Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)(=[O:12])=[O:11])=[CH:5][CH:4]=1.N1C=CC=CC=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH:2]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)(=[O:12])=[O:11])=[CH:7][CH:8]=1)=[O:1]
Reactant: O=S(=O)(Nc1ccc(CO)cc1)c1ccccn1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=Cc1ccc(NS(=O)(=O)c2ccccn2)cc1
Yield: 60.2 %

Procedure:
To a stirred solution of pyridine-2-sulfonic acid (4-hydroxymethyl-phenyl)-amide (200 mg, 0.76 mmol), and pyridine (612 uL) in anhydrous CH2Cl2 (3 mL) was added Dess-Martin periodiane (450 mg, 1.06 mmol). The resultant solution was stirred at room temperature for 1 h. The mixture was diluted with 100 mL CH2Cl2, filtered through celite, and concentrated. The crude material was purified by recrystallisation from cold CH2Cl2 to give the title compound (120 mg, 60%) as a yellow powder. 1H NMR (300 MHz, CDCl3) δ 7.34 (d, 2H, J=8.4 Hz), 7.49-7.50 (m, 1H), 7.74 (br s, 1H), 7.75 (d, 2H, J=8.4 Hz), 7.89-7.70 (m, 1H), 8.03 (d, 1H, J=8.1 Hz), 8.70 (d, 1H, J=4.2 Hz), 9.87 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]2([C:30]([F:33])([F:32])[F:31])[CH2:17][CH2:16][N:15]([C:18]3[N:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[C:21]([CH2:28]O)=[CH:20][CH:19]=3)[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C([N:38](CC)CC)C.CS(Cl)(=O)=O.O.N>C(#N)C>[F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]2([C:30]([F:33])([F:32])[F:31])[CH2:17][CH2:16][N:15]([C:18]3[N:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[C:21]([CH2:28][NH2:38])=[CH:20][CH:19]=3)[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CCN(CC)CC
Reactant: OCc1ccc(N2CCC(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)(C(F)(F)F)C2)nc1C(F)(F)F
Agent: CS(=O)(=O)Cl
Agent: N
Solvent: CC#N
Solvent: O
Product: NCc1ccc(N2CCC(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)(C(F)(F)F)C2)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.6 %

Procedure:
[6-{3-[3,5-Bis(trifluoromethyl)phenyl]-3-(trifluoromethyl)pyrrolidin-1-yl}-2-(trifluoromethyl)pyridin-3-yl]methanol (1.55 g) and triethylamine (0.4 g) were added to acetonitrile (30 ml), and an acetonitrile solution (10 ml) of methanesulfonyl chloride (0.4 g) was added dropwise thereto under ice cooling. Upon the completion of the dropwise addition, the reaction liquid was stirred at room temperature for 1 hour, and then the resulting solution was added dropwise to a mixture solution containing 28% ammonia water (30 ml) and acetonitrile (50 ml), which had been prepared separately, under ice cooling. After stirring at room temperature for 12 hours, the reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, the solvent was distilled off under reduced pressure and the purified by silica gel chromatography to obtain 1-[6-{3-[3,5-bis(trifluoromethyl)phenyl]-3-(trifluoromethyl)pyrrolidin-1-yl}-2-(trifluoromethyl)pyridin-3-yl]methanamine (1.0 g).
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:14][C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=1)[NH:18]C(=O)C>>[NH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:4](=[O:6])[C:3]3[C:2]([NH:18][C:17]=2[CH:16]=1)=[CH:10][C:9]([N+:11]([O-:13])=[O:12])=[CH:8][CH:7]=3
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1Cl
Reactant: CC(=O)Nc1cccc(N)c1
Product: Nc1ccc2c(=O)c3ccc([N+](=O)[O-])cc3[nH]c2c1

Procedure:
The compound S3 (Y═NH) was prepared using 2-chloro-4-nitrobenzoic acid and 3′-aminoacetanilide in the same way as S3 (Y═O). 1H-NMR (DMSO-d6) δ 11.54 (s, 1H), 8.32 (d, J=8.8, 1H), 8.26 (d, J=2.0, 1H), 7.92 (d, J=8.8, 1H), 7.86 (d, J=2.0, 8.4, 1H), 6.60 (dd, J=2.0, 8.8, 1H), 6.43 (d, J=2.0, 1H), 6.36 (bs, 2H). ESI-MS m/z (M+H) calc'd: 256.1. found 256.1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@@H:11]([CH3:22])[CH2:10]2)=[CH:4][C:3]=1[F:23].[CH3:24][C@H]1CN(CC2C=CC(NC)=CC=2)CCN1C(OC(C)(C)C)=O.[BH4-].[Na+]>>[F:23][C:3]1[CH:4]=[C:5]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[C@@H:11]([CH3:22])[CH2:10]2)[CH:6]=[CH:7][C:2]=1[NH:1][CH3:24]
Reactant: CNc1ccc(CN2CCN(C(=O)OC(C)(C)C)[C@@H](C)C2)cc1
Reactant: C[C@H]1CN(Cc2ccc(N)c(F)c2)CCN1C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Product: CNc1ccc(CN2CCN(C(=O)OC(C)(C)C)[C@@H](C)C2)cc1F
Temperature: 50 °C

Procedure:
The title compound was prepared from 1,1-dimethylethyl (2S)-4-[(4-amino-3-fluorophenyl)methyl]-2-methyl-1-piperazinecarboxylate (D63) using a method similar to that described for D3 in Description 3A although the reaction was heated at 50° C. overnight prior to and after addition of sodium borohydride. δH (CDCl3, 400 MHz) 6.96 (2H, m), 6.61 (1H, m), 4.17 (1H, br.s), 3.89 (1H, br.s), 3.79 (1H, d), 3.41 (1H, d), 3.28 (1H, d), 3.08 (1H, td), 2.87 (3H, s), 2.74 (1H, m), 2.57 (1H, m), 2.08 (1H, dd), 1.95 (1H, m), 1.45 (9H, s), 1.22 (3H, d).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[NH:14][N:15]=[C:16]([CH3:17])[C:3]=12.[CH2:18]1[CH2:24][CH:23]2[NH:25][CH:20]([CH2:21][CH2:22]2)[CH2:19]1>>[CH:23]12[NH:25][CH:20]([CH2:21][CH2:22]1)[CH2:19][CH:18]([N:14]1[C:4]3=[N:5][N:6]=[C:7]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:2]([Cl:1])=[C:3]3[C:16]([CH3:17])=[N:15]1)[CH2:24]2
Reactant: C1CC2CCC(C1)N2
Reactant: Cc1n[nH]c2nnc(-c3ccccc3)c(Cl)c12
Product: Cc1nn(C2CC3CCC(C2)N3)c2nnc(-c3ccccc3)c(Cl)c12

Procedure:
Compound XIIIa was synthesized from 4-chloro-3-methyl-5-phenyl-1H-pyrazolo[3,4-c]pyridazine and nortropane following the general procedure for the Mitsunobu reaction described in Example 20.
Reaction SMILES: [Br:1]Br.[N+:3]([C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:7]=1[OH:16])([O-:5])=[O:4]>CC(O)=O>[Br:1][C:8]1[CH:9]=[C:10]([C:12]([F:13])([F:14])[F:15])[CH:11]=[C:6]([N+:3]([O-:5])=[O:4])[C:7]=1[OH:16]
Reactant: BrBr
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(C(F)(F)F)cc(Br)c1O
Temperature: 40 °C
Reaction time: 65 h

Procedure:
4.0 g of bromine in 7.3 mL of AcOH was added dropwise to a solution of 4.0 g of 2-nitro-4-trifluoromethyl-phenol and 300 mg FeCl3 in 23.1 mL of AcOH at 0° C. Reaction was then heated at 40° C. for 1.5 h. and then allowed to stir for 65 h at rt. Solvent was then removed, placed solid back into EtOAc, filtered through celite and concentrated in vacuo. 5 g of title compound was collected.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])[CH3:3].Cl[CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[S:24]([CH2:27][C:28]([O:30][CH3:31])=[O:29])(=[O:26])=[O:25].Cl>C(N(CC)CC)C>[CH3:4][C:2]([C:5]1[CH:10]=[C:9]([S:11][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]2[S:24]([CH2:27][C:28]([O:30][CH3:31])=[O:29])(=[O:26])=[O:25])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:1])[CH3:3]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: COC(=O)CS(=O)(=O)C1CCCCC1Cl
Agent: Cl
Solvent: CCN(CC)CC
Product: COC(=O)CS(=O)(=O)C1CCCCC1Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C

Procedure:
2,6-bis(1,1-Dimethylethyl)-4-mercaptophenol (3.2 g, 0.013 mole) was added to a solution of methyl [(2-chlorocyclohexyl)sulfonyl]acetate (0.85 g, 0.0033 mole) in triethylamine (13 ml) and the reaction mixture was refluxed for 5 hours. The reaction mixture was cooled to room temperature and poured into 1N hydrochloric acid (150 ml). The mixture was extracted twice with 50 ml of diethyl ether, then washed twice with 20 ml of 1.5N hydrochloric acid and once with brine (10 ml), dried over anhydrous magnesium sulfate, filtered and concentrated in a rotary evaporator to give the crude product as an oil. The product was purified by silica gel chromatography to give a solid m.p. ca. 105° C. The structure was supported by NMR, and infrared spectroscopy and elemental analysis.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[C:5]([O:14][CH3:15])=[CH:4][N:3]=1.[N+:16]([C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1)([O-:18])=[O:17].C([O-])([O-])=O.[Na+].[Na+]>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>[CH3:15][O:14][C:5]1[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:7][C:2]([C:23]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:16]([O-:18])=[O:17])[CH:24]=2)=[N:3][CH:4]=1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: COc1cnc(Cl)nc1N1CCOCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1cnc(-c2cccc([N+](=O)[O-])c2)nc1N1CCOCC1
Temperature: 80 °C
Yield: 39.9 %

Procedure:
A mixture of 4-(2-chloro-5-methoxy-pyrimidin-4-yl)-morpholine (0.2 g, 1.0 eq), 3-nitrophenyl boronic acid (0.17 g, 1.2 eq), (PPh3)4Pd (0.10 g, 0.1 eq) and 2 M Na2CO3 (1.3 ml, 3.0 eq) was heated at 80° C. and refluxed overnight. The solvent was removed in vacuo, and the residue was extracted with EA and water. The combined organic layers were washed with brine, dried and evaporated in vacuo. The crude was purified by chromatography to give a yellow solid (0.11 g, 39.97%).
Reaction SMILES: CN1CCCC1=O.[CH3:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([NH2:18])[CH:10]=1.[Cl:19][C:20]1[CH:25]=[C:24](Cl)[N:23]=[CH:22][N:21]=1.C([O-])([O-])=O.[Na+].[Na+]>O>[Cl:19][C:20]1[N:21]=[CH:22][N:23]=[C:24]([NH:18][N:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:9]([CH3:8])=[CH:10]2)[CH:25]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: Cc1cn(N)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1cn(Nc2cc(Cl)ncn2)c2ccccc12
Temperature: 120 °C
Reaction time: 4 h

Procedure:
To 125 ml of 1-methyl-2-pyrrolidinone was added 3-methyl-1H-indol-1-amine (10.0 g), and this mixture was heated to 120° C. Then 4,6-dichloropyrimidine (10.43 g), was added to the hot solution and this mixture was stirred for four hours. The reaction was cooled, poured into water, basified with Na2CO3 (aq) extracted with ethyl acetate and the organic layer washed with water and dried (sat. NaCl, anhy. MgSO4).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[O:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[C:14]([C@@H:15]3[CH2:17][C@H:16]3[CH2:18][NH2:19])[C:9]=2[CH2:8][CH2:7]1.[Na+].[Cl-]>>[O:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[C:14]([C@@H:15]3[CH2:17][C@H:16]3[CH2:18][NH:19][C:1](=[O:4])[CH2:2][CH3:3])[C:9]=2[CH2:8][CH2:7]1
Reactant: CCC(=O)Cl
Reactant: NC[C@@H]1C[C@H]1c1cccc2c1CCO2
Agent: [Cl-]
Agent: [Na+]
Product: CCC(=O)NC[C@@H]1C[C@H]1c1cccc2c1CCO2

Procedure:
This compound was prepared similar to the above procedure using propionyl chloride and (-)-(trans)-2-(2,3-dihydrobenzofuran-4-yl)-cyclopropanemethanamine to give an oil that solidified upon standing to an off-white solid (61%, mp: 71°-72° C.). IR (NaCl Film): 3298, 1645, 1548, 1459, 1235 cm-1. [α]D25 : -17.3°; Anal. Calc'd for C15H19NO2 : C, 73.44; H, 7.87; N, 5.71; Found: C, 73.28; H, 7.68; N, 5.58.
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[CH:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[C:18](OC(=O)C)(=[O:20])[CH3:19].B(F)(F)F>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:10]([C:18](=[O:20])[CH3:19])=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: Fc1ccc(-c2cc3cccc(Cl)n3n2)cc1
Reactant: CC(=O)OC(C)=O
Agent: FB(F)F
Solvent: Cc1ccccc1
Product: CC(=O)c1c(-c2ccc(F)cc2)nn2c(Cl)cccc12
Temperature: 25 °C
Yield: 77 %

Procedure:
To a solution of 7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine (10.0 g, 40.5 mmol) in toluene (225 mL) at room temperature was added acetic anhydride (4.6 mL, 48.6 mmol). Boron trifluoride diethyletherate (5.6 mL, 44.6 mmol) was then added dropwise and the resultant solution was heated to reflux for 3.5 hours. The reaction mixture was cooled to room temperature and quenched by the dropwise addition of aqueous sodium bicarbonate. Ether was added and the organic layer was washed with brine. The aqueous layer was extracted with ether and the combined organics were dried over magnesium sulfate, filtered and concentrated. The residue was purified by recrystallization from ethyl acetate-hexanes to give 1-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]ethanone (9.0 g, 77%) as redish needles. 1H NMR (CDCl3): δ 8.41 (d, 1 H), 7.59 (m, 2 H), 7.45 (dd, 1 H), 7.26-7.13 (m 3 H), 2.15 (s, 3 H); 19F NMR (CDCl3) δ −112.06; MS m/289 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])[C:15]=3[N:14]=[C:13](Cl)[C:12]=2[CH2:11][CH2:10]1.[NH2:29][CH2:30][CH2:31][CH2:32][CH2:33][OH:34]>C(O)COCCO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])[C:15]=3[N:14]=[C:13]([NH:29][CH2:30][CH2:31][CH2:32][CH2:33][OH:34])[C:12]=2[CH2:11][CH2:10]1
Reactant: NCCCCO
Reactant: COc1ccccc1N1CCc2c(Cl)nc3c(OCC(F)(F)F)cccc3c21
Solvent: OCCOCCO
Product: COc1ccccc1N1CCc2c(NCCCCO)nc3c(OCC(F)(F)F)cccc3c21
Yield: 21.7 %

Procedure:
1-(2-Methoxyphenyl)-4-chloro-6-β,β,β-trifluoroethoxy-2,3-dihydropyrrolo[3,2-c]quinoline(500 mg, 1.2 mmol) was dissolved in diethylene glycol(10 ml) and 4-amino-1-butanol(175 μl, 1.9 mmol) was added. It was reacted at the same condition of Step 3 in the Example 38 to obtain 120 mg of desired compound as solid in 39% of yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[C:5]([C:12]2[CH2:17][C:16]([CH3:19])([CH3:18])[CH2:15][C:14]([CH3:21])([CH3:20])[CH:13]=2)[CH:4]=1.CO>[Pd].O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[C:5]([CH:12]2[CH2:17][C:16]([CH3:19])([CH3:18])[CH2:15][C:14]([CH3:21])([CH3:20])[CH2:13]2)[CH:4]=1
Reactant: COc1ccc([N+](=O)[O-])c(C2=CC(C)(C)CC(C)(C)C2)c1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(N)c(C2CC(C)(C)CC(C)(C)C2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-methoxy-1-nitro-2-(3,3,5,5-tetramethylcyclohex-1-enyl)benzene (1.0 g, 3.46 mmol) produced in Example (85a), 10% palladium on carbon (500 mg, wet), methanol (8 mL) and tetrahydrofuran (2 mL) was stirred overnight at room temperature and atmospheric pressure under a hydrogen atmosphere. The mixture was filtered through Celite to remove the catalyst, and the filtrate was concentrated. A crude product of the title compound was obtained as a brown oil. The crude product was used without purification for the following reaction.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]([OH:14])=[O:13])[C:6](=[CH:10][CH:11]=1)[C:7]([OH:9])=O.S(Cl)(Cl)=O.C1N2CCN(CC2)C1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6](=[CH:10][CH:11]=1)[C:7](=[O:9])[O:14][C:12]2=[O:13]
Reactant: COc1ccc(C(=O)O)c(C(=O)O)c1
Agent: C1CN2CCN1CC2
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: COc1ccc2c(c1)C(=O)OC2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.1 %

Procedure:
To a mixture of 4-methoxy-phthalic acid (1.8 g, 9.18 mmol), thionyl chloride (1.4 mL, 19.79 mmol) in CH2Cl2 (15 mL) is added DABCO (1.1 g, 9.81 mmol). The reaction mixture is stirred at room temperature for 2 hours. The reaction mixture is diluted with CH2Cl2 (100 mL), washed with H2O (75 mL×2), dried with Na2SO4 and filtered. The filtrate is concentrated under reduced pressure to afford 5-methoxy-isobenzofuran-1,3-dione (950 mg, 58%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:31])[C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:30])[NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:32]([OH:34])=[O:33].C[O-].[Na+:37].CO>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:31])[C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:30])[NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:32]([O-:34])=[O:33].[Na+:37]
Reactant: O=C(NCCc1ccc(Cl)cc1)c1ccc(Oc2c(Cl)cc3c(c2Cl)OCCC3C(=O)O)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(NCCc1ccc(Cl)cc1)c1ccc(Oc2c(Cl)cc3c(c2Cl)OCCC3C(=O)[O-])cc1
Reaction time: 1 h
Yield: 99 %

Procedure:
6,8-Dichloro-7-(4-(4-chlorophenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid (22.78 g, 43.26 mmol) was dissolved in THF (100 ml) and 0.5M NaOMe solution in MeOH (86.52 ml, 43.26 mmol) was added at ambient temperature. The mixture was stirred for 1 hour and concentrated. A very thick light brown solid was obtained. The crude solid was treated with EtOH-hexanes and filtered to provide 23.4 g of the title compound as a white solid (99%). MS (apci) m/z=520.1 (M+2H-Na).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH2:14][C:15]#[N:16].[C:17]([O:21][CH2:22][CH3:23])(=[O:20])[CH:18]=[CH2:19].[C:24]([OH:29])(=[O:28])[C:25]([OH:27])=[O:26]>C(O)C.C(OCC)(=O)C>[C:24]([OH:29])(=[O:28])[C:25]([OH:27])=[O:26].[C:2]([CH2:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH2:14][CH2:15][NH:16][CH2:19][CH2:18][C:17]([O:21][CH2:22][CH3:23])=[O:20])#[N:1]
Reactant: COc1cc(CC#N)c(CCN)cc1OC
Reactant: C=CC(=O)OCC
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)CCNCCc1cc(OC)c(OC)cc1CC#N
Temperature: 25 °C
Reaction time: 20 h
Yield: 78.3 %

Procedure:
A mixture of [2-(2-aminoethyl)-4,5-dimethoxyphenyl]acetonitrile (6.5 g, 29.5 mmol) and ethyl acrylate (3.9 ml, 36 mmol, 1.2 eq.) in 120 mL of ethanol is stirred for 20 hours at ambient temperature. The reaction mixture is subjected to drying in vacuo; then the crude reaction mixture is taken up in a mixture of ethyl acetate (133 mL) and ethanol (13 mL) and is heated at reflux in the presence of oxalic acid (2.52 g, 28 mmol, 0.95 eq.). Precipitation from the mixture occurs during contact at reflux. After returning to ambient temperature, the mixture is filtered and washed with 19 ml of ethyl acetate to obtain a white powder (9 g) corresponding to the title compound.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[N:8]=[C:9]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)[S:10][CH:11]=2)[O:6]CCO1.[Cl:19][C:20]1[CH:21]=[C:22]([C:26]2[O:30][C:29]([CH3:31])=[N:28][C:27]=2[C:32](O)=[O:33])[CH:23]=[CH:24][CH:25]=1>>[C:2]([C:7]1[N:8]=[C:9]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:32]([C:27]3[N:28]=[C:29]([CH3:31])[O:30][C:26]=3[C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([Cl:19])[CH:21]=3)=[O:33])[CH:15]=[N:14]2)[S:10][CH:11]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2csc(Cn3ncc(N)n3)n2)OCCO1
Reactant: Cc1nc(C(=O)O)c(-c2cccc(Cl)c2)o1
Product: CC(=O)c1csc(Cn2ncc(NC(=O)c3nc(C)oc3-c3cccc(Cl)c3)n2)n1

Procedure:
Following general procedure A followed by B, starting from 2-[4-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-(3-chloro-phenyl)-2-methyl-oxazole-4-carboxylic acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@:8]1([CH3:20])[N:16]=[C:15]([NH2:17])[C:11]2([CH2:14][CH2:13][CH2:12]2)[S:10](=[O:19])(=[O:18])[CH2:9]1.S(=O)(=O)(O)O.[N+:26]([O-])([OH:28])=[O:27].[OH-].[Na+]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:26]([O-:28])=[O:27])=[CH:4][C:3]=1[C@@:8]1([CH3:20])[N:16]=[C:15]([NH2:17])[C:11]2([CH2:12][CH2:13][CH2:14]2)[S:10](=[O:19])(=[O:18])[CH2:9]1
Reactant: O=[N+]([O-])O
Reactant: C[C@@]1(c2ccccc2F)CS(=O)(=O)C2(CCC2)C(N)=N1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: C[C@@]1(c2cc([N+](=O)[O-])ccc2F)CS(=O)(=O)C2(CCC2)C(N)=N1
Temperature: 0 °C
Reaction time: 2 h
Yield: 106.2 %

Procedure:
(R)-7-(2-Fluoro-phenyl)-7-methyl-5,5-dioxo-5λ6-thia-8-aza-spiro[3.5]non-8-en-9-ylamine (385 mg, 1.3 mmol, Eq: 1.00) was dissolved in conc. sulfuric acid (6.37 g, 3.46 ml, 65.0 mmol, Eq: 50). At 0° C., fuming nitric acid (123 mg, 87.1 μl, 1.95 mmol, Eq: 1.5) was added dropwise. The light brown solution was stirred at 0° C. for 2 hours. The reaction mixture was poured on ice and basified with 3 N NaOH followed by extraction with dichloromethane. The organic layer was separated, dried over Na2SO4, filtered and evaporated to dryness to give the crude and pure (R)-7-(2-fluoro-5-nitro-phenyl)-7-methyl-5,5-dioxo-5λ6-thia-8-aza-spiro[3.5]non-8-en-9-ylamine (470 mg, 1.38 mmol, 106% yield) as a light brown foam. MS (ISP): m/z=342.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:37]2[CH:42]=[CH:41][C:40]([O:43][CH2:44][O:45][CH3:46])=[CH:39][CH:38]=2)[C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]=2[S:21]([N:24]2[CH2:29][CH2:28][N:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[Cl:36])[CH2:26][CH2:25]2)(=[O:23])=[O:22])=[CH:7][CH:6]=1.Cl.[O:48]1[CH2:53][CH2:52][N:51]([CH2:54][CH2:55]Cl)[CH2:50][CH2:49]1>>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:37]2[CH:38]=[CH:39][C:40]([O:43][CH2:44][O:45][CH3:46])=[CH:41][CH:42]=2)[C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:55][CH2:54][N:51]3[CH2:52][CH2:53][O:48][CH2:49][CH2:50]3)[C:13]=2[S:21]([N:24]2[CH2:29][CH2:28][N:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[Cl:36])[CH2:26][CH2:25]2)(=[O:22])=[O:23])=[CH:7][CH:6]=1
Reactant: ClCCN1CCOCC1
Reactant: COCOc1ccc(C(c2ccc(OCOC)cc2)c2c(S(=O)(=O)N3CCN(c4ccccc4Cl)CC3)[nH]c3ccccc23)cc1
Agent: Cl
Product: COCOc1ccc(C(c2ccc(OCOC)cc2)c2c(S(=O)(=O)N3CCN(c4ccccc4Cl)CC3)n(CCN3CCOCC3)c3ccccc23)cc1

Procedure:
Substantially the same procedure as in Example 243 was repeated using Compound 241 (1.1 g, 1.66 mmol) obtained in Example 242 and 2-morpholinoethylchloride hydrochloride (310 mg, 1.66 mmol) to give 1.3 g (quantitative) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[CH:9]([C:11]([CH3:13])=O)=[CH2:10]>C(O)(=O)C.[Cl-].[Zn+2].[Cl-]>[CH3:13][C:11]1[C:5]2[C:3](=[C:2]([CH3:1])[CH:8]=[CH:7][CH:6]=2)[N:4]=[CH:10][CH:9]=1
Reactant: Cc1ccccc1N
Reactant: C=CC(C)=O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)O
Product: Cc1ccnc2c(C)cccc12
Temperature: 70 °C
Reaction time: 0.08 h
Yield: 65 %

Procedure:
To a stirred solution of 2-methylaniline (1 g. 9.3 mmol.) in acetic acid (10 ml), activated silferc (1.5 g., ferric chloride 9.3 mmol) was added under nitrogen atmosphere. The reaction mixture was stirred for 5 minutes and methyl vinyl ketone (MVK) (0.72 g, 10.2 mmol) was added slowly over a period of 15 minutes. The reaction mixture was heated to 70° C. and maintained between 70-75° C. for one hour. Anhydrous zinc chloride (1.27 g. 9.3 mmol) was added and the reaction was further refluxed for two hours. The reaction mixture was cooled, filtered, basified with 10% NaOH solution, extracted with ethyl acetate (3×20 ml), dried over Na2SO4 and evaporated to give the product; Yield 65%.
Reaction SMILES: [Cl:1][C:2]1[C:8]([I:9])=[CH:7][C:5]([NH2:6])=[C:4]([O:10][CH3:11])[CH:3]=1.[H-].[Na+].[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28]Br)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]>C1COCC1>[Cl:1][C:2]1[C:8]([I:9])=[CH:7][C:5]([NH:6][CH2:28][CH2:27][N:24]2[CH2:25][CH2:26][N:21]([C:19]([O:18][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:20])[CH2:22][CH2:23]2)=[C:4]([O:10][CH3:11])[CH:3]=1
Reactant: COc1cc(Cl)c(I)cc1N
Reactant: CC(C)(C)OC(=O)N1CCN(CCBr)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(Cl)c(I)cc1NCCN1CCN(C(=O)OC(C)(C)C)CC1
Yield: 21.2 %

Procedure:
To a stirred solution of 4-chloro-5-iodo-2-methoxyaniline (968 mg, 3.42 mmol) in anhydrous THF (20 mL) at 0° C., NaH (60% in mineral oil, 205.2 mg, 5.13 mmol) was added and the resulting mixture was stirred at reflux under nitrogen for 1 h. To this mixture, tert-butyl-4-(2-bromoethyl)piperazine-1-carboxylate (500 mg, 1.71 mmol) was added and the resulting mixture was stirred at room temperature for 15 h. The mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (10-30% ethyl acetate/petroleum ether) to afford the desired product (180 mg, 21% yield) as a solid.