), dried (magnesium sulphate) and concentrated under reduced pressure to give 1-amino-6-methoxyisoquinoline (11 g, 75%), ESI-MS: 175.2 [M+H]+
Reaction SMILES: Br[C:2]1[CH:27]=[CH:26][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH2:19][C:20]5[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=5)[N:16]=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.[CH3:28][C:29]([OH:46])([CH3:45])[CH2:30][N:31]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[N:32]1>>[CH3:28][C:29]([OH:46])([CH3:45])[CH2:30][N:31]1[CH:35]=[C:34]([C:2]2[CH:27]=[CH:26][C:5]3[C:6]4[N:7]=[C:8]([C:14]5[N:15]([CH2:19][C:20]6[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=6)[N:16]=[CH:17][N:18]=5)[S:9][C:10]=4[CH2:11][CH2:12][O:13][C:4]=3[CH:3]=2)[CH:33]=[N:32]1
Reactant: Brc1ccc2c(c1)OCCc1sc(-c3ncnn3Cc3ccncc3)nc1-2
Reactant: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: CC(C)(O)Cn1cc(-c2ccc3c(c2)OCCc2sc(-c4ncnn4Cc4ccncc4)nc2-3)cn1

Procedure:
Following the procedure for 114, 8-Bromo-2-(2-pyridin-4-ylmethyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene was reacted with 2-Methyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-propan-2-ol to give 354. MS(ESI+) 500.1. 1H NMR (400 MHz, DMSO) δ 8.56 (dd, J=4.5, 1.6, 2H), 8.24 (s, 1H), 8.15 (s, 1H), 8.03 (d, J=8.3, 1H), 7.93 (s, 1H), 7.32 (dd, J=8.3, 1.8, 1H), 7.26 (d, J=1.8, 1H), 7.23-7.19 (m, 2H), 6.12 (s, 2H), 4.71 (s, 1H), 4.35 (t, J=5.0, 2H), 4.03 (s, 2H), 3.43 (t, J=5.0, 2H), 1.09 (s, 6H)
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:22]([CH2:23][CH2:24][C:25]([OH:27])=O)[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[N:15]=2)=[CH:10][CH:9]=1.[CH3:28][NH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(N(CC)CC)C>CN(C)C=O>[ClH:4].[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[N:22]([CH2:23][CH2:24][C:25]([N:29]([CH3:28])[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:27])[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[N:15]=2)=[CH:12][CH:13]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CNc1ccccc1
Reactant: O=C(O)CCn1c(-c2ccc(Cl)cc2)nc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C(=O)CCn1c(-c2ccc(Cl)cc2)nc2cccnc21)c1ccccc1
Product: Cl
Temperature: 0 °C
Yield: 27.2 %

Procedure:
Under nitrogen atmosphere, oxalyl chloride (2.18 g, 0.0172 mole) was added dropwise, slowly, to a stirred and chilled (10° C.) suspension of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-propanoic acid (5.0 g, 0.0166 mole) in anhydrous dimethylformamide (75 ml). The reaction mixture was stirred at room temperature for 1.5 hours and then additional oxalyl chloride (0.73 g, 0.00573 mole) was added. After stirring at room temperature for 0.5 hour, the reaction mixture was cooled to ice and methylaniline (1.91 g, 0.0178 mole) was added. The reaction mixture was stirred at room temperature for 2.25 hours and then poured into ice water (400 ml) with stirring. Addition of triethylamine (6 ml) precipitated a solid. The solution was decanted from the gum and the gum was dissolved in hot isopropyl alcohol, treated with charcoal and filtered hot. Attempts to crystallize the free base failed. The product, in isopropyl alcohol, was treated with hydrogen chloride in isopropyl alcohol until acidic. Addition of isopropyl ether caused a tan solid to precipitate. The solid was filtered, rinsed with isopropyl ether and dried under high vacuum to give 1.93 g of title compound, mp. 178°-182° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].N1C=CC=CC=1.[C:18](Cl)(=[O:22])[CH2:19][CH2:20][CH3:21]>ClCCl>[OH:11][C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[NH:1][C:18](=[O:22])[CH2:19][CH2:20][CH3:21]
Reactant: CCCC(=O)Cl
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCC(=O)Nc1cc([N+](=O)[O-])ccc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34 %

Procedure:
To a solution of 2-amino-4-nitrophenol (10 g, 64.9 mmol) in dichloromethane (250 mL) under nitrogen at 0° C. was added pyridine (10.5 mL, 129.9 mmol) followed by butyryl chloride (7.05 mL, 68.2 mmol) over a period of 5 min. After 30 min at 0° C., the solution was left warming up to room temperature for 2 days. The organic layer was washed with aqueous copper sulfate solution and brine. Insoluble material from the aqueous layer was filtered off and washed with water to afford 4.95 g (34%) of the title compound.
Reaction SMILES: [CH3:1][CH:2]([S:4]Cl)[CH3:3].[O:6]1[CH2:10][CH2:9][NH:8][C:7]1=[O:11].CN(C)CC1C=CC=CC=1>ClC1C=CC=CC=1.CN(C)C=O>[CH3:1][CH:2]([S:4][N:8]1[CH2:9][CH2:10][O:6][C:7]1=[O:11])[CH3:3]
Reactant: O=C1NCCO1
Reactant: CC(C)SCl
Agent: CN(C)Cc1ccccc1
Solvent: Clc1ccccc1
Solvent: CN(C)C=O
Product: CC(C)SN1CCOC1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 60 %

Procedure:
A solution of 0.6 mol of 2-propylsulphenyl chloride in 200 ml of chlorobenzene was added dropwise at 0° to 10° C. to 52.2 g (0.6 mol) of oxazolidin-2-one and 85 g (0.62 mol) of dimethylbenzylamine in 200 ml of chlorobenzene and 50 ml of dimethylformamide. After stirring for 1.5 hours at room temperature, the mother liquor was filtered from precipitated amine hydrochloride, washed with water and dried over sodium sulphate and the solvent was subsequently removed in vacuo at 40° C. 58 g of 3-(2-propylthio)oxazolidin-2-one were obtained as a brown oil.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([C:15]2[C:16]([F:33])=[C:17]([C@H:22]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:23][CH3:24])[CH:18]=[CH:19][C:20]=2[Cl:21])=[O:14])=[CH:9][C:8]=1[O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(N(CC)CC)C>ClCCl>[CH2:35]([O:34][C:8]1[CH:9]=[C:10]([C:13]([C:15]2[C:16]([F:33])=[C:17]([C@H:22]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[CH2:23][CH3:24])[CH:18]=[CH:19][C:20]=2[Cl:21])=[O:14])[CH:11]=[CH:12][C:7]=1[NH:6][C:3](=[O:4])[CH2:2][Cl:1])[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)c1ccc(Cl)c(C(=O)c2ccc(N)c(OCc3ccccc3)c2)c1F
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@@H](NC(=O)OC(C)(C)C)c1ccc(Cl)c(C(=O)c2ccc(NC(=O)CCl)c(OCc3ccccc3)c2)c1F
Yield: 95.4 %

Procedure:
Step 4 Chloroacetyl chloride (0.323 ml, 4.05 mmol) was added to a mixture of tert-butyl N-[(1R)-1-(3-{[4-amino-3-(benzyloxy)phenyl]carbonyl}-4-chloro-2-fluorophenyl)propyl]carbamate (1.6 g, 3.12 mmol), triethylamine (0.651 ml, 4.68 mmol) and dichloromethane (30 ml) at room temperature. After 30 minutes a small additional portion of chloroacetyl chloride was added and in 60 minutes the reaction was complete. The reaction mixture was washed with dilute citric acid solution and dilute sodium bicarbonate and then concentrated. The residue was purified on silica eluting with 30-70% ethyl acetate/petrol to furnish tert-butyl N-[(1R)-1-(3-{[3-(benzyloxy)-4-(2-chloroacetamido)-phenyl]-carbonyl}-4-chloro-2-fluorophenyl)propyl]carbamate as a yellow oil (1.754 g). [M−H]−=587
Reaction SMILES: C1COCC1.Br.[CH3:7][N:8]([CH2:10][CH2:11][CH2:12][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:9].O=[C:33]1[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=2[CH2:40][CH2:39][C:38]2[CH:37]=[C:36]([CH:47]=[CH:48][C:49]([O:51][CH2:52][CH3:53])=[O:50])[S:35][C:34]1=2.[ClH:54].O1CCOCC1>O1CCOCC1>[ClH:54].[CH3:7][N:8]([CH3:9])[CH2:10][CH2:11]/[CH:12]=[C:33]1\[C:34]2[S:35][C:36](/[CH:47]=[CH:48]/[C:49]([O:51][CH2:52][CH3:53])=[O:50])=[CH:37][C:38]=2[CH2:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]\1=2
Reactant: CN(C)CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)C=Cc1cc2c(s1)C(=O)c1ccccc1CC2
Agent: Br
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CCOC(=O)/C=C/c1cc2c(s1)/C(=C\CCN(C)C)c1ccccc1CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 6 %

Procedure:
A 1.6 mol/L n-butyllithium-hexane solution (42 mL) was added to a THF (100 mL) solution of dimethylaminopropyltriphenylphosphonium hydrobromide (23.5 g) under ice-cooling, and the mixed solution was stirred at room temperature for 1 hour. A THF (100 mL) solution of the compound obtained in Example 1 (6.11 g) was added to this solution, and the mixture was further stirred overnight. The solvent was distilled off under a reduced pressure, an aqueous saturated ammonium chloride solution was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated sodium chloride solution, and then dried over anhydrous sodium sulfate, and the solvent was distilled off under a reduced pressure. The residue was purified by silica gel column chromatography (chloroform-methanol=9:1), the purified product obtained was dissolved in 1,4-dioxane (20 mL), a 4 mol/L hydrogen chloride-dioxane solution (1.1 mL) was thereto, and the mixture was stirred at room temperature for 1 hour. The solvents were distilled off under a reduced pressure, and the precipitated crystals were filtered off and dried, to give 0.51 g (6%) of the captioned compound as a mixture of E-form and Z-form.
Reaction SMILES: C(O[C:4](=O)[C:5]([O:7][CH2:8][CH3:9])=[O:6])C.[CH3:11][C:12](=O)[CH2:13][CH2:14][CH3:15].[Na].C(O)(=O)C.[CH3:22][NH:23][NH2:24]>C(O)C>[CH3:22][N:23]1[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:11][C:12]([CH2:13][CH2:14][CH3:15])=[N:24]1
Reactant: CNN
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCCC(C)=O
Agent: [Na]
Solvent: CC(=O)O
Solvent: CCO
Product: CCCc1cc(C(=O)OCC)n(C)n1
Temperature: 60 °C
Reaction time: 5 h
Yield: 15.5 %

Procedure:
A solution of diethyloxalate (27.2 ml, 0.2 mol) in 2-pentanone (21.2 ml, 0.2 mol) was added dropwise to a solution of sodium (4.83 g, 0.21 mol) in ethanol (200 ml), and the reaction stirred at 60° C. for 5 hours, then cooled in an ice-bath. The solution was neutralised using acetic acid (11.5 ml, 0.2 mol) and N-methyl hydrazine (10.6 ml, 0.2 mol) then added dropwise. The mixture was stirred for a further 4 hours at room temperature and concentrated under reduced pressure. The residue was partitioned between dichloromethane (300 ml) and water (200 ml), and the phases separated. The aqueous layer was extracted with dichloromethane (3×100 ml), the combined organic solutions were dried (MgSO4) and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel, using ethyl acetate: hexane (25:75) as eluant to give ethyl 1-methyl-3-n-propyl-pyrazole-5-carboxylate (6.1 g) and the title compound (22.1 g, 56%).
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(CC)CC.[NH2:30][C:31]1[C:32]([C:38]([OH:40])=O)=[N:33][C:34]([Br:37])=[CH:35][N:36]=1.[C:41]([NH:49][NH2:50])(=[O:48])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>CN(C=O)C.O>[NH2:30][C:31]1[C:32]([C:38]([N:49]([C:41]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[O:48])[NH2:50])=[O:40])=[N:33][C:34]([Br:37])=[CH:35][N:36]=1
Reactant: NNC(=O)c1ccccc1
Reactant: Nc1ncc(Br)nc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: Nc1ncc(Br)nc1C(=O)N(N)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
TBTU (22.09 g, 68.80 mmol) and Et3N (4.642 g, 6.394 mL, 45.87 mmol) were added to a solution of 3-amino-6-bromo-pyrazine-2-carboxylic acid (10 g, 45.87 mmol) and benzohydrazide (7.494 g, 55.04 mmol) in DMF (100.0 mL) and the resulting solution stirred at ambient temperature overnight. The reaction mixture was poured into water and the resultant precipitate was filtered and dried under vacuum. This was triturated with hot EtOAc and the resulting precipitate filtered and dried to give the desired product (13.11 g, 85% Yield).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][N:3]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:31][O:32][C:33]1[C:34](=[O:57])[C:35]([CH3:56])=[C:36]([CH2:42][C:43]2[CH:44]=[CH:45][C:46]([O:52][C:53](=[O:55])[CH3:54])=[C:47]([CH:51]=2)[C:48](O)=[O:49])[C:37](=[O:41])[C:38]=1[O:39][CH3:40]>C(Cl)Cl>[C:9]([O:8][C:6]([C:5]1[CH:13]=[CH:14][C:2]([NH:1][C:48](=[O:49])[C:47]2[CH:51]=[C:43]([CH2:42][C:36]3[C:37](=[O:41])[C:38]([O:39][CH3:40])=[C:33]([O:32][CH3:31])[C:34](=[O:57])[C:35]=3[CH3:56])[CH:44]=[CH:45][C:46]=2[O:52][C:53](=[O:55])[CH3:54])=[N:3][CH:4]=1)=[O:7])([CH3:10])([CH3:11])[CH3:12]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)O)c2)=C(C)C1=O
Reactant: CC(C)(C)OC(=O)c1ccc(N)nc1
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3ccc(C(=O)OC(C)(C)C)cn3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 54.4 %

Procedure:
tert-Butyl 6-aminonicotinate (0.467 g, 2.406 mmol), triethylamine (0.244 g, 2.406 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.407 g, 2.406 mmol) were added to a methylene chloride solution (100 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.300 g, 0.802 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) to obtain the titled compound (0.240 g, 0.436 mmol, 54%).
Reaction SMILES: [N+](C1C=C(C=CC=1)C(O)=O)([O-])=O.CCl.NCC(O)=O.[CH3:20][O:21][C:22](=[O:36])[CH2:23][NH:24][C:25](=[O:35])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([N+:32]([O-])=O)[CH:27]=1>>[CH3:20][O:21][C:22](=[O:36])[CH2:23][NH:24][C:25](=[O:35])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([NH2:32])[CH:27]=1
Reactant: COC(=O)CNC(=O)c1cccc([N+](=O)[O-])c1
Agent: CCl
Agent: NCC(=O)O
Agent: O=C(O)c1cccc([N+](=O)[O-])c1
Product: COC(=O)CNC(=O)c1cccc(N)c1

Procedure:
3-Nitro-benzoic acid was reacted with glycine methyl hydrochloride and the resulting (3-nitro-benzoylamino)-acetic acid methyl ester was hydrogenated to afford (3-amino-benzoylamino)-acetic acid methyl ester. This was reacted with 5-(2-adamantan-1-yl-ethyl)-2-cyclohexyl-1H-imidazole-4-carboxylic acid (Example 252) according to the procedure of Example 20, step d. The methyl ester was hydrolysed using the same procedure as in Example 36, step d to afford the title compound. 1H NMR (300 MHz, d6-DMSO) 10.54 (1H, br s), 8.80 (1H, t), 8.25 (1H, s), 7.91 (1H, d), 7.61 (1H, d), 7.45 (1H, d), 3.92 (2H, m), 2.93 (3H, m), 1.98-1.33 (27H, m). The acid was converted to the N-methyl-D-glucamine salt and lyophilised from water/dioxan. Found: C, 57.22; H, 8.30; N, 8.81%. C38H57N5O9.4.0 mols H2O requires: C, 57.06; H, 8.19; N, 8.75%.
Reaction SMILES: [CH3:1][CH:2]([CH3:4])[O-:3].[Na+].[Cl:6][C:7]1[CH:12]=[C:11](Cl)[C:10]([N+:14]([O-:16])=[O:15])=[CH:9][N:8]=1.O>CN(C=O)C>[Cl:6][C:7]1[CH:12]=[C:11]([O:3][CH:2]([CH3:4])[CH3:1])[C:10]([N+:14]([O-:16])=[O:15])=[CH:9][N:8]=1
Reactant: CC(C)[O-]
Reactant: O=[N+]([O-])c1cnc(Cl)cc1Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Oc1cc(Cl)ncc1[N+](=O)[O-]
Reaction time: 0.25 h
Yield: 61 %

Procedure:
3.38 g of sodium isopropoxide are added to a solution of 2.6 g of 2.4-dichloro-5-nitropyridine in 39 ml of DMF. The reaction medium is stirred at ambient temperature for 1 h 15 and 3.18 g of sodium isopropoxide are added. The reaction medium is stirred for a further 15 minutes and then the mixture is poured into 200 ml of water and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification is carried out by flash chromatography on silica gel (40-63 microns), elution being carried out with a heptane/ethyl acetate mixture (90/10 to 80/20). 1.78 g of 2-chloro-5-nitro-4-(propan-2-yloxy)pyridine are obtained in the form of a pale yellow solid.
Reaction SMILES: [CH:1]1([C:5]2[N:6]=[C:7]([NH:10][C:11]([C:13]3[CH:39]=[CH:38][N:16]4[C:17](=[O:37])[C:18](/[CH:28]=[CH:29]/[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[C:19]([N:21]5[CH2:26][CH2:25][CH2:24][CH:23]([OH:27])[CH2:22]5)[N:20]=[C:15]4[CH:14]=3)=[O:12])[S:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.ClC(Cl)(Cl)[C:42]([N:44]=C=O)=[O:43]>C(OCC)(=O)C>[NH2:44][C:42]([O:27][CH:23]1[CH2:24][CH2:25][CH2:26][N:21]([C:19]2[N:20]=[C:15]3[CH:14]=[C:13]([C:11]([NH:10][C:7]4[S:8][CH:9]=[C:5]([CH:1]5[CH2:4][CH2:3][CH2:2]5)[N:6]=4)=[O:12])[CH:39]=[CH:38][N:16]3[C:17](=[O:37])[C:18]=2/[CH:28]=[CH:29]/[C:30]([O:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:31])[CH2:22]1)=[O:43]
Reactant: CC(C)(C)OC(=O)/C=C/c1c(N2CCCC(O)C2)nc2cc(C(=O)Nc3nc(C4CCC4)cs3)ccn2c1=O
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)/C=C/c1c(N2CCCC(OC(N)=O)C2)nc2cc(C(=O)Nc3nc(C4CCC4)cs3)ccn2c1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
tert-Butyl (E)-3-[8-{[(4-cyclobutyl-1,3-thiazol-2-yl)amino]carbonyl}-2-(3-hydroxypiperidino)-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl]-2-propenoate (16 mg, 0.029 mmol) was dissolved in ethyl acetate (3 ml), added with trichloroacetyl isocyanate (10 μl) under ice cooling, stirred at 0° C. for 1 hour, then further added with trichloroacetyl isocyanate (10 μl), and further stirred for 30 minutes. Then, the reaction solution was concentrated under reduced pressure, and the resulting residue was added with methanol (2 ml), water (0.2 ml) and sodium formate (12 mg) at room temperature and stirred at room temperature for 7 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by thin layer silica gel chromatography (chloroform:methanol=30:1) to obtain 20 mg of the title compound.