Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:11]/[O:12][CH3:13])/[C:8]([OH:10])=O)[N:6]=1.C(N(CC)C(C)C)(C)C.CS(Cl)(=O)=O.[NH2:28][C@@H:29]1[C:57](=[O:58])[N:31]2[C:32]([C:45]([O:47][CH2:48][C:49]3[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][CH:50]=3)=[O:46])=[C:33]([C@@H:36]3[CH2:40][CH2:39][C@H:38]([C:41]([O:43][CH3:44])=[O:42])[O:37]3)[CH2:34][S:35][C@H:30]12>CN(C)C=O.N1C=CC=CC=1>[CH3:44][O:43][C:41]([C@@H:38]1[O:37][C@H:36]([C:33]2[CH2:34][S:35][C@@H:30]3[C@H:29]([NH:28][C:8](=[O:10])/[C:7](/[C:5]4[N:6]=[C:2]([NH2:1])[S:3][CH:4]=4)=[N:11]\[O:12][CH3:13])[C:57](=[O:58])[N:31]3[C:32]=2[C:45]([O:47][CH2:48][C:49]2[CH:50]=[CH:51][C:52]([O:55][CH3:56])=[CH:53][CH:54]=2)=[O:46])[CH2:40][CH2:39]1)=[O:42]
Reactant: COC(=O)[C@H]1CC[C@@H](C2=C(C(=O)OCc3ccc(OC)cc3)N3C(=O)[C@@H](N)[C@H]3SC2)O1
Reactant: CO/N=C(\C(=O)O)c1csc(N)n1
Agent: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OCc3ccc(OC)cc3)=C([C@@H]3CC[C@H](C(=O)OC)O3)CS[C@H]12)c1csc(N)n1
Reaction time: 0.5 h
Yield: 53.7 %

Procedure:
A stirred solution of 2-(2-aminothiazol-4-yl)-2-(Z)-methoxyiminoacetic acid (20.1mg) and N,N-diisopropylethylamine (0.0176ml) in dimethylformamide (0.3ml) was cooled to -55 to -60° C. and methanesulphonyl chloride (0.0081ml) was added. The mixture was stirred at the same temperature for 0.5h and then a solution of 4-methoxybenzyl (6R,7R)-7-amino-3-[(2S,5R)-5-methoxycarbonyltetrahydrofuran-2-yl]ceph-3-em-4-carboxylate (41mg) in dimethylformamide (0.3ml) was added followed by pyridine (0.0073ml). The mixture was then stored at 0° C. for 1h and then at room temperature for 0.5h. The reaction mixture was partitioned between ethyl acetate and aqueous citric acid solution and the organic phase washed with water and brine. The solution was dried over magnesium sulphate and evaporated, and the title compound (31mg) isolated by column chromatography of the residue (silica gel, ethyl acetate as eluent); vmax (CHCl3) 3496, 3397, 1784, 1733 and 1684cm-1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]([C:12](Cl)=[O:13])[CH2:7][C:6]=2[CH:15]=1.[F:16][C:17]([F:32])([F:31])[C:18]1[CH:19]=[C:20]([C:24]2([OH:30])[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:21]=[CH:22][CH:23]=1.C(N(C(C)C)CC)(C)C>ClCCl.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]([C:12]([N:27]3[CH2:26][CH2:25][C:24]([C:20]4[CH:21]=[CH:22][CH:23]=[C:18]([C:17]([F:16])([F:31])[F:32])[CH:19]=4)([OH:30])[CH2:29][CH2:28]3)=[O:13])[CH2:7][C:6]=2[CH:15]=1
Reactant: OC1(c2cccc(C(F)(F)F)c2)CCNCC1
Reactant: O=C(Cl)N1CCOc2ccc(Br)cc2C1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N1CCC(O)(c2cccc(C(F)(F)F)c2)CC1)N1CCOc2ccc(Br)cc2C1
Yield: 99.8 %

Procedure:
A solution of 7-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carbonyl chloride (example 2) (0.400 g, 1.38 mmol), 4-(3-(trifluoromethyl)phenyl)piperidin-4-ol (0.371 g, 1.51 mmol), and diisopropylethylamine (0.535 g, 4.14 mmol) in dichloromethane (3 mL) was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate (50 mL), washed with 10% citric acid (20 mL) and brine (20 mL). The organic layer was dried over sodium sulfate. Filtration and concentration afforded 1-[(7-bromo-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl)carbonyl]-4-[3-(trifluoromethyl)phenyl]piperidin-4-ol (0.688 g, 100%) as a white solid that was used without further purification. MS (EI) for C22H22BrF3N2O3: 500 (MH+).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[C:7]([C:9]2[CH:10]=[N:11][C:12]([C@@H:15]([NH2:17])[CH3:16])=[CH:13][CH:14]=2)[CH:6]=[CH:5][N:4]=1.[F:20][C@H:21]([C@H:23]1[CH2:27][O:26][C:25](=[O:28])[N:24]1[C:29]1[CH:34]=[CH:33][N:32]=[C:31](F)[N:30]=1)[CH3:22].CCN(C(C)C)C(C)C>CS(C)=O>[F:20][C@H:21]([C@H:23]1[CH2:27][O:26][C:25](=[O:28])[N:24]1[C:29]1[CH:34]=[CH:33][N:32]=[C:31]([NH:17][C@H:15]([C:12]2[N:11]=[CH:10][C:9]([C:7]3[CH:6]=[CH:5][N:4]=[C:3]([C:2]([F:1])([F:18])[F:19])[CH:8]=3)=[CH:14][CH:13]=2)[CH3:16])[N:30]=1)[CH3:22]
Reactant: C[C@H](N)c1ccc(-c2ccnc(C(F)(F)F)c2)cn1
Reactant: C[C@H](F)[C@H]1COC(=O)N1c1ccnc(F)n1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1nccc(N2C(=O)OC[C@@H]2[C@H](C)F)n1)c1ccc(-c2ccnc(C(F)(F)F)c2)cn1
Temperature: 25 °C
Yield: 67.2 %

Procedure:
A solution of (S)-1-(2′-(trifluoromethyl)-[3,4′-bipyridin]-6-yl)ethanamine (27 mg, 0.10 mmol), (R)-4-((S)-1-fluoroethyl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one (23 mg, 0.10 mmol) and DIPEA (52.4 μl, 0.30 mmol) in DMSO (500 μl) was heated at 110° C. for 1 hr. The solution was then cooled to rt and RP-HPLC purification (acetonitrile:water) provided the 32 mg of the major product as a white solid. 1H NMR (400 MHz, MeOD) δ 8.98 (s, 1H), 8.79 (d, J=5.1 Hz, 1H), 8.23 (dd, J=8.2, 2.4 Hz, 1H), 8.17 (br s, 1H), 8.17-8.12 (m, 1H), 7.98 (dd, J=5.1, 1.7 Hz, 1H), 7.59 (d, J=8.3 Hz, 1H), 7.40 (d, J=5.8 Hz, 1H), 5.11 (br s, 1H), 4.69 (br d, J=27.2 Hz, 1H), 4.55-4.12 (m, 3H), 1.60 (d, J=7.1 Hz, 3H), 1.03 (br s, 3H); HRMS (B) m/z 477.1699 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][CH:7]=[CH:8][C:9]=1[CH3:10])=[O:4].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[H-].[Na+].[Cl-].[NH4+]>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:8][C:9]=1[CH3:10])=[O:4]
Reactant: COC(=O)c1[nH]ccc1C
Reactant: BrCc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COC(=O)c1c(C)ccn1Cc1ccccc1
Temperature: 0 °C

Procedure:
To an ice/water-bath cooled solution of 3-methyl-1H-pyrrole-2-carboxylic acid methyl ester (1.196 g, prepared according to the literature: W. G. Terry, G. W. Kenner, and G. Kornis J. Chem. Soc. 1965, 4389-4393) and benzyl bromide (1.15 mL) in N,N-dimethylformamide (17 mL) was carefully added NaH (413 mg, 60% purity in mineral oil) under nitrogen. The mixture was stirred in the ice bath for 25 min and then quenched saturated ammonium chloride solution (5 mL). It was extracted with EtOAc, and the organic phase was washed with water and saturated NaCl solution, dried over anhydrous sodium sulfate, filtered and concentrated. The crude residue was column-purified to give the title compound (1.536 g) as white solid. 1H NMR (200 MHz, CDCl3) δ=7.32-6.98 (m, 5H), 6.75 (d, 1H, J=2.5 Hz), 6.02 (d, 1H, J=2.5 Hz), 5.48 (s, 2H), 3.75 (s, 3H), 2.33 (s, 3H).
Reaction SMILES: CN(C)C=O.[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[OH:18])[N:14]=[CH:13][CH:12]=[C:11]2[O:19][C:20]1[C:21]([CH3:30])=[N:22][C:23]2[C:28]([CH:29]=1)=[CH:27][CH:26]=[CH:25][CH:24]=2.C(=O)([O-])[O-].[K+].[K+].[CH2:37]([C@H:39]1[O:41][CH2:40]1)Cl>O>[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH2:37][C@@H:39]1[CH2:40][O:41]1)[N:14]=[CH:13][CH:12]=[C:11]2[O:19][C:20]1[C:21]([CH3:30])=[N:22][C:23]2[C:28]([CH:29]=1)=[CH:27][CH:26]=[CH:25][CH:24]=2
Reactant: ClC[C@@H]1CO1
Reactant: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OC[C@@H]1CO1
Temperature: 90 °C
Reaction time: 8 h
Yield: 56.5 %

Procedure:
N,N-Dimethylformamide (2 ml) was added to 6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-7-ol (compound 352) (50 mg), potassium carbonate (62 mg), and (S)-epichlorohydrin (42 mg), and the mixture was stirred at 90° C. overnight. The reaction solution was cooled to room temperature, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using hexane-acetone to give (S)-6-methoxy-4-(2-methyl-quinolin-3-yloxy)-7-oxiranylmethoxy-quinoline (33 mg, yield 54%).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[NH:7][C:6](=O)[C:5]=1[N+:14]([O-:16])=[O:15])[CH3:2].O=P(Cl)(Cl)[Cl:19]>>[Cl:19][C:6]1[C:5]([N+:14]([O-:16])=[O:15])=[C:4]([NH:3][CH2:1][CH3:2])[CH:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCNc1cc(C(C)C)[nH]c(=O)c1[N+](=O)[O-]
Product: CCNc1cc(C(C)C)nc(Cl)c1[N+](=O)[O-]

Procedure:
A mixture of 4-ethylamino-6-isopropyl-3-nitro-1H-pyridin-2-one (520 mg, 2.31 mmol) in POCl3 is stirred at reflux for 1.5 h. After cooling, the solution is concentrated in vacuo. The reaction flask is then placed in an ice bath and crushed ice is added to the residue. The mixture is swirled vigorously for a few minutes and then stirred at 0° C. for 1 h. The mixture is then extracted with EtOAc. The extract is washed with additional H2O (20 mL) and brine (20 mL). The extract is dried over Na2SO4 and concentrated to afford (2-chloro-6-isopropyl-3-nitro-pyridin-4-yl)-ethyl-amine as a yellow solid. The material is sufficiently pure to be used without further purification. 1H NMR (CDCl2, 400 MHz) δ 6.62 (br, 1H), 6.44 (s, 1H), 3.31 (m, 2H), 2.91 (sept, J=6.8 Hz, 1H), 1.33 (t, J=7.4 Hz, 3H), 1.26 (d, J=6.8 Hz, 6H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[S-:11][C:12]#[N:13].[K+]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:13]=[C:12]=[S:11])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: N#C[S-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C(N=C=S)c1ccc(F)cc1
Yield: 96.3 %

Procedure:
A mixture o 4-fluorobenzoyl chloride (50 g), potassium thiocyanate (36.7 g) and anhydrous toluene (100 ml) is refluxed for six hours. After cooling, the reaction mixture is filtered, and the filtrate is concentrated under reduced pressure. The residue is purified by distillation under reduced pressure to give 4-fluorobenzoyl isothiocyanate (55 g), b.p. 92° C/3 mmHg.
Reaction SMILES: [NH2:1][C@@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20]([OH:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1>C(O)C>[C:14]1([CH3:24])[CH:15]=[CH:16][C:17]([S:20]([OH:23])(=[O:21])=[O:22])=[CH:18][CH:19]=1.[CH2:14]([O:11][C:10](=[O:12])[C@@H:2]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[NH2:1])[CH3:15]
Reactant: N[C@H](Cc1ccccc1)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: O
Product: CCOC(=O)[C@H](N)Cc1ccccc1
Temperature: 25 °C
Yield: 88.5 %

Procedure:
A mixture of D-phenylalanine (5.0 g, 30 mmol) and p-toluenesulfonic acid monohydrate (12.7 g, 67 mmol) in 150 mL of anhydrous ethanol was refluxed for 24 hours. After cooling to room temperature, the solvent was removed by rotary evaporator, the residue triturated with diethyl ether, filtered and dried in vacuo over P2O5 to give the p-toluenesulfonate salt of the title compound (9.7 g) as a white solid and the structure verified by NMR.
Reaction SMILES: [C:1]1([C:6]([OH:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH:2]=1.[Br:9]Br.Br>O>[Br:9][C:1]1([C:6]([OH:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C1=CCCC1
Reactant: BrBr
Agent: Br
Solvent: O
Product: O=C(O)C1(Br)CCCC1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
20 g (0.176 mol) of cyclopentaencarboxylic acid are mixed with red phosphorus (2.5 g). 17.9 ml (0.352 mol) of bromine are added dropwise thereto over the course of 2 hours; thereupon, a vigorous reaction is observed, with liberation of hydrogen bromide. The reaction contents are then stirred for 3 hours at 60°C. The oil, which shows a heavy dark coloration, is cooled and poured into water and the resulting reaction mixture is extracted three times with ether. The collected ether phases are washed with water and dried. After distilling off the ether, the oily residue is distilled in a high vacuum.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15]O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.CS(Cl)(=O)=O.[F:29][C:30]1[C:39]([F:40])=[CH:38][C:33]2[N:34]=[C:35]([SH:37])[NH:36][C:32]=2[CH:31]=1.C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>C1COCC1.CN(C)C1C=CN=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][S:37][C:35]2[NH:36][C:32]3[CH:31]=[C:30]([F:29])[C:39]([F:40])=[CH:38][C:33]=3[N:34]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(CCO)CC1
Reactant: Fc1cc2nc(S)[nH]c2cc1F
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(CCSc2nc3cc(F)c(F)cc3[nH]2)CC1
Yield: 67.8 %

Procedure:
To a solution of 1-tert-butoxycarbonyl-4-(2-hydroxyethyl)piperazine (7.40 g, 32.13 mmol) in THF (100 mL), triethylamine (4.36 g, 43.09 mmol), 4-dimethylaminopyridine (200 mg, 1.64 mmol) and methanesulfonyl chloride (7.40 g, 38.76 mmol) were successively added under ice cooling and stirring. The temperature of the reaction mixture was allowed to rise to room temperature, at which the reaction mixture was stirred for 50 minutes. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in DMF (200 mL). At room temperature, 5,6-difluoro-2-mercaptobenzimidazole (5.00 g, 26.86 mmol), potassium carbonate (8.64 g, 62.51 mmol) and 18-crown-6 (500 mg, 1.92 mmol) were successively added, followed by stirring at 80° C. for 90 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (silica gel: 200 g; developer: hexane:acetone=8:1→1:1). Crystallization was conducted from acetone-ethyl ether-hexane to obtain the title compound (7.26 g, yield: 68%) as colorless crystals.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[S:3]([NH2:6])(=[O:5])=[O:4].[OH-].[Na+].[F:11][C:12](=[C:17]([F:19])[F:18])[CH2:13][C:14](Cl)=[O:15]>>[F:11][C:12](=[C:17]([F:19])[F:18])[CH2:13][C:14]([NH:6][S:3]([C:2]([F:8])([F:7])[F:1])(=[O:5])=[O:4])=[O:15]
Reactant: O=C(Cl)CC(F)=C(F)F
Reactant: NS(=O)(=O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Product: O=C(CC(F)=C(F)F)NS(=O)(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.03 h
Yield: 16.4 %

Procedure:
To an ice-cooled solution of trifluoromethanesulfonamide (2.75 g, 18.4 mmol) in 7.4 ml, of 2.5N sodium hydroxide was added 3,4,4-trifluoro-3-butenoyl chloride (2.93 g, 18.5 mmol) with stirring in 2 min. The mixture was stirred in cold for 30 min and the white precipitate formed was filtered, washed with cold water (10 mL) and dried to give 0.82 g (16%) of the desired product as a white solid. m.p. 115°-120° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].[CH2:9]([C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1)[CH3:10]>>[CH2:9]([C:11]1[CH:17]=[CH:16][C:14]([NH:15][C:1]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=2)=[NH:2])=[CH:13][CH:12]=1)[CH3:10]
Reactant: N#Cc1ccccn1
Reactant: CCc1ccc(N)cc1
Product: CCc1ccc(NC(=N)c2ccccn2)cc1
Yield: 71 %

Procedure:
The title compound was prepared from 2-cyanopyridine (8.5 g, 82 mmol) and 4-ethylaniline (10 g, 82 mmol) by following the procedure described in preparation 10 (13.22 g, yield 71%, mp 75-77 C, purity 99.9% by HPLC). 1H-NMR (CDCl3):δ 1.22-1.26 (t, 3H), 2.61-2.66 (q, 2H), 6.93-6.95 (d, 2H), 7.18-7.25 (m, 2H), 7.36-7.39 (m, 1H), 7.78-7.82 (m, 1H), 8.40-8.42 (d, 1H), 8.56-8.57 (d, 1H). MS m/z: 227.3 (M+).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[C:4](=[CH:8][C:9]2[CH:27]=[CH:26][C:12]([O:13][C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=3[C:22]([F:25])([F:24])[F:23])=[C:11]([O:28][CH3:29])[CH:10]=2)[S:3]1.Cl[CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.C([O-])([O-])=O.[K+].[K+].[Al]>CN(C=O)C>[CH3:29][O:28][C:11]1[CH:10]=[C:9]([CH:8]=[C:4]2[S:3][C:2](=[O:1])[N:6]([CH2:31][CH2:32][N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[C:5]2=[O:7])[CH:27]=[CH:26][C:12]=1[O:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=1[C:22]([F:23])([F:24])[F:25]
Reactant: COc1cc(C=C2SC(=O)NC2=O)ccc1Oc1ccc(C#N)cc1C(F)(F)F
Reactant: ClCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Al]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(C=C2SC(=O)N(CCN3CCOCC3)C2=O)ccc1Oc1ccc(C#N)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 4-[4-(2,4-Dioxo-thiazolidin-5-ylidenemethyl)-2-methoxy-phenoxy]-3-trifluoromethyl-benzonitrile (40 mg, 0.095 mmol) and 4-(2-Chloro-ethyl)-morpholine (0.095 mmol) in DMF (1.5 mL) was treated with K2CO3 (33 mg, 0.24 mmol) and heated to 80° C. in an aluminum heating block. After 12 h, the reaction was cooled to RT and partitioned between EtOAc (5 mL) and H2O (5 mL). The organic phase was washed with H2O (2×5 mL), dried over Na2SO4 and concentrated in vacuo. Silica gel chromatography (MeOH/CH2Cl2) afforded the title compound. 1H NMR (400 Hz, CDCl3) δ 7.97 (d, 1H), 7.87 (s, 1H), 7.68 (dd, 1H), 7.19 (m, 3H), 6.76 (d, 1H), 3.90 (t, 2H), 3.82 (s, 3H), 3.67 (bs, 4H), 2.64 (t, 2H), 2.51 (bs, 4H); LC/MS (m/z) [M+1]+ 534.2 (calculated for C25H23F3N3O5S, 534.12).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([F:15])[CH:14]=1)[C:8]([O:10]C)=[O:9])[CH3:3].O.[OH-].[Li+]>O1CCCC1.O>[CH3:3][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([F:15])[CH:14]=1)[C:8]([OH:10])=[O:9])[CH3:1]
Reactant: COC(=O)c1cc(F)cc(CN(C)C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)Cc1cc(F)cc(C(=O)O)c1
Reaction time: 3 h
Yield: 58.7 %

Procedure:
Methyl 3-[(dimethylamino)methyl]-5-fluorobenzoate (0.040 g, 0.19 mmol from Step 3) was dissolved in tetrahydrofuran (3 mL) and lithium hydroxide monohydrate (0.0954 g, 2.27 mmol) dissolved in water (1 mL) was added. The reaction was stirred for 3 hours. The crude reaction mixture was purified by preparative HPLC-MS (C18, eluting with a gradient of H2O/MeCN containing 0.15% NH4OH). The eluent containing the desired mass was evaporated using rotary evaporation to afford product (22 mg, 59%), which was used directly in Step 5. LCMS (M+H)+: 198.1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][S:16]([OH:19])(=O)=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:23])=O>CN(C)C=O.O1CCCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][S:16]([Cl:23])(=[O:19])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(O)Cc1ccccc1OCc1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=S(=O)(Cl)Cc1ccccc1OCc1ccccc1
Reaction time: 3 h
Yield: 77.5 %

Procedure:
Tetrahydrofuran (10 ml), (2-Benzyloxy-phenyl)-methanesulfonic acid (138 mg), and N,N-dimethylformamide (2 drops) was cooled to −78° C. and oxalyl chloride (315 mg) was added slowly. The reaction mixture was stirred for 3 h from −78° C. to 0° C. The reaction mixture was clarified by filtration. The filtrate was washed with iced-water and heptane, and dried to give (2-benzyloxy-phenyl)-methanesulfonyl chloride (114 mg, 77%). 1H NMR (400 MHz, CDCl3): δ 5.06 (s, 2 H) 5.15 (s, 2 H) 7.04 (m, 2 H) 7.42 (m, 7 H).
Reaction SMILES: [O:1]=[S:2]1(=[O:15])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]2[CH2:12][CH2:13][CH2:14][C:4]2=[N:3]1>C1(C)C=CC=CC=1>[O:15]=[S:2]1(=[O:1])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]2[CH2:12][CH2:13][CH2:14][C@@H:4]2[NH:3]1
Reactant: O=S1(=O)N=C2CCCN2c2ccccc21
Solvent: Cc1ccccc1
Product: O=S1(=O)N[C@H]2CCCN2c2ccccc21
Temperature: 50 °C

Procedure:
To 40 g of 5,5-dioxo-2,3-dihydro-1H-pyrrolo[2,1-c][1,2,4]benzothiadiazine dissolved in 450 ml of toluene previously degassed using nitrogen there are added 90.5 mg of catalyst (R)-BINAP RuCl2 (R,R)-DPEN of formula (III) and then a solution, previously heated to 50° C., of potassium tert-butoxide (20.2 g) in isopropanol (150 ml).
Reaction SMILES: CS([C:4]1[N:9]=[C:8]([C:10]2[N:14]3[CH:15]=[CH:16][CH:17]=[C:18]([C:19]([OH:22])([CH3:21])[CH3:20])[C:13]3=[N:12][CH:11]=2)[CH:7]=[CH:6][N:5]=1)=O.[CH3:23][S:24]([CH2:27][CH:28]1[CH2:33][CH2:32][CH:31]([NH2:34])[CH2:30][CH2:29]1)(=[O:26])=[O:25]>CN1C(=O)CCC1.O>[CH3:23][S:24]([CH2:27][CH:28]1[CH2:33][CH2:32][CH:31]([NH:34][C:4]2[N:9]=[C:8]([C:10]3[N:14]4[CH:15]=[CH:16][CH:17]=[C:18]([C:19]([OH:22])([CH3:20])[CH3:21])[C:13]4=[N:12][CH:11]=3)[CH:7]=[CH:6][N:5]=2)[CH2:30][CH2:29]1)(=[O:25])=[O:26]
Reactant: CS(=O)c1nccc(-c2cnc3c(C(C)(C)O)cccn23)n1
Reactant: CS(=O)(=O)CC1CCC(N)CC1
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)(O)c1cccn2c(-c3ccnc(NC4CCC(CS(C)(=O)=O)CC4)n3)cnc12
Temperature: 100 °C
Reaction time: 8 h
Yield: 52.8 %

Procedure:
A mixture of 2-[3-(2-methylsulfinyl-pyrimidin-4-yl)-imidazo[1,2-a]pyridin-8-yl]-propan-2-ol (75 mg), 4-methanesulfonylmethyl-cyclohexylamine (162 mg), and TEA (0.165 mL) in NMP (2 mL) was stirred at 100° C. overnight. The reaction mixture was then cooled to RT, and diluted with water. The resulting precipitate was filtered and dried, then purified by ISCO using 100% DCM to 10% MeOH/DCM. The fractions were collected, concentrated, and titurated with EtOAc. The resulting solid was filtered and dried at 50° C. under vacuum overnight to provide 2-{3-[2-(4-methanesulfonylmethyl-cyclohexylamino)-pyrimidin-4-yl]-imidazo[1,2-a]pyridin-8-yl}-propan-2-ol (Compound 1, 55.5 mg). Mp=223-224° C.
Reaction SMILES: [Mg].Cl[CH:3]1[CH2:7][CH2:6][CH:5]=[CH:4]1.[CH:8](=[O:14])[C:9]1[O:13][CH:12]=[CH:11][CH:10]=1.[Cl-].[NH4+]>O1CCCC1>[C:5]1([C:9]2([CH2:8][OH:14])[CH2:10][CH:11]=[CH:12][O:13]2)[CH2:6][CH2:7][CH2:3][CH:4]=1
Reactant: ClC1C=CCC1
Reactant: O=Cc1ccco1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OCC1(C2=CCCC2)CC=CO1
Temperature: 20 °C
Reaction time: 2 h
Yield: 73.8 %

Procedure:
Magnesium (36 g, 1.5 mole) and tetrahydrofuran (THF) (300 ml) were added to a reactor, and a solution of 3-chloro-1-cyclopentene (184.5 g, 1.8 mole) in THF (200 ml) was added dropwise at 0° to 10° C. to prepare a Grignard reagent. Thereafter, to this THF solution of the Grignard reagent was added dropwise a solution of furfural (106 g, 1.1 mole) in THF (150 ml) at 0° to 10° C. over about 1 hour, followed by stirring at 20° C. for further 2 hours. After completion of the reaction, the reaction solution was poured into an aqueous ammonium chloride solution (about 1 liter), followed by extraction with ether. The extract was washed with water, dried and concentrated. The residue obtained was distilled under reduced pressure to obtain 135 g (yield, 75%) of pure 2-cyclopentenyl-2-furyl methanol having a boiling point of 80°-86° C./3 mmHg.
Reaction SMILES: C[O:2][C:3](=[O:32])[C@@H:4]([O:29][CH2:30][CH3:31])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[N:15]=[C:16]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)[O:17][C:18]=2[CH3:19])=[CH:8][C:7]=1[O:27][CH3:28].[Li+].[OH-]>>[Cl:26][C:22]1[CH:21]=[C:20]([C:16]2[O:17][C:18]([CH3:19])=[C:14]([CH2:13][O:12][C:9]3[CH:10]=[CH:11][C:6]([CH2:5][C@H:4]([O:29][CH2:30][CH3:31])[C:3]([OH:32])=[O:2])=[C:7]([O:27][CH3:28])[CH:8]=3)[N:15]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: CCO[C@@H](Cc1ccc(OCc2nc(-c3cccc(Cl)c3)oc2C)cc1OC)C(=O)OC
Agent: [Li+]
Agent: [OH-]
Product: CCO[C@@H](Cc1ccc(OCc2nc(-c3cccc(Cl)c3)oc2C)cc1OC)C(=O)O

Procedure:
In analogy to the procedure described in example 1 g], (S)-3-{4-[2-(3-chloro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methoxy-phenyl}-2-ethoxy-propionic acid methyl ester was treated with LiOH to obtain (S)-3-{4-[2-(3-chloro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methoxy-phenyl}-2-ethoxy-propionic acid as colorless liquid.
Reaction SMILES: Cl.Cl.Cl.[NH:4]([C:6]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:9]=[C:8]([CH3:18])[N:7]=1)[NH2:5].[C:19]([C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:31])[CH3:30])=[CH:24][CH:23]=1)(=O)[CH3:20]>C(O)C>[CH3:18][C:8]1[N:7]=[C:6]([NH:4][N:5]=[C:19]([C:22]2[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:31])[CH3:30])=[CH:24][CH:23]=2)[CH3:20])[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:9]=1
Reactant: CC(=O)Nc1ccc(C(C)=O)cc1
Reactant: Cc1nc(NN)cc(-c2ccccc2)n1
Agent: Cl
Solvent: CCO
Product: CC(=O)Nc1ccc(C(C)=NNc2cc(-c3ccccc3)nc(C)n2)cc1

Procedure:
The title compound was prepared from 4-hydrazino-2-methyl-6-phenylpyrimidine trihydrochloride (300 mg, 0.97 mmol) and N-(4-acetyl-phenyl)acetamide (515 mg, 2.91 mmol) in ethanol (10.0 mL) by a procedure similar to example 1, step 4 yielding 43 mg (12%) of a brown solid. HPLC Purity: 95%.