Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][C:30]1[C:31]([O:41][CH2:42][CH2:43][O:44][CH3:45])=[CH:32][C:33]([N+:38]([O-])=O)=[C:34]([CH:37]=1)[C:35]#[N:36])[CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][C:8]1[C:9]([O:19][CH2:20][CH2:21][O:22][CH3:23])=[CH:10][C:11]([N+:16]([O-])=O)=[C:12]([CH:15]=1)[C:13]#[N:14]>CC(O)=O.CC(O)C.[Fe]>[O:1]([CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][C:8]1[C:9]([O:19][CH2:20][CH2:21][O:22][CH3:23])=[CH:10][C:11]([NH2:16])=[C:12]([CH:15]=1)[C:13]#[N:14])[CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][C:30]1[C:31]([O:41][CH2:42][CH2:43][O:44][CH3:45])=[CH:32][C:33]([NH2:38])=[C:34]([CH:37]=1)[C:35]#[N:36]
Reactant: COCCOc1cc([N+](=O)[O-])c(C#N)cc1OCCOCCOCCOCCOc1cc(C#N)c([N+](=O)[O-])cc1OCCOC
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CC(C)O
Product: COCCOc1cc(N)c(C#N)cc1OCCOCCOCCOCCOc1cc(C#N)c(N)cc1OCCOC
Temperature: 25 °C
Yield: 82.8 %

Procedure:
To a solution of 5,5′-((((oxybis(ethane-2,1-diyl))bis(oxy))bis(ethane-2,1-diyl))bis(oxy))bis(4-(2-methoxyethoxy)-2-nitrobenzonitrile) (0.2 g) in AcOH (10 mL) and i-PrOH (10 mL) was added iron powder (0.5 g). The resulting mixture was heated to reflux for 1 h. After reaction finished, the mixture was cooled to room temperature, filtered, the precipitate washed with EA (10 mL). The combined washings and filtrate were concentrated under reduced pressure and purification by silica chromatography to give 0.15 g of 5,5′-((((oxybis(ethane-2,1-diyl))bis(oxy))bis(ethane-2,1-diyl))bis(oxy))bis(2-amino-4-(2-methoxyethoxy)benzonitrile). 1H-NMR (400 MHz, CDCl3): δ: 6.90 (s, 2H), 6.25 (s, 2H), 4.20-4.16 (br, 4H), 4.15-4.02 (m, 8H), 3.82-3.79 (m, 4H), 3.77-3.75 (m, 4H), 3.72-3.70 (m, 4H), 3.68-3.66 (m, 4H), 3.43 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.Cl[C:24](Cl)([O:26][C:27](=[O:33])OC(Cl)(Cl)Cl)Cl.[CH:35]1(O)[CH2:41][CH2:40]C[CH2:38][CH2:37][CH2:36]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:27](=[O:33])[O:26][CH:24]2[CH2:38][CH2:37][CH2:36][CH2:35][CH2:41][CH2:40]2)=[CH:18][CH:17]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: OC1CCCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2ncnc(Oc3ccc(NC(=O)OC4CCCCCC4)cc3)c2cc1OC
Yield: 84.3 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (77 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 1-cycloheptanol (30 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (62 mg, yield 72%).
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[CH:11]=[C:10]([CH3:12])[O:9][N:8]=1.[C:13]([C:17]1[C:26]([O:27][SiH:28]([CH3:30])[CH3:29])=[CH:25][CH:24]=[CH:23][C:18]=1[C:19](OC)=[O:20])([CH3:16])([CH3:15])[CH3:14].[Cl-].[NH4+]>CCCCCC.O1CCCC1>[CH3:6][C:7]1[CH:11]=[C:10]([CH2:12][C:19]([C:18]2[CH:23]=[CH:24][CH:25]=[C:26]([O:27][SiH:28]([CH3:30])[CH3:29])[C:17]=2[C:13]([CH3:16])([CH3:15])[CH3:14])=[O:20])[O:9][N:8]=1
Reactant: Cc1cc(C)on1
Reactant: COC(=O)c1cccc(O[SiH](C)C)c1C(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cc(CC(=O)c2cccc(O[SiH](C)C)c2C(C)(C)C)on1
Temperature: -20 °C
Yield: 50.4 %

Procedure:
52 ml of 1N solution of n-butyllithium in hexane were added to a solution of 6 g of 3,5-dimethylisoxazol in 200 ml of tetrahydrofuran at -78° C. After stirring for 1 h 15 g of methyl 2-tert.butyldimethylsiloxybenzoate in 50 ml of tetrahydrofuran were added at the same temperature. The reaction mixture was slowly warmed up to -20° C. A saturated aqueous solution of ammonium chloride was added, the mixture was extracted several times with ethylacetate. The organic phase was separated, washed with water and dried over magnesium sulfate. Chromatography on silica gel with heptane/ethylacetate gave 9.4 g of the product.
Reaction SMILES: N#N.C(N[C@@H](C(NCCCC1C=CC=CC=1)=[O:9])C)C.FC1C(OC(=O)[C@H](CC2C=CC(OCC3C=CC=CC=3)=CC=2)NC(OCC2C=CC=CC=2)=O)=C(F)C(F)=C(F)C=1F.C(N(C(C)C)CC)(C)C.[CH2:70]([O:77][C:78]([NH:80][C@H:81]([C:97]([N:99]([CH2:114][CH3:115])[C@@H:100]([C:102]([NH:104][CH2:105][CH2:106][CH2:107][C:108]1[CH:113]=[CH:112][CH:111]=[CH:110][CH:109]=1)=[O:103])[CH3:101])=[O:98])[CH2:82][C:83]1[CH:88]=[CH:87][C:86]([O:89][CH2:90][C:91]2[CH:96]=[CH:95][CH:94]=[CH:93][CH:92]=2)=[CH:85][CH:84]=1)=[O:79])[C:71]1[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=1>O1CCCC1.CN(C)C=O>[NH:80]([C:78]([O:77][CH2:70][C:71]1[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=1)=[O:79])[C@H:81]([C:97]([N:99]([CH2:114][CH3:115])[C@@H:100]([C:102]([NH:104][CH2:105][CH2:106][CH2:107][C:108]1[CH:109]=[CH:110][CH:111]=[CH:112][CH:113]=1)=[O:103])[CH3:101])=[O:98])[CH2:82][C:83]1[CH:88]=[CH:87][C:86]([O:89][C:90]([C:91]2[CH:92]=[CH:93][CH:94]=[CH:95][CH:96]=2)=[O:9])=[CH:85][CH:84]=1
Reactant: CCN(C(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)OCc1ccccc1)[C@H](C)C(=O)NCCCc1ccccc1
Reactant: CCN[C@H](C)C(=O)NCCCc1ccccc1
Agent: N#N
Agent: O=C(N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)Oc1c(F)c(F)c(F)c(F)c1F)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCN(C(=O)[C@H](Cc1ccc(OC(=O)c2ccccc2)cc1)NC(=O)OCc1ccccc1)[C@H](C)C(=O)NCCCc1ccccc1

Procedure:
A solution of N2 -ethyl-N-(3-phenylpropyl)-D-alaninamide (2.71 g.), N-benzyloxycarbonyl-O-benzyl-L-tyrosine pentafluorophenyl ester (5.71 g.) and diisopropylethylamine (1.29 g.) in tetrahydrofuran (65 ml.) was stirred overnight at room temperature. Dimethylformamide (10 ml.) and more N-benzyloxycarbonyl-O-benzyl-L-tyrosine pentafluorophenyl ester (5.71 g.) were added, stirring was continued over the weekend, and the mixture was concentrated. A solution of the residual syrup in ethyl acetate was washed with water, dilute hydrochloric acid, aqueous sodium chloride, aqueous sodium hydroxide (1N, 20 ml.) and aqueous sodium chloride again, then dried and stripped of ethyl acetate. High pressure liquid chromatography of the residue (9.2 g.) on silica gel (350 g.) using hexane-ethyl acetate (55:45) as the eluant (200 ml./min.) afforded in the fractions having a k' value range of 2.5-4.5 (N-benzyloxycarbonyl-O-benzyl-L-tyrosyl)-N2 -ethyl-N-(3-phenylpropyl)-D-alaninamide as a syrup which crystallized (2.291 g.).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N:9]([CH2:21][C:22]2[CH:41]=[CH:40][C:25]([CH2:26][O:27][C:28]3[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][C:36]([O:38]C)=[O:37])=[CH:30][CH:29]=3)=[CH:24][CH:23]=2)[C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1CCCC1.O.[OH-].[Li+].Cl>O.CO>[C:1]1([CH2:7][CH2:8][N:9]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([CH2:26][O:27][C:28]3[CH:29]=[CH:30][C:31]([CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[CH:32][CH:33]=3)=[CH:40][CH:41]=2)[C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)CCc1ccc(OCc2ccc(CN(CCc3ccccc3)c3nc(-c4ccccc4)cs3)cc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCc1ccc(OCc2ccc(CN(CCc3ccccc3)c3nc(-c4ccccc4)cs3)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.5 %

Procedure:
A mixture of methyl 3-[4-[[4-[[(2-phenylethyl)(4-phenyl-1,3-thiazol-2-yl)amino]methyl]benzyl]oxy]phenyl]propanoate (270 mg, 0.480 mmol), tetrahydrofuran (15 mL), methanol (10 mL), water (10 mL) and lithium hydroxide monohydrate (60.4 mg, 1.44 mmol) was stirred at room temperature for 3 hr. The reaction mixture was neutralized with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (162 mg, yield 62%) as colorless crystals.
Reaction SMILES: [CH:1]1[N:2]=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.CCOCC.[C:15]1([C:21]2[CH:30]=[CH:29][C:24]([C:25](=[O:28])[CH2:26][Br:27])=[CH:23][CH:22]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O1CCCC1>[Br-:27].[C:15]1([C:21]2[CH:22]=[CH:23][C:24]([C:25]([CH2:26][N+:2]3[CH:1]=[C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][N:4]4[CH:3]=3)=[O:28])=[CH:29][CH:30]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: c1ccn2cncc2c1
Reactant: O=C(CBr)c1ccc(-c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(C[n+]1cc2ccccn2c1)c1ccc(-c2ccccc2)cc1
Product: [Br-]
Reaction time: 96 h

Procedure:
Imidazo[3,4-a]pyridine (7.1 g., 60 mmoles), dissolved in 150 ml. of ether, was mixed with p-phenylphenacyl bromide dissolved in 100 ml. of tetrahydrofuran and stirred for 4 hours at room temperature. A first crop of crystalline 2-(4-phenylbenzoylmethyl)imidazo[3,4-a]pyridinium bromide [7.8 g., m.p. 258°-260° C. (dec.)] was recovered by filtration. After standing four days at room temperature, a second crop of crystallized product [9.5 g., m.p. 262°-264° C. (dec.)] was recovered from the filtrate.
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[C:10]([CH3:12])([CH3:11])[C:8](=[O:9])[N:7]([CH2:13][CH2:14]O)[C:5]1=[O:6].C(OC(=O)C)(=O)C>N1C=CC=CC=1>[CH3:11][C:10]1([CH3:12])[N:4]([CH:3]=[CH2:2])[C:5](=[O:6])[N:7]([CH:13]=[CH2:14])[C:8]1=[O:9]
Reactant: CC1(C)C(=O)N(CCO)C(=O)N1CCO
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: C=CN1C(=O)N(C=C)C(C)(C)C1=O
Reaction time: 2 h
Yield: 67 %

Procedure:
Alternatively, 5,5-dimethyl-1,3-divinylhydantoin was prepared by acetylating at 80° C for 2 hours 216 grams (1 mole) of 1,3-bis(2-hydroxyethyl)-5,5-dimethylhydantoin with 408 grams (4 moles) of acetic anhydride in the presence of 20 ml. of pyridine to form the corresponding diacetate ester. Pyrolysis of said diacetate ester by passing through a hot tube at 550° C gave the above product in a 67% yield (at 39% conversion), boiling at 89°-92° C/0.1 mm. (Compound 1).
Reaction SMILES: C(OC1N=[C:7]([CH:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][N:11]([C:26](OC3C=CC([N+]([O-])=O)=CC=3)=[O:27])[CH2:10]2)[O:6]N=1)C.[CH2:38](N(CC)CC)C.Cl[C:46](OC1C=CC([N+]([O-])=O)=CC=1)=[O:47]>C(O)(=O)C.[Pd].[Pt](=O)=O>[C:26]([N:11]1[CH2:12][CH:13]([C:15]2[CH:16]=[CH:17][C:18]([CH2:21][C:22]([F:23])([F:25])[F:24])=[CH:19][CH:20]=2)[CH2:14][CH:9]([C:7]([O:47][CH3:46])=[O:6])[CH2:10]1)(=[O:27])[CH3:38]
Reactant: CCN(CC)CC
Reactant: CCOc1noc(C2CC(c3ccc(CC(F)(F)F)cc3)CN(C(=O)Oc3ccc([N+](=O)[O-])cc3)C2)n1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: O=[Pt]=O
Agent: [Pd]
Solvent: CC(=O)O
Product: COC(=O)C1CC(c2ccc(CC(F)(F)F)cc2)CN(C(C)=O)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 7.00 g (23.4 mmol) of the compound from Example 62A in concentrated acetic acid (150 ml) was admixed with 3.00 g of palladium/carbon (10% palladium) and 5.50 g of platinum(IV) oxide and then hydrogenated under a hydrogen atmosphere at standard pressure until conversion is complete. The reaction solution was filtered through Celite, the filter residue was washed with methanol/water and the combined filtrates were concentrated under reduced pressure. The residue (10.5 g) was taken up in dichloromethane (315 ml) and then admixed with 18.2 ml (13.2 g, 131 mmol) of triethylamine, and then admixed at 0° C. with 5.86 g (29.1 mmol) of 4-nitrophenyl chloroformate. The mixture was stirred at 0° C. for 2 h, then warmed to RT and stirred overnight. The reaction solution was washed with saturated aqueous sodium hydrogencarbonate solution and water, and the organic phase was dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue was purified by means of preparative HPLC and the title compound was thus obtained as a by-product. Yield: 1.32 g (14% of theory, purity 85%)
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11]([N:12]2[C:24](=[O:25])[C:23]3[S:22][C:21]4[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=4[C:15]=3[CH2:14][CH2:13]2)=[CH:10][C:9]([F:26])=[CH:8][C:7]=1[C:27]1[N:35]=[C:34]2[C:30]([N:31]=[CH:32][NH:33]2)=[C:29]([NH:36][C:37]2[CH:42]=[CH:41][C:40]([N:43]3[CH2:48][CH2:47][N:46]([CH:49]4[CH2:52][O:51][CH2:50]4)[CH2:45][CH2:44]3)=[CH:39][CH:38]=2)[N:28]=1)(=O)C.[OH-].[Li+]>C(O)(C)C.C1COCC1.O>[F:26][C:9]1[CH:8]=[C:7]([C:27]2[N:35]=[C:34]3[C:30]([N:31]=[CH:32][NH:33]3)=[C:29]([NH:36][C:37]3[CH:38]=[CH:39][C:40]([N:43]4[CH2:44][CH2:45][N:46]([CH:49]5[CH2:50][O:51][CH2:52]5)[CH2:47][CH2:48]4)=[CH:41][CH:42]=3)[N:28]=2)[C:6]([CH2:5][OH:4])=[C:11]([N:12]2[CH2:13][CH2:14][C:15]3[C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=4[S:22][C:23]=3[C:24]2=[O:25])[CH:10]=1
Reactant: CC(=O)OCc1c(-c2nc(Nc3ccc(N4CCN(C5COC5)CC4)cc3)c3nc[nH]c3n2)cc(F)cc1N1CCc2c(sc3c2CCCC3)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Solvent: C1CCOC1
Product: O=C1c2sc3c(c2CCN1c1cc(F)cc(-c2nc(Nc4ccc(N5CCN(C6COC6)CC5)cc4)c4nc[nH]c4n2)c1CO)CCCC3
Temperature: 30 °C
Reaction time: 1 h
Yield: 59.5 %

Procedure:
A mixture of 119b (150 mg, 0.210 mmol) and lithium hydroxide (50 mg, 2.10 mmol) in i-propanol/THF (1:1, 4 mL) and water (1 mL) was stirred at 30° C. for 1 h. The mixture was evaporated in vacuo and the residue was diluted with water (5 mL). It was then extracted with ethyl acetate (2×10 mL). The combined ethyl acetate extract was concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 119 (85 mg, 58%) as a yellow solid. MS-ESI: [M+H]+ 681.3. 1H NMR (500 MHz, CDCl3) δ 12.72 (s, 1H), 8.45 (s, 1H), 7.93 (d, J=7.5 Hz, 1H), 7.79 (s, 1H), 7.72 (d, J=9.0 Hz, 2H), 7.12 (d, J=8.0 Hz, 1H), 6.98 (d, J=9.0 Hz, 2H), 4.74-4.67 (m, 6H), 4.09-4.04 (m, 1H), 3.78-3.73 (m, 1H), 3.57 (t, J=6.5 Hz, 1H), 3.24-3.22 (m, 4H), 2.99-2.93 (m, 1H), 2.88-2.83 (m, 3H), 2.53-2.51 (m, 6H), 1.93-1.81 (m, 5H).
Reaction SMILES: CC1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7](O)=[CH:6][CH:5]=2.F[C:13]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16].FC1C=C(F)C=CC=1C(OCC)=[O:28]>>[NH2:3][C:4]1[C:9]([CH3:10])=[C:8]([CH:7]=[CH:6][CH:5]=1)[O:28][C:13]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)c1ccc(F)cc1F
Reactant: CCOC(=O)c1ccc(F)cc1F
Reactant: Cc1cc2cc(O)ccc2[nH]1
Product: COC(=O)c1ccc(F)cc1Oc1cccc(N)c1C

Procedure:
The title compound was prepared by substituting 3-amino-2-methylphenol for 2-methyl-5-indolol and methyl 2,4-difluorobenzoate for ethyl 2,4-difluorobenzoate in EXAMPLE 3A.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[O:7].[OH-].[Na+].[CH3:13]OS([O-])(=O)=O.C([S+](C)C)CCCCCCCCCCC.C1(C)C=CC=CC=1>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]1[O:7][CH2:13]1
Reactant: COS(=O)(=O)[O-]
Reactant: COc1cccc(C=O)c1
Agent: CCCCCCCCCCCC[S+](C)C
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cccc(C2CO2)c1

Procedure:
A mixture of 3-methoxybenzaldehyde (13.4 g, 0.098 mol), a solution of sodium hydroxide (200 g) in water (200 ml), dodecyl-dimethylsulfonium methyl sulfate (51 g, 0.15 mol) and toluene (150 ml) is stirred for 17 hours. Ice is then added and the organic phase is separated, washed with water (3×50 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure. The above product is recovered from the thus obtained residue by distillation at 135°-140° C. and 30 mmHg.
Reaction SMILES: [H-].[Na+].FC1C(F)=CC=CC=1[CH2:11][S:12]([C:15]1[N:20]=[C:19]([N:21]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)[S:22]([N:25]2[CH2:28][CH2:27][CH2:26]2)(=[O:24])=[O:23])[CH:18]=[C:17]([O:38][CH3:39])[N:16]=1)(=O)=O.[CH:40]1[CH:45]=[CH:44][C:43]([CH2:46]CS)=[CH:42][CH:41]=1>CN(C=O)C.CCOC(C)=O>[CH3:37][O:36][C:33]1[CH:32]=[CH:31][C:30]([CH2:29][N:21]([C:19]2[CH:18]=[C:17]([O:38][CH3:39])[N:16]=[C:15]([S:12][CH2:11][CH2:46][C:43]3[CH:44]=[CH:45][CH:40]=[CH:41][CH:42]=3)[N:20]=2)[S:22]([N:25]2[CH2:28][CH2:27][CH2:26]2)(=[O:23])=[O:24])=[CH:35][CH:34]=1
Reactant: COc1ccc(CN(c2cc(OC)nc(S(=O)(=O)Cc3cccc(F)c3F)n2)S(=O)(=O)N2CCC2)cc1
Reactant: SCCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(CN(c2cc(OC)nc(SCCc3ccccc3)n2)S(=O)(=O)N2CCC2)cc1

Procedure:
60% Sodium hydride (29 mg) was added to a solution of the product of step ii) (0.36 g) and 2-phenylethylthiol (0.1 g) in anhydrous DMF (4 ml) stirred under nitrogen. The reaction mixture was stirred for 18 h, diluted with EtOAc and washed with H2O. The separated organic solution was dried (MgSO4), filtered and the solvent evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel using Et2O/isohexane (3:7) as eluent to give the product as a white solid. Yield: 0.17 g.
Reaction SMILES: C([O-])(=O)C.[NH4+:5].C([O:8][C:9]([C:11]1[N:12]([CH:21]2[CH2:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][C:27]=3[CH2:30][C:31]([NH:33][S:34]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)(=[O:36])=[O:35])=[O:32])[C:22]2=O)[CH:13]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:15]=1)=O)C.C(O)(=O)C>O>[C:37]1([S:34]([NH:33][C:31]([CH2:30][C:27]2[C:28]3[CH2:29][C:21]4[N:12]5[CH:13]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:15]=[C:11]5[C:9](=[O:8])[NH:5][C:22]=4[C:23]=3[CH:24]=[CH:25][CH:26]=2)=[O:32])(=[O:35])=[O:36])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: [NH4+]
Reactant: CCOC(=O)c1cn(C2Cc3c(CC(=O)NS(=O)(=O)c4ccccc4)cccc3C2=O)c(C(=O)OCC)n1
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1cn2c3c([nH]c(=O)c2n1)-c1cccc(CC(=O)NS(=O)(=O)c2ccccc2)c1C3
Temperature: 0 °C
Yield: 48 %

Procedure:
3 g of ammonium acetate are added, with stirring, to a solution of 2.1 g of 2-(2,4-diethoxycarbonylimidazol-1-yl)-4-benzenesulphonamidocarbonylmethylindan-1-one and 55 ml of acetic acid. The reaction medium is heated at boiling temperature for 3 hours and then cooled and poured into a mixture of 60 g of ice and 60 ml of distilled water. The suspension thus obtained is filtered on sintered glass, washed twice with 20 ml of water, 10 ml of acetone and dried under reduced pressure at 53° C. 0.92 g of ethyl 9-bezenesulphonamidocarbonylmethyl-4-oxo-4,5-dihydro-10H-imidazo[1,2-a]indeno[1,2-e]-pyrazine-2-carboxylate is thus obtained in the form of a grey solid melting above 260° C. (Analysis: C24H20N4O6S1 : % calculated C: 58.53, H: 4.09, N: 11.38, S: 6.54; % found C: 58.3, H: 4.1, N: 11.5, S: 6.9).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[CH:11]=[C:10]([C:12]([OH:14])=O)[NH:9][C:6]2=[CH:7][N:8]=1)#[N:2].Cl.[NH2:16][CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:19].CN1CCOCC1.C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-]>C1COCC1>[O:19]=[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:17][NH:16][C:12]([C:10]1[NH:9][C:6]2=[CH:7][N:8]=[C:3]([C:1]#[N:2])[CH:4]=[C:5]2[CH:11]=1)=[O:14]
Reactant: N#Cc1cc2cc(C(=O)O)[nH]c2cn1
Reactant: NCC(=O)c1ccccc1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: N#Cc1cc2cc(C(=O)NCC(=O)c3ccccc3)[nH]c2cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5-cyano-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Preparation 62, 0.035 g, 0.19 mmol) in THF (15 mL) under argon was added 2-aminoacetophenone hydrochloride (0.036 g, 0.21 mmol), N-methylmorpholine (25 μM, 0.23 mmol) and DMTMM (0.072 g, 0.27 mmol). The reaction mixture was stirred at rt for 16 h. The reaction mixture was concentrated to dryness in vacuo. The residue was partitioned between ethyl acetate (100 mL) and water (50 mL). The organic phase was separated and the aqueous phase was further extracted with ethyl acetate (100 mL). The combined organic extract was washed with 1N NaOH (40 mL), saturated sodium chloride (40 mL), dried (MgSO4), filtered and concentrated in vacuo. Crude material was purified by chromatography in hexane/ethyl acetate (1:2) and recrystallised from methanol to give the title compound. m/z (ES+)=304 [M+H]+; RT=4.37.
Reaction SMILES: [C:1]([Sn:5]([Cl:11])(F)[C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:4])([CH3:3])[CH3:2].CCCCC.[C:17]([Li])([CH3:20])([CH3:19])[CH3:18]>CCCCCCC>[C:1]([Sn:5]([Cl:11])([C:17]([CH3:20])([CH3:19])[CH3:18])[C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [Li]C(C)(C)C
Reactant: CC(C)(C)[Sn](F)(Cl)C(C)(C)C
Solvent: CCCCC
Solvent: CCCCCCC
Product: CC(C)(C)[Sn](Cl)(C(C)(C)C)C(C)(C)C
Temperature: -78 °C
Reaction time: 2 h

Procedure:
A suspension of di-t-butyltin chloride fluoride (5.0 g., 0.017 mole) in heptane (100 ml.) was cooled to -78° C., and a pentane solution of t-butyl-lithium (20 ml., 1.95 M) was added dropwise. After the addition was completed, stirring was continued for 2 hrs., the cooling bath was removed, and the mixture was allowed to warm to room temperature with stirring for 6 more hrs. The resulting pale yellow mixture was worked up to give a thick, pale yellow oil which was chromatographed with pentane. Evaporation of the solvent left a clear oil which solidified spontaneously (5.0 g., 88.3%), m.p. 31-32; (b.p. 122°-123°/5 mm. (Found: C, 44.15; H, 8.15; Cl, 10.95. C12H27ClSn requires C, 44.3; H, 8.35; Cl, 10.9%); n.m.r. 61.35 (s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:13]=3[N:12]3[C:21]([CH3:24])=[N:22][N:23]=[C:11]3[C@H:10]([CH2:25][C:26]([O:28]C)=[O:27])[N:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:13]=3[N:12]3[C:21]([CH3:24])=[N:22][N:23]=[C:11]3[C@H:10]([CH2:25][C:26]([OH:28])=[O:27])[N:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2cc(OC)ccc2-n2c(C)nnc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(c1ccc(Cl)cc1)=N[C@@H](CC(=O)O)c1nnc(C)n1-2
Reaction time: 5 h
Yield: 98 %

Procedure:
To a solution of methyl [(4S)-6-(4-chlorophenyl)-1-methyl-8-(methyloxy)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]acetate (for a preparation see Reference compound G) (7.4 g, 18.1 mmol) in THF (130 ml) at room temperature was added 1N sodium hydroxide (36.2 ml, 36.2 mmol). The reaction mixture was stirred at this temperature for 5 h before being quenched with 1N HCl (36.2 ml) and concentrated in vacuo. Water is then added and the aqueous layer was extracted with DCM (×3) and the combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (7 g, 98% yield) as a pale yellow solid.