Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([CH3:24])=[CH:21][CH:22]=3)[N:17]=[C:16]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[OH:31])[N:15]=2)[CH2:10]1.Cl[C:33]([O:35][CH2:36][CH:37]([CH3:39])[CH3:38])=[O:34]>CN(C=O)C>[OH:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:16]1[N:15]=[C:14]([N:11]2[CH2:12][CH2:13][C@@H:9]([NH:8][C:33](=[O:34])[O:35][CH2:36][CH:37]([CH3:39])[CH3:38])[CH2:10]2)[C:23]2[C:18](=[CH:19][C:20]([CH3:24])=[CH:21][CH:22]=2)[N:17]=1
Reactant: CC(C)COC(=O)Cl
Reactant: Cc1ccc2c(N3CC[C@@H](N)C3)nc(-c3ccccc3O)nc2c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc2c(N3CC[C@@H](NC(=O)OCC(C)C)C3)nc(-c3ccccc3O)nc2c1
Temperature: -20 °C
Reaction time: 0.25 h
Yield: 58.2 %

Procedure:
Under an N2 atmosphere, triethylamine (0.35 mL, 2.5 mmol) was added to a solution of (R)-2-(4-(3-aminopyrrolidin-1-yl)-7-methylquinazolin-2-yl)phenol (0.40 g, 1.25 mmol) in DMF (6.0 mL). The reaction mixture was cooled to −20° C. external temperature, and isobutyl chloroformate (180 μL, 1.38 mmol) was added dropwise. The reaction was stirred for 10 minutes at −20° C. and 15 minutes at RT. The mixture was quenched with H2O, and partitioned between CH2Cl2 and H2O, and the aqueous layer was extracted once more with CH2Cl2. The organic phase was dried over Na2SO4, filtered and purified via silica gel chromatography using 6% EtOAc in a 1:1 mixture of hexanes and CH2Cl2 to yield (R)-isobutyl 1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamate (compound 5) (306 mg, 58%). 1H NMR (400 MHz, DMSO-d6) δ 8.43 (m, 1H), 8.18 (d, J=8.6 Hz, 1H), 7.59 (s, 2H), 7.35 (m, 2H), 6.92 (m, 2H), 4.06 (m, 5H), 3.75 (d, J=4.4 Hz, 2H), 2.49 (s, 3H), 2.23 (m, 1H), 2.03 (m, 1H), 1.83 (m, 1H), 0.87 (d, J=6.5 Hz, 6H) ppm. LC/MS: m/z 421.3 (M+H)+ at 2.54 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [ClH:1].Cl.[CH2:3]([C:7]1[N:8]=[N:9][C:10]([O:26][CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:11][C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:15][CH:14]=1)[CH2:4][CH2:5][CH3:6].Br[CH2:34][CH2:35][CH:36]1[O:41][CH2:40][CH2:39][CH2:38][O:37]1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C=O)C.O.CCOC(C)=O.C(Cl)Cl.CCOCC>[ClH:1].[ClH:1].[CH2:3]([C:7]1[N:8]=[N:9][C:10]([O:26][CH:27]2[CH2:32][CH2:31][N:30]([CH2:34][CH2:35][CH:36]3[O:41][CH2:40][CH2:39][CH2:38][O:37]3)[CH2:29][CH2:28]2)=[CH:11][C:12]=1[C:13]1[CH:14]=[CH:15][C:16]([O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:17][CH:18]=1)[CH2:4][CH2:5][CH3:6]
Reactant: BrCCC1OCCCO1
Reactant: CCCCc1nnc(OC2CCNCC2)cc1-c1ccc(OC2CCCCC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: ClCCl
Product: CCCCc1nnc(OC2CCN(CCC3OCCCO3)CC2)cc1-c1ccc(OC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.7 %

Procedure:
To a solution of 3-butyl-4-(4-cyclohexyloxy-phenyl)-6-(piperidin-4-yloxy)-pyridazine dihydrochloride (Example 14, 0.1 mmol, 49 mg) in DMF (1 mL) was added 2-(2-bromoethyl)-1,3-dioxane (0.3 mmol, 40 μL), and potassium carbonate (0.4 mmol, 56 mg). The mixture was stirred at room temperature for 3 hours. It was then diluted with water/EtOAc. The organic layers were combined, dried, and condensed in vacuo and the residue was purified by silica gel chromatography (DCM to DCM+10% 2N ammonia in MeOH) to give a colorless sticky solid, which was dissolved in DCM (1 mL), 1N HCl in ether (1 mL) was added, kept at room temperature for 10 min, condensed, triturated with hexanes to provide the title compound (22 mg). LCMS: m/z 525 [M+1]. 1H NMR (400 MHz, CD3OD): δ 7.72 and 7.81 (1H, s), 7.44-7.49 (2H, m), 7.12-7.17 (2H, m), 5.38-5.57 (1H, m), 4.76-4.79 (1H, m), 4.41-4.48 (1H, m), 4.06-4.13 (2H, m), 3.72-3.86 (3H, m), 3.55-3.60 (1H, m), 3.22-3.39 (4H, m), 3.12-3.17 (2H, m), 2.23-2.57 (3H, m), 1.98-2.17 (6H, m), 1.79-1.86 (2H, m), 1.23-1.64 (11H, m), 0.82 (3H, t).
Reaction SMILES: S(Cl)([Cl:3])=O.O[C@@H:6]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7]([OH:9])=[O:8].N1C=CC=CC=1.O>C(COC)OC>[Cl:3][C@H:6]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7]([OH:9])=[O:8]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)[C@@H](O)Cc1ccccc1
Solvent: c1ccncc1
Solvent: COCCOC
Solvent: O
Product: O=C(O)[C@H](Cl)Cc1ccccc1
Reaction time: 15 h
Yield: 60.9 %

Procedure:
Thionyl chloride (0.18 ml, 2.4 mmol) was added dropwise to a solution of 200 mg (1.2 mmol) of (2S)-2-hydroxy-3-phenylpropionic acid (optical purity 100% ee (S)) in 2 ml of dimethoxyethane at room temperature, and the mixture was stirred for 15 hours. To that reaction mixture was added 0.01 ml (0.12 mmol) of pyridine, and the mixture was stirred at 60° C. for 4 hours. Water (10 ml) was added to the reaction mixture and, after 30 minutes of stirring, the mixture was extracted with 50 ml of ethyl acetate. The organic phase was washed with 10 ml of a saturated aqueous solution of sodium chloride and dried over sodium sulfate. The solvent was distilled off under reduced pressure to give 135 mg (yield 61%) of the desired (2R)-2-chloro-3-phenylpropionic acid. The optical purity of the product as determined by the same method as in Example 12 was 97.6% ee (R) (rate of configurational inversion 97.6%).
Reaction SMILES: Br[C:2]1[C:3](=[O:25])[N:4]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[N:5]=[CH:6][C:7]=1[NH:8][C@@H:9]1[CH2:14][C@@H:13]2[CH2:15][C@@H:11]([C:12]2([CH3:17])[CH3:16])[C@H:10]1[CH3:18].[OH-:26].[K+].[Cl-].[NH4+]>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C>[OH:26][C:2]1[C:3](=[O:25])[N:4]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[N:5]=[CH:6][C:7]=1[NH:8][C@@H:9]1[CH2:14][C@@H:13]2[CH2:15][C@@H:11]([C:12]2([CH3:17])[CH3:16])[C@H:10]1[CH3:18]
Reactant: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cnn(C3CCCCO3)c(=O)c1Br)C2(C)C
Reactant: [OH-]
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cnn(C3CCCCO3)c(=O)c1O)C2(C)C
Yield: 99.9 %

Procedure:
4-Bromo-2-(tetrahydro-2H-pyran-2-yl)-5-{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-3(2H)-one (200 mg, 0.49 mmol), tris(dibenzylideneacetone)dipalladium (9 mg, 0.01 mmol), potassium hydroxide (82 mg, 1.46 mmol) and 2-di-t-butylphosphino-2′,4′,6′-triisopropylbiphenyl (17 mg, 0.04 mmol) in 1,4-dioxane-water (1/1) were stirred in an argon stream at 100° C. for 1 hour. After completion of the reaction, the reaction solution was mixed with saturated aqueous ammonium chloride and extracted with chloroform three times, and the organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/1 to 1/1) to give the desired product (170 mg, 100% yield).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:6]=1[Br:12])C=C.[C:13]1(C)[CH:18]=C(C)C=C(C)[CH:14]=1>>[CH2:18]([C:10]1[C:9]([F:11])=[CH:8][CH:7]=[C:6]([Br:12])[C:5]=1[OH:4])[CH:13]=[CH2:14]
Reactant: Cc1cc(C)cc(C)c1
Reactant: C=CCOc1cc(F)ccc1Br
Product: C=CCc1c(F)ccc(Br)c1O
Yield: 95 %

Procedure:
Treatment of 2-(allyloxy)-1-bromo-4-fluorobenzene (12.00 g, 0.052 mol) in refluxing mesitylene generally according to the reaction procedure described for Intermediate 8 provided 11.5 g (95%) of 2-allyl-6-bromo-3-fluorophenol as a pale yellow oil. Rf=0.48 (silica, ethyl acetate:hexanes 1:4); Anal. calcd. for C9H8BrFO: C, 46.78; H, 3.49. Found: C, 47.59; H, 3.47.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.ClC1N=CC2C=CNC=2N=1.C([Si](Cl)(C(C)C)C(C)C)(C)C.[H-].[Na+]>O1CCCC1>[N:5]1[C:4]2[NH:8][CH:9]=[CH:10][C:3]=2[CH:2]=[N:7][CH:6]=1
Reactant: Clc1ncnc2[nH]ccc12
Agent: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: Clc1ncc2cc[nH]c2n1
Agent: [H-]
Solvent: C1CCOC1
Product: c1ncc2cc[nH]c2n1

Procedure:
Compounds of Formula I or II, where P is a suitable protecting group, are prepared by reacting 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1) or 2-chloro-7H-pyrrolo[2,3-d]pyrimidine (2), respectively, with an appropriate reagent to introduce a suitable protecting group (P—X, e.g. triisopropylsilylchloride) and a base (e.g. sodium hydride) in a solvent (e.g. tetrahydrofuran) typically at room temperature for 8-12 hours. The desired compound is isolated by conventional means (e.g. extraction).
Reaction SMILES: Br[C:2]1[CH:14]=[N:13][C:5]2[NH:6][C:7](=[O:12])[CH2:8][N:9]([CH3:11])[CH2:10][C:4]=2[CH:3]=1.[C:15]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])(=[O:18])[CH:16]=[CH2:17].C(N(C(C)C)C(C)C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)CC.CN(C=O)C.C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:20]([O:19][C:15](=[O:18])/[CH:16]=[CH:17]/[C:2]1[CH:14]=[N:13][C:5]2[NH:6][C:7](=[O:12])[CH2:8][N:9]([CH3:11])[CH2:10][C:4]=2[CH:3]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: CN1CC(=O)Nc2ncc(Br)cc2C1
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCC#N
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN1CC(=O)Nc2ncc(/C=C/C(=O)OC(C)(C)C)cc2C1
Reaction time: 0.42 h
Yield: 79.1 %

Procedure:
A suspension of 7-bromo-4-methyl-1,3,4,5-tetrahydro-pyrido[2,3-e][1,4]diazepin-2-one (0.63 g, 2.5 mmol) in propionitrile (10 mL) and DMF (3 mL) was de-oxygenated with Ar for 25 min. The mixture was treated with tert-butyl acrylate (1.5 mL, 10 mmol) and (i-Pr)2EtN (0.9 mL, 5 mmol) and was de-oxygenated with Ar for 10 min. Pd(OAc)2 (56 mg, 0.25 mmol) and P(o-tol)3 (150 mg, 0.49 mmol) were added simultaneously, and the mixture was de-oxygenated a third time for 5 min. The mixture was heated to reflux for 18 h, then allowed to cool. The resulting precipitate was isolated by filtration, dissolved in CH2Cl2, filtered through Celite, and the solvent was removed in vacuo to give the title compound (0.60 g, 80%) as an off-white solid: 1H NMR (300 MHz, CDCl3) δ 8.63 (s, 1H), 8.41 (d, J=2.0 Hz, 1H), 7.62 (d, J=1.7 Hz, 1H), 7.52 (d, J=16.0 Hz, 1H), 6.37 (d, J=16.0 Hz, 1H), 3.96 (s, 2H), 3.77 (s, 2H), 2.49 (s, 3H), 1.53 (s, 9H); MS (ESI) m/e 304 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[F:16][C:17]([F:34])([F:33])[C:18]1[CH:23]=[CH:22][C:21]([C:24]([C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)=[O:25])=[CH:20][CH:19]=1>>[F:16][C:17]([F:33])([F:34])[C:18]1[CH:19]=[CH:20][C:21]([C:24]([C:26]2[CH:31]=[CH:30][C:29]([O:32][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=4)[N:5]=[CH:4][CH:3]=3)=[CH:28][CH:27]=2)=[O:25])=[CH:22][CH:23]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: O=C(c1ccc(O)cc1)c1ccc(C(F)(F)F)cc1
Product: COc1cc2nccc(Oc3ccc(C(=O)c4ccc(C(F)(F)F)cc4)cc3)c2cc1OC
Temperature: 180 °C
Reaction time: 0.33 h
Yield: 59.7 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (81 mg) and 4-hydroxyphenyl 4-trifluoromethylphenyl ketone (288 mg) obtained in Example 23 were mixed and stirred at 180° C. for 20 minutes, and the reaction mixture was then purified by thin layer chromatography on silica gel eluting with hexane/acetone (2/1) to obtain 98 mg of the title compound (yield: 60%).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.Cl.[NH2:49][CH:50]1[CH2:55][CH2:54][CH2:53][CH2:52][CH:51]1[OH:56]>CN(C=O)C>[Br:1][C:2]1[C:3]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH:49][CH:50]1[CH2:55][CH2:54][CH2:53][CH2:52][CH:51]1[OH:56])=[O:9]
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(Br)c1
Reactant: NC1CCCCC1O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NC1CCCCC1O)c1cnc(OCC(F)(F)F)c(Br)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 81.7 %

Procedure:
5-Bromo-6-(2,2,2-trifluoro-ethoxy)-nicotinic acid (75.0 g, 0.25 mol) was dissolved in DMF (850 mL). To the solution was added TBTU (91.0 g, 0.275 mol), N,N-diisopropylethyl amine (214 mL, 1.25 mol) and (1SR,2RS)-2-amino-cyclohexanol hydrochloride (41.7 g, 0.275 mol). The reaction mixture was stirred for 1.5 h at room temperature. The solvent was evaporated in vacuo, the residue was partitioned between ethyl acetate (2500 mL) and 1 N sodium hydroxide solution (2000 mL), the water phase was separated, extracted once more with ethyl acetate (1000 mL) and the organic phases were washed 2 times with water (2×1500 mL). Organic phases were pooled, dried with MgSO4 and concentrated to about 900 mL. The product precipitated upon stirring and cooling to 0° C. Filtration, washing with ethyl acetate/n-heptane (1:1) and drying in vacuo gave the title compound (81.1 g) as a white solid; MS (ISP) 397, 399 (M)+.
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:10]([Cl:11])=[C:9]([CH3:12])[N:8]=[C:7]([C:13]2[N:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)[N:6]=1)[CH:2]=[CH2:3].C(N(CC)CC)C.[Cl:27][CH2:28][C:29](Cl)=[O:30]>C1COCC1>[CH2:1]([O:4][C:5]1[C:10]([Cl:11])=[C:9]([CH3:12])[N:8]=[C:7]([C:13]2[N:18]=[CH:17][C:16]([NH:19][C:29](=[O:30])[CH2:28][Cl:27])=[CH:15][CH:14]=2)[N:6]=1)[CH:2]=[CH2:3]
Reactant: O=C(Cl)CCl
Reactant: C=CCOc1nc(-c2ccc(N)cn2)nc(C)c1Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CCOc1nc(-c2ccc(NC(=O)CCl)cn2)nc(C)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of compound of example 55 (0.064 g, 0.231 mmol) in THF (4 mL), at 0° C. was added triethylamine (0.035 g, 0.346 mmol) and chloroacetylchloride (0.039 g, 0.346 mmol), and the reaction mixture was stirred at room temperature for 30 minutes. THF was removed under reduced pressure, and the reaction mixture was quenched with water and extracted with ethyl acetate (3×10 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by column chromatography using silica gel and 1% methanol in chloroform as an eluent to obtain the title compound.
Reaction SMILES: [F:1][CH:2]([F:40])[O:3][C:4]1[CH:11]=[C:10]([O:12][CH2:13][C:14]2[S:18][C:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)=[N:16][C:15]=2[CH2:29][N:30]2[CH2:35][CH2:34][CH:33]([C:36]([F:39])([F:38])[F:37])[CH2:32][CH2:31]2)[CH:9]=[CH:8][C:5]=1[C:6]#[N:7].C(N(CC)CC)C.Cl.[NH2:49][OH:50].O>CO>[F:40][CH:2]([F:1])[O:3][C:4]1[CH:11]=[C:10]([O:12][CH2:13][C:14]2[S:18][C:17]([C:19]3[CH:20]=[CH:21][C:22]([C:25]([F:26])([F:27])[F:28])=[CH:23][CH:24]=3)=[N:16][C:15]=2[CH2:29][N:30]2[CH2:31][CH2:32][CH:33]([C:36]([F:39])([F:38])[F:37])[CH2:34][CH2:35]2)[CH:9]=[CH:8][C:5]=1[C:6]([NH:49][OH:50])=[NH:7]
Reactant: N#Cc1ccc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CN2CCC(C(F)(F)F)CC2)cc1OC(F)F
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CO
Product: N=C(NO)c1ccc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CN2CCC(C(F)(F)F)CC2)cc1OC(F)F
Temperature: 140 °C
Yield: 54.8 %

Procedure:
To a solution of 830 mg of 2-difluoromethoxy-4-[2-(4-trifluoromethyl-phenyl)-4-(4-trifluoromethyl-piperidin-1-ylmethyl)-thiazol-5-ylmethoxy]-benzonitrile in 13 mL of methanol was added 5.7 mL of triethylamine followed by 430 mg of hydroxylamine hydrochloride. The resulting mixture was heated in a sealed tube to 140° C. under microwave irradiation for 30 minutes. After allowing it to cool down to room temperature, the mixture was poured into water and extracted with dichloromethane. The organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (gradient from heptane 100 to heptane 60/ethyl acetate 40) to give 480 mg of 2-difluoromethoxy-N-hydroxy-4-[2-(4-trifluoromethyl-phenyl)-4-(4-trifluoromethyl-piperidin-1-ylmethyl)-thiazol-5-ylmethoxy]-benzamidine.
Reaction SMILES: Br[CH:2]=[CH:3][CH:4]([CH3:6])[CH3:5].O.O.[C:9]1([CH3:18])[CH:14]=[CH:13][C:12]([S:15]([O-:17])=[O:16])=[CH:11][CH:10]=1.[Na+]>CN(C)C=O>[C:9]1([CH3:18])[CH:14]=[CH:13][C:12]([S:15]([CH2:2][CH:3]=[C:4]([CH3:6])[CH3:5])(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: CC(C)C=CBr
Reactant: Cc1ccc(S(=O)[O-])cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)=CCS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.3 %

Procedure:
In dimethylformamide (20 ml) was dissolved 1-bromo-3-methyl-butene(1.49 g, 10 m moles) and sodium p-toluenesulfinate dihydrate (2.5 g, 1.16 equiv.), the solution was stirred at room temperature for 3 hours. The product was isolated in the usual manner and recrystallized from n-hexane to give 1-(p-toluenesulfonyl)-3-methyl-2-butene (2.16 g, 96.4%), melting point: 71°-72° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:31][CH2:30][CH2:29][CH2:28][C:5]=2[C:6]=1[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]2[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=2)=[CH:12][CH:11]=1)=[O:8].N1C=CC=CC=1.[Cl:38][CH2:39][C:40]1[CH:41]=[C:42]([CH:46]=[CH:47][CH:48]=1)[C:43](Cl)=[O:44]>C(Cl)Cl>[Cl:38][CH2:39][C:40]1[CH:41]=[C:42]([CH:46]=[CH:47][CH:48]=1)[C:43]([NH:1][C:2]1[S:3][C:4]2[CH2:31][CH2:30][CH2:29][CH2:28][C:5]=2[C:6]=1[C:7]([NH:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:26][CH:27]=2)=[CH:14][CH:15]=1)=[O:8])=[O:44]
Reactant: COC(=O)c1ccc(CCc2ccc(NC(=O)c3c(N)sc4c3CCCC4)cc2)cc1
Reactant: O=C(Cl)c1cccc(CCl)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(CCc2ccc(NC(=O)c3c(NC(=O)c4cccc(CCl)c4)sc4c3CCCC4)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
To a mixture of 6.9 g of methyl 4-[2-(4-{[(2-amino-4,5,6,7-tetrahydro-1-benzothiophen-3-yl)carbonyl]amino}phenyl)ethyl]benzoate, 1.5 mL of pyridine and 69 mL of methylene chloride was added dropwise 3.27 g of 3-(chloromethyl)benzoyl chloride, followed by stirring for 1 hour at room temperature. The reaction mixture was concentrated under reduced pressure, ethanol was added thereto, and the precipitated solid was collected by filtration, thereby obtaining 9.27 g of methyl 4-[2-(4-{[(2-{[3-(chloromethyl)benzoyl]amino}-4,5,6,7-tetrahydro-1-benzothiophen-3-yl)carbonyl]amino}phenyl)ethyl]benzoate.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:6]=[C:7]([S:18]([NH2:21])(=[O:20])=[O:19])[CH:8]=[CH:9][C:10]=1[NH:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)([O-:4])=[O:3].C(N(CC)CC)C.Br[CH2:30][CH:31]=[CH2:32]>CN(C)C=O>[CH2:32]([N:15]1[CH2:16][CH2:17][CH:12]([NH:11][C:10]2[CH:9]=[CH:8][C:7]([S:18]([NH2:21])(=[O:19])=[O:20])=[CH:6][C:5]=2[N+:2]([O-:4])=[O:3])[CH2:13][CH2:14]1)[CH:31]=[CH2:30]
Reactant: C=CCBr
Reactant: NS(=O)(=O)c1ccc(NC2CCNCC2)c([N+](=O)[O-])c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C=CCN1CCC(Nc2ccc(S(N)(=O)=O)cc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-nitro-4-(piperidin-4-ylamino)benzenesulfonamide hydrochloride (0.27 g), triethylamine (0.2 mL) and 3-bromoprop-1-ene (0.1 g) was dissolved in N,N-dimethylformamide (5 mL). The mixture was stirred at room temperature overnight. The solvent was dried under vacuum. The mixture was chromatographed on silica gel with 0-20% methanol in dichloromethane.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:4]2[C:5]([O:7][C:8](=[O:9])[C:3]=12)=O.Cl.[NH2:14][CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22].C([O-])(=O)C.[Na+]>C(O)(=O)C>[O:22]=[C:16]1[CH:15]([N:14]2[C:8](=[O:9])[C:3]3[C:4](=[CH:10][CH:11]=[CH:12][C:2]=3[Cl:1])[C:5]2=[O:7])[CH2:20][CH2:19][C:18](=[O:21])[NH:17]1
Reactant: NC1CCC(=O)NC1=O
Reactant: O=C1OC(=O)c2c(Cl)cccc21
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1CCC(N2C(=O)c3cccc(Cl)c3C2=O)C(=O)N1

Procedure:
2-(2,6-Dioxo(3-piperidyl))-4-chloroisoindoline-1,3-dione was prepared by the procedure of Example 1 from 3-chlorophthalic anhydride (0.40 g, 2.2 mmol), 3-aminopiperidine-2,6-dione hydrogen chloride (0.36 g, 2.2 mmol) and sodium acetate (0.19 g, 2.4 mmol) in acetic acid (10 mL). The product was a white solid (0.44 g, 69% yield); mp, 290.0-291.5° C.; 1H NMR (DMSO-d6) δ2.05-2.11 (m, 1H, CHH), 2.49-2.64 (m, 2H, CH2), 2.64-2.92 (m, 1H, CHH), 5.17 (dd, J=5.2, 12.7 Hz, 1H, NCH), 7.86-7.94 (m, 3H, Ar), 11.17 (br s, 1H, NH); 13C NMR (DMSO-d6) δ21.83, 30.91, 49.12, 122.41, 126.94, 129.84, 133.52, 136.11, 136.39, 164.77, 165.76, 169.73, 172.77; Anal Calcd for C13H9N2O4Cl: C, 53.35; H, 3.10; N, 9.57; Cl, 12.11. Found: C, 53.37; H, 2.94; N, 9.30, Cl, 11.97.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][CH2:11][CH2:12][OH:13])=[CH:4][CH:3]=1.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl>[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20]([O:13][CH2:12][CH2:11][CH2:10][C:9]#[C:8][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCCC#Cc1ccc(Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCCC#Cc2ccc(Cl)cc2)cc1
Reaction time: 0.5 h
Yield: 49.9 %

Procedure:
5-(4-Chlorophenyl)pent-4-yn-1-ol (35.7 g, 182 mmol), 4-dimetylamino-pyridine (8.9 g, 73 mmol), p-toluenesulfonyl chloride (34.7 g, 182 mmol), and 62 ml of triethylamine were combined in 330 ml of dichloromethane at 0° C. The mixture was stirred for 30 min. at 0° then 18 hours at room temperature. Dilution with 200 ml of dichloromethane followed by washing with brine, drying over magnesium sulfate, filtration through silica gel with hexane-ethyl acetate, 8:1, gave a yellow solid on evaporation. Crystallization from ether gave 5-(4-Chlorophenyl)pent-4-yn-1-ol p-toluenesulfonate as colorless crystals (31.7 g, 49% yield). This was converted to the title compound by reaction with sodium iodide in acetone, and was used in subsequent reactions with no further purification; MS m/z 303.9.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[C:9]1[C:21]([O:23]CC)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[Li].O>C1COCC1.CCO.O>[CH2:1]([N:8]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[C:9]1[C:21]([OH:23])=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(-c2ccc(Cl)cc2)c(C)cn1Cc1ccccc1
Agent: [Li]O
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cn(Cc2ccccc2)c(C(=O)O)c1-c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
To a suspension of ethyl 1-benzyl-3-(4-chlorophenyl)-4-methyl-1H-pyrrole-2-carboxylate (8.50 g, 24.0 mmol) in THF (15 mL), EtOH (15 mL) and H2O (15 mL) was added LiOH.H2O (10.1 g, 240 mmol). The reaction mixture was stirred at reflux temperature for 2 h. To the reaction mixture were added extra H2O (45 mL) and EtOH (30 mL) and the reaction mixture was stirred at reflux temperature overnight. The reaction mixture was allowed to cool to room temperature and was almost completely concentrated. Aqueous 1 M KHSO4 (˜240 mL) was added to the reaction mixture while cooling with an ice-bath (pH reached 1), followed by the addition of EtOAc (500 mL). The organic layer was separated, washed with brine (2×400 mL), dried (Na2SO4) and concentrated. The residue was washed with a minimal amount of i-Pr2O and dried on a filter for 1 h to give ACI-02 (7.26 g, 93%).