Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[CH2:6][C@H:5]([C:7]([OH:9])=[O:8])[CH2:4][CH2:3][C@H:2]1[CH2:10][NH2:11].[C:12]([O:16][CH:17]([O:21][C:22](ON1C(=O)CCC1=O)=[O:23])[CH:18]([CH3:20])[CH3:19])(=[O:15])[CH2:13][CH3:14]>CC(OC)(C)C.CC(C)=O.O>[C:12]([O:16][CH:17]([O:21][C:22]([NH:11][CH2:10][C@H:2]1[CH2:3][CH2:4][C@H:5]([C:7]([OH:9])=[O:8])[CH2:6][CH2:1]1)=[O:23])[CH:18]([CH3:19])[CH3:20])(=[O:15])[CH2:13][CH3:14]
Reactant: CCC(=O)OC(OC(=O)ON1C(=O)CCC1=O)C(C)C
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Solvent: CC(C)=O
Solvent: COC(C)(C)C
Solvent: O
Product: CCC(=O)OC(OC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1)C(C)C

Procedure:
Following the general nucleophilic carbamoylation procedure, tranexamic acid (250 mg, 1.6 mmol) and 1-[(2,5-dioxopyrrolidinyl)oxycarbonyloxy]-2-methylpropyl propanoate (230 mg, 0.80 mmol) were reacted in the MTBE/acetone/water mixture (16 mL) to yield the title compound 41 (70 mg, 21% yield) as a white powder after work-up and mass-guided preparative HPLC purification. 1H NMR (400 MHz, DMSO-d6): δ=0.85-0.92 (m, 8H), 1.08 (t, J=7.2 Hz, 3H), 1.17-1.32 (br. m, 3H), 1.68 (d, J=12 Hz, 2H), 1.85-1.96 (br. m, 3H), 2.05-2.12 (m, 1H), 2.25-2.36 (br. m, 2H), 2.80 (t, J=6.4 Hz, 2H), 6.42 (d, J=5.2 Hz, 1H), 7.38 (t, J=6.0 Hz, 1H), 11.97 (br. s, 1H). MS (ESI) m/z 352.12 (M+Na)+; 328.14 (M−H)−.
Reaction SMILES: C(O[C:6](=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][CH2:15][C:16](=[O:33])[N:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)[CH2:19][CH2:18]2)[CH2:10][CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+].FC1[CH:50]=[CH:51][C:52]([N+:59]([O-:61])=[O:60])=[C:53]([C:55]([F:58])([F:57])[F:56])[CH:54]=1>CS(C)=O.ClCCl>[N+:59]([C:52]1[CH:51]=[CH:50][C:6]([NH:7][C@H:8]2[CH2:9][CH2:10][C@H:11]([CH2:14][CH2:15][C:16]([N:17]3[CH2:22][CH2:21][N:20]([C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=4)[CH2:19][CH2:18]3)=[O:33])[CH2:12][CH2:13]2)=[CH:54][C:53]=1[C:55]([F:56])([F:57])[F:58])([O-:61])=[O:60]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCC(=O)N2CCN(c3ccc(C(F)(F)F)cc3)CC2)CC1
Reactant: O=[N+]([O-])c1ccc(F)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Product: O=C(CC[C@H]1CC[C@H](Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1)N1CCN(c2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(Trans-4-{3-oxo-3-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-propyl}-cyclohexyl)-carbamic acid tert-butyl ester (23 mg, 0.06 mmol, prepared in accordance with Example 40) was combined with a 50% (vol/vol) solution of trifluoroacetic acid and dichloromethane (3 mL). The resulting mixture was stirred for 30 min at room temperature. The mixture was then concentrated under vacuum to form a crude residue. The crude residue was dissolved in dimethylsulfoxide (3 mL). Afterward, potassium carbonate was added (17 mg, 0.12 mmol). 5-Fluoro-2-nitrobenzotrifluoride (15 mg, 0.07 mmol) was then added. The resulting mixture was reacted at 120° C. for 18 hr. The mixture was then cooled to room temperature, diluted with dichloromethane (15 mL), washed with water (4×8 mL), washed with saturated aqueous ammonium chloride (8 mL), washed with water (8 mL), washed with saturated aqueous hydrogencarbonate (2×8 mL), and washed with water (2×8 mL). The organic phase was collected, dried over magnesium sulfate, and concentrated under vacuum to form a crude residue. The crude residue was purified by preparative HPLC. Following lyophilization of the fractions of interest, the desired product was isolated as a solid (17 mg, 48% yield). The structure was confirmed using Protocol I-A. Calculated mass=573; observed mass=553; HPLC retention time=4.98 min. It is believed that the discrepancy between the actual and observed masses stems from a loss of HF upon ionization.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[CH3:9][N:10](C=O)C>CCOC(C)=O.[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:9]#[N:10])[N:7]=1
Reactant: CN(C)C=O
Reactant: Cc1ccnc(Cl)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: Cc1ccnc(C#N)n1
Temperature: 110 °C
Yield: 56 %

Procedure:
A mixture of 2-chloro-4-methylpyrimidine (725 mg, 5.63 mmol, 1 eq), zinccyanide (396 mg, 3.38 mmol, 0.6 eq) and tetrakis(triphenylphosphine)palladium(0) (716 mg, 0.562, 0.1 eq) in DMF (10 ml) was heated at 110° C. under nitrogen for 1 hr. The mixture was cooled to r.t., diluted with EtOAc and washed twice with 2N ammonium hydroxide (50 ml). The organic layer was washed with brine (20 ml) dried over sodium sulphate and concentrated in vacuum to provide the crude mixture. The crude product was then purified by column chromatography (30% EtOAc in Hexane) to afford 4-methylpyrimidine-2-carbonitrile Yield: 380 mg (56%). 1H NMR (400 MHz, CDCl3): δ2.61 (s, 3H), 7.36 (d, 1H, J=5.2 Hz), 8.66 (d, 1H, J=5.2 Hz),
Reaction SMILES: [N:1]#[C:2][NH2:3].C(N(C(C)C)CC)(C)C.[CH3:13][S:14]([NH:17][C:18]1[N:23]=[CH:22][C:21]([N:24]=[C:25]=[N:26][CH:27]([CH3:32])[C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:20][CH:19]=1)(=[O:16])=[O:15]>C(Cl)(Cl)Cl>[CH3:13][S:14]([NH:17][C:18]1[N:23]=[CH:22][C:21]([NH:24][C:25]([NH:26][CH:27]([CH3:32])[C:28]([CH3:31])([CH3:30])[CH3:29])=[N:3][C:2]#[N:1])=[CH:20][CH:19]=1)(=[O:15])=[O:16]
Reactant: CC(N=C=Nc1ccc(NS(C)(=O)=O)nc1)C(C)(C)C
Reactant: N#CN
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(NC(=NC#N)Nc1ccc(NS(C)(=O)=O)nc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.9 %

Procedure:
Cyanamide (172 mg, 4.1 mmol) and diisopropylethylamine (711 μl, 4.1 mmol) were added to 1 ml of a solution of N-(6-methanesulfonylamino-3-pyridyl)-N'-(1,2,2-trimethylpropyl)carbodiimide (121 mg, 0.41 mmol) in chloroform and the mixture was stirred at room temperature for 16 hours. After an insoluble matter was removed by filtration, the filtrate was concentrated. The residue was purified by silica gel column chromatography [eluent: chloroform alone to chloroform:methanol=5:1 (v/v)] and subjected to recrystallization from chloroform-ether to obtain 97 mg of the intended product (yield: 72%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=O)[NH:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[N+:16]([O-:18])=[O:17])(=[O:3])[CH3:2].[Br:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23].Cl.N>O=P(Cl)(Cl)Cl.C(O)(C)C>[C:1]([NH:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([NH:23][C:22]3[CH:24]=[CH:25][CH:26]=[C:20]([Br:19])[CH:21]=3)=[N:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[N+:16]([O-:18])=[O:17])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cc2nc[nH]c(=O)c2cc1[N+](=O)[O-]
Reactant: Nc1cccc(Br)c1
Agent: Cl
Agent: N
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC(C)O
Product: CC(=O)Nc1cc2ncnc(Nc3cccc(Br)c3)c2cc1[N+](=O)[O-]
Yield: 45 %

Procedure:
A solution of 7-acetamido-6-nitro-3H-quinazolin-4-one (5.00 g, 20 mmol) in POCl3 (250 mL) is heated under reflux for 2 h, the excess of POCl3 is removed under vacuum, and the residue is dissolved in CH2Cl2 and washed with aqueous Na2CO3 solution. Workup gives the crude 4-chloro derivative, which is coupled directly with 3-bromoaniline in isopropanol as above, and the resulting hydrochloride is converted directly to the free base, by treatment with aqueous NH3, to give 7-acetamido-4-(3-bromoanilino)-6-nitroquinazoline (3.60 g, 45%). 1H NMR (DMSO) δ10.56 (1H, s), 10.29 (1H, s), 9.34 (1H, s), 8.70 (1H, s), 8.19 (1H, brs), 7.97 (1H, s), 7.88 (1H, d, J=6.0 Hz), 7.43-7.35 (2H, m), 2.13 (3H, s).
Reaction SMILES: [CH2:1]1[CH2:13][O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:15]1[C:16]2[CH:28]=[C:27]([Cl:29])[S:26][C:17]=2[N:18]=[C:19]([C:21]2[O:25][N:24]=[CH:23][CH:22]=2)[N:20]=1>>[O:25]1[C:21]([C:19]2[N:20]=[C:15]([NH:8][CH2:7][CH2:6][C:5]3[CH:9]=[CH:10][C:11]4[O:12][CH2:13][CH2:1][O:2][C:3]=4[CH:4]=3)[C:16]3[CH:28]=[C:27]([Cl:29])[S:26][C:17]=3[N:18]=2)=[CH:22][CH:23]=[N:24]1
Reactant: NCCc1ccc2c(c1)OCCO2
Reactant: Clc1cc2c(Cl)nc(-c3ccno3)nc2s1
Product: Clc1cc2c(NCCc3ccc4c(c3)OCCO4)nc(-c3ccno3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-ethylenedioxyphenethylamine with 4-chloro-2-(isoxazol-5-yl)-6-chloro-thieno-[2,3-d]-pyrimidine yields 2-(isoxazol-5-yl)-4-(3,4-ethylenedioxyphenethylamino)-6-chloro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6](/[CH:11]=[CH:12]/[C:13]([N:15]2[CH2:20][CH2:19][CH:18]([CH:21]=[O:22])[CH2:17][CH2:16]2)=[O:14])[CH:7]=[C:8]([F:10])[CH:9]=1.[CH3:23]S(C)=O>>[F:10][C:8]1[CH:7]=[C:6](/[CH:11]=[CH:12]/[C:13]([N:15]2[CH2:16][CH2:17][CH:18]([CH:21]3[CH2:23][O:22]3)[CH2:19][CH2:20]2)=[O:14])[CH:5]=[C:4]([F:3])[CH:9]=1
Reactant: CS(C)=O
Reactant: O=CC1CCN(C(=O)/C=C/c2cc(F)cc(F)c2)CC1
Agent: [H-]
Agent: [Na+]
Product: O=C(/C=C/c1cc(F)cc(F)c1)N1CCC(C2CO2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 58 %

Procedure:
An oven dried 500-mL flask was charged with (CH3)3SOI (46.14 g, 210 mmol, 1.3 eq) and 250 mL dry DMSO. NaH (95%, 5.30 g, 210 mmol, 1.3 eq) was added in around 10 batches and solution was then cooled to 0° C. The resulting mixture was stirred at 0° C. for 30 min. The aldehyde (Intermediate 2, 45 g, 161 mmol, 1.0 eq) in 150 mL dry DMSO solution was added dropwise and the resulting solution was stirred at 0° C. for 30 min. LCMS showed completed reaction. The reaction was then quenched with 800 mL water and poured into 1200 mL diethyl ether. The organic layer was separated and washed with 2×150 mL water and dried over MgSO4 and concentrated. Crude LCMS showed >90% purity for the desired product in 58% yield as a light yellow oil which solidified to a yellow solid overnight. MS (ES) m/e 294 [M+H]+. 1HNMR (CDCl3) δ(ppm): 7.56 (d, 1H), 7.04 (dd, 2H), 6.91 (d, 1H), 6.80 (m, 1H), 4.74 (m, 1H), 4.11 (m, 1H), 3.05 (m, 1H), 2.77 (s, 2H), 2.61 (m, 1H), 1.95 (m, 1H), 1.70-1.80 (m, 1H), 1.30-1.60 (m, 4H).
Reaction SMILES: [OH-].[Li+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:30][CH3:31])=[C:8]([CH:21]=1)[C:9]([O:11]CC1C=CC=CC=1OC)=[O:10]>O.C1COCC1>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:30][CH3:31])=[C:8]([CH:21]=1)[C:9]([OH:11])=[O:10]
Reactant: COc1ccccc1COC(=O)c1cc(Br)ccc1OCc1ccccc1OC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccccc1COc1ccc(Br)cc1C(=O)O
Temperature: 20 °C
Reaction time: 16 h

Procedure:
A solution of lithium hydroxide (385 mg, 9.18 mmol) in water (20 ml) was added dropwise to a stirred solution of [2-(methyloxy)phenyl]methyl 5-bromo-2-({[2-(methyloxy)phenyl]methyl}oxy)benzoate (may be prepared as described in Description 31; 420 mg, 0.92 mmol) in THF (20 ml) over 5 min. The reaction mixture was stirred at 20° C. for 16 h. The organic phase was evaporated and the aqueous phase (20 ml) was extracted with ethyl acetate (20 ml). The aqueous phase (20 ml) was adjusted to pH 2 with 2M hydrochloric acid (1 ml). The aqueous phase was then extracted with ethyl acetate (3×20 ml). The organic phase was then evaporated in vacuo to yield the title compound as a light yellow solid. 280 mg.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11].[CH:12]1([NH2:15])[CH2:14][CH2:13]1>>[CH:12]1([NH:15][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=2[CH3:11])[CH2:14][CH2:13]1
Reactant: NC1CC1
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Product: Cc1cc([N+](=O)[O-])ccc1NC1CC1
Temperature: 0 °C

Procedure:
1-Fluoro-2-methyl-4-nitrobenzene (3.7 g, 24.8 mmoles) is refluxed for 5 hours with 8.1 g (0.14 moles) of cyclopropylamine. After that, the reaction product is poured onto 250 g of ice/water and the solid obtained is recrystallized from ethanol. A yellow solid with a melting point of 35°-37° C. is obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[C:7]([NH:13][CH3:14])=[CH:6][C:5]=1[O:15][CH3:16]>[Pd]>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([NH2:10])[C:7]([NH:13][CH3:14])=[CH:6][C:5]=1[O:15][CH3:16]
Reactant: CNc1cc(OC)c(C(=O)OC)cc1[N+](=O)[O-]
Agent: [Pd]
Product: CNc1cc(OC)c(C(=O)OC)cc1N
Yield: 90.5 %

Procedure:
5-Amino-2-methoxy-4-methylamino-benzoic acid methyl ester (95 mg) was prepared by following General Procedure B starting from 2-methoxy-4-methylamino-5-nitro-benzoic acid methyl ester (120 mg) and Pd/C (10% by weight, 12 mg). The crude product was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C@H:9]([C:13]([OH:15])=[O:14])[CH:10]([CH3:12])[CH3:11])=[CH:4][CH:3]=1.[C:16](Cl)(Cl)=[O:17]>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:9]([CH:10]([CH3:12])[CH3:11])[C:13](=[O:15])[O:14][C:16]2=[O:17])=[CH:6][CH:7]=1
Reactant: CC(C)[C@H](Nc1ccc(Cl)cc1)C(=O)O
Reactant: O=C(Cl)Cl
Solvent: C1COCCO1
Product: CC(C)C1C(=O)OC(=O)N1c1ccc(Cl)cc1
Reaction time: 45 h

Procedure:
To 4.9 g of N-(4-chlorophenyl)valine (0.0215 mole) in 50 ml of 1,4-dioxane is slowly passed a stream of phosgene gas as the solution is stirred. Cooling is applied to keep the solution at RT. When the solution is saturated with phosgene, the phosgene is shut off and the mixture is allowed to stir under nitrogen at RT. After 45 hr, about two-thirds of the dioxane is removed by distilling at aspirator pressure. The residue is diluted with hexane, then allowed to crystallize overnight at RT. The solid is collected by filtration and washed with hexane, with care being taken to minimize exposure to air. The solid is dried in vacuo to yield 3-(4-chlorophenyl)-4-isopropyloxazolidine-2,5-dione, m.p. 137°-138°.
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][N:3]1[CH2:20][C:21]([OH:23])=O.[CH3:24][C:25]1([CH3:32])[NH:30][CH2:29][CH2:28][NH:27][C:26]1=[O:31].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>ClCCl>[CH3:24][C:25]1([CH3:32])[N:30]([C:21](=[O:23])[CH2:20][N:3]2[CH2:4][CH2:5][CH2:6][C:7]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:2]2=[O:1])[CH2:29][CH2:28][NH:27][C:26]1=[O:31]
Reactant: O=C(O)CN1CCCC(c2ccccc2)(c2ccccc2)C1=O
Reactant: CC1(C)NCCNC1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)C(=O)NCCN1C(=O)CN1CCCC(c2ccccc2)(c2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(2-oxo-3,3-diphenylpiperidin-1-yl)acetic acid (0.15 g, 0.485 mmol) and 3,3-dimethylpiperazin-2-one (CAS 22476-74-0) (0.062 g, 0.485 mmol) in dichloromethane (3 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.184, 0.485 mmol) and diisopropylethylamine (0.53 mL, 2.91 mmol). The reaction mixture was stirred at ambient temperature overnight and then concentrated followed by chromatographic purification on an Analogix silica gel column eluting with 5% methanol/dichloromethane to yield the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.05-8.11 (m, 1H), 7.16-7.32 (m, 10H), 4.20 (s, 2H), 3.46-3.52 (m, 2H), 3.33-3.41 (m, 2H), 3.16-3.22 (m, 2H), 2.51-2.57 (m, 2H), 1.63-1.75 (m, 2H), 1.60 (s, 6H); MS (DCI+) m/z 420 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].Cl[CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].CC(C)([O-])C.[K+].Cl>O1CCCC1>[N+:10]([C:3]1[C:2]([Cl:1])=[CH:7][C:6]([Cl:8])=[C:5]([Cl:9])[C:4]=1[CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)cc1Cl
Reactant: CC(C)(C)OC(=O)CCl
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Cc1c(Cl)c(Cl)cc(Cl)c1[N+](=O)[O-]
Temperature: -40 °C
Yield: 58.6 %

Procedure:
A solution of 2,4,5-trichloronitrobenzene (Jpn. Kokai Tokyo Koho JP 81,169,651 (1980), Chem. Abstr. 1981,96, 162307 q)(103 g, 0.46 mol) and t-butyl chloroacetate (79 ml, 0.55 mol) in dry tetrahydrofuran (400 ml) was added dropwise over 30 minutes to a solution of potassium t-butoxide (128 g, 1.14 mol) in dry tetrahydrofuran (800 ml) with stirring, under nitrogen keeping the temperature at -40° C. After the addition was complete, the resulting dark blue solution was stirred for a further 30 minutes. The mixture was poured into 0.5M hydrochloric acid (2 L) and the product was extracted into ethyl acetate (2.5L and 1 L). The combined organic solutions were dried (MgSO4) and evaporated onto silica gel (70-200 m, 200 g). The silica gel was applied to the top of a silica gel chromatography column (800 g), and the product was eluted using a hexane/ethyl acetate gradient. Product-containing fractions were combined and evaporated to give a yellow solid, which was triturated with hexane to give t-butyl 2-nitro-3,5,6-trichlorophenylacetate (91.8 g, 59%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[C:11]1([S:17]([NH2:20])(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[N:20][S:17]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)(=[O:19])=[O:18])=[CH:5][CH:4]=1
Reactant: NS(=O)(=O)c1ccccc1
Reactant: COc1ccc(C=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(C=NS(=O)(=O)c2ccccc2)cc1
Temperature: 25 °C

Procedure:
An equimolar mixture of 25.0 g (0.18 mol) 4-methoxybenzaldehyde and 28.3 g (0.18 mol) benzenesulfonamide was placed into toluene. 100 mg p-toluenesulfonic acid was added as a catalyst. The mixture was then heated under reflux on a water separator until the theoretically calculated quantity of water had separated. The reaction mixture was cooled first to room temperature and then in a refrigerator to 10° C. The precipitated solid was then filtered off and dried under vacuum. Yield: 37.6 g (74.3%); 1H-NMR (400 MHz, DMSO-d6): δ [ppm]=7.13 (d, 2H); 7.69 (m, 2H); 7.77 (d, 1H); 7.96 (d, 2H); 8.04 (d, 2H); 9.11 (s, 1H); 13C-NMR (400 MHz, DMSO-d6): δ [ppm]=55.6; 114.7; 124.9; 127.5; 129.6; 133.8; 134.0; 138.8; 165.0; 170.8.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:11])=[CH:8][CH:9]=2)[S:4][C:3]=1[C:12](=[O:18])[CH2:13][C:14]([O:16][CH3:17])=[O:15].C(O[N:25]=O)CC(C)C>C(O)(=O)C.O1CCOCC1>[C:14]([C:13]1[N:25]=[N:1][C:2]2[C:10]3[CH:9]=[CH:8][C:7]([CH3:11])=[N:6][C:5]=3[S:4][C:3]=2[C:12]=1[OH:18])([O:16][CH3:17])=[O:15]
Reactant: COC(=O)CC(=O)c1sc2nc(C)ccc2c1N
Reactant: CC(C)CCON=O
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: COC(=O)c1nnc2c(sc3nc(C)ccc32)c1O
Reaction time: 24 h
Yield: 66 %

Procedure:
To a solution of 6 g (0.022 mol) of 3-amino-2-carbomethoxyacetyl-6-methyl-thieno[2,3-b]pyridine in 1.8 ml acetic acid and 180 ml dioxane was slowly added 4.8 g (4.2 ml, 0.041 mol) of isoamylnitrite and stirring continued for 24 hours. It was then poured on ice-water, filtered and washed with water. The crude product was crystallized from DMSO/H2O to give 4.0 g (64%) of 3-carbomethoxy-4-hydroxy-7-methylpyrido[3',2':4,5]-thieno[3,2-c]pyridazine; m.p., 265°-268° C.
Reaction SMILES: [H-].[Na+].[O:3]1[C:7]2([CH2:12][CH2:11][C:10]([C:13]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([C:22]#[N:23])[CH:20]=4)[NH:15][CH:14]=3)=[CH:9][CH2:8]2)[O:6][CH2:5][CH2:4]1.[CH3:24]I>CN(C)C=O>[O:6]1[C:7]2([CH2:12][CH2:11][C:10]([C:13]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([C:22]#[N:23])[CH:20]=4)[N:15]([CH3:24])[CH:14]=3)=[CH:9][CH2:8]2)[O:3][CH2:4][CH2:5]1
Reactant: CI
Reactant: N#Cc1ccc2[nH]cc(C3=CCC4(CC3)OCCO4)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cc(C2=CCC3(CC2)OCCO3)c2cc(C#N)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 24.7 %

Procedure:
To a suspension of sodium hydride (60%, 1.74 g, 0.073 mol) in anhydrous N,N-dimethylformamide (100 ml) was added 3-(1,4-dioxa-spiro[4,5]dec-7-en-8-yl)-5-cyano-1H-indole (9.9 g, 0.035 mol) at room temperature. The mixture was stirred for 30 minutes at room temperature, then methyl iodide (9 ml, 0.14 mol) was added at room temperature. The reaction was allowed to stir for 1 hour, then quenched with water (50 ml). The mixture was extracted with methylene chloride (3×150 ml) and water (3×150 ml). The organic layer was dried over anhydrous magnesium sulfate and filtered. The solvent was removed under vacuum. Chromatography (5% methanol-methylene chloride) afforded 2.54 g (24%) of product as a light yellow solid: mp 65-67° C.
Reaction SMILES: [O:1]1CCCC1.[CH2:6]([O:13][C:14](=[O:27])[NH:15][C@H:16]1[C@H:23]2[C@H:19]([O:20][C:21]([CH3:25])([CH3:24])[O:22]2)[C:18](=[CH2:26])[CH2:17]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[OH-].[Na+].OO>O>[CH2:6]([O:13][C:14](=[O:27])[NH:15][C@H:16]1[C@H:23]2[C@H:19]([O:20][C:21]([CH3:24])([CH3:25])[O:22]2)[C@H:18]([CH2:26][OH:1])[CH2:17]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C=C1C[C@@H](NC(=O)OCc2ccccc2)[C@@H]2OC(C)(C)O[C@H]12
Reactant: C1CCOC1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1(C)O[C@@H]2[C@H](CO)C[C@@H](NC(=O)OCc3ccccc3)[C@@H]2O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.1 %

Procedure:
Borane-THF complex in tetrahydrofuran (1M, 0.99 mL, 0.99 mmol) was added to a 0° C. solution of benzyl((3aS,4R,6aR)-2,2-dimethyl-6-methylenetetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)carbamate (0.150 g, 0.494 mmol) in tetrahydrofuran (10 mL, 0.1 mol). Some bubbling initially observed, the mixture stirred at room temperature for 1 hour. The reaction was quenched via the addition of aqueous sodium hydroxide (4M, 1.24 mL, 0.00494 mol) and hydrogen peroxide 35% (35%, 0.425 ml, 4.94 mmol) were added and reaction stirred at room temperature for 2.5 hours. Water (5 ml) added to the reaction and the aqueous was extracted with ether (3×50 mls). The combined organics were dried with MgSO4 and purified by FC (Hex/EtOAc 1:1) to yield benzyl((3aS,4R,6S,6aR)-6-(hydroxymethyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)carbamate (0.070 g, 44%) as a thick colorless oil: MS (ESI+) for C17H23NO5 m/z 344.2 [M+Na]+; MS (ESI−) for C17H23NO5 m/z 320.3 [M−H]−;
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]2[S:6](=[O:10])(=[O:9])[CH2:7][CH2:8][C:4]=2[C:3]=1[C:13]([OH:15])=O.[CH:16]([NH2:18])=O.O>CN(C)C=O>[O:9]=[S:6]1(=[O:10])[C:5]2=[CH:11][CH:12]=[C:2]3[C:3]([C:13](=[O:15])[NH:18][CH:16]=[N:1]3)=[C:4]2[CH2:8][CH2:7]1
Reactant: Nc1ccc2c(c1C(=O)O)CCS2(=O)=O
Reactant: NC=O
Solvent: CN(C)C=O
Solvent: O
Product: O=c1[nH]cnc2ccc3c(c12)CCS3(=O)=O
Reaction time: 0.67 h
Yield: 48.6 %

Procedure:
0.87 g (3.83 mmol) of 5-amino-1,1-dioxo-2,3-dihydro-1H-1λ6-benzo[b]-thiophene-4-carboxylic acid was suspended in 2.0 ml of N,N-dimethyl-formamide and, after addition of 0.76 ml (19.14 mmol) of formamide, reacted in a microwave at 150° C. and 60 W for 40 min. During the reaction, the pressure in the microwave rose to 20 bar. The reaction mixture was then added to water. The precipitated solid was filtered off with suction and washed successively with water and diethyl ether and dried in vacuo overnight. 440 mg of the desired compound were obtained.