Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([C:14]2([C:24]3[CH:29]=[C:28]([CH3:30])[C:27]([O:31][Si](C(C)(C)C)(C)C)=[C:26]([CH3:39])[CH:25]=3)[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:23])=[CH:9][C:8]=1[CH3:40])(C)(C)C.CC(C)([O-])C.[K+].C1COCC1.[CH3:54][O:55][C:56]1[CH:63]=[CH:62][C:59]([CH2:60]Cl)=[CH:58][CH:57]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CN(C=O)C.O>[OH:31][C:27]1[C:26]([CH3:39])=[CH:25][C:24]([C:14]2([C:10]3[CH:9]=[C:8]([CH3:40])[C:7]([OH:6])=[C:12]([CH3:13])[CH:11]=3)[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH2:60][C:59]3[CH:62]=[CH:63][C:56]([O:55][CH3:54])=[CH:57][CH:58]=3)[C:15]2=[O:23])=[CH:29][C:28]=1[CH3:30]
Reactant: COc1ccc(CCl)cc1
Reactant: Cc1cc(C2(c3cc(C)c(O[Si](C)(C)C(C)(C)C)c(C)c3)C(=O)Nc3ccccc32)cc(C)c1O[Si](C)(C)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CN2C(=O)C(c3cc(C)c(O)c(C)c3)(c3cc(C)c(O)c(C)c3)c3ccccc32)cc1
Reaction time: 0.08 h
Yield: 130.5 %

Procedure:
Dissolve 3,3-bis-[4-(tert-butyl-dimethyl-silanyloxy)-3,5-dimethyl-phenyl]-1,3-dihydro-indol-2-one (150 mg, 0.25 mmol) in anhydrous DMF (1.5 mL) under nitrogen. Add slowly a 1M solution of potassium t-butoxide in THF (0.260 mL, 0.260 mmol). Stir 5 min and add 4-methoxybenzyl chloride (0.037 mL, 0.275 mmol). After 1 h add a 1M solution of tetrabutylammonium fluoride in THF (0.625 mL, 0.625 mmol) and stir 2 h. Dilute with water (10 mL) and extract with ethyl acetate (3×15 mL). Wash combined organic portions with water, brine, dry (Na2SO4), filter and concentrate in vacuo to obtain 161 mg of a residue. Recrystallize from CH2Cl2 and hexane to obtain 63 mg (51%) of the title compound as a white solid. MS (ES): m/z=494 (M+1), 492 (M−1); 1H NMR(DMSO-d6): δ8.24 (s, 2H), 7.30-7.20 (m, 4H), 7.04 (m, 2H), 6.89 (d, J=8.7 Hz, 2H), 6.68 (s, 4H), 5.77 (s, 2H), 3.72 (s, 3H), 2.07 (s, 12H).
Reaction SMILES: Cl[C:2]1[C:10]2[NH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[N:7][C:6]=2[C:5]([N+:15]([O-:17])=[O:16])=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19].[Na].[CH2:23]([SH:29])[CH2:24][CH:25]=[CH:26][CH2:27][CH3:28]>>[CH2:23]([S:29][C:2]1[C:10]2[NH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[N:7][C:6]=2[C:5]([N+:15]([O-:17])=[O:16])=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19])[CH2:24][CH:25]=[CH:26][CH2:27][CH3:28]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)c2[nH]c(C(F)(F)F)nc12
Reactant: CCC=CCCS
Agent: [Na]
Product: CCC=CCCSc1c(C(F)(F)F)cc([N+](=O)[O-])c2nc(C(F)(F)F)[nH]c12

Procedure:
4-Chloro-7-nitro-2,5-bis(trifluoromethyl)benzimidazole is reacted with the sodium salt of 3-hexene-1-thiol to obtain 4-(3-hexenylthio)-7-nitro-2,5-bis(trifluoromethyl)-benzimidazole, m.w., 413.4.
Reaction SMILES: [N+:1]([CH3:4])([O-:3])=[O:2].C1CCN2C(=NCCC2)CC1.CS(C)=O.[CH2:20]([O:22][C:23](=[O:30])[CH:24]=[CH:25][CH2:26][CH:27]([CH3:29])[CH3:28])[CH3:21]>C(Cl)Cl>[CH2:20]([O:22][C:23](=[O:30])[CH2:24][CH:25]([CH2:4][N+:1]([O-:3])=[O:2])[CH2:26][CH:27]([CH3:29])[CH3:28])[CH3:21]
Reactant: CCOC(=O)C=CCC(C)C
Reactant: C[N+](=O)[O-]
Solvent: CS(C)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CCOC(=O)CC(CC(C)C)C[N+](=O)[O-]

Procedure:
7.0 g of nitromethane and 3.3 mL of DBU (1,8-diazabicyclo[5.4.0]undece-7-en) were added to the DMSO solution of α,β-unsaturated ester VII. The reaction mixture was stirred until complete conversion was detected by GC. 20 mL of CH2Cl2 were added and the resulting mixture was washed with 2×20 mL of 1M aqueous H2SO4 and 1×20 mL of 0.5M aqueous NaHCO3. The organic layer was dried and the solvent was removed under reduced pressure. 3.6 g of γ-nitroester VIII were obtained (yield over two steps: 75%).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([CH3:9])[CH2:4]1.[S:10](Cl)([C:13]1[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=1)(=[O:12])=[O:11]>ClCCl>[S:10]([O:1][CH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([CH3:9])[CH2:4]1)([C:13]1[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=1)(=[O:12])=[O:11]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CN1CCC[C@@H](CO)C1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2CCCN(C)C2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 42.3 %

Procedure:
A solution of (R)-3-hydroxymethyl-1 -methylpiperidine (2.6 g, 20 mmol) in dichloromethane (70 mL) was cooled to 5° C. and tosyl chloride (3.8 g, 20 mmol) was added in portions during 15 minutes. After the addition was complete, the reaction was allowed to warm to room temperature and was stirred for 20 hours. The reaction mixture was then concentrated and the residue partitioned between 10% potassium hydroxide (50 mL) and ether (100 mL). The ether layer was removed and the aqueous phase extracted once again with ether (50 mL). The combined ether layers were dried over magnesium sulfate and concentrated to afford (R)-3-tosyloxymethyl-1 -methylpiperidine as a white solid (2.4 g, 42%), m.p. 74.5-81.0° C.
Reaction SMILES: FC(F)(F)C([NH:5][C@H:6]([C:21]([N:23]1[CH2:28][CH2:27][CH:26]([CH3:29])[CH2:25][CH2:24]1)=[O:22])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14]C(=O)C)=[C:10]([N+:18]([O-:20])=[O:19])[CH:9]=1)=O.[OH-].[Na+]>C(O)C>[NH2:14][C:11]1[CH:12]=[CH:13][C:8]([CH2:7][C@@H:6]([C:21]([N:23]2[CH2:24][CH2:25][CH:26]([CH3:29])[CH2:27][CH2:28]2)=[O:22])[NH2:5])=[CH:9][C:10]=1[N+:18]([O-:20])=[O:19]
Reactant: CC(=O)Nc1ccc(C[C@H](NC(=O)C(F)(F)F)C(=O)N2CCC(C)CC2)cc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1CCN(C(=O)[C@@H](N)Cc2ccc(N)c([N+](=O)[O-])c2)CC1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To a suspension of 4.85 g (10.9 mMol) of N-trifluoroacetyl-4-acetylamino-3-nitro-phenylalanyl-(4-methyl-piperidine) in 10 ml of ethanol 28.0 ml of 1N sodium hydroxide solution are added dropwise at 20° C. After 3 hours' stirring at 50° C. the mixture is cooled, then after another 2 hours it is suction filtered and washed with a little ice water.
Reaction SMILES: N1([C:7](=[N:9][NH:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[CH3:8])CCOCC1.[N:20]([CH2:23][CH2:24][CH3:25])=[C:21]=[O:22]>CN(C)C1C=CN=CC=1.ClCCl>[CH3:8][C:7]1[N:20]([CH2:23][CH2:24][CH3:25])[C:21](=[O:22])[N:10]([C:11]2[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=2)[N:9]=1
Reactant: CC(=NNc1ccc([N+](=O)[O-])cc1)N1CCOCC1
Reactant: CCCN=C=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCn1c(C)nn(-c2ccc([N+](=O)[O-])cc2)c1=O
Reaction time: 3 h
Yield: 65 %

Procedure:
A mixture of 13 parts of 1-[1-(4-morpholinyl)ethylidene-2-(4-nitrophenyl)hydrazine, 8.5 parts of 1-isocyanatopropane, 1 part of N,N-dimethyl-4-pyridinamine and 39 parts of dichloromethane was stirred and refluxed for 2 hours. The whole was evaporated and 90 parts of dimethylbenzene were added to the residue. Stirring at reflux was continued for 3 hours. The reaction mixture was cooled and filtered over diatomaceous earth. The filtrate was saturated with petroleum ether. The precipitated product was filtered off and crystallized from 2-propanol, yielding 8.5 parts (65%) of 2,4-dihydro-5-methyl-2-(4-nitrophenyl)-4-propyl-3H-1,2,4-triazol-3-one; mp. 125.4° C. (int. 20).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([CH2:13]O)[N:10]=[CH:9]2)=[CH:4][CH:3]=1.O=S(Cl)[Cl:17]>>[Cl:17][CH2:13][C:11]1[N:10]=[CH:9][N:8]([C:5]2[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=2)[CH:12]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cn(-c2ccc(I)cc2)cn1
Product: ClCc1cn(-c2ccc(I)cc2)cn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The compound 4-hydroxymethyl 1-(4-iodophenyl)imidazole 9.3 (0.810 g, 2.70 mmol) was dissolved in SOCl2 (6 mL). The solution was stirred at room temperature for 15 min. It was then concentrated in vacuo. The residue was partitioned between EtOAc and 5% aq. NaHCO3. The organic layer was separated, dried over Na2SO4, concentrated in vacuo to give 4-(chloromethyl)-1-(4-iodophenyl)-1H-imidazole 9.5 as a solid (0.780 g). MS 318.9 and 320.9 (M+H, Cl pattern)
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:19])([CH3:18])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][O:16][CH3:17])[CH:9]=1)([CH3:4])[CH3:3].[Li]CCCC.Cl[C:26](=[O:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28]>CCCCCC.O1CCCC1>[CH3:4][C:2]([Si:5]([CH3:18])([CH3:19])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][O:16][CH3:17])[C:9]=1[C:26](=[O:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28])([CH3:1])[CH3:3]
Reactant: COCOc1cccc(CO[Si](C)(C)C(C)(C)C)c1
Reactant: CCOC(=O)C(=O)Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)c1c(CO[Si](C)(C)C(C)(C)C)cccc1OCOC
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.7 %

Procedure:
To a solution of (1,1-dimethylethyl)(dimethyl){[(3-{[(methyloxy)methyl]oxy}phenyl)methyl]oxy}silane (Intermediate 103, 3 g) in dry n-hexane (30 mL) a solution of BuLi in hexane (1.6M, 7.63 mL, 12.21 mmol) was added and the reaction mixture was stirred for 2 hours at room temperature The reaction mixture was cooled to −78° C. and it was added (via cannulation) to a solution of ethyl chloro(oxo)acetate (1.780 mL, 15.93 mmol) in dry tetrahydrofuran (20 mL) at −78° C. The reaction was quenched with water (20 ml) and extracted with ethyl acetate (2×30 ml). The organic layer was dried over sodium sulphate, filtered and evaporated and the residue was purified by flash chromatography (Biotage system) on silica gel using a 100 g SNAP column and cyclohexane to cyclohexane/ethyl acetate 8:2 as eluents. This afforded the title compound as a yellow pale oil (2.67 g).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][C:10](=[O:13])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[OH-].[Na+].[C:18]1(C)C=CC=CC=1>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH2:8][CH2:9][C:10]3([O:13][CH2:18]3)[CH2:11][CH2:12]2)=[CH:14][CH:15]=1
Reactant: Cc1ccccc1
Reactant: O=C1CCN(Cc2ccc(F)cc2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Product: Fc1ccc(CN2CCC3(CC2)CO3)cc1
Temperature: 80 °C

Procedure:
61.00 g (0.295 mol) of 1-(4-fluorobenzyl)-4-piperidone crude product was added to a reaction bottle, to which 260 mL of toluene was added. The reaction was heated and stirred at 80° C. in an oil bath, and to the reaction 70.00 g (0.318 mol) of trimethylsulfoxide iodide and 2.70 g (0.0080 mol) of tetrabutylammonium hydrogen sulfate were added in sequence, then 28.00 g (0.700 mol) sodium hydroxide dissolved in 120 mL of aqueous solution was added dropwise under stirring. After the addition, the reaction was continuously stirred at 80° C. bath temperature overnight. On the next day, the reaction was cooled, washed with water twice, extracted with a small amount of toluene, combined and dried, and the solvent was recovered to obtain light yellow liquid, 47.50 g (72.8%), i.e., a crude target product, 1H-NMR (CDCl3, ppm) δ: 7.298 (2H, m), 7.007 (2H, m), 3.519 (2H, s), 2.565 (2H, s), 2.559 (4H, m), 1.827 (2H, m), 1.534 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[C:3]([Si](C)(C)C)=[C:4]([C:7]([OH:9])=[O:8])[S:5][CH:6]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(=O)(O)[O-].[Na+]>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:7]([OH:9])=[O:8])[S:5][CH:6]=1
Reactant: C[Si](C)(C)c1c(Cl)csc1C(=O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc(Cl)cs1

Procedure:
A 300 mg (1.278 mmol) sample of 4-chloro-3-trimethylsilyl-2-thiophene carboxylic acid was dissolved in 10 mL of tetrahydrofuran with 0.3 mL of water and cooled to -5° C. (ice/brine bath). A 2.6 mL aliquot of the 1M tetrahydrofuran solution of tetra-n-butyl ammonium fluoride was slowly added to the reaction solution. After 4 hours the reaction was poured into 50 mL of 5% aqueous sodium bicarbonate. The entire reaction solution was transferred to a separatory funnel and washed with ethyl acetate (2×25 mL). The basic aqueous solution was acidified with concentrated hydrochloric acid to pH2 and then extracted with ethyl acetate (3×30 mL). The organic extract was then dried (sodium sulfate), filtered, and evaporated to 216 mg of product as a white solid. Recrystallization using hot heptane gave 85 mg of pure crystalline product, mp 138° C.
Reaction SMILES: [SH:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].C(N(CC)CC)C.[CH3:19][N:20]=[C:21]=[O:22].Cl>O.O1CCCC1>[CH3:19][NH:20][C:21]([S:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4])=[O:22]
Reactant: O=C(O)C(S)c1ccccc1
Reactant: CN=C=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)SC(C(=O)O)c1ccccc1

Procedure:
10.08 g. (60 mM) of α-mercaptophenylacetic acid and 6.6 g. (60 mM) of triethylamine are dissolved in 50 ml. of tetrahydrofuran and 3.42 g. (60 mM) of methylisocyanate dissolved in 20 ml. of tetrahydrofuran are added dropwise with stirring. After stirring for 2 hours, the solvent is drawn off in a vacuum and the oily residue is dissolved in water. The mixture is then acidified with 2N hydrochloric acid and extracted three times each with 20 ml. of ether. After drying off the ether, 10.5 g. of white crystalline DL-[(methylcarbamoyl)thio]phenylacetic acid are obtained, which is recrystallized from ether/petroleum ether, m.p. 128°-129°.
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13]#[N:14])[CH:9]=[CH:10][CH:11]=1.[N-:20]=[N+:21]=[N-:22].[Na+].[Cl-].[NH4+].C(OCC)(=O)C>CN(C)C=O.CCCCCC>[CH3:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:9]=[CH:10][CH:11]=1)[CH2:12][C:13]1[NH:22][N:21]=[N:20][N:14]=1
Reactant: Cc1cccc(C)c1COc1cccc(CC#N)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cccc(C)c1COc1cccc(Cc2nnn[nH]2)c1
Temperature: 90 °C

Procedure:
A mixture of 2-(3-(2,6-Dimethylbenzyloxy)phenyl)acetonitrile (Step B, 3.2 g, 12.7 mmol), sodium azide (1.28 g, 16.7 mmol) and ammonium chloride (1.08 g, 20.2 mmol) in dry dimethylformamide (30 ml) was heated under argon at 90° C. for 9 hours or until all the starting material is consumed and the reaction mixture was concentrated under reduced pressure. The reaction mixture was taken in ethyl acetate and washed with water (2×), dried over Na2SO4, filtered, concentrated and purified by flash chromatography on a silica gel column (methylene chloride:methanol 9:1) to give the oily product. The oil was stirred with 1:2 ethyl acetate:hexane for 10 minutes, and solid was filtered to give product as a white solid.
Reaction SMILES: [OH-].[NH4+:2].[Cl:3][C:4]1[C:5]([F:17])=[C:6]([CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[C:12]=1F)[C:7]([OH:9])=[O:8].Cl>O>[NH2:2][C:12]1[C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([F:17])[C:4]=1[Cl:3]
Reactant: [NH4+]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(F)c(Cl)c1F
Agent: Cl
Agent: [OH-]
Solvent: O
Product: Nc1c([N+](=O)[O-])cc(C(=O)O)c(F)c1Cl
Temperature: 25 °C
Yield: 85.8 %

Procedure:
Ammonium hydroxide solution (6.88 g, −30% in water, 58.9 mmol) is added to a solution of 3-chloro-2,4-difluoro-5-nitro-benzoic acid 2a (3.5 g, 14.7 mmol) in water (16 mL) at 0° C. with stirring. Upon completion of the ammonium hydroxide addition the reaction mixture is warmed to room temperature. After 5 hours the reaction mixture is cooled to 0° C. and concentrated HCl is carefully added until the pH of the reaction mixture is near zero. The solid is collected by filtration and washed with water and diethyl ether. The solids are transferred to a round bottom flask as a solution in MeOH and EtOAc and concentrated under reduced pressure to give 2.96 g of a yellow solid. The filtrate is partitioned between diethyl ether and water and the organic layer is washed with brine. The combined organic extracts are dried (Na2SO4) and concentrated under reduced pressure to give 0.65 g of product. Recovered a total of 3.61 g (104%) of pure desired product that is carried forward without further purification.
Reaction SMILES: CCN(C(C)C)C(C)C.[Cl:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15]([OH:29])=[C:16]([C:24](OCC)=[O:25])[C:17](=[O:23])[C:18]2([CH3:22])[CH3:21])=[CH:13][CH:12]=1.Cl.[C:31]([O:35][C:36](=[O:39])[CH2:37][NH2:38])([CH3:34])([CH3:33])[CH3:32]>O1CCOCC1.CCOCC>[Cl:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15]([OH:29])=[C:16]([C:24]([NH:38][CH2:37][C:36]([O:35][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:39])=[O:25])[C:17](=[O:23])[C:18]2([CH3:22])[CH3:21])=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)CN
Reactant: CCOC(=O)C1=C(O)c2ccc(Cl)cc2C(C)(C)C1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2ccc(Cl)cc2C(C)(C)C1=O
Temperature: 85 °C
Reaction time: 2 h
Yield: 115.8 %

Procedure:
DIPEA (0.718 mL, 4.12 mmol) was added to a mixture of ethyl 7-chloro-4-hydroxy-1,1-dimethyl-2-oxo-naphthalene-3-carboxylate (810 mg, 2.75 mmol) and glycine tert-butyl ester hydrochloride (553 mg, 3.30 mmol) in dioxane (25 mL). The reaction mixture was stirred at 85° C. for 2 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo to give a yellow solid. The crude solid was suspended in ether and filtered to give the desired ester as a white solid (1.21 g). MS (m/e)=324.1 (M+H-tBu)+.
Reaction SMILES: COCCOC[O:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[O:16]COCCOC)[CH:11]=O.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:28][C:29]#[N:30]>>[OH:7][C:8]1[CH:9]=[C:10](/[CH:11]=[C:28](/[C:27]2[CH:31]=[CH:32][C:33]([O:34][CH3:35])=[C:25]([O:24][CH3:23])[CH:26]=2)\[C:29]#[N:30])[CH:13]=[CH:14][C:15]=1[OH:16]
Reactant: COCCOCOc1ccc(C=O)cc1OCOCCOC
Reactant: COc1ccc(CC#N)cc1OC
Product: COc1ccc(/C(C#N)=C/c2ccc(O)c(O)c2)cc1OC
Yield: 48.3 %

Procedure:
The hydroxyl groups of 3,4-dihydroxybenzaldehyde (2.0 g) were protected by use of 2-methoxyethoxymethyl chloride (3.6 g) in accordance with (production process 1), to thereby produce 3,4-bis(methoxyethoxymethoxy)benzaldehyde (3.6 g, yield: 89%). The thus-produced 3,4-bis(methoxyethoxymethoxy)benzaldehyde (3.5 g) and 3,4-dimethoxybenzyl cyanide (2.0 g) were subjected to condensation in accordance with process A of (production process 2), to thereby yield an MEM form of the target product. Subsequently, the protective group was removed from the MEM form in accordance with (production process 3), to thereby produce the target product (1.6 g, yield: 50%).
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][NH2:12])[CH2:7][CH2:6]1)=[O:4].C([O-])([O-])=O.[K+].[K+].[C:19]12[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=1)[NH:24]C(=O)O[C:20]2=[O:21]>CC#N>[CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][NH:12][C:20](=[O:21])[C:19]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[NH2:24])[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)[C@H]1CC[C@H](CN)CC1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)[C@H]1CC[C@H](CNC(=O)c2ccccc2N)CC1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a solution of trans-4-Aminomethyl-cyclohexanecarboxylic acid methyl ester (21.7 g, 127 mmol) in CH3CN (500 mL), K2CO3 (35 g, 254 mmol) and isatoic anhydride (20.7 g, 127 mmol) were added. The reaction was stirred at 70° C. overnight. The mixture was concentrated under reduced pressure and the residue was washed with 200 mL of H2O and the solid obtained was filtered. The titled compound (31.1 g, quantitative yield) was obtained as a white solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]([C:9]1[N:10]=[N:11][C:12](Cl)=[CH:13][CH:14]=1)=[O:8].[N:16]1([C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]([F:33])([F:32])[F:31])=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]([C:9]1[N:10]=[N:11][C:12]([N:19]2[CH2:20][CH2:21][N:16]([C:22](=[O:23])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([F:33])([F:31])[F:32])[CH2:17][CH2:18]2)=[CH:13][CH:14]=1)=[O:8]
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Reactant: O=C(NCCCCO)c1ccc(Cl)nn1
Product: O=C(NCCCCO)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 15, making variations only as required to use 6-chloropyridazine-3-carboxylic acid (4-hydroxybutyl)amide in place of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl)amide to react with piperazin-1-yl-(2-trifluoromethylphenyl)methanone, the title compound was obtained as a white powder (30% yield). 1H NMR (500 MHz, CDCl3) δ 8.05, 7.98, 7.75, 7.63, 7.57, 7.37, 6.99, 4.06, 3.88, 3.82-3.67, 3.52, 3.36, 1.70.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[N:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)[C:10]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:9]1[C:37]([O:39]CC1C=CC=CC=1)=[O:38])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCO.[Pd]>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[N:17]2[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:28])([CH3:29])[CH3:27])=[O:24])[CH2:21][CH2:22]2)[C:10]([CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[C:9]1[C:37]([OH:39])=[O:38])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3c(Cc4ccccc4)c(C(=O)OCc4ccccc4)n(C(=O)OC(C)(C)C)c23)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2cccc3c(Cc4ccccc4)c(C(=O)O)n(C(=O)OC(C)(C)C)c23)CC1
Reaction time: 1 h
Yield: 84 %

Procedure:
3-Benzyl-7-(4-tert-butoxycarbonyl-piperazin-1-yl)-indole-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester (100 mg, 0.16 mmol) in EtOH (20 ml) was added to a Parr vessel containing catalytic amount of 5% Pd on carbon. The vessel was purged with 2.76 Bar of hydrogen After shaking for one hour, the reaction mixture was filtered through Celite and concentrated under reduced pressure to give 3-benzyl-7-(4-tert-butoxycarbonyl-piperazin-1-yl)-indole-1,2-dicarboxylic acid 1-tert-butyl ester (72 mg, 84%). MS: (M+H)+ 536.4.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[C:15]([C:18]1[CH:52]=[CH:51][C:21]([C:22]([N:24]2[CH2:28][C@@H:27]([N:29]3[CH2:34][CH2:33][N:32]([S:35]([CH3:38])(=[O:37])=[O:36])[CH2:31][CH2:30]3)[CH2:26][C@H:25]2[C:39]([NH:41][C:42]2[CH:50]=[CH:49][C:45]([C:46]([OH:48])=[O:47])=[CH:44][CH:43]=2)=[O:40])=[O:23])=[CH:20][CH:19]=1)(=[NH:17])[NH2:16]>C(O)C.S(=O)(=O)(O)O>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[C:15]([C:18]1[CH:19]=[CH:20][C:21]([C:22]([N:24]2[CH2:28][C@@H:27]([N:29]3[CH2:34][CH2:33][N:32]([S:35]([CH3:38])(=[O:37])=[O:36])[CH2:31][CH2:30]3)[CH2:26][C@H:25]2[C:39]([NH:41][C:42]2[CH:43]=[CH:44][C:45]([C:46]([O:48][CH2:2][CH3:3])=[O:47])=[CH:49][CH:50]=2)=[O:40])=[O:23])=[CH:51][CH:52]=1)(=[NH:16])[NH2:17]
Reactant: CS(=O)(=O)N1CCN([C@H]2C[C@@H](C(=O)Nc3ccc(C(=O)O)cc3)N(C(=O)c3ccc(C(=N)N)cc3)C2)CC1
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: CCOC(=O)c1ccc(NC(=O)[C@@H]2C[C@H](N3CCN(S(C)(=O)=O)CC3)CN2C(=O)c2ccc(C(=N)N)cc2)cc1
Temperature: 60 °C
Reaction time: 44 h
Yield: 118.5 %

Procedure:
To a stirred solution of compound prepared in Example 20 (500 mg) in ethanol (25 mL) was added concentrated sulfuric acid (20 drops) at 0° C. The resulting mixture was stirred at 60° C. for 44 h whereupon the mixture was concentrated in vacuo. The resulting residue was purified by Prep-HPLC (0.1% TFA containing CH3CN—H2O gradient) to provide the title compound (307 mg).