Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([SH:9])[CH:5]=[CH:6][C:7]=1[F:8].[OH-].[Na+].I[CH2:13][CH3:14]>CO>[Br:1][C:2]1[CH:3]=[C:4]([S:9][CH2:13][CH3:14])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Fc1ccc(S)cc1Br
Reactant: CCI
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCSc1ccc(F)c(Br)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 98.5 %

Procedure:
A mixture of 3-bromo-4-fluorobenzenethiol (3.89 g, 18.79 mmol) and sodium hydroxide (3.95 mL, 19.73 mmol) in MeOH was stirred at 0° C. for 10 minutes. To this solution was added iodoethane (1.803 mL, 22.54 mmol). The reaction mixture was stirred at ambient temperature for 6 hours. The solvent was removed, and the residue was partitioned between water and ethyl acetate. The aqueous layer was extracted with addition ethyl acetate three times. The combined organic layers were washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated to give the title compound (4.35 g, 18.50 mmol, 98% yield). It was used directly for the next reaction.
Reaction SMILES: [I:1]Cl.Cl.[N+:4]([C:7]1[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=1)([O-:6])=[O:5]>O>[I:1][C:12]1[CH:13]=[C:7]([N+:4]([O-:6])=[O:5])[CH:8]=[CH:9][C:10]=1[NH2:11]
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: ClI
Agent: Cl
Solvent: O
Product: Nc1ccc([N+](=O)[O-])cc1I
Temperature: 20 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
A solution of iodine monochloride (25.8 mL, 514 mmol) in water (220 mL) at 0° C. was treated with concentrated hydrogen chloride (87 mL, 2800 mmol) and stirred until the iodine monochloride dissolved. This cooled ICl solution was then added to a solution of p-nitroaniline (71 g, 510 mmol) in water (590 mL) and concentrated hydrogen chloride (50 mL, 2000 mmol) and stirred at 20° C. for 3 hours. The reaction mixture was filtered, washed with water, and dried to give the desired product (132 g, 94%) as a yellow solid. LCMS for C6H61N2O2 (M+H)+: m/z=264.7.
Reaction SMILES: CO.[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[O:11])[CH3:10].[BH4-].[Na+]>O>[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([OH:11])[CH3:10]
Reactant: CC(=O)c1ccccn1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(O)c1ccccn1
Reaction time: 4 h
Yield: 88.5 %

Procedure:
A methanol solution (100 mL) of 1-pyridin-2-ylethanone (10.0 g) was cooled to 0° C., sodium borohydride (6.2 g) was added thereto and stirred at that temperature for 4 hours. Then water was added to the reaction solution, and the organic solvent was evaporated off under reduced pressure. The resulting residue was extracted with ethyl acetate. The organic layer was dried with anhydrous magnesium sulfate, and the solvent was evaporated off under reduced pressure. The resulting residue was purified through silica gel column chromatography (hexane/ethyl acetate=4/1 to 3/2) to obtain the entitled compound (9.0 g).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[CH:5][C:6]([I:12])=[C:7]([CH:11]=1)[C:8](O)=[O:9].O>C1COCC1>[F:13][C:2]([F:1])([F:14])[C:3]1[CH:4]=[CH:5][C:6]([I:12])=[C:7]([CH:11]=1)[CH2:8][OH:9]
Reactant: O=C(O)c1cc(C(F)(F)F)ccc1I
Solvent: C1CCOC1
Solvent: O
Product: OCc1cc(C(F)(F)F)ccc1I
Temperature: 25 °C
Reaction time: 12 h

Procedure:
5-Trifluoromethyl-2-iodobenzoic acid (50 g, 158 mmol) is dissolved in anhydrous THF (200 mL) and cooled in an ice-salt bath until the temperature reaches −5° C. Borane-THF complex is added dropwise as a 1.0 M solution in THF (350 mL, 350 mmol) at −5° C. After addition is complete, the reaction mixture is slowly warmed to room temperature and stirred for 12 hours. Water (40 mL) is carefully added dropwise (foaming) and the reaction mixture stirred for 30 minutes. Additional water (350 mL) is added and the mixture is concentrated by rotary evaporator to remove most of the THF. Additional water (250 mL) is added to form a precipitate, which is isolated by filtration to give 5-trifluoromethyl-2-iodobenzyl alcohol (m.p. 81–82° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=O)=[CH:5][CH:4]=1.Cl.[NH2:20][OH:21].[OH-].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([C:7](=[N:20][OH:21])[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: NO
Reactant: COc1ccc(C(=O)c2ccc(OC)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(C(=NO)c2ccc(OC)cc2)cc1
Yield: 93.3 %

Procedure:
242 g (1 mole) of 4,4'-dimethoxybenzophenone was suspended in 2,000 ml of ethanol and 210 g (3 mole) of hydroxylamine hydrochloride and 300 ml (3 mole) of a 10N aqueous solution of NaOH were added thereto. Then the obtained mixture was heated under reflux. After two or three hours, the ethanol was distilled off in vacuo and then a saline solution was added thereto followed by extracting with chloroform. The chloroform phase was washed with water and dried over magnesium sulfate. After distilling the chloroform off, the residue was recrystallized from ethanol. Thus 240 g of the title compound was obtained in the form of colorless needles.
Reaction SMILES: C([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([N+:17]([O-])=O)[CH:14]=2)[CH2:9]1)C1C=CC=CC=1.Cl>CCO.[OH-].[OH-].[Pd+2]>[NH2:17][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH2:9][NH:8][CH2:16]2
Reactant: O=[N+]([O-])c1ccc2c(c1)CN(Cc1ccccc1)C2
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCO
Product: Nc1ccc2c(c1)CNC2
Reaction time: 1 h

Procedure:
Part B. To a solution of the isoindoline (5.40 g, 21.3 mmol) made above in EtOH (266 mL) under N2 was added 20% Pd(OH)2/C (3.00 g, 4.25 mmol). The reaction mixture was hydrogenated at 45 psi for 1 h. TLC analysis indicated that the nitro functionality was reduced and the Bn group was still intact. Therefore, concentrated HCl (1.6 mL, 19.1 mmol) was added to the reaction mixture and hydrogenation (50 psi) was continued overnight. The mixture was filtered through Celite®, washed with MeOH, and the filtrate was concentrated to one fourth of the volume. The precipitate was filtered off to provide the 5-aminoisoindoline.HCl (1.32 g, 36% yield): 1H NMR (500 MHz, CDCl3) δ 9.88 (s, br, 2H), 7.00 (d, 1H), 6.54 (m, 2H), 5.44 (s, br, 2H), 4.32 (s, 2H), 4.28 (s, 2H); ESI MS m/z 135 (M-HCl+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[OH:11].[Br:12]N1C(=O)CCC1=O>C(Cl)Cl>[Br:12][C:7]1[CH:6]=[C:5]([O:9][CH3:10])[C:4]([OH:11])=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cccc(OC)c1O
Solvent: ClCCl
Product: COc1cc(Br)cc(OC)c1O
Temperature: -78 °C
Reaction time: 4 h

Procedure:
To a cooled (−78° C.) solution of 2,6-dimetoxyphenol (13)(15 g, 97.35 mmol) in CH2Cl2 (200 ml) was added N-bromosuccinimide (17.4 g, 97.35 mmol) portionwise over twenty minutes. The reaction mixture was stirred at −78° C. under an inert atmosphere for four hours before being allowed to warm to room temperature where it was stirred for a further 16 hours. The solvent was then removed in vacuo to give a slurry that was purified by flash chromatography (SiO2) (7:3—CH2Cl2:Hexanes) and then re-crystallised from CH3Cl/hexanes to give the title compound as a white solid that was analytically clean (9.66 g, 42.57%). m/z (LC-MS, ESP): 231 [M−H]−, R/T=3.17 mins
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:11])[CH3:2].[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.CCCCCC>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][Br:13])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1ccccc1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCCCCC
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1ccccc1CBr
Temperature: 25 °C
Reaction time: 1 h
Yield: 109.2 %

Procedure:
2-Methylbenzoic acid ethyl ester (2.00 g, 11.9 mmol) was dissolved in carbon tetrachloride (60 ml), and the solution was added with N-bromosuccinimide (2.56 g, 14.4 mmol) and a catalytic amount of benzoylperoxide and then heated under reflux. After one hour, the reaction mixture was cooled to room temperature and added with hexane (40 ml) to remove insoluble solids by filtration. The filtrate was evaporated under reduced pressure to obtain the title compound 3.16 g as yellow oil. the product was used in the next reaction without purification.
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]([CH3:13])[CH3:12])[C:5]=1[NH2:6])([CH3:3])[CH3:2].[Br:14]Br.C(Cl)(Cl)Cl.[OH-].[Na+]>CO>[Br:14][C:9]1[CH:10]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]([NH2:6])=[C:7]([CH:11]([CH3:13])[CH3:12])[CH:8]=1
Reactant: BrBr
Reactant: CC(C)c1cccc(C(C)C)c1N
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(C)c1cc(Br)cc(C(C)C)c1N
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 2,6-diisopropylaniline (2.0 mL, 11 mmol) in methanol (80 mL) was treated dropwise with bromine (543 μL, 10.6 mmol). The solution was stirred at room temperature for 15 min. Chloroform and 0.1 N NaOH were added and the organic layer was dried (Na2SO4), filtered and concentrated to an orange liquid. Kugelrohr distillation (110° C. @ 0.06 Torr) afforded a colorless liquid (2.22 g 79%): 1H NMR (400 MHz) δ1.25 (d, J=6.4 Hz, 12H), 2.88 (m, 2H), 3.70 (brs, 2H), 7.11 (s, 2H); 13C NMR δ22.1, 27.9, 111.0, 125.6, 134.5, 139.3; Anal calcd for C12H19BrN: C, 56.26; H, 7.08; Br, 31.19; Found, C, 56.24; H, 7.07; Br, 30.98.
Reaction SMILES: [S:1]1[C:5]2[C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.C1(C)C=CC=CC=1.S(Cl)([Cl:22])=O>CN(C)C=O>[S:1]1[C:5]2[C:6]([C:10]([Cl:22])=[O:12])=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cccc2nnsc12
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)c1cccc2nnsc12
Temperature: 85 °C

Procedure:
290 g of benzo-1,2,3-thiadiazole-7-carboxylic acid are suspended in 1.61 of toluene, 3.5 ml of dimethylformamide and 129 ml of thionyl chloride are added and the mixture is stirred at 80-90° C., the suspension turning into a solution as the release of gas progresses. When the reaction has ended, the solution is cooled and filtered over a little Hyflo, the residue is rinsed with toluene and the filtrate is evaporated. 297 g (93%) of crude acid chloride, which can be further reacted directly, result.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:4]=1[NH2:5])[CH3:2].[N:13](OC(C)(C)C)=O>C(O)(=O)C.C(OCC)(=O)C>[CH3:2][C:1]1[C:3]2[C:4](=[CH:6][C:7]([N+:10]([O-:12])=[O:11])=[CH:8][CH:9]=2)[NH:5][N:13]=1
Reactant: CC(C)(C)ON=O
Reactant: CCc1ccc([N+](=O)[O-])cc1N
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cc1n[nH]c2cc([N+](=O)[O-])ccc12
Reaction time: 0.5 h
Yield: 97.8 %

Procedure:
To a solution of 10 g (0.06 mol) of 2-ethyl-5-nitroaniline (prepared by nitration of 2-ethylaniline: Bergman and Sand, Tetrahedron 1990, 46, 6085–6112) in 300 ml of glacial acetic acid, at room temperature, was added a solution of 8.98 ml (0.06 mol) of tert-butyl nitrite in 40 ml of acetic acid dropwise over 15 min. After the addition was complete the solution was allowed to stir for 30 min. The acetic acid was removed in vacuo to afford an orange solid. The solid was dissolved in approximately 120 ml of ethyl acetate and washed with 3×100 ml sat. aqueous NaHCO3. The organic layer was dried over MgSO4 and the solvent was removed in vocuo to afford 3-methyl-6-nitroindazole as a yellow solid (10.4 g, 98%).
Reaction SMILES: C(N(CC)CC)C.[N:8]1([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.Cl[C:22]1[C:23]2[C@H:30]([CH3:31])[CH2:29][CH2:28][C:24]=2[N:25]=[CH:26][N:27]=1.C(OCC)(=O)C>CCCCO>[CH3:31][C@H:30]1[C:23]2[C:22]([N:11]3[CH2:12][CH2:13][N:8]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9][CH2:10]3)=[N:27][CH:26]=[N:25][C:24]=2[CH2:28][CH2:29]1
Reactant: C[C@@H]1CCc2ncnc(Cl)c21
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCCCO
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C[C@@H]1CCc2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Reaction time: 17 h
Yield: 74.1 %

Procedure:
Neat POCl3 (463.9 ml, 5067 mmol) was added slowly by addition funnel to a 0° C. solution of (R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ol (152.2 g, 1013 mmol) in DCE (1.2 L). After the addition was complete, the reaction mixture was warmed to room temperature, then heated to reflux and stirred for 70 minutes. The reaction was complete as determined by HPLC. The reaction mixture was cooled to room temperature, and the excess POCl3 was quenched in 4 portions as follows: Reaction mixture transferred to separatory funnel and dripped into a beaker containing ice and saturated NaHCO3 solution cooled in an ice bath. Once the addition of each portion of the reaction mixture was completed, the quenched mixture was stirred 30 minutes to ensure complete destruction of POCl3 prior to transfer to separatory funnel. The mixture was transferred to the separatory funnel and extracted twice with DCM. The combined extracts were dried (Na2SO4), filtered, and concentrated. The crude was purified on silica gel as follows: silica gel (1 kg) was slurried in 9:1 hexane:ethyl acetate onto a 3 L fritted funnel, silica settled under vacuum, topped with sand. The crude was loaded with a DCM/hexane mixture, and the compound was eluted using 1 L sidearm flasks under vacuum. High Rf byproducts eluted first, then (R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (104.4 g, 61.09% yield) as a brown oil. Triethylamine (93.0 ml, 534 mmol) and tert-butyl piperazine-1-carboxylate (34.8 g, 187 mmol) was added to a solution of (R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (30.0 g, 178 mmol) in n-BuOH (250 mL). The reaction mixture was heated to reflux under nitrogen and stirred overnight (17 hours), after which it was concentrated on a rotavap. The resulting oil was dissolved in DCM, washed with H2O, dried (Na2SO4), filtered, and was concentrated. The resulting brown oil was purified on silica gel eluting first with 2:1 hexanes:ethyl acetate until product eluting cleanly, then gradient 1:1 to 1:5 DCM:ethyl acetate to give (R)-tertbutyl 4-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (42.0 g, 74.1% yield) as a beige powder. LC/MS (APCI+) m/z 319.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].[Br:14]Br>C(Cl)(Cl)Cl>[Br:14][C:9]1[C:10]([O:12][CH3:13])=[CH:11][C:3]([O:2][CH3:1])=[C:4]([CH:8]=1)[C:5]([OH:7])=[O:6]
Reactant: BrBr
Reactant: COc1ccc(C(=O)O)c(OC)c1
Solvent: ClC(Cl)Cl
Product: COc1cc(OC)c(C(=O)O)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
To a solution of 2.4-dimethoxybenzoic acid (4.0 g. 0.022 mol) in chloroform (60 ml) was added bromine (1.13 ml. 0.022 mol) in chloroform (20 ml) dropwise. After stirring overnight at room temperature the precipitate was filtered off and dried to afford the title compound as a white solid (2.87 g).
Reaction SMILES: [CH2:1]([S:6][C:7]1[CH:12]=[CH:11][C:10](Br)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[Mg].[I:15]I.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>O1CCCC1.O>[CH2:1]([S:6][C:7]1[CH:12]=[CH:11][C:10]([I:15])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: II
Reactant: CCCCCSc1ccc(Br)cc1
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Mg]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCSc1ccc(I)cc1
Reaction time: 16 h

Procedure:
The Grignard reagent from the product of Step 2.1 (15 g) was prepared using magnesium in tetrahydrofuran (60 ml). Iodine (16.2 g) was added over 10 min and the mixture was stirred for 16 hrs. Water was added and then 10% sodium metabisulphite (100 ml). The product was extracted into petroleum ether and distilled. Yield 10.5 g.
Reaction SMILES: [CH3:1][C:2]([CH3:13])=[CH:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.Cl[CH2:15][CH2:16][NH:17][C:18](=[O:22])[O:19][CH2:20][CH3:21].C(=O)([O-])[O-].[K+].[K+]>O>[CH3:1][C:2]([CH3:13])=[CH:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][CH2:15][CH2:16][NH:17][C:18](=[O:22])[O:19][CH2:20][CH3:21])=[CH:10][CH:11]=1
Reactant: CCOC(=O)NCCCl
Reactant: CC(C)=CCOc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)NCCOc1ccc(OCC=C(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4-(3-methyl-2-butenoxy)phenol (1.64 g, 9.2 mmol), ethyl 2-chloroethylcarbamate (1.81 g, 11.9 mmol), and potassium carbonate (2.54 g, 18.4 mmol) in 20 ml of dimethylformamide (DMF)is heated at 85° for 18 hours. The reaction mixture is cooled to room temperature (RT), poured into water and extracted with ether. The combined ether extracts are washed with water until neutral followed with brine and dried over calcium sulfate. The solvent was removed in vacuo and the residue was placed under high vacuum at 80° for ca. 2 hours to remove the excess ethyl 2-chloroethylcarbamate. Purification by preparative thin layer chromatography (prep. TLC) gave ethyl N-{2-[4-(3-methyl-2-butenoxy)phenoxy]ethyl}carbamate (compound 1, Table A).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH3:21][CH:22]([Si:24](Cl)([CH:28]([CH3:30])[CH3:29])[CH:25]([CH3:27])[CH3:26])[CH3:23]>O1CCCC1.CCOCC>[Br:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][N:8]([Si:24]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:23])[CH3:21])[C:5]2=[N:6][CH:7]=1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: Brc1cnc2[nH]ccc2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(Br)cnc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a mixture of 5-bromo-1H-pyrrolo[2,3-b]pyridine (15.4 g) in tetrahydrofuran (250 mL) was added 1M lithium hexamethyldisilazide in tetrahydrofuran (86 mL), and after 10 minutes, TIPS-Cl (triisopropylchlorosilane) (18.2 mL) was added. The mixture was stirred at room temperature for 24 hours. The reaction was diluted with ether, and the resulting solution was washed twice with water. The extracts were dried (Na2SO4), filtered, and concentrated. The crude product was chromatographed on silica gel with 10% ethyl acetate/hexanes.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]1[CH:12]2[CH2:13][C:14](=[O:16])[CH2:15][CH:11]2[CH2:10][NH:9]1.[N:17]1([C:22](Cl)=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18]1.C(N(CC)CC)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl>[N:17]1([C:22]([N:9]2[CH2:10][CH:11]3[CH2:15][C:14](=[O:16])[CH2:13][CH:12]3[CH2:8]2)=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: O=C(Cl)N1CCCC1
Reactant: O=C1CC2CNCC2C1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC2CN(C(=O)N3CCCC3)CC2C1
Yield: 58.5 %

Procedure:
Hexahydro-cyclopenta[c]pyrrol-5-one trifluoroacetate 1f (478 mg, 2 mmol) was dissolved in 20 mL of dichloromethane followed by addition of pyrrolidine-1-carbonyl chloride (0.276 mL, 2.5 mmol) and triethylamine (0.84 mL, 6 mmol). The reaction mixture was reacted overnight at room temperature. The mixture was adjusted to pH 4 with a solution of 10% citric acid. The mixture was extracted with dichloromethane (50 mL×3). The combined organic extracts were washed with 50 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 2-(pyrrolidine-1-carbonyl)-hexahydro-cyclopenta[c]pyrrol-5-one 8a (0.26 g, yield 58.5%) as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]([CH2:14][C:15]([OH:17])=O)[CH2:7][CH2:8][C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)=[O:5])[CH3:2].CN(C=O)C.[Cl-].C(Cl)(=O)C([Cl:27])=O>ClCCl>[CH2:1]([O:3][C:4]([N:6]([CH2:14][C:15]([Cl:27])=[O:17])[CH2:7][CH2:8][C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)=[O:5])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCOC(=O)N(CCc1cccs1)CC(=O)O
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)N(CCc1cccs1)CC(=O)Cl

Procedure:
Compound 1025 (14 g, 54.41 mmol) was dissolved in dry dichloromethane (300 mL). To this suspension was added 0.1 mL of DMF, followed by the careful addition of oxayl chloride (10.4 g, 81.93 mmol). The reaction mixture was stirred at room temperature for 1 hour, at which time 0.5 mL of additional oxalyl chloride was added. The solvent was evaporated under vacuum to give 2-(N-(ethoxycarbonyl)-N-(2-(thiophen-2-yl)ethyl)amino)acetyl chloride. This acid chloride was re-dissolved in dry DCM (300 mL) and AlCl3 (18.1 g, 135.74 mmol) was added at room temperature. The reaction was kept at room temperature for 1 hour then quenched by the slow addition of ethanol (about 10 mL). The mixture was then poured into ice and stirred for 1 hr. The aqueous mixture was extracted with DCM (3×150 mL). The combined organic layers were dried over MgSO4, filtered, and the volatiles removed under reduced pressure to give a residue, which was purified by silica gel chromatography to produce ethyl 4,5,7,8-tetrahydro-4-oxothieno[3,2-d]azepine-6-carboxylate (Compound 1026, 7.4 g, 30.92 mmol).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[N:12]3[CH:19]=[CH:20][CH:21]=[C:11]3[CH2:10][CH2:9]2)=[O:7])=[C:4]([Cl:24])[CH:3]=1.[F:25][C:26]1[C:27]([CH3:35])=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](Cl)=[O:30].C1(CS(NC2C=CC(C(N3C4C=CC=CC=4CN4C=CC=C4C3)=O)=CC=2)(=O)=O)C=CC=CC=1.[OH-].[Na+]>ClCCl.C(N(CC)CC)C>[CH:18]1[C:13]2[N:12]3[CH:19]=[CH:20][CH:21]=[C:11]3[CH2:10][CH2:9][N:8]([C:6]([C:5]3[CH:22]=[CH:23][C:2]([NH:1][C:29](=[O:30])[C:28]4[CH:32]=[CH:33][CH:34]=[C:26]([F:25])[C:27]=4[CH3:35])=[CH:3][C:4]=3[Cl:24])=[O:7])[C:14]=2[CH:15]=[CH:16][CH:17]=1
Reactant: Nc1ccc(C(=O)N2CCc3cccn3-c3ccccc32)c(Cl)c1
Reactant: Cc1c(F)cccc1C(=O)Cl
Agent: O=C(c1ccc(NS(=O)(=O)Cc2ccccc2)cc1)N1Cc2cccn2Cc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c(F)cccc1C(=O)Nc1ccc(C(=O)N2CCc3cccn3-c3ccccc32)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 106.9 %

Procedure:
To a mixture of 0.10 g of 6,7-dihydro-5-(4-amino-2-chlorobenzoyl)-5H-pyrrolo-[1,2-a][1,5]benzodiazepine and 0.06 g of triethylamine in 6 ml of dichloromethane is added 0.08 g of 3-fluoro-2-methylbenzoyl chloride in 0.5 ml of dichloromethane. The mixture is stirred for 2 hours at room temperature and then 2 ml of 1 NaOH added. The volatiles are evaporated under vacuum and the residue dissolved in 2 ml of tetrahydrofuran and 1 ml of methanol. The mixture is stirred for 2 hours and evaporated and the residue diluted with 2 ml of 1 N NaOH and 5 ml of water. The mixture is extracted with ethyl acetate (15 ml) and the extract washed with brine and dried (Na2SO4). The solvent is removed and the residue triturated with diethyl ether-hexane to give 0.15 g of white solid: Mass Spectrum (CI)474(M+H, Cl35); 476(M+H, Cl37).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][C:3]=1[CH3:16].[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=1[N:25]=[C:26]=[O:27].CCN(CC)CC>C1COCC1>[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=1[NH:25][C:26](=[O:27])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])=[CH:4][C:3]=1[CH3:16]
Reactant: O=C=Nc1c(Cl)cccc1Cl
Reactant: Cc1cc(CC(=O)OC(C)(C)C)ccc1N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(CC(=O)OC(C)(C)C)ccc1NC(=O)Nc1c(Cl)cccc1Cl
Reaction time: 3 h
Yield: 74.1 %

Procedure:
To a mixture of tert-butyl 4-amino-3-methylphenylacetate (1.88 g, 8.51 mmol), 2,6-dichlorophenyl isocyanate (1.60 g, 8.51 mmol) in THF (40 ml) was added Et3N (0.24 ml, 1.70 mmol) at room temperature. After 3 h stirring, the reaction mixture was concentrated in vacuo. The residue was triturated by the addition of n-hexane, to give tert-butyl 4-[N′-(2,6-dichlorophenyl)ureido]-3-methylphenylacetate (2.58 g, 74%) as a colorless powder. mp 243-244° C. (dec.); 1H-NMR (CDCl3) δ1.45 (s, 9H), 2.30 (s, 3H), 3.49 (s, 2H), 6.24 (s, 2H), 7.12-7.16 (m, 3H), 7.35 (d, J=8.3 Hz, 2H), 7.51 (d, J 7.8H, 1H).