Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]([C:9]1[CH:14]=[C:13]([C:15]([C:21]([F:24])([F:23])[F:22])([OH:20])[C:16]([F:19])([F:18])[F:17])[CH:12]=[CH:11][C:10]=1[CH3:25])([OH:8])[C:4]([F:7])([F:6])[F:5].C(N(CC)CC)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>C(Cl)Cl>[F:1][C:2]([F:26])([F:27])[C:3]([C:9]1[CH:14]=[C:13]([C:15]([C:16]([F:17])([F:18])[F:19])([O:20][S:36]([CH3:35])(=[O:38])=[O:37])[C:21]([F:23])([F:22])[F:24])[CH:12]=[CH:11][C:10]=1[CH3:25])([O:8][S:36]([CH3:35])(=[O:38])=[O:37])[C:4]([F:7])([F:6])[F:5]
Reactant: Cc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1C(O)(C(F)(F)F)C(F)(F)F
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(C(OS(C)(=O)=O)(C(F)(F)F)C(F)(F)F)cc1C(OS(C)(=O)=O)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 50 %

Procedure:
4.25 g (10 mmol) of 2,4-bis-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethylethyl)-toluene were dissolved in 50 ml of methylene chloride, and 2.5 g (25 mmol) of triethylamine were added. 2.86 g (25 mmol) of methanesulfonyl chloride were added dropwise at 5° to 10° C. The mixture was stirred for 16 hours at room temperature, separated off from the precipitated salt, washed with water, dried and evaporated down. The residue was chromatographed over a silica gel column with methylene chloride/n-hexane (1:1). After the eluate had been evaporated down, 2.9 g of 2,4- bis-(2,2,2-trifluoro-1-methanesulfonyloxy-1-trifluoromethylethyl)-toluene were obtained (colorless crystals, m.p.: 107° C.).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=3)[S:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:28][C:29]([O:31][CH3:32])=[O:30]>C(#N)C>[C:1]1([C:7]2[N:8]=[C:9]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:23]=[CH:24][CH:25]=3)[O:26][CH2:28][C:29]([O:31][CH3:32])=[O:30])[S:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Oc1cccc(CCc2nc(-c3ccccc3)c(-c3ccccc3)s2)c1
Reactant: COC(=O)CBr
Solvent: CC#N
Product: COC(=O)COc1cccc(CCc2nc(-c3ccccc3)c(-c3ccccc3)s2)c1
Yield: 84.5 %

Procedure:
A mixture of 3-[2-(4,5-diphenyl-2-thiazolyl)-ethyl]phenol (3.65 g, 10 mmol), methyl bromoacetate (1.72 g, 1.06 mL, 11 mmol) potassium carbonate (1.69 g, 12 mmol) and acetonitrile (60 mL) was stirred at reflux for 90 minutes. The mixture was filtered and concentrated to leave an oil which was subjected to chromatography on a column of silica gel. Elution with a mixture of hexanes and diethyl ether (2:1) afforded methyl [3-[2-(4,5-diphenyl-2-thiazolyl)-ethyl]phenoxy]acetate (3.63 g, 82%) as an oil.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[N:12]=[C:11]4[CH:14]=[C:15]([N:19]5[CH2:24][CH2:23][NH:22][CH:21]([CH3:25])[CH2:20]5)[C:16]([F:18])=[CH:17][C:10]4=[CH:9][C:8]=3[C:7](=[O:26])[C:6]([C:27]([OH:29])=[O:28])=[CH:5]2)[CH2:3][CH2:2]1.[CH2:30]=O>C(O)=O>[CH:1]1([N:4]2[C:13]3[N:12]=[C:11]4[CH:14]=[C:15]([N:19]5[CH2:24][CH2:23][N:22]([CH3:30])[CH:21]([CH3:25])[CH2:20]5)[C:16]([F:18])=[CH:17][C:10]4=[CH:9][C:8]=3[C:7](=[O:26])[C:6]([C:27]([OH:29])=[O:28])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CC1CN(c2cc3nc4c(cc3cc2F)c(=O)c(C(=O)O)cn4C2CC2)CCN1
Reactant: C=O
Solvent: O=CO
Product: CC1CN(c2cc3nc4c(cc3cc2F)c(=O)c(C(=O)O)cn4C2CC2)CCN1C

Procedure:
1-Cyclopropyl-8-(3,4-dimethyl-1-piperazinyl)- 7-fluoro-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid is prepared under the conditions of Reference Example 21 but starting from 1.9 g of 1-cyclopropyl-7-fluoro-8-(3-methyl-1-piperazinyl)-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid, 1.38 cm3 of formic acid and 3.30 cm3 of a 30% aqueous solution of formaldehyde. After recrystallizing crude product from 50 cm3 of ethanol, 1.3 g of 1the cyclopropyl-8-(3,4-dimethyl-1-piperazinyl)-7-fluoro-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid are obtained in the form of a yellow solid melting at 219° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10](Cl)=[O:11])=[CH:9][C:4]=2[CH:3]=[CH:2]1.[CH3:13][NH:14][O:15][CH3:16].Cl.C(N(CC)CC)C>C(Cl)Cl>[CH3:16][O:15][N:14]([CH3:13])[C:10]([C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH:2]=[CH:3][C:4]=2[CH:9]=1)=[O:11]
Reactant: O=C(Cl)c1ccc2occc2c1
Reactant: CNOC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1ccc2occc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Benzofuran-5-carbonyl chloride (1 g, 5.54 mmol) in dry DCM (40 ml) is treated with N,O-dimethylhydroxylamine.HCl (0.594 g, 6.09 mmol) followed by triethylamine (1.930 ml, 13.84 mmol). After stirring at RT overnight, the mixture is diluted with DCM and washed with H2O, 1M HCl, 1M NaOH, brine, dried (MgSO4) and evaporated down to give a brown oil which is used without further purification; MS: m/z 206.1 [M+H]+
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]([C:20]1[O:21][C:22]2[CH:28]=[CH:27][C:26]([CH:29]([CH3:31])[CH3:30])=[CH:25][C:23]=2[CH:24]=1)=[O:19].Cl>CN(C)C=O>[CH:29]([C:26]1[CH:27]=[CH:28][C:22]2[O:21][C:20]([C:18](=[O:19])[CH2:17][O:1][C:2]3[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=3)=[CH:24][C:23]=2[CH:25]=1)([CH3:31])[CH3:30]
Reactant: O=Cc1ccc(O)cc1
Reactant: CC(C)c1ccc2oc(C(=O)CBr)cc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)c1ccc2oc(C(=O)COc3ccc(C=O)cc3)cc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.2 %

Procedure:
p-Hydroxybenzaldehyde (12.2 g) was dissolved in 200 ml of N,N-dimethylformamide, 13.8 g of anhydrous potassium carbonate was added and, with stirring at room temperature, 28.1 g of 2-bromoacetyl-5-isopropylbenzofuran was added thereto within 30 minutes. The mixture was stirred at room temperature for 2 hours more. The reaction mixture was poured into aqueous solution of hydrochloric acid and the resulting crystals were collected by filtration and washed with water. The crystals were then dissolved in ethyl acetate, the solution was washed with water and the ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated in vacuo whereupon the residue was crystallized. Ether was added to the crystals and then collected by filtraton to give 18.1 g of crystals.
Reaction SMILES: CS(O[C@@H:6]1[C@@H:11]([CH3:12])[CH2:10][N:9]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[N:19]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:8][C@H:7]1[NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])(=O)=O.[N-:42]=[N+:43]=[N-:44].[Na+]>CN(C=O)C>[N:42]([C@H:6]1[C@@H:11]([CH3:12])[CH2:10][N:9]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[N:19]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:27](=[O:28])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:8][C@H:7]1[NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[N+:43]=[N-:44]
Reactant: [N-]=[N+]=[N-]
Reactant: C[C@H]1CN(c2ccncc2N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1OS(C)(=O)=O
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@H]1CN(c2ccncc2N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 60 %

Procedure:
To a solution of (3R,4R,5S)-1-(3-(bis(tert-butoxycarbonyl)amino)pyridin-4-yl)-3-((tert-butoxycarbonyl)amino)-5-methylpiperidin-4-yl methanesulfonate (1.0 equiv.) in DMF (0.13 M) was added NaN3 (5.0 equiv.). The solution was submerged in an 80° C. oil bath and left stirring under Ar for 24 hrs. The solution was cooled to rt and left stirring under Ar overnight. The solution was partitioned between EtOAc and H2O. The organic layer was washed with Na2CO3(sat), NaCl(sat), dried over MgSO4, filtered, concentrated to yield tert-butyl (4-((3R,4S,5S)-4-azido-3-((tert-butoxycarbonyl)amino)-5-methylpiperidin-1-yl)pyridin-3-yl)(tert-butoxycarbonyl)carbamate in 60% yield. LC/MS (m/z)=548.4 (MH+), Rt=0.94 min. 1H NMR (400 MHz, <cdcl3>) δ ppm 0.97-1.13 (m, 3 H), 1.33-1.52 (m, 30 H), 2.03-2.19 (m, 1 H), 2.66-2.87 (m, 2 H), 3.16 (dd, J=12.72, 2.15 Hz, 1 H), 3.22-3.32 (m, 1 H), 3.81-4.01 (m, 2 H), 4.78 (d, J=9.00 Hz, 1 H), 6.76-6.88 (m, 1 H), 8.05-8.18 (m, 1 H), 8.26-8.37 (m, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C:4]([S:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:22])=[O:21])([CH:6]1[CH2:18][CH2:17][C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([Br:19])[CH:14]=3)[NH:9][C:8]=2[CH2:7]1)[CH3:5].[C:30]([O:34][C:35](=O)[O:36]C(C)(C)C)([CH3:33])([CH3:32])[CH3:31].CCOC(C)=O.C([O-])(O)=O.[Na+]>C1COCC1.CN(C1C=CN=CC=1)C>[C:30]([O:34][C:35]([N:9]1[C:8]2[CH2:7][CH:6]([C:4]([S:20]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)(=[O:22])=[O:21])([C:3]([O:2][CH3:1])=[O:29])[CH3:5])[CH2:18][CH2:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[C:13]([Br:19])[CH:14]=2)=[O:36])([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: COC(=O)C(C)(C1CCc2c([nH]c3ccc(Br)cc23)C1)S(=O)(=O)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)C(C)(C1CCc2c(n(C(=O)OC(C)(C)C)c3ccc(Br)cc23)C1)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.5 %

Procedure:
To 1.2 g (2.52 mmol) of (RS,SR)-2-benzenesulfonyl-2-(6-bromo-2,3,4,9-tetrahydro-1H-carbazol-2-yl)-propionic acid methyl ester (from example 99) in 40 mL of THF were added 31 mg (0.25 mmol, 0.1 eq) of DMAP and 660 mg (3.02 mmol, 1.2 eq) of carbonic acid di-tert-butyl ester at 0° C. The reaction mixture was stirred at RT for 2 hours. EtOAc and a solution of aqueous NaHCO3 were added, the phases were separated, and the organic one was extracted with 1M KHSO4. The organic phases were dried over Na2SO4, filtered and evaporated. Column chromatography afforded 1.3 g (90%) of (RS,SR)-2-(-1-benzenesulfonyl-1-methoxycarbonyl-ethyl)-6-bromo-1,2,3,4-tetrahydro-carbazole-9-carboxylic acid tert-butyl ester as white solid, MS: 575 (M,1Br).
Reaction SMILES: IC.[C:3](=O)([O-])[O-].[K+].[K+].[Br:9][C:10]1[CH:24]=[N:23][C:13]2[NH:14][C:15](=[S:22])[N:16]([CH2:19][CH2:20][CH3:21])[C:17](=[O:18])[C:12]=2[CH:11]=1.C([O-])(O)=O.[Na+]>CN(C)C=O>[Br:9][C:10]1[CH:24]=[N:23][C:13]2[N:14]=[C:15]([S:22][CH3:3])[N:16]([CH2:19][CH2:20][CH3:21])[C:17](=[O:18])[C:12]=2[CH:11]=1
Reactant: O=C([O-])[O-]
Reactant: CCCn1c(=S)[nH]c2ncc(Br)cc2c1=O
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCCn1c(SC)nc2ncc(Br)cc2c1=O
Yield: 75.2 %

Procedure:
A mixture of iodomethane (1.33 g, 0.58 mL), 8.7 g potassium carbonate and 1.88 g of the title compound of Step B was stirred at room temperature in 50 mL of dimethylformamide for 3 h. A 1 mL portion of saturated aqueous NaHCO3 was added and the reaction mixture was concentrated to dryness under reduced pressure. The resulting residue was partitioned between 200 mL each of methylene chloride and water, and the organic layer was removed. Further washing of the organic phase with water and saturated aqueous NaCl followed by drying (Na2SO4) and concentration under reduced pressure delivered 1.8 g of the crude product. This material was then subjected to silica gel chromatography using 70:30 hexane:ethyl acetate as eluant to afford 1.48 g of the title compound of Step C, a compound of the invention, as a white solid melting at 124-127° C. 1H NMR (400 MHz, CDCl3): δ 1.03 (t,3H), 1.76-1.90 (m,2H), 2.7 (s,3H), 4.1 (t,2H), 8.63 (s,1H), 8.89 (s,1H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:12])=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].Cl.[CH3:14][N:15](C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.Cl.CNO>C1COCC1>[NH2:1][C:2]1[C:3]([F:12])=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([NH:15][CH3:14])=[O:8]
Reactant: Nc1cc(C(=O)O)c(F)cc1F
Reactant: CCN=C=NCCCN(C)C
Agent: CNO
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CNC(=O)c1cc(N)c(F)cc1F
Reaction time: 5 h
Yield: 77.6 %

Procedure:
5-amino-2,4-difluoro-benzoic acid (6 g, 34.6 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (13.3 g, 69.3 mmol) and 1-hydroxybenzotriazole (9.3 g, 69.3 mmol) was stirred in THF (100 ml). Diisopropylethylamine (7.2 ml, 41.5 mmol) and methylhydroxyamine hydrochloride (4.3 g, 51.9 mmol) were added thereto, and the solution was stirred for 5 hours. The resulting solution was extracted with ethylacetate and washed with salt solution. The resulting residue was recrystallized with diethylether to obtain the title compound 5 g (yield: 71%).
Reaction SMILES: [ClH:1].Cl.[Cl:3][C:4]1C(C2SC3C=CC=C(C(N)=O)C=3C=2)=NC(NCCC2CCN(C)CC2)=NC=1.[CH:32]1([NH:35][C:36]([C:38]2[C:46]3[CH:45]=[C:44]([C:47]4[C:52]([CH3:53])=[CH:51][N:50]=[C:49]([NH:54][CH2:55][CH2:56][CH2:57][CH:58]5[CH2:63][CH2:62][CH2:61][NH:60][CH2:59]5)[N:48]=4)[S:43][C:42]=3[CH:41]=[CH:40][CH:39]=2)=[O:37])[CH2:34][CH2:33]1>>[ClH:3].[ClH:1].[CH:32]1([NH:35][C:36]([C:38]2[C:46]3[CH:45]=[C:44]([C:47]4[C:52]([CH3:53])=[CH:51][N:50]=[C:49]([NH:54][CH2:55][CH2:56][CH2:57][CH:58]5[CH2:63][CH2:62][CH2:61][N:60]([CH3:4])[CH2:59]5)[N:48]=4)[S:43][C:42]=3[CH:41]=[CH:40][CH:39]=2)=[O:37])[CH2:34][CH2:33]1
Reactant: Cc1cnc(NCCCC2CCCNC2)nc1-c1cc2c(C(=O)NC3CC3)cccc2s1
Reactant: CN1CCC(CCNc2ncc(Cl)c(-c3cc4c(C(N)=O)cccc4s3)n2)CC1
Agent: Cl
Product: Cc1cnc(NCCCC2CCCN(C)C2)nc1-c1cc2c(C(=O)NC3CC3)cccc2s1

Procedure:
Using the method of 2-{5-chloro-2-[2-(1-methylpiperidin-4-yl)-ethylamino]-pyrimidin-4-yl}-benzo[b]thiophene-4-carboxylic acid amide di-hydrochloride, the title compound is synthesized from racemic 2-[5-methyl-2-(3-piperidin-3-yl-propylamino)-pyrimidin-4-yl]-benzo[b]thiophene-4-carboxylic acid cyclopropylamide and isolated as a yellow solid. ES+(m/z) 464 [M(free base)+H].
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH:14]=[C:13]([Br:15])[CH:12]=[CH:11][C:4]=2[S:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].[Cl:16][CH2:17][C:18]#[N:19]>Cl.O1CCOCC1>[NH2:19][C:18](=[N:1][C:2]1[C:3]2[CH:14]=[C:13]([Br:15])[CH:12]=[CH:11][C:4]=2[S:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8])[CH2:17][Cl:16]
Reactant: N#CCCl
Reactant: COC(=O)c1sc2ccc(Br)cc2c1N
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)c1sc2ccc(Br)cc2c1N=C(N)CCl

Procedure:
A suspension of EXAMPLE 1A (7.2 g, 25.16 mmol) in 4N hydrochloric acid in dioxane (70 mL) was treated with 2-chloroacetonitrile (3.18 mL, 50.32 mmol) at ambient temperature for 3 hours. The white solid was collected by filtration and dried to give the title compound as the hydrochloride salt. LCMS (APCI) m/z: 362(M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:27])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]2([CH2:18][O:17][C:16]3[CH:19]=[C:20]4[C:24](=[CH:25][C:15]2=3)[CH2:23][CH2:22][CH2:21]4)[C:7]1=[O:26])C.C(OC(=O)CN1C2C(=CC=CC=2)C2(C3=CC4OCOC=4C=C3OC2)C1=O)C>>[O:26]=[C:7]1[C:8]2([CH2:18][O:17][C:16]3[CH:19]=[C:20]4[C:24](=[CH:25][C:15]2=3)[CH2:23][CH2:22][CH2:21]4)[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:6]1[CH2:5][C:4]([OH:27])=[O:3]
Reactant: CCOC(=O)CN1C(=O)C2(COc3cc4c(cc32)CCC4)c2ccccc21
Agent: CCOC(=O)CN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21
Product: O=C(O)CN1C(=O)C2(COc3cc4c(cc32)CCC4)c2ccccc21
Yield: 74 %

Procedure:
Following the procedure as described in EXAMPLE 2, and making non-critical variations using ethyl(2′-oxo-6,7-dihydro-5H-spiro[indeno[5,6-b]furan-3,3′-indol]-1′(2′H)-yl)acetate to replace ethyl(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetate, the title compound was obtained in 74% yield; MS (ES−) m/z 354 (M−1).
Reaction SMILES: [CH2:1]([N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[C:9]1[S:13][C:12]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH:20][C:21](=[O:23])[CH3:22])[CH:15]=2)=[N:11][C:10]=1Br)[CH:2]=[CH2:3].[Br-].[CH2:26]([Zn+])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O1CCCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH2:1]([N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[C:9]1[S:13][C:12]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH:20][C:21](=[O:23])[CH3:22])[CH:15]=2)=[N:11][C:10]=1[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH:2]=[CH2:3]
Reactant: [Zn+]Cc1ccccc1
Reactant: C=CCn1ccnc1-c1sc(-c2ccnc(NC(C)=O)c2)nc1Br
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Br-]
Solvent: C1CCOC1
Product: C=CCn1ccnc1-c1sc(-c2ccnc(NC(C)=O)c2)nc1Cc1ccccc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 21.3 %

Procedure:
To a solution of N-{4-[5-(1-allyl-1H-imidazol-2-yl)-4-bromo-1,3-thiazol-2-yl]pyridin-2-yl}acetamide (0.0500 g, 0.124 mmol) in tetrahydrofuran (0.86 mL) was added benzylzinc bromide (0.50M solution in tetrahydrofuran, 0.495 mL, 0.247 mmol) and bis(tri-t-butylphosphine)palladium(0) (0.00474 g, 0.00928 mmol) under argon. The solution was stirred at 60° C. for 2 hours then cooled to room temperature. The solvent was evaporated in vacuo. Column chromatography was performed to yield the title compound (0.0110 g, 21%). LCMS: (FA) ES+ , 416. 1H NMR (400 MHz, d4-methanol) δ: 8.70-8.65 (m, 1H), 8.41-8.36 (m, 1H), 7.66-7.61 (m, 1H), 7.34-7.05 (m, 7H), 5.81-5.70 (m, 1H), 5.16-5.10 (m, 1H), 4.95-4.88 (m, 1H), 4.38-4.33 (m, 2H), 4.13 (s, 2H), 2.20 (s, 3H).
Reaction SMILES: OCC[CH:4]1[C:9]2([O:14][CH2:13][CH2:12][CH2:11][O:10]2)[CH2:8][CH2:7][CH2:6][CH2:5]1.[C:15]1(=O)CCCCC1>>[CH2:8]1[C:9]2([O:10][CH2:15][CH:11]=[CH:12][CH2:13][O:14]2)[CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: OCCC1CCCCC12OCCCO2
Reactant: O=C1CCCCC1
Product: C1=CCOC2(CCCCC2)OC1

Procedure:
Described herein is a process for the preparation of 9 (2-hydroxyethyl)-7, 11-dioxaspiro (5,5) undecane by reacting Cis-but-2-2ene-1,4 diol with cyclohexanone in the presence of a heterogeneous sulphonated nitro coal acid catalyst to obtain 7, 12-dioxaspiro (5,6) dodec-9-ene which is reacted with syngas in the presence of a catalyst, namely RhH (CO) (TPP)3, to obtain 9-formyl-7, 12-dioxaspiro (5,6) dodecane which is reduced and the reduced product is rearranged to yield 9-(2-hydroxyethyl)-7,11-dioxaspiro [5,5] undecane.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:9])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.C(=O)([O-])O.[Na+].O.[CH3:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([CH3:28])[C:25]=1[O:26][CH3:27])[C:20](Cl)=[O:21]>C(OCC)(=O)C>[Cl:8][C:5]1[N:4]=[C:3]([Cl:9])[C:2]([NH:1][C:20](=[O:21])[C:19]2[CH:23]=[C:24]([CH3:28])[C:25]([O:26][CH3:27])=[C:17]([CH3:16])[CH:18]=2)=[CH:7][N:6]=1
Reactant: Nc1cnc(Cl)nc1Cl
Reactant: COc1c(C)cc(C(=O)Cl)cc1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COc1c(C)cc(C(=O)Nc2cnc(Cl)nc2Cl)cc1C
Yield: 43 %

Procedure:
A solution of 3.2 g of 5-amino-2,4-dichloro-pyrimidine in 50 ml of ethyl acetate was added to a mixture of 25 ml of a saturated aqueous solution of sodium hydrogencarbonate and 25 ml of water. Then a solution of 4.9 g of 3,5-dimethyl-4-methoxybenzoyl chloride was added at room temperature over a period of 15 min. The mixture was mixed intensively for 4 h. Then the layers were separated and the aqueous layer was extracted twice with ethyl acetate. After drying over sodium sulfate and filtration the solvent was removed in vacuo to give 7.54 g of raw product. The raw product was triturated with 25 ml of isopropanol. After filtration and washing with 10 ml of isopropanol, 2.74 g of the title compound were obtained as a white solid.
Reaction SMILES: [NH3:1].[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:3]=1.[Cl-].[NH4+]>C(OCC)(=O)C>[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8]([NH2:1])(=[O:10])=[O:9])[CH:3]=1
Reactant: N
Reactant: O=S(=O)(Cl)c1cccnc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: NS(=O)(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
A 25% aqueous ammonia solution (2 mL) was added to pyridine-3-sulfonyl chloride (300 mg, 1.7 mmol) and the mixture was stirred at room temperature for 2 hours. Then, a saturated aqueous ammonium chloride solution was added to the reaction mixture, and extraction with ethyl acetate was performed, followed by washing with brine and drying over anhydrous magnesium sulfate. The solvent was evaporated off under reduced pressure and thereby Compound FA (154 mg, yield: 58%) was obtained.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH3:10])[CH:3]=1.[CH3:11][S-:12].[Na+]>CN(C=O)C.C(OCC)(=O)C>[CH3:10][C:4]1[CH:3]=[C:2]([S:12][CH3:11])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: Cc1cc(Br)ccc1C#N
Reactant: C[S-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CSc1ccc(C#N)c(C)c1

Procedure:
A solution of 500 mg of 4-bromo-2-methylbenzonitrile and 268 mg of sodium thiomethoxide in 3 mL of DMF was stirred for 1 h. The reaction mixture was diluted with ethyl acetate, washed with H2O, dried (MgSO4) and evaporated to afford 2-methyl-4-(methylthio)benzonitrile. 400 mg of 2-methyl-4-(methylthio)benzonitrile was reacted via Procedure T to give 2-methyl-4-(methylthio)benzoic acid. 430 mg of 2-methyl-4-(methylthio)benzoic acid was reacted via Procedure R to yield 2-methyl-4-(methylsulfonyl)benzoic acid. 60 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 2-methyl-4-(methylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methyl-4-(methylsulfonyl)benzamide. MS (Q1) 401.0 (M)+.
Reaction SMILES: [CH3:1][C@@:2]12[CH2:9][CH2:8][CH2:7][N:6]1[C@@H:5]([C:10]([Cl:13])([Cl:12])[Cl:11])[O:4][C:3]2=[O:14].C(NC(C)C)(C)C.ClC(Cl)(Cl)[C@H]1OC(=O)[C@H]2N1CCC2.C(Br)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[CH2:1]([C@@:2]12[CH2:9][CH2:8][CH2:7][N:6]1[C@@H:5]([C:10]([Cl:13])([Cl:12])[Cl:11])[O:4][C:3]2=[O:14])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: C[C@@]12CCCN1[C@@H](C(Cl)(Cl)Cl)OC2=O
Reactant: BrCc1ccccc1
Agent: O=C1O[C@H](C(Cl)(Cl)Cl)N2CCC[C@@H]12
Solvent: CC(C)NC(C)C
Product: O=C1O[C@H](C(Cl)(Cl)Cl)N2CCC[C@@]12Cc1ccccc1
Yield: 21.6 %

Procedure:
(Wang et al. Synlett 1999, 1, 33). The reaction was carried out following a similar procedure to that described for the preparation of oxazolidinone 8 using n-butyllithium (1.31 M, 5.53 cm3, 7.2 mmol), diisopropylamine (1.01 cm3, 7.24 mmol), oxazolidinone 7 (1.18 g, 4.8 mmol) and benzyl bromide (1.72 cm3, 14.5 mmol) to afford oxazolidinone 11 (0.52 g, 32%) as a colourless crystalline solid: mp 75-77° C. (lit. Wang 72-77): δH (400 MHz; CDCl3) 1.32-1.55 (2H, m, Proγ-H2), 1.93-2.13 (2H, m, Proβ-H2), 2.58-2.65 (1H, m, Proδ-H2), 2.92 (1H, d, J 13.6, PhCHAHB), 2.98-3.03 (1H, m, Proδ-H2), 3.32 (1H, d, J 13.6, PhCHAHB), 4.99 (1H, s, NCH) and 7.21-7.35 (5H, m, PhH); δC (100 MHz; CDCl3) 24.8 (CH2, Proγ-C), 34.6 (CH2, Proβ-C), 41.6 (CH2, Proδ-C), 58.4 (CH2, PhCH2), 72.3 (quat., Proα-C), 100.6 (quat., CCl3), 102.8 (CH, NCH), 127.0 (CH, Ph), 128.2 (CH, Ph), 130.9 (CH, Ph), 135.5 (quat., Ph) and 176.6 (quat., C═O); m/z (EI+) 333.0081 [(M+H)+.C14H1435Cl3NO2 requires 333.0090], 335.0069 [(M+H)+.C14H1435Cl237ClNO2 requires 335.0061], 337.0014 [(M+H)+.C14H1435Cl37Cl2NO2 requires 337.0031] and 339.0009 [(M+H)+.C14H1437Cl3NO2 requires 339.0002].
Reaction SMILES: [C:1]1([N:7]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:8]([C:10]2[CH:29]=[CH:28][C:13]3[N:14]([CH3:27])[C:15]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:37].C(O)C.C(=O)([O-])[O-].[NH4+:45].[NH4+]>ClCCl.C(O)C>[ClH:37].[C:1]1([N:7]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:8]([C:10]2[CH:29]=[CH:28][C:13]3[N:14]([CH3:27])[C:15]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][C:22]([C:25](=[NH:45])[NH2:26])=[CH:21][CH:20]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CCc1ccc(C#N)cc1)n2C)c1ccccc1
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CCc1ccc(C(=N)N)cc1)n2C)c1ccccc1
Yield: 86 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[2-(4-cyanophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 86% of theory, C29H31N5O3 (497.6) Rf value: 0.11 (silica gel; dichloromethane/ethanol=4:1) ##EQU40##