Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH3:9])[N:3]=1.[OH-:10].[K+]>C(O)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH3:9])[N+:3]=1[O-:10]
Reactant: CCc1cccc(Br)n1
Reactant: [OH-]
Agent: [K+]
Solvent: CC(=O)O
Product: CCc1cccc(Br)[n+]1[O-]
Temperature: 50 °C
Reaction time: 5 h
Yield: 100 %

Procedure:
To a solution of 2-bromo-6-ethyl-pyridine (15.4 g, 82.8 mmol) (S. G. Davies and M. R. Shipton, J. Chem. Soc., Perkin Trans. 1, 1991, 3, 501) in acetic acid (15 ml) peracetic acid (26 ml of a 39%) solution) was added maintaining T<50° C. After completed addition the mixture was stirred at 50° C. for 5 hr and then cooled to rt. Crushed ice (40 g) was added and the mixture was made basic (pH 12) using 40% KOH solution. After extraction with CHCl3 (6×60 ml) the combined organic phases were dried (Na2CO3) and evaporated to give 20.0 g (>100%) of the title compound, MS: m/e=201 (M+) as a yellow oil.
Reaction SMILES: [SH2:1].[SH:2][C:3]1[S:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1>C(=S)=S>[CH:9]1[CH:8]=[C:6]2[N:7]=[C:3]([S:2][S:1][C:3]3[S:4][C:5]4[C:6](=[CH:8][CH:9]=[CH:10][CH:11]=4)[N:7]=3)[S:4][C:5]2=[CH:11][CH:10]=1
Reactant: S
Reactant: Sc1nc2ccccc2s1
Solvent: S=C=S
Product: c1ccc2sc(SSc3nc4ccccc4s3)nc2c1

Procedure:
2-Mercaptobenzothiazole can be produced from aniline by the following synthesis approach. Here, carbon disulfide can be generated and separated for example by reacting mustard oil, which is contained about 0.4% in leaf mustard, with hydrogen sulfide. The method allows to produce the vulcanization accelerator without petroleum resources. Dibenzothiazyl disulfide is synthesized by oxidizing thus produced 2-mercaptobenzothiazole.
Reaction SMILES: S(=O)(=O)(O)O.[C:6]([O:11][CH2:12][CH3:13])(=[O:10])[C:7]([CH3:9])=O.Cl.[Br:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22]N)=[CH:18][CH:17]=1>C(O)C>[Br:15][C:16]1[CH:17]=[C:18]2[C:19](=[CH:20][CH:21]=1)[NH:22][C:7]([C:6]([O:11][CH2:12][CH3:13])=[O:10])=[CH:9]2
Reactant: NNc1ccc(Br)cc1
Reactant: CCOC(=O)C(C)=O
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CCOC(=O)c1cc2cc(Br)ccc2[nH]1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a 500 ml flask, 14 g of 4-bromophenylhydrazine hydrochloride was dissolved in 170 ml of ethanol, and 1.2 ml of sulfuric acid and 8.5 ml of ethyl pyruvate were added. The reaction mixture was stirred for about 2 hours at room temperature and evaporated under reduced pressure to dryness. To the residue was added 23 ml of polyphosphoric acid, and the resulting solution was then stirred for 2 hours at 100° C.-110° C. After water was added, the reaction solution was neutralized with saturated aqueous NaHCO3 solution and then extracted to times with ethyl acetate. The extracts were combined, dried over MgSO4 and then evaporated. The residue was purified with silica gel column chromatography [eluent: n-hexane/ethyl acetate(9:1)] to obtain 10 g of the title compound as a brown solid.
Reaction SMILES: [F:1][C:2]([F:20])([CH:17]([F:19])[F:18])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[CH:14][NH:13][C:12]2=[O:16])=[CH:7][CH:6]=1.[H][H]>[C].[Pd].C(O)(=O)C>[F:20][C:2]([F:1])([CH:17]([F:19])[F:18])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:15][CH2:14][NH:13][C:12]2=[O:16])=[CH:7][CH:6]=1
Reactant: [H][H]
Reactant: O=c1[nH]ccn1-c1ccc(OCC(F)(F)C(F)F)cc1
Agent: [Pd]
Solvent: CC(=O)O
Product: O=C1NCCN1c1ccc(OCC(F)(F)C(F)F)cc1
Yield: 92.4 %

Procedure:
To a solution of 10 ml of acetic acid and 2.0 g of 1-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2-(1H,3H)-imidazolone was added 0.5 g of 10% palladium-carbon. The mixture was stirred in a hydrogen atmosphere for 7.5 hours. The catalyst was separated by filtration, washed with acetic acid and the filtrate and the washing were collected, followed by distilling off the solvent under reduced pressure. To the residue were added 40 ml of water and 40 ml of ethyl acetate to fractionate, and the ethyl acetate phase was dried over magnesium sulfate and the solvent was distilled off under reduced pressure. to give colorless crystals. The obtained colorless crystals were washed with diisopropyl ether to give 1.86 g of 1-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2-imidazolidinone as colorless crystals.
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:13][C:12](=[N:14][O:15][CH3:16])[CH2:11][C@H:10]2[C:17](=[N:19][OH:20])[NH2:18])=[O:8])=[CH:3][CH:2]=1.[C:27]([O:31][C:32](=[O:47])[CH2:33][CH2:34][C@H:35]([NH:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[C:36](O)=O)([CH3:30])([CH3:29])[CH3:28]>>[C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:2]=[CH:3][C:4]([C:7]([N:9]2[CH2:13][C:12](=[N:14][O:15][CH3:16])[CH2:11][C@H:10]2[C:17]2[N:18]=[C:36]([C@@H:35]([NH:39][C:40]([O:42][C:43]([CH3:44])([CH3:46])[CH3:45])=[O:41])[CH2:34][CH2:33][C:32]([O:31][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:47])[O:20][N:19]=2)=[O:8])=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CON=C1C[C@@H](C(N)=NO)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Product: CON=C1C[C@@H](c2noc([C@H](CCC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)n2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Yield: 75 %

Procedure:
Following the general method as outlined in Example 15, starting from (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N′-hydroxy-4-(methoxyimino)-2-pyrrolidinecarboximidamide (Intermediate 8) and (2S)-5-tert-butoxy-2-[(tert-butoxycarbonyl)amino]-5-oxopentanoic acid, the title compound was obtained in 75% yield (78.9% purity by HPLC).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[O:15][CH2:16][CH2:17][CH3:18].[Cl:19][C:20]1[N:21]=[C:22]([C:27](O)=[O:28])[NH:23][C:24]=1[CH2:25][CH3:26].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>ClCCl.CC(N(C)C)=O>[Cl:19][C:20]1[N:21]=[C:22]([C:27]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4][C@H:3]2[O:15][CH2:16][CH2:17][CH3:18])=[O:28])[NH:23][C:24]=1[CH2:25][CH3:26]
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Reactant: CCCO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: CCCO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Yield: 76.6 %

Procedure:
The same operation as in Example (106d) was performed using tert-butyl cis(±)-4-amino-3-propoxypiperidine-1-carboxylate obtained in Example (113d) (0.73 g, 2.8 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid (85% content, 0.61 g, 2.98 mmol), WSC hydrochloride (1.15 g, 6 mmol), HOBt (0.61 g, 4.5 mmol), DMA (15 mL) and dichloromethane (15 mL). The resulting residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=1/4, 2/3, 3/2, 4/1) to obtain 0.89 g of the title compound as a colorless solid (77%).
Reaction SMILES: [NH2:1][C@@H:2]([CH:5]([CH3:7])[CH3:6])[CH2:3][OH:4].[OH-].[K+].C1(C)C=CC=CC=1.[C:17](Cl)(Cl)=[O:18]>O>[CH3:6][CH:5]([C@H:2]1[CH2:3][O:4][C:17](=[O:18])[NH:1]1)[CH3:7]
Reactant: O=C(Cl)Cl
Reactant: CC(C)[C@H](N)CO
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)[C@H]1COC(=O)N1
Reaction time: 0.5 h

Procedure:
A mixture of 9.4 grams (0.091 mole) of (S)-2-amino-3-methyl-1-butanol, 36 grams (0.0546 mole) of 85% potassium hydroxide, 175 mL of toluene, and 240 mL of water was stirred rapidly as 140 mL (0.273 mole) of a toluene solution containing 20% phosgene was added dropwise during a 15 minute period. Upon completion of addition, the resulting hot solution was stirred an additional 30 minutes. The reaction mixture was cooled, and the organic and aqueous layers were separated. The organic layer was washed with water and dried with magnesium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure, yielding 15.0 grams of (S)-4-(1-methylethyl)-2-oxazolidinone as a solid. Recrystallization from cyclohexane yielded purer compound, m.p. 71.5°-72.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH2:10])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[Cl:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][C:22]=1[N+:30]([O-:32])=[O:31]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:25](=[O:26])[C:24]2[CH:28]=[CH:29][C:21]([Cl:20])=[C:22]([N+:30]([O-:32])=[O:31])[CH:23]=2)=[CH:4][CH:3]=1
Reactant: NCCc1ccc(Cl)cc1
Reactant: O=C(Cl)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCc1ccc(Cl)cc1)c1ccc(Cl)c([N+](=O)[O-])c1
Reaction time: 0.5 h
Yield: 84.2 %

Procedure:
2-(4-chlorophenyl)ethanamine (2.3 ml, 16 mmol) was diluted with DCM (40 mL) followed by the addition of DIEA (2.9 ml, 16 mmol) and 4-chloro-3-nitrobenzoyl chloride (3.0 g, 14 mmol) dropwise in 10 mL of DCM. After stirring for 30 minutes, the reaction was loaded onto silica gel and eluted with hexanes/ethyl acetate (2/1) to yield N-(4-chlorophenethyl)-4-chloro-3-nitrobenzamide (4.0 g, 86% yield) as a white solid.
Reaction SMILES: [CH3:1][C:2]([C:4]1([CH3:7])[CH2:6][CH2:5]1)=[O:3].[CH:8]1[C:13]([CH:14]=O)=[CH:12][C:11]2[O:16][CH2:17][O:18][C:10]=2[CH:9]=1>>[CH3:7][C:4]1([C:2]([CH:1]=[CH:14][C:13]2[CH:8]=[CH:9][C:10]3[O:18][CH2:17][O:16][C:11]=3[CH:12]=2)=[O:3])[CH2:6][CH2:5]1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: CC(=O)C1(C)CC1
Product: CC1(C(=O)C=Cc2ccc3c(c2)OCO3)CC1

Procedure:
2-(3,4-Methylenedioxyphenyl)vinyl 1-methylcyclopropyl ketone [III; Ar is 3,4-methylenedioxyphenyl, R is CH3 ] was prepared from 25.6 g. of 1-methylcyclopropyl methyl ketone and 39.3 g. of piperonal according to the procedure described above in Preparation A1, affording 29.5 g. of crystalline product.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][C:8]=1[C:17]([O:19][CH3:20])=[O:18])(=O)=O.CN(C=O)C.[F:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][C:30]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[F:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][C:30]=1[C:7]1[C:8]([C:17]([O:19][CH3:20])=[O:18])=[CH:9][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:15][CH:16]=1
Reactant: COc1ccc(F)c(B(O)O)c1
Reactant: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(C(=O)OC)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(C(=O)OC)c1
Temperature: 90 °C
Reaction time: 18 h

Procedure:
To a stirred solution of dimethyl 4-(trifluoromethylsulfonyloxy)isophthalate T4.1 (39.00 g, 114 mmol) in DMF (228 mL, 114 mmol) at 23° C. was added 2-fluoro-5-methoxyphenylboronic acid (29 g, 171 mmol) (commercially available from Sigma-Aldrich, St. Louis, Mo., USA), and potassium carbonate (47 g, 342 mmol), followed by tetrakis(triphenylphosphine)palladium (9.2 g, 8.0 mmol). The mixture was heated to 90° C. and stirred for 18 hours. The reaction was cooled to room temperature. Water was then added to the reaction, and the resulting mixture was extracted with EtOAc. The combined organic layers were dried over MgSO4, and concentrated. The crude product was purified by silica gel flash chromatography (0-20% EtOAc/hexane) to afford dimethyl 2′-fluoro-5′-(methyloxy)-1,1′-biphenyl-2,4-dicarboxylate T4.2 as a clear oil (32.00 g, 88% yield). MS ESI (pos.) m/e: 319.1 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:11]2[S:12][C:13]([CH3:16])=[C:14]([CH3:15])[C:10]=2[C:9]([C:17]2[CH:22]=[C:21]([CH:23]([CH3:25])[CH3:24])[C:20]([OH:26])=[C:19]([CH:27]([CH3:29])[CH3:28])[CH:18]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2.Br[CH2:31][C:32]([O:34][CH3:35])=[O:33].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH3:35][O:34][C:32](=[O:33])[CH2:31][O:26][C:20]1[C:21]([CH:23]([CH3:24])[CH3:25])=[CH:22][C:17]([C:9]2[C:10]3[C:14]([CH3:15])=[C:13]([CH3:16])[S:12][C:11]=3[C:2]([Br:1])=[C:3]3[C:8]=2[CH:7]=[CH:6][CH:5]=[CH:4]3)=[CH:18][C:19]=1[CH:27]([CH3:29])[CH3:28]
Reactant: COC(=O)CBr
Reactant: Cc1sc2c(Br)c3ccccc3c(-c3cc(C(C)C)c(O)c(C(C)C)c3)c2c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COc1c(C(C)C)cc(-c2c3ccccc3c(Br)c3sc(C)c(C)c23)cc1C(C)C
Yield: 87.5 %

Procedure:
A solution of 4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diisopropyl-phenol (0.42 g, 0.89 mmol), methyl bromoacetate (0.36 mL, 3.8 mmol), and potassium carbonate (0.42 g, 3.0 mmol) in anhydrous N,N-dimethylformamide (3.5 mL) at room temperature under nitrogen was stirred for 2 days. The reaction mixture was diluted with water and extracted with diethyl ether. Concentration under reduced pressure and chromatography with petroleum ether:ethyl acetate (95:5) gave the title compound as a white solid (0.42 g, 87%): NMR (DMSO-d6): δ 8.20 (d, 1H), 7.66-7.61 (m, 1H), 7.48 (d, 2H), 7.11 (s, 2H), 4.56 (s, 2H), 3.77 (s, 3H), 3.42-3.27 (m, 2H), 2.42 (s, 3H), 1.51 (s, 3H), 1.18 and 1.16 (two doublets, 12H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:17])([CH3:16])[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.Cl.[NH2:32][C:33]1[C:41]([NH2:42])=[CH:40][CH:39]=[CH:38][C:34]=1[C:35]([NH2:37])=[O:36].N>N1C=CC=CC=1.CN(C=O)C>[NH2:32][C:33]1[C:34]([C:35]([NH2:37])=[O:36])=[CH:38][CH:39]=[CH:40][C:41]=1[NH:42][C:13](=[O:15])[C:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([CH3:17])[CH3:16]
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)O
Reactant: NC(=O)c1cccc(N)c1N
Agent: Cl
Agent: N
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC(C)(NC(=O)OCc1ccccc1)C(=O)Nc1cccc(C(N)=O)c1N
Temperature: 40 °C
Reaction time: 8 h

Procedure:
2-{[(Benzyloxy)carbonyl]amino}-2-methylpropanoic acid (5.18 g, 21.83 mmol) in a mixture of pyridine (25 mL) and DMF (25 mL) was treated with 1,1′-carbonyldiimidazole (3.72 g, 22.92 mmol) and heated at 40° C. for 2 hours. 2,3-Diaminobenzamide dihydrochloride (4.89 g, 21.83 mmol), prepared as described in WO0026192, was added and the mixture was stirred at room temperature overnight. The solvents were removed under vacuum and the residue was partitioned between ethyl acetate and diluted sodium bicarbonate aqueous solution. The formed slightly yellow solid material was collected by filtration, washed with water and ethyl acetate, and dried to give Example 1A. MS (DCI/NH3) m/z 371 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=3)=[C:19]([Cl:30])[N:18]=[CH:17][N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:31][CH2:32][CH2:33][OH:34].Cl>>[ClH:30].[NH2:31][CH2:32][CH2:33][O:34][C:19]1[N:18]=[CH:17][N:16]=[C:15]([NH:14][S:11]([C:8]2[CH:7]=[CH:6][C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])=[CH:10][CH:9]=2)(=[O:13])=[O:12])[C:20]=1[O:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=1
Reactant: COc1cccc(Oc2c(Cl)ncnc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c1
Reactant: NCCO
Agent: Cl
Product: COc1cccc(Oc2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCN)c1

Procedure:
After treating 4-tert-butyl-N-{6-chloro-5-(3-methoxyphenoxy)-pyrimidin-4-yl}benzenesulfonamide and 2-aminoethanol in the same manner as in Example 1, the precipitated crystals are converted into a hydrochloride thereof to give N-{6-(2-aminoethoxy)-5-(3-methoxyphenoxy)pyrimidin-4-yl}-4-tert-butylbenzenesulfonamide hydrochloride (Compound A).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.CN1CCCC1=O.[NH2:18][CH2:19][CH2:20][CH2:21][N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1.C([O-])([O-])=O.[K+].[K+]>O>[N:22]1([CH2:21][CH2:20][CH2:19][NH:18][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: NCCCN1CCCC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1ccc(NCCCN2CCCC2)cc1
Temperature: 60 °C
Yield: 93.4 %

Procedure:
2 g of 4-fluoronitrobenzene were added to a solution of 20 ml of N-methyl-pyrrolidinone, 2.18 g of N-(3-aminopropyl)pyrrolidine and 2.35 g of K2CO3. The reaction medium was heated at 60° C. for 12 hours and, after cooling to room temperature, was then poured into a water and ice mixture. The yellow precipitate formed was filtered off, reslurried in water and then dried over P2O5. 3.3 g of N-(3-pyrrolidin-1-ylpropyl)-4-nitro-1-aminobenzene (13) were obtained.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:14])[CH:9]=[C:8]2[CH2:15][C:16]1[CH:34]=[CH:33][C:19]([C:20]([NH:22][S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH3:32])(=[O:25])=[O:24])=[O:21])=[CH:18][C:17]=1[O:35][CH3:36])=[O:4].[OH-].[Na+].Cl>O1CCCC1>[C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:14])[CH:9]=[C:8]2[CH2:15][C:16]1[CH:34]=[CH:33][C:19]([C:20]([NH:22][S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH3:32])(=[O:25])=[O:24])=[O:21])=[CH:18][C:17]=1[O:35][CH3:36])([OH:4])=[O:2]
Reactant: COC(=O)c1ccc2c(c1)c(Cc1ccc(C(=O)NS(=O)(=O)c3ccccc3C)cc1OC)cn2C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc(C(=O)NS(=O)(=O)c2ccccc2C)ccc1Cc1cn(C)c2ccc(C(=O)O)cc12
Temperature: 60 °C
Yield: 10.2 %

Procedure:
A mixture of 4-(5-methoxycarbonyl-1-methylindol-3-ylmethyl)-3-methoxy-N-(2-methylphenylsulfonyl)benzamide (130.0 g), tetrahydrofuran (1.0 L) and 1N sodium hydroxide (1.0 L) was heated to about 60° C. overnight, then treated with additional 1N sodium hydroxide (200 mL) and heated an additional 5 hours at 60° C. (likely unnecessary). The cooled reaction mixture was acidified with 6N hydrochloric acid (250 mL) and extracted with ethyl acetate. The ethyl acetate solution was washed with brine (three times), dried (MgSO4) and evaporated to give a solid which was dried at 50° C. under vacuum to give 4-(5-carboxy-1-methylindol-3-ylmethyl)-3-methoxy-N-(2-methylphenylsulfonyl)benzamide (12.9 g, 100% when calculated as 0.45 hydrate), mp 255°-257° C.; NMR (300 MHz, DMSO-d6): 2.60 (s, 3H, ArCH3), 3.76 (s, 3H, NCH3), 3.91 (s, 3H, OCH3), 4.05 (s, 2H, ArCH2Ar'), 7.15 (d, 1H), 7.19 (s, 1H), 7.39-7.51 (m, 5H), 7.58 (br t, 1H), 7.72 (dd, 1H), 8.03 (dd, 1H), 8.14 (d, 1H).
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:6]=[C:7]([OH:14])[N:8]2[C:12]([N:13]=1)=[N:11][CH:10]=[N:9]2)([OH:3])=O.[CH:15]([NH:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH2:16]>CN(C)C=O>[OH:14][C:7]1[N:8]2[C:12]([N:13]=[C:5]([CH2:4][C:1](=[O:3])[N:17]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:15]=[CH2:16])[CH:6]=1)=[N:11][CH:10]=[N:9]2
Reactant: O=C(O)Cc1cc(O)n2ncnc2n1
Reactant: C=CNCc1ccccc1
Solvent: CN(C)C=O
Product: C=CN(Cc1ccccc1)C(=O)Cc1cc(O)n2ncnc2n1
Temperature: 25 °C
Yield: 79.1 %

Procedure:
143 g of 6-carboxymethyl-4-hydroxy-1,3,3a,7-tetraazaindene prepared in Synthesis Example 1 and 98 g of vinylbenzylamine were dissolved in 1 l of dimethylformamide with stirring at room temperature. To the solution, 152 g of N,N-dicyclohexylcarbodiimide was added dropwise. After addition, the mixture was stirred at room temperature for 6 hours to separate white crystals (N,N-dicyclohexylurea). After the reaction, the separated crystals were filtered off and the filtrate was poured into 2 l of water to separate white crystals. The separated crystals were filtered out and recrystallized from acetonitrile to obtain 180 g of the desired 4-hydroxy-6-(N-vinylbenzylcarbamoylmethyl)-1,3,3a,7-tetraazaindene.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[O:10][CH3:11].[CH3:12][N:13]1[C:17](=[O:18])[CH2:16][NH:15][C:14]1=[O:19]>>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[C:16]2[NH:15][C:14](=[O:19])[N:13]([CH3:12])[C:17]2=[O:18])=[CH:4][C:3]=1[O:10][CH3:11]
Reactant: CN1C(=O)CNC1=O
Reactant: COc1cc(C=O)ccc1O
Product: COc1cc(C=C2NC(=O)N(C)C2=O)ccc1O
Yield: 13.4 %

Procedure:
Prepared according to the procedure described in Example 93 using 4-hydroxy-3-methoxybenzaldehyde (3.2 g, 21 mmoles) and 3-methyl hydantoin (3.0 g, 21 mmoles). Recrystallization from ethyl acetate gave the pure product (0.7 g), mp 227°-228° C.
Reaction SMILES: [C:1]([N:11]([CH3:22])[C@H:12]([C:19]([OH:21])=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[NH2:23][C@H:24]([C:37]([NH2:39])=[O:38])[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[C:28]([C:33]([CH3:36])([CH3:35])[CH3:34])[CH:27]=1.C1C=CC2N(O)N=NC=2C=1.CC(C)N=C=NC(C)C>CN(C=O)C.C(OCC)(=O)C>[C:1]([N:11]([CH3:22])[C@H:12]([C:19]([NH:23][C@H:24]([C:37]([NH2:39])=[O:38])[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[C:28]([C:33]([CH3:36])([CH3:34])[CH3:35])[CH:27]=1)=[O:21])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: CN(C(=O)OCc1ccccc1)[C@H](C(=O)O)c1ccccc1
Reactant: CC(C)(C)c1cc(C[C@H](N)C(N)=O)ccc1O
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C(=O)OCc1ccccc1)[C@H](C(=O)N[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O)c1ccccc1
Reaction time: 4 h

Procedure:
To a solution of 3.28 g (11.0 mmol) of Z-N-Me-Phg-OH, 2.16 g (9.17 mmol) of Tyr(3-tBu)-NH2 and 1.40 g (9.17 mmol) of HOBT in 60 ml of DMF, 1.42 ml (9.17 mmol) of DIC was added dropwise under cooling with ice and the mixture was stirred for 4 hours under cooling with ice. The reaction mixture was diluted with ethyl acetate and washed with saturated brine. The organic layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure; the resulting residue was subjected to silica gel column chromatography (eluting solvent consisting of methylene chloride, methanol and aqueous ammonia at a ratio of 100:5:1) to give Z-N-Me-Phg-Tyr(3-tBu)-NH2 in the amount of 4.03 g (85%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:29])=[C:14]([C:24](OCC)=[O:25])[C:15](=[O:23])[N:16]3[CH2:19][CH2:20][CH2:21][OH:22])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:30][CH2:31][CH:32]([OH:34])[CH3:33]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:29])=[C:14]([C:24]([NH:30][CH2:31][CH:32]([OH:34])[CH3:33])=[O:25])[C:15](=[O:23])[N:16]3[CH2:19][CH2:20][CH2:21][OH:22])=[N:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCO)c1=O
Reactant: CC(O)CN
Product: CC(O)CNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCO)c1=O
Yield: 34 %

Procedure:
In a similar manner to that described in example 196, from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-(3-hydroxypropyl)-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (60 mg, 0.15mmol) and 1-amino-2-propanol (0.05 mL) was prepared 7-[(4-fluorophenyl)methyl]-4-hydroxy-N-(2-hydroxypropyl)-1-(3-hydroxypropyl)-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (22 mg, 34% yield) as a yellow solid after purification by reverse phase HPLC. 1H NMR (CDCl3) δ 10.27 (br s, 1 H), 8.49 (s, 1 H), 7.52 (s, 1 H), 7.14-7.10 (m, 2 H), 6.99-6.94 (m, 2 H), 4.26 (m, 2 H), 4.09 (s, 2 H), 3.95 (m, 1 H), 3.55-3.47 (m, 3 H), 3.29 (m, 1 H), 1.79 (m, 2 H), 1.19 (d, J=6 Hz, 3 H); MS m/z 430 (M+1).