Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:6][C:7]1[NH:8][C:9](=[O:31])[C:10]2[N:11]=[CH:12][N:13]([C:29]=2[N:30]=1)[C@@H:14]1[O:28][C@H:25]([CH2:26][OH:27])[C@@H:23]([OH:24])[C@H:15]1[O:16][CH2:17][CH2:18][O:19][N:20]([CH3:22])[CH3:21])(=[O:5])[CH:2]([CH3:4])[CH3:3].[C:32](Cl)([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)([C:41]1[CH:48]=[CH:47][C:44]([O:45][CH3:46])=[CH:43][CH:42]=1)[C:33]1[CH:40]=[CH:39][C:36]([O:37][CH3:38])=[CH:35][CH:34]=1.CO>N1C=CC=CC=1.CCOC(C)=O.CN(C1C=CC=CN=1)C>[CH3:46][O:45][C:44]1[CH:43]=[CH:42][C:41]([C:32]([O:27][CH2:26][C@H:25]2[O:28][C@@H:14]([N:13]3[C:29]4[N:30]=[C:7]([NH:6][C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])[NH:8][C:9](=[O:31])[C:10]=4[N:11]=[CH:12]3)[C@H:15]([O:16][CH2:17][CH2:18][O:19][N:20]([CH3:22])[CH3:21])[C@@H:23]2[OH:24])([C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)[C:33]2[CH:40]=[CH:39][C:36]([O:37][CH3:38])=[CH:35][CH:34]=2)=[CH:48][CH:47]=1
Reactant: CC(C)C(=O)Nc1nc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2OCCON(C)C)c(=O)[nH]1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: CN(C)c1ccccn1
Solvent: CCOC(C)=O
Solvent: CO
Solvent: c1ccncc1
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3cnc4c(=O)[nH]c(NC(=O)C(C)C)nc43)[C@H](OCCON(C)C)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To N2-isobutyryl-2′-O-(dimethylaminooxyethyl) guanosine (42.63 g, 27.44 mmol) and dimethylaminopyridine (168 mg, 1.37 mmol) dissolved in anhydrous pyridine (274 mL) was added DMT-Cl (9.30 g, 27.44 mmol). After several hours additional DMT-Cl (9.30 g, 27.44 mmol) was added. After several more hours MeOH (22 mL, 543 mmol) was added, and the reaction mixture was stirred for 30 minute. The solvent was evaporated in vacuo to give an oil which was dissolved in EtOAc (550 mL). The resulting suspension was washed with a mixture of H2O (50 mL) and brine (25 mL) twice, then with brine (50 mL). NEt3 (5 mL) was added, the organic phase was dried with MgSO4 and the solvent was evaporated in vacuo to give a foam. The foam was purified by column chromatography (silica pretreated with 1% NEt3) using CH2Cl2-EtOAc-MeOH-NEt3, 75:25:10:1, to afford the title compound as a foam (16.3 g, 80%).
Reaction SMILES: Cl.[F:2][CH:3]1[CH2:6][NH:5][CH2:4]1.C[O-].[Na+].[CH3:10][O:11][C:12]1[CH:13]=[C:14]([NH:25][C:26]2[N:31]=[C:30]([CH:32]=O)[CH:29]=[C:28]([CH2:34][O:35][CH2:36][C:37]([F:40])([F:39])[F:38])[N:27]=2)[CH:15]=[CH:16][C:17]=1[C:18]1[CH:23]=[C:22]([CH3:24])[N:21]=[N:20][CH:19]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>O.CO>[F:2][CH:3]1[CH2:6][N:5]([CH2:32][C:30]2[CH:29]=[C:28]([CH2:34][O:35][CH2:36][C:37]([F:39])([F:40])[F:38])[N:27]=[C:26]([NH:25][C:14]3[CH:15]=[CH:16][C:17]([C:18]4[CH:23]=[C:22]([CH3:24])[N:21]=[N:20][CH:19]=4)=[C:12]([O:11][CH3:10])[CH:13]=3)[N:31]=2)[CH2:4]1
Reactant: COc1cc(Nc2nc(C=O)cc(COCC(F)(F)F)n2)ccc1-c1cnnc(C)c1
Reactant: FC1CNC1
Agent: C[O-]
Agent: Cl
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: COc1cc(Nc2nc(COCC(F)(F)F)cc(CN3CC(F)C3)n2)ccc1-c1cnnc(C)c1
Reaction time: 0.03 h

Procedure:
3-Fluoroazetidine hydrochloride (31 mg, 0.28 mmol) was mixed with methanol (5 mL). Sodium methoxide (0.051 mL, 0.28 mmol) was added followed by 2-(3-methoxy-4-(6-methylpyridazin-4-yl)phenylamino)-6-((2,2,2-trifluoroethoxy)methyl)pyrimidine-4-carbaldehyde (100 mg, 0.23 mmol). The mixture was stirred for 2 min. Acetic acid (0.042 mL, 0.74 mmol) was added. The mixture was stirred for 5 min. Sodium cyanoborohydride (20 mg, 0.32 mmol) was added and the mixture was stirred at rt under nitrogen atmosphere for 1 h. Water was added and the mixture was stirred for 5 min. The solvents were evaporated and the residue was purified by preparative HPLC to give the title compound as a solid, 48 mg (42%).
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([CH2:11][B-](F)(F)F)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[K+].ClCCl.FC(F)(F)S(O[C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([C@:36]3([CH3:42])[CH2:40][O:39][C:38](=[O:41])[NH:37]3)[CH:32]=2)[CH:27]=1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1.O>CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([CH2:11][C:26]2[CH:27]=[C:28]3[C:33](=[CH:34][CH:35]=2)[CH:32]=[C:31]([C@:36]2([CH3:42])[CH2:40][O:39][C:38](=[O:41])[NH:37]2)[CH:30]=[CH:29]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@]1(c2ccc3cc(OS(=O)(=O)C(F)(F)F)ccc3c2)COC(=O)N1
Reactant: CC(C)(C)C1CCC(C[B-](F)(F)F)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)C1CCC(Cc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 12.8 %

Procedure:
A solution of potassium 4-tert-butylcyclohexylmethyltrifluoroborate (100 mg, 0.0004 mol), [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (31.4 mg, 0.0000384 mol), (R)-6-(4-methyl-2-oxooxazolidin-4-yl)naphthalen-2-yl trifluoromethanesulfonate (144 mg, 0.000384 mol) and cesium carbonate (0.376 g, 0.00115 mol) in 1,4-dioxane (4.6 mL, 0.059 mol) and water (0.5 mL, 0.03 mol) was heated at reflux under a nitrogen atmosphere. The reaction mixture was stirred at 100° C. overnight, then cooled to room temperature, and diluted with EtOAc, filtrate, followed by extraction of ether. The organic layers were combined and dried over MgSO4, and filtered. The concentrated residue was chromatographed with silica gel under 0-100% EtOAc/hexane to give (R)-4-(6-((4-tert-butylcyclohexyl)methyl)naphthalen-2-yl)-4-methyloxazolidin-2-one as a solid (18.6 mg, 12.8%). 1H NMR (400 MHz, CHLOROFORM-d) δ=7.84 (d, J=8.7 Hz, 1 H), 7.79 (br. s., 1 H), 7.77 (d, J=8.5 Hz, 1 H), 7.60 (s, 1 H), 7.45 (dd, J=1.9, 8.6 Hz, 1 H), 7.38 (d, J=8.4 Hz, 1 H), 5.83 (br. s., 1 H), 4.46-4.39 (m, 2 H), 2.82 (d, J=7.9 Hz, 2 H), 2.09 (m., 1 H), 1.87 (s, 3 H), 1.68-1.40 (m, 5 H), 1.39-1.24 (m, 2 H), 1.08-0.96 (m, 1 H), 0.91 (s, 9 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:17][CH3:18])[C:12](=[CH2:16])[C:13]([OH:15])=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CCOC(OC(OCC)=O)=O.[F:30][C:31]([F:57])([F:56])[C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[C:42]([CH2:44][NH2:45])[CH:41]=[C:40]([C:46]3[CH:51]=[CH:50][C:49]([C:52]([F:55])([F:54])[F:53])=[CH:48][CH:47]=3)[N:39]=2)=[CH:34][CH:33]=1>C1COCC1>[F:57][C:31]([F:30])([F:56])[C:32]1[CH:33]=[CH:34][C:35]([C:38]2[CH:43]=[C:42]([CH2:44][NH:45][C:13](=[O:15])[C:12]([N:11]([S:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)(=[O:9])=[O:10])[CH2:17][CH3:18])=[CH2:16])[CH:41]=[C:40]([C:46]3[CH:51]=[CH:50][C:49]([C:52]([F:55])([F:53])[F:54])=[CH:48][CH:47]=3)[N:39]=2)=[CH:36][CH:37]=1
Reactant: NCc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: C=C(C(=O)O)N(CC)S(=O)(=O)c1ccc(Cl)cc1
Agent: CCOC(=O)OC(=O)OCC
Solvent: C1CCOC1
Product: C=C(C(=O)NCc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2ccc(C(F)(F)F)cc2)c1)N(CC)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21 %

Procedure:
Acid 4D (289.74 mg, 1 mmol) was dissolved in 10 ml of THF and at rt DEPC (1.1 equiv, 0.15 ml) and [2,6-bis[4-(trifluoromethyl)phenyl]-4-pyridyl]methanamine 29A (1.1 equiv., 400 mg) were added to the solution. The mixture was stirred at rt overnight then evaporated. The residue was dissolved in AcOEt (30 ml) and washed with water (1×20 ml) and brine. The organic phase was dried over sodium sulfate and concentrated under vacuum. The purification of the crude by chromatographic column (3:7 EtOAc:petroleum ether) afforded 140 mg of a white solid. Yield=21% 1HNMR (DMSO, 400 MHz) δ 1.25 (3H, t), 3.40 (2H, q), 4.60 (2H, d), 5.18 (1H, s), 6.18 (1H, s), 7.70 (2H, d), 7.82 (2H, d), 7.86 (4H, d), 8.02 (2H, s), 8.40 (4H, d), 8.89 (1H, bt) [M+1] 668.9 (C31H24ClF6N3O3S requires 668.05).
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:6]=[C:7]([O:17][C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)[CH:8]=[C:9]2[C:13]=1[NH:12][C:11]([C:14](=[S:16])[NH2:15])=[CH:10]2)[CH3:3].[C:28]([O:33][CH2:34][CH3:35])(=[O:32])[C:29]#[C:30][CH3:31].C(P(CCCC)CCCC)CCC.O1CCCC1>C1(C)C=CC=CC=1>[CH3:3][CH:2]([O:4][C:5]1[CH:6]=[C:7]([O:17][C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:25])=[O:26])=[CH:20][CH:19]=2)[CH:8]=[C:9]2[C:13]=1[NH:12][C:11]([C:14]1[S:16][CH:30]([CH2:29][C:28]([O:33][CH2:34][CH3:35])=[O:32])[CH2:31][N:15]=1)=[CH:10]2)[CH3:1]
Reactant: CC#CC(=O)OCC
Reactant: CC(C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2cc(C(N)=S)[nH]c12
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)cc4)cc(OC(C)C)c3[nH]2)S1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 41 %

Procedure:
A mixture of 7-(1-methylethoxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carbothioamide (857 mg), ethyl 2-butynoate (0.6 mL), tributylphosphine (0.6 mL), tetrahydrofuran (10 mL) and toluene (15 mL) was stirred at 60° C. for 1.5 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/99 to 40/60, volume ratio) to give the title compound (381 mg, 41%) as a yellow amorphous solid. MS 517 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][N:4]([C:10]2[N:19]=[CH:18][C:17]3[CH2:16][CH2:15][C:14]4[CH:20]=[C:21]([O:24][CH3:25])[CH:22]=[CH:23][C:13]=4[C:12]=3[N:11]=2)[N:3]=1.C[N:27](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.ClC1N=CC2CCC3C=C(OC)C=CC=3C=2N=1>CN(C=O)C>[NH2:1][C:2]1[C:6]([C:7]([NH2:27])=[O:9])=[CH:5][N:4]([C:10]2[N:19]=[CH:18][C:17]3[CH2:16][CH2:15][C:14]4[CH:20]=[C:21]([O:24][CH3:25])[CH:22]=[CH:23][C:13]=4[C:12]=3[N:11]=2)[N:3]=1
Reactant: COc1ccc2c(c1)CCc1cnc(-n3cc(C(=O)O)c(N)n3)nc1-2
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: COc1ccc2c(c1)CCc1cnc(Cl)nc1-2
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCc1cnc(-n3cc(C(N)=O)c(N)n3)nc1-2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3-amino-1-(8-methoxy-5,6-dihydrobenzo[h]quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid 1 (0.084 g, 0.25 mmol), HBTU (0.113 g, 0.3 mmol) and DIEA (0.18 mL, 1 mmol) in DMF (1 mL) was added amine 2 (0.3 mmol). Resulting reaction mixture was stirred at room temperature for 18 h. After completion of the reaction, solvent was removed on rotavap and residue was purified by preparative HPLC to give 3-amino-1-(8-methoxy-5,6-dihydrobenzo[h]quinazolin-2-yl)-1H-pyrazole-4-carboxylic amide 3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([CH3:9])=[CH:4][CH:3]=1.[Br:10]Br>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[Br:10][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[C:5]=1[CH3:9]
Reactant: Cc1ccc(Cl)cc1Cl
Reactant: BrBr
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1c(Cl)cc(Cl)cc1Br
Yield: 213.1 %

Procedure:
To a mixture of 32 g of 4,6-dichlorotoluene and 0.3 g of anhydrous FeCl3, add, with stirring, 10 g of bromine in 1 g portions while maintaining a temperature of 20°-25° C. Add thereto a solution of 22 g of bromine in 100 mL of CCl4 slowly while maintaining a temperature of 20°-25° C. After the addition of bromine is complete, stir the mixture so formed for 15 min, and dilute the reaction mixture with 200 mL of CH2Cl2, and wash the organic solution with 5% aqueous sodium thiosulfate. Dry the organic layer over anhydrous K2CO3, filter, and evaporate to a residue. Recrystallize the residue from CH3CN to give 32 g of 2-bromo-4,6-dichlorotoluene, mp 84°-5° C.
Reaction SMILES: [Li]CCCC.[NH2:6][C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][N:8]=1.C([O:16][C:17]([C:19]1[N:23]2[CH:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:22]2=[N:21][C:20]=1[CH3:29])=O)C.[Cl-].[NH4+]>O1CCCC1>[CH3:13][C:11]1[CH:10]=[CH:9][N:8]=[C:7]([NH:6][C:17]([C:19]2[N:23]3[CH:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:22]3=[N:21][C:20]=2[CH3:29])=[O:16])[CH:12]=1
Reactant: Cc1ccnc(N)c1
Reactant: CCOC(=O)c1c(C)nc2cc(C)ccn12
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1ccnc(NC(=O)c2c(C)nc3cc(C)ccn23)c1
Temperature: 25 °C
Yield: 68 %

Procedure:
37 ml n-BuLi (1.6 M in hexane) were added dropwise to a solution of 3.2 g 2-amino-4-methylpyridine in 57 ml tetrahydrofuran (THF) at 0° C., while stirring. After warming to room temperature, the mixture was stirred for one hour. The reaction solution was cooled to −78° C., 5.8 g 2,7-dimethylimidazo[1,2-a]pyridine-3-carboxylic acid ethyl ester, dissolved in 10 ml THF, were slowly added dropwise, and the mixture was stirred for one hour. After addition of 60 ml ammonium chloride at room temperature, the mixture was extracted with methylene chloride, the organic phases were dried over sodium sulfate, and the solvent was removed. The product was purified by boiling and precipitation in hexane and was obtained with a yield of 68%.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([C@@H:14]([C:16]2[C:21]([F:22])=[CH:20][CH:19]=[CH:18][N:17]=2)[NH2:15])[CH:6]=[CH:7][C:8]=1[O:9][C:10]([F:13])([F:12])[F:11].CCCP(=O)=O.[N:29]1[CH:30]=[CH:31][N:32]2[CH:37]=[C:36]([C:38](O)=[O:39])[CH:35]=[CH:34][C:33]=12.CCN(C(C)C)C(C)C>CCOC(C)=O>[F:2][C:3]1[CH:4]=[C:5]([C@@H:14]([C:16]2[C:21]([F:22])=[CH:20][CH:19]=[CH:18][N:17]=2)[NH:15][C:38]([C:36]2[CH:35]=[CH:34][C:33]3[N:32]([CH:31]=[CH:30][N:29]=3)[CH:37]=2)=[O:39])[CH:6]=[CH:7][C:8]=1[O:9][C:10]([F:13])([F:12])[F:11]
Reactant: N[C@@H](c1ccc(OC(F)(F)F)c(F)c1)c1ncccc1F
Reactant: O=C(O)c1ccc2nccn2c1
Agent: CCCP(=O)=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@@H](c1ccc(OC(F)(F)F)c(F)c1)c1ncccc1F)c1ccc2nccn2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (S)-(3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methanamine hydrochloride (81 mg, 0.238 mmol, Intermediate 6) and EtOAc (3 mL) was added 50% propylphosphonic anhydride in EtOAc (0.28 mL, 0.470 mmol), imidazo[1,2-a]pyridine-6-carboxylic acid (47 mg, 0.290 mmol) and DIPEA (0.12 mL, 0.689 mmol). The solution was stirred at room temperature. After 16 h, the reaction product was adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep® pre-packed silica gel column (4 g), eluting with 0 to 100% EtOAc in hexane, to provide the title compound as a white solid. 1H NMR (300 MHz, MeOH-d4) δ ppm 9.06-9.16 (m, 1H), 8.44-8.55 (m, 1H), 7.96 (s, 1H), 7.76 (dd, J=9.5, 1.8 Hz, 1H), 7.56-7.71 (m, 3H), 7.42-7.51 (m, 2H), 7.32-7.42 (m, 2H), 6.68-6.76 (m, 1H). MS (ESI pos. ion) m/z: 449.0 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11](CS([O-])(=O)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:19]=[N+:20]=[N-:21].[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:19]=[N+:20]=[N-:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CS(=O)(=O)[O-])CC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(N=[N+]=[N-])CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
N-tert-butyloxycarbonyl-4-piperidinemethanesulfonate (10.0 g, 36 mmol) was dissolved in DMF (100 mL), sodium azide (NaN3, 7.0 g, 108 mmol) was added, the reaction mixture was warmed to 100° C., and the reaction was performed overnight. The solvent in the resultant mixture was evaporated under reduced pressure, water (100 mL) and ethyl acetate (100 mL) were added, the organic phase was separated, washed with water (100 mL×2) and saturated brine successively, dried over anhydrous sodium sulfate, and then evaporated under reduced pressure to remove ethyl acetate so as to yield the target product as light yellow liquid (8.2 g, 36 mmol; yield=100%). The crude produce was directly used for the reaction in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][CH3:10].Cl.[CH:12](O)=O>>[CH3:10][N:9]1[C:3]2[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=2[N:1]=[CH:12]1
Reactant: O=CO
Reactant: CNc1cc(C)ccc1N
Agent: Cl
Product: Cc1ccc2ncn(C)c2c1
Yield: 57 %

Procedure:
A mixture of 6.60 g of 1-amino-4-methyl-2-(N-methylamino)benzene and a solution of 3.5 ml of formic acid in 50 ml of a 4N HCl was stirred at 100° C. for 3.5 hours. The reaction solution was concentrated under reduced pressure and water was added to the residue. After washing with ethyl acetate, the aqueous phase was rendered alkaline with aqueous potassium carbonate followed by extraction with chloroform. The chloroform layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (40 g). Elution with ethyl acetate followed by recyrstallization from ethyl acetate-hexane gave 4.01 g (57%) of 1,6-dimethylbenzimidazole.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([Cl:21])[CH:3]=1.BrC1C=CC(C(O)=O)=C(Cl)C=1.N1(C2CCNCC2)CCCC1.BrC1C(C)=C(C(N2CCC(N3CCCC3)CC2)=O)C=CC=1.[F:65][C:66]([F:77])([F:76])[C:67]1[CH:68]=[C:69](B(O)O)[CH:70]=[CH:71][CH:72]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:21][C:4]1[CH:3]=[C:2]([C:71]2[CH:70]=[CH:69][CH:68]=[C:67]([C:66]([F:77])([F:76])[F:65])[CH:72]=2)[CH:7]=[CH:6][C:5]=1[C:8]([N:10]1[CH2:15][CH2:14][CH:13]([N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:12][CH2:11]1)=[O:9]
Reactant: O=C(c1ccc(Br)cc1Cl)N1CCC(N2CCCC2)CC1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: [Pd]
Agent: C1CCN(C2CCNCC2)C1
Agent: Cc1c(Br)cccc1C(=O)N1CCC(N2CCCC2)CC1
Solvent: CN(C)C=O
Product: O=C(c1ccc(-c2cccc(C(F)(F)F)c2)cc1Cl)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for example 1, (4-bromo-2-chloro-phenyl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (prepared from 4-bromo-2-chloro-benzoic acid and 4-pyrrolidin-1-yl-piperidine in analogy to the procedure described for the preparation of intermediate 2), was reacted with 3-trifluoromethyl-phenyl boronic acid, potassium phosphate solution and tetrakis-(triphenylphosphine)-palladium in DMF while keeping the temperature at RT instead of 80° C. to give the title compound as light brown oil. MS: 437.2 (MH+, 1Cl).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl.[CH2:56]([O:58][C:59](=[O:68])[CH2:60][N:61]1[CH2:66][CH2:65][CH2:64][CH:63]([NH2:67])[CH2:62]1)[CH3:57]>CN(C=O)C>[CH2:56]([O:58][C:59](=[O:68])[CH2:60][N:61]1[CH2:66][CH2:65][CH2:64][CH:63]([NH:67][C:19]([C:18]2[CH:17]=[N:16][C:15]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)=[N:5][O:6][C:2]=3[CH3:1])=[CH:23][CH:22]=2)=[O:21])[CH2:62]1)[CH3:57]
Reactant: CCOC(=O)CN1CCCC(N)C1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CN1CCCC(NC(=O)c2ccc(OCc3c(-c4ccccc4)noc3C)nc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.2 %

Procedure:
To a solution of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (500 mg, 1.6 mmol) in DMF (10 mL) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (569 mg, 1.8 mmol), N,N-diisopropyl ethyl amine (1.38 mL, 8.1 mmol) and (3-amino-piperidin-1-yl)-acetic acid ethyl ester hydrochloride (459 mg, 1.8 mmol). The resulting reaction mixture was stirred overnight at room temperature. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:1 and then dichloromethane:methanol=9:1) afforded the title compound (622 mg, 81%) as a light brown gum. MS: m/e=479.1 [M+H]+.
Reaction SMILES: C([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:55][O:56][CH3:57])[C:27]([NH:29][CH:30]2[C:37](=[O:38])[N:36]3[CH:31]2[CH2:32][S:33][C:34]([S:46][C:47]2[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][CH:48]=2)=[C:35]3[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])=[O:28])[N:25]=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C(O)=O>[NH2:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:55][O:56][CH3:57])[C:27]([NH:29][CH:30]2[C:37](=[O:38])[N:36]3[CH:31]2[CH2:32][S:33][C:34]([S:46][C:47]2[CH:48]=[CH:49][C:50]([O:53][CH3:54])=[CH:51][CH:52]=2)=[C:35]3[C:39]([O:41][C:42]([CH3:43])([CH3:44])[CH3:45])=[O:40])=[O:28])[N:25]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(C)(C)C)=C(Sc3ccc(OC)cc3)SCC12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: O=CO
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(C)(C)C)=C(Sc3ccc(OC)cc3)SCC12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.4 %

Procedure:
810 mg of the product of Step B dissolved in 10 ml of 66% formic acid were stirred for one hour at ambient temperature and filtered. The filtrate was concentrated to dryness under reduced pressure at less than 30° C. and the residue was dissolved in a mixture of acetonitrile and methanol. The solvents were evaporated and the residue was crystallized from ether to obtain 516 mg of racemic 1,1-dimethylethyl 7-[2-(2-aminothiazol-4-yl)-2-methoxyimino-acetamido]-3-(4-methoxyphenylthio)-8-oxo-4-thia-1-azabicyclo[4,2,0]oct-2-ene-2-carboxylate.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][O:6][C:5](=[O:8])[N:4]1[C:9]1[CH:14]=[CH:13][C:12]([C:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[C:28]([CH3:29])=[CH:27][C:26]([CH3:30])=[C:25]([CH3:31])[N:24]=3)[CH2:19][CH2:18]2)=[O:16])=[CH:11][CH:10]=1.Br[CH2:33][CH2:34][O:35][CH3:36]>>[CH3:36][O:35][CH2:34][CH2:33][O:1][CH2:2][C@@H:3]1[CH2:7][O:6][C:5](=[O:8])[N:4]1[C:9]1[CH:14]=[CH:13][C:12]([C:15]([N:17]2[CH2:18][CH2:19][N:20]([C:23]3[C:28]([CH3:29])=[CH:27][C:26]([CH3:30])=[C:25]([CH3:31])[N:24]=3)[CH2:21][CH2:22]2)=[O:16])=[CH:11][CH:10]=1
Reactant: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4CO)cc3)CC2)nc1C
Reactant: COCCBr
Product: COCCOC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCN(c3nc(C)c(C)cc3C)CC2)cc1
Yield: 37.1 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 93 and using (R)-4-hydroxymethyl-3-{4-[4-(3,5,6-trimethylpyridin-2-yl)piperazine-1-carbonyl]phenyl}-oxazolidin-2-one (424 mg) described in Example 294 and 1-bromo-2-methoxyethane (167 mg), the title compound (179 mg) was obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH3:11])[CH:7]=[C:8]([CH3:10])[CH:9]=1)([O-])=O>CO.[Pd]>[CH3:10][C:8]1[CH:9]=[C:4]([NH2:1])[CH:5]=[C:6]([CH3:11])[CH:7]=1
Reactant: Cc1cc(C)cc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: Cc1cc(C)cc(N)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A suspension of 5-nitro-m-xylene (1.51 g) and 10% Pd/C (80 mg) in MeOH (50 mL) was stirred at room temperature under H2 balloon for 16 h. The reaction mixture was filtered through a Celite pad, washed with EtOAc, concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, EtOAc:Hexane=5:95 to 40:60) to give 3,5-dimethyl-phenylamine as a yellow oil: MS (m/z) 122 (M+1); 1H NMR (CDCl3, 400 MHz) δ 6.41 (s, 1H), 6.33 (s, 2H), 3.52 (s, 2H), 2.22 (s, 6H).