Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[O:14]1[CH2:19]O[CH2:17][O:16][CH2:15]1.CS(O)(=O)=O>C(O)(=O)C.O>[N:13]1([S:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)(=[O:11])=[O:12])[CH2:17][O:16][CH2:15][O:14][CH2:19]1
Reactant: C1OCOCO1
Reactant: NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: CS(=O)(=O)O
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1ccc(S(=O)(=O)N2COCOC2)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 34.8 %

Procedure:
4-Nitrobenzenesulphonamide (2.02 g, 10 mmol) was added to a solution of 1,3,5-trioxane (1.96 g, 20 mmol) in acetic acid (5 ml). The mixture was stirred for 5 minutes and methanesulphonic acid (10 ml) was added slowly. The mixture was then stirred at 35° C. for 20 minutes, cooled to 0° C., diluted with water and extracted with ethyl acetate. The combined extracts were washed twice with water and twice with 5% aqueous sodium hydrogen carbonate solution, and then dried and the volatiles removed by evaporation. The residue was recrystallized from ethanol to give the title compound (955 mg, 35% yield). NMR: 4.87 (s, 2H), 5.30 (s, 4H), 8.20 (d, 2H), 8.42 (d, 2H).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:14]([CH:16]1[O:18][CH2:17]1)Cl>CC(C)=O.C1(C)C=CC=CC=1>[O:18]1[CH2:17][CH:16]1[CH2:14][O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: ClCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Product: c1ccc(OCC2CO2)cc1
Yield: 59.9 %

Procedure:
A mixture of 9.4 gm (0.1 mole) of phenol, 28 gm (0.2 mole) of potassium carbonate and 30 mL (0.4 mole) of epichlorohydrin in 250 mL acetone was heated to reflux for 12 hours. The reaction medium was then filtered and evaporated leaving an oil which was taken up in toluene and successively washed with 100 mL water, 2×100 mL 1.0 N sodium hydroxide and 2×100 mL water. The toluene phase was dried with magnesium sulfate and evaporated to provide a clear oil which was chromatographed on a Prep-500 silica gel column employing hexane: ethyl acetate (9:1) as the mobile phase. Collection of the major peak and evaporation of solvent provided 9 gm (60%) of a clear oil whose NMR and IR spectra were consistent with the assigned structure.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].[NH2:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][N:13]1[C:21]2[C:20]([CH3:22])=[C:19]([CH3:23])[N:18]=[C:17]([NH2:24])[C:16]=2[N:15]=[C:14]1[CH3:25].C(N(CC)CC)C>C(Cl)(Cl)Cl>[NH2:24][C:17]1[C:16]2[N:15]=[C:14]([CH3:25])[N:13]([CH2:12][CH2:11][O:10][CH2:9][CH2:8][NH:7][C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])[C:21]=2[C:20]([CH3:22])=[C:19]([CH3:23])[N:18]=1
Reactant: CC(C)C(=O)Cl
Reactant: Cc1nc(N)c2nc(C)n(CCOCCN)c2c1C
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1nc(N)c2nc(C)n(CCOCCNC(=O)C(C)C)c2c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 36.4 %

Procedure:
Under a nitrogen atmosphere, isobutyryl chloride (330 μL, 3.15 mmol) was added to a solution of 1-[2-(2-aminoethoxy)ethyl]-2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-4-amine (0.757 g, 2.875 mmol) in chloroform (11 mL) and triethylamine (520 μL, 3.78 mmol). The reaction mixture was stirred at ambient temperature for about 3 hours; then it was diluted with chloroform (20 mL) and washed with saturated sodium bicarbonate solution. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (10 g of silica gel eluting with 2% methanol in chloroform containing 0.5% triethylamine) to provide 0.3486 g of N-{2-[2-(4-amino-2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-1-yl)ethoxy]ethyl}-2-methylpropanamide as a solid, m.p. 179.5–182° C.
Reaction SMILES: [F:1][C:2]1[C:3]([OH:12])=[C:4]([C:9](=O)[CH3:10])[CH:5]=[C:6]([F:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][C:21]([CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)=[O:22]>CN(C)C=O>[CH:23]1([C:21]([C:20]2[O:12][C:3]3[C:2]([F:1])=[CH:7][C:6]([F:8])=[CH:5][C:4]=3[C:9]=2[CH3:10])=[O:22])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: CC(=O)c1cc(F)cc(F)c1O
Reactant: O=C(CBr)C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(C(=O)C2CCCCC2)oc2c(F)cc(F)cc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.5 %

Procedure:
To a solution (50 mL) of 1-(3,5-difluoro-2-hydroxyphenyl)ethanone (2.8 g) in N,N-dimethylformamide were added potassium carbonate (6.7 g) and 2-bromo-1-cyclohexylethanone (4.0 g) synthesized in Example A51(1) at room temperature, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was allowed to cool to room temperature, and filtered through celite. Water was added to the filtrate, and the mixture was extracted with diethyl ether. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in N,N-dimethylformamide (50 mL) again, 1,8-diazabicyclo[5.4.0]undec-7-ene (2.6 mL) was added to the solution, and the mixture was stirred at 110° C. 1 hr with heating. After cooling to room temperature, the reaction mixture was quenched with 1N hydrochloric acid, and the reaction mixture was extracted with diethyl ether. The extract was concentrated under reduced pressure, and the precipitated compound was recrystallized from diisopropyl ether-hexane to give the title object compound (3.1 g, 70%) as a colorless solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1)(=[O:9])[NH2:8].[CH3:17][C:18]1[CH:28]=[CH:27][CH:26]=[CH:25][C:19]=1[CH:20]=[CH:21][C:22](Cl)=[O:23]>CC(C)=O.O>[CH3:17][C:18]1[CH:28]=[CH:27][CH:26]=[CH:25][C:19]=1[CH:20]=[CH:21][C:22]([NH:14][C:13]1[CH:15]=[CH:16][C:10]([C:7](=[O:9])[NH2:8])=[CH:11][CH:12]=1)=[O:23]
Reactant: Cc1ccccc1C=CC(=O)Cl
Reactant: NC(=O)c1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: Cc1ccccc1C=CC(=O)Nc1ccc(C(N)=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.7 %

Procedure:
4.1 g of potassium carbonate was added to a solution of 2.0 g of 4-carbamoylaniline in 40 ml of acetone and 40 ml of water. To the mixture was gradually added 3.2 g of 2-methylcinnamoyl chloride with ice-cooling. The resulting mixture was stirred at room temperature overnight. The reaction mixture was mixed with water. The resulting precipitate was collected by filtration, washed with water and dried to obtain 3.2 g of N-(2-methylcinnamoyl)-4-carbamoylaniline as a white powder.
Reaction SMILES: [N:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:10][C:11]1[CH:12]=[CH:13][C:14]([NH:17][NH2:18])=[N:15][CH:16]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:10][C:11]1[CH:12]=[CH:13][C:14]([NH:17][NH:18][C:7]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:8])=[N:15][CH:16]=1
Reactant: O=C(Cl)N1CCCCC1
Reactant: NNc1ccc(F)cn1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NNc1ccc(F)cn1)N1CCCCC1
Yield: 84 %

Procedure:
1-Piperidine carbonyl chloride (348 mg, 0.30 mL, 2.36 mmol) was added dropwise to a solution of 5-fluoro-2-hydrazinyl-pyridine (see for reference WO 2010/022076, which is incorporated herein by reference in its entirety; 0.30 g, 2.36 mmol) and DIPEA (1.2 mL, 7.08 mmol) in DCM (10 mL) at RT under nitrogen and the mixture stirred for 2 h. The solution was washed with water (2×15 mL) and dried (Na2SO4). The solvent was evaporated and the residue triturated (diethyl ether) and filtered to afford the title compound as an off-white solid (475 mg, 84%). LCMS (Method 1): Rt 1.82 min, m/z 239 [MH+].
Reaction SMILES: [Li]C(CC)C.[Si:6]([O:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[F:21])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].CN([CH:25]=[O:26])C.Cl>C1COCC1>[Si:6]([O:13][C:14]1[C:15]([F:21])=[C:16]([CH:17]=[C:18]([F:20])[CH:19]=1)[CH:25]=[O:26])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(F)ccc1F
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1cc(F)cc(C=O)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.4 %

Procedure:
A 1.0 M solution of sec-BuLi (21.5 ml, 21.5 mmol) was added dropwise to a stirred solution of O-tert-butyldimethylsilyl-2,5-difluorophenol (5.0 g, 20 mmol) in THF (20 mL) at -78° C. After 0.5 hr DMF (1.9 ml, 24.6 mmol) was added dropwise while the temperature was kept below -70° C. After 30 min, the mixture was allowed to warm to room temperature over 30 min. To the mixture was added 3N HCl (30 ml) and stirring was continued for 30 min. The mixture was extracted with ether (100 ml) and the extract was washed with water (100 ml), brine (100 ml), dried (sodium sulfate) and evaporated. Column chromatography (silica gel) of the residue eluting with n-hexane gave 3.56 g (64%) of the titled compound as a colorless oil.
Reaction SMILES: [NH:1]([C:5]1[CH:15]=[CH:14][C:8]2[O:9][CH2:10][CH2:11][CH2:12][O:13][C:7]=2[CH:6]=1)[C:2]([CH3:4])=[O:3].[N+:16]([O-])([OH:18])=[O:17]>C(O)(=O)C>[NH:1]([C:5]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:8]2[O:9][CH2:10][CH2:11][CH2:12][O:13][C:7]=2[CH:6]=1)[C:2]([CH3:4])=[O:3]
Reactant: CC(=O)Nc1ccc2c(c1)OCCCO2
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])OCCCO2
Reaction time: 3 h
Yield: 94.9 %

Procedure:
13.5 g of 7-acetamino-3,4-dihydro-2H-1,5-benzodioxepine were placed in 50 ml of glacial acetic acid and nitrated at 15°-20° C. with 7 ml of nitric acid in 20 ml of glacial acetic acid by dropwise addition, the crystals passing into solution only after the addition of a quarter of the nitric acid. The product separated out, but was stirred for an additional 3 hours, then removed under suction and washed with water and methanol. 15.6 g (94.9% of theory) of 7-acetamino-8-nitro-3,4-dihydro-2H-1,5-benzodioxepine of melting point 139°-140° C. were obtained.
Reaction SMILES: [CH3:1][C:2]1([C:5]#[C:6][C:7]2[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:8]=2[NH2:9])[CH2:4][CH2:3]1.N1C=CC=CC=1.[C:23](Cl)(=[O:27])[CH2:24][CH2:25][CH3:26]>C(Cl)Cl>[CH3:1][C:2]1([C:5]#[C:6][C:7]2[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:8]=2[NH:9][C:23](=[O:27])[CH2:24][CH2:25][CH3:26])[CH2:4][CH2:3]1
Reactant: CC1(C#Cc2cc([N+](=O)[O-])ccc2N)CC1
Reactant: CCCC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCC(=O)Nc1ccc([N+](=O)[O-])cc1C#CC1(C)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.3 %

Procedure:
To a solution of 2-((1-methylcyclopropyl)ethynyl)-4-nitroaniline (220 mg, 1.0 mmol) and pyridine (160 mg, 2.0 mol) in CH2Cl2 (20 mL) was added butyryl chloride (140 mg, 1.3 mmol) at 0° C. The mixture was warmed to room temperature and stirred for 3 h. The mixture was poured into ice-water. The organic layer was separated and the aqueous phase was extracted with CH2Cl2 (30 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under reduced pressure to obtain N-[2-(1-methyl-cyclopropyl-ethynyl)-4-nitro-phenyl]-butyramide (230 mg, 82%), which was directly used in the next step.
Reaction SMILES: [CH3:1][C:2]1([CH3:46])[C:6](=[O:7])[N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:20])[CH2:16][N:17]([CH3:19])[CH3:18])=[C:10]([C:21]([F:24])([F:23])[F:22])[CH:9]=2)[C:4](=[O:25])[N:3]1[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][S:35][CH2:36][CH2:37][CH2:38][C:39]([F:45])([F:44])[C:40]([F:43])([F:42])[F:41].CC1(C)N(CCCCCCCCCSCCCC(F)(F)C(F)(F)F)C(=[O:73])N(C2C=CC([N+]([O-])=O)=C(C(F)(F)F)C=2)C1=O>>[CH3:1][C:2]1([CH3:46])[C:6](=[O:7])[N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:20])[CH2:16][N:17]([CH3:18])[CH3:19])=[C:10]([C:21]([F:24])([F:23])[F:22])[CH:9]=2)[C:4](=[O:25])[N:3]1[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][S:35]([CH2:36][CH2:37][CH2:38][C:39]([F:45])([F:44])[C:40]([F:41])([F:42])[F:43])=[O:73]
Reactant: CC1(C)C(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C(=O)N1CCCCCCCCCSCCCC(F)(F)C(F)(F)F
Reactant: CN(C)CC(=O)Nc1ccc(N2C(=O)N(CCCCCCCCCSCCCC(F)(F)C(F)(F)F)C(C)(C)C2=O)cc1C(F)(F)F
Product: CN(C)CC(=O)Nc1ccc(N2C(=O)N(CCCCCCCCCS(=O)CCCC(F)(F)C(F)(F)F)C(C)(C)C2=O)cc1C(F)(F)F
Yield: 65 %

Procedure:
Compound 43a described below was synthesized according to a method similar to that described in Example 2 using the compound of Example 42 as starting reagent replacing the compound of Example 1. The expected compound is obtained in the form of a pale yellow oil with a yield of 65%.
Reaction SMILES: [C:1]([C:5]1[O:6][C:7]2[CH:13]=[C:12]([N+:14]([O-])=[O:15])[C:11]([Cl:17])=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+]>C(O)C.O.[Zn]>[C:1]([C:5]1[O:6][C:7]2[CH:13]=[C:12]([NH:14][OH:15])[C:11]([Cl:17])=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1nc2cc(Cl)c([N+](=O)[O-])cc2o1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CCO
Product: CC(C)(C)c1nc2cc(Cl)c(NO)cc2o1
Reaction time: 1 h
Yield: 80.9 %

Procedure:
200 g of 2-tert-butyl-5-chloro-6-nitrobenzoxazole was dispersed in a mixture of 600 ml of ethanol and 300 ml of water and to the mixture was added 42 g of ammonium chloride and then was gradually added zinc powder. The temperature rose to 70° C. due to generation of heat. The mixture was stirred for one hour and then, the inorganic substances were removed by filtration. To the filtrate was added 1.8 liters of water, and the crystals thusdeposited were collected by filtration. The crystals were dried to obtain 153 g of the desired compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([NH2:11])[CH:5]=1.Cl[C:14](Cl)([O:16]C(=O)OC(Cl)(Cl)Cl)Cl.CCN(CC)CC>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]=[C:14]=[O:16])[CH:5]=1
Reactant: COC(=O)c1ccc(C)c(N)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(C)c(N=C=O)c1

Procedure:
In analogy to the procedure described in example 9.1, 3-amino-4-methyl-benzoic acid methyl ester ([18595-18-1]) was reacted with triphosgene in the presence of Et3N in CH2Cl2 under reflux conditions for 16 h to give the title compound as brown solid which was used in the next step without further purification. MS: m/e=191 [M+].
Reaction SMILES: [OH-].[Na+].[NH:3]1[CH2:11][CH2:10][CH2:9][CH:5]([C:6]([OH:8])=[O:7])[CH2:4]1.[CH2:12]([S:16](Cl)(=[O:18])=[O:17])[CH2:13][CH2:14][CH3:15]>>[CH2:12]([S:16]([N:3]1[CH2:11][CH2:10][CH2:9][CH:5]([C:6]([OH:8])=[O:7])[CH2:4]1)(=[O:18])=[O:17])[CH2:13][CH2:14][CH3:15]
Reactant: CCCCS(=O)(=O)Cl
Reactant: O=C(O)C1CCCNC1
Agent: [Na+]
Agent: [OH-]
Product: CCCCS(=O)(=O)N1CCCC(C(=O)O)C1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
1N-sodium hydroxide aqueous solution (4.1 mL) was added to nipecotic acid (500 mg, 3.87 mmol), and, under ice-cooling, butanesulfonylchloride (0.98 mL, 7.74 mmol) was added dropwise. The mixture was raised to room temperature, and stirred for 15 hours. The reaction mixture was then extracted with chloroform. The organic layer was collected, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was then purified using silica gel column chromatography to obtain the target (354 mg, 37%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[F:16][C:17]([F:24])([F:23])[CH2:18][S:19](Cl)(=[O:21])=[O:20]>>[C:14]([C:11]1[N:12]([CH3:13])[C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:19]([CH2:18][C:17]([F:24])([F:23])[F:16])(=[O:21])=[O:20])=[CH:3][CH:4]=2)=[CH:9][CH:10]=1)#[N:15]
Reactant: Cn1c(C#N)ccc1-c1ccc(N)cc1
Reactant: O=S(=O)(Cl)CC(F)(F)F
Product: Cn1c(C#N)ccc1-c1ccc(NS(=O)(=O)CC(F)(F)F)cc1

Procedure:
The title compound was prepared according to general procedure for sulfonylation of 5-(4-aminophenyl)-1-methyl-1H-pyrrole-2-carbonitrile using 2,2,2-trifluoro-ethanesulfonyl chloride (55 μL, 0.55 mmol) to provide N-[4-(5-cyano-1-methyl-1H-pyrrol-2-yl)phenyl]-2,2,2-trifluoroethanesulfonamide (0.014 g).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:9]3[O:10][CH2:11][O:12][C:8]=3[C:7]=2[C:15]2[C:16]3[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22]([CH3:32])=[C:21]([C:33]([O:35]CC)=[O:34])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.[Li+].[OH-]>O1CCOCC1>[CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:9]3[O:10][CH2:11][O:12][C:8]=3[C:7]=2[C:15]2[C:16]3[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:31])[CH3:29])[C:22]([CH3:32])=[C:21]([C:33]([OH:35])=[O:34])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1c(C)n(COCC[Si](C)(C)C)c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1c(C(=O)O)c2ncnc(-c3c(OCC4CC4)ccc4c3OCO4)c2n1COCC[Si](C)(C)C
Temperature: 80 °C

Procedure:
Ethyl 4-[5-(cyclopropylmethoxy)-1,3-benzodioxol-4-yl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylate from example D.b1 (15.28 g; 29.0 mmol) is dissolved in 1,4-dioxane (150 mL) and aqueous LiOH (prepared from 1.04 g; 43.5 mmol; and 75 mL of water). The stirred reaction mixture is heated to 80° C. until the starting material is consumed according to LC-MS. The mixture is concentrated under reduced pressure, and diluted with water. The product is precipitated by addition of 2M citric acid to adjust pH to 5, isolated by suction filtration, washed with several small portions of water and dried in high vacuo at 40° C. to yield 13.55 g of the title compound as pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([C:8](=O)[CH3:9])[CH:7]=1.[NH2:12][NH2:13]>O>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:13][N:12]=[C:8]2[CH3:9]
Reactant: CC(=O)c1cc(Br)ccc1F
Reactant: NN
Solvent: O
Product: Cc1n[nH]c2ccc(Br)cc12
Temperature: 117 °C
Yield: 94 %

Procedure:
Compound (4c) (66.0 g, 304 mmol) and 350 ml anhydrous hydrazine were charged into a 1 Liter round bottom flask. The resulting reaction mixture was refluxed at 117° C. for 5 hours. After the reaction mixture was allowed to cool down to room temperature, the excess hydrazine was evaporated under reduced pressure to yield a white solid. 400 ml water was poured into the resulting solid and water was filtered off. The solid was washed with 400 ml water twice. To remove the trace amount of hydrazine, the white solid was taken up in 600 ml EtOAc and washed with 300 ml water twice and saturated brine solution. The EtOAc layer was then dried over sodium sulfate. Removal of the solvent gave the desired product as a white amorphous solid (60.0 g, yield=94%). The product was used directly for the next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[C:22](=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18][C:8]=2[N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:10]=1)=[O:5])[CH3:2].[I-].[Na+].C(N(CC)CC)C.[CH3:33][Si:34](Cl)([CH3:36])[CH3:35]>C(#N)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[C:22]([O:23][Si:34]([CH3:36])([CH3:35])[CH3:33])=[CH:21][CH2:20][CH2:19][CH2:18][C:8]=2[N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:15])[CH3:16])=[O:12])[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn(C(=O)OC(C)(C)C)c2c1C(=O)CCCC2
Reactant: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)c1cn(C(=O)OC(C)(C)C)c2c1C(O[Si](C)(C)C)=CCCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To a mixture of 4-oxo-5,6,7,8-tetrahydro-4H-cyclohepta[b]pyrrole-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (4.6 mmol), sodium iodide (9.3 mmol), and triethylamine (13.9 mmol) in 15 mL acetonitrile is added trimethylsilyl chloride (9.3 mmol). After stirring at RT for 2 hours it is quenched with 20 mL saturated NaHCO3 solution and extracted several times with EtOAc. The combined organic layers are dried over Na2SO4 and evaporated in vacuo yielding 4-trimethylsilanyloxy-7,8-dihydro-6H-cyclohepta[b]pyrrole-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester as a brown oil (95%). 1H NMR (CDCl3) 0.15 (s, 9H), 1.32 (t, 3H), 1.60 (s, 9H), 1.83-1.97 (m, 2H), 1.99-2.06 (m, 2H), 3.00 (t, 2H), 4.33 (q, 2H), 5.40 (t, 1H), 7.62 (s, 1H). Step 2:
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])[C:5]([NH2:18])=[CH:4][CH:3]=1.Cl[S:20]([C:23]1[CH:27]=[CH:26][S:25][C:24]=1[C:28]([O:30][CH3:31])=[O:29])(=[O:22])=[O:21]>>[F:8][C:7]1[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])=[C:5]([NH:18][S:20]([C:23]2[CH:27]=[CH:26][S:25][C:24]=2[C:28]([O:30][CH3:31])=[O:29])(=[O:21])=[O:22])[CH:4]=[CH:3][C:2]=1[F:1]
Reactant: Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F
Reactant: COC(=O)c1sccc1S(=O)(=O)Cl
Product: COC(=O)c1sccc1S(=O)(=O)Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F

Procedure:
According to the general procedure B, 5,6-difluoro-N1-(2-fluoro-4-iodophenyl)benzene 1,2-diamine was reacted with methyl 3-(chlorosulfonyl)thiophene-2-carboxylate to obtain the title compound. 1H NMR (300 MHz, CDCl3): δ 8.58 (s, 1H), 7.43 (dd, J=5.1 & 10.8 Hz, 2H), 7.35 (dd, J=1.8 & 10.2 Hz, 1H), 7.31 (ddd, J=2.1, 4.2 & 9.3 Hz, 1H), 7.04 (m, 2H), 5.88 (dt, J=2.7, 8.7 & 17.4 Hz, 1H), 5.65 (br s, 1H), 3.85 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:10]2[C:6](=[CH:7][N:8]([C:13]([O:15][CH2:16][C:17]([Cl:20])([Cl:19])[Cl:18])=[O:14])[CH:9]=2)[CH:5]=1)([O-])=O.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH2:9][N:8]([C:13]([O:15][CH2:16][C:17]([Cl:20])([Cl:18])[Cl:19])=[O:14])[CH2:7]2
Reactant: O=C(OCC(Cl)(Cl)Cl)n1cc2ccc([N+](=O)[O-])cc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: Nc1ccc2c(c1)CN(C(=O)OCC(Cl)(Cl)Cl)C2
Yield: 88.6 %

Procedure:
A solution of 5-nitroisoindol-2-carboxylic acid, 2,2,2-trichloroethyl ester (2.0 g, 5.9 mmol, title A compound) in ethyl acetate (20 mL) was treated with stannous chloride hydrate (6.6 g, 29.3 mmol) and the reaction mixture was heated under reflux for three hours. It was basified with saturated potassium carbonate solution, diluted with ethyl acetate (200 mL) and filtered through a celite pad. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with brine (100 mL), dried over anhydrous magnesium sulfate and evaporated in vacuo to give the title compound (1.6 g, 88.6%) as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH2:10][C@H:9]1[CH:23]=[N:24][CH2:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[F:33])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].O>CO>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH2:10][C@H:9]1[CH2:23][NH:24][CH2:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[F:33])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(CS[C@@H]2C[C@@H](C=NCc3cc(F)ccc3F)N(C(=O)OC(C)(C)C)C2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc(CS[C@@H]2C[C@@H](CNCc3cc(F)ccc3F)N(C(=O)OC(C)(C)C)C2)cc1
Reaction time: 1.5 h
Yield: 66.6 %

Procedure:
To 17.31 g (36.32 mmol) (2S,4R)-2-[(2,5-difluoro-benzylimino)-methyl]-4-(4-methoxy-benzylsulfanyl)-pyrrolidine-1-carboxylic acid tert-butyl ester in 120 ml MeOH were added 1.64 g (43.58 mmol, 1.2 eq) NaBH4 slowly at 40° C. The solution was stirred at that temperature for additional 90 min, water was added carefully and the solution was concentrated. The residue was redissolved in EtOAc and washed with NaHCO3 and brine, dried over Na2SO4 and evaporated. Flash chromatography with EtOAc/hexane 1:1 yielded 11.57 g (67%) (2S,4R)-2-[(2,5-difluoro-benzylamino)-methyl]-4-(4-methoxy-benzylsulfanyl)-pyrrolidine-1-carboxylic acid tert-butyl ester as yellow oil, MS: 479 (MH+).