Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([OH:9])=O)[C:3]([CH3:6])([CH3:5])[CH3:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH2:48]([O:55][C:56](=[O:82])[NH:57][CH2:58][C:59]([N:61]1[CH2:65][CH:64]([C:66](=[O:78])[NH:67][C:68]2[C:77]3[C:72](=[CH:73][CH:74]=[CH:75][CH:76]=3)[CH:71]=[CH:70][CH:69]=2)[CH:63]2[NH:79][CH2:80][CH2:81][CH:62]12)=[O:60])[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>CN1C(=O)CCC1.CCOC(C)=O>[C:13]([O:12][C:10](=[O:11])[NH:1][CH:2]([C:7]([N:79]1[CH2:80][CH2:81][CH:62]2[N:61]([C:59](=[O:60])[CH2:58][NH:57][C:56]([O:55][CH2:48][C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)=[O:82])[CH2:65][CH:64]([C:66](=[O:78])[NH:67][C:68]3[C:77]4[C:72](=[CH:73][CH:74]=[CH:75][CH:76]=4)[CH:71]=[CH:70][CH:69]=3)[CH:63]12)=[O:9])[C:3]([CH3:4])([CH3:5])[CH3:6])([CH3:16])([CH3:15])[CH3:14]
Reactant: O=C(NCC(=O)N1CC(C(=O)Nc2cccc3ccccc23)C2NCCC21)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC(C(=O)N1CCC2C1C(C(=O)Nc1cccc3ccccc13)CN2C(=O)CNC(=O)OCc1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 109.4 %

Procedure:
A solution of Boc-Tle-OH (176 mg, 0.76 mmol) in NMP (3 mL) was cooled to 0° C. and treated with HATU (318 mg, 0.83 mmol) followed by NMM (0.15 mL). After 10 min, 56 (360 mg, 0.76 mmol) in NMP (2 mL) was added. The reaction mixture was allowed to warm to ambient temperature overnight. The solution was diluted with EtOAc, washed successively with 1M HCl, saturated NaHCO3, dried over anhydrous Na2SO4, filtered and concentrated to afford 57 (570 mg) which was used without further purification. Mass spectrum, m/z [686.4] (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)([CH2:13][CH2:14]S(C)(=O)=O)[CH2:9]1)=[O:7].I.[NH:35]1[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2[N:37]=[C:36]1[C:44]([CH:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1)=[O:45]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:49]2[CH2:50][CH2:51][CH:46]([C:44]([C:36]3[NH:35][C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=4[N:37]=3)=[O:45])[CH2:47][CH2:48]2)([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)[CH2:9]1)=[O:7]
Reactant: O=C(c1nc2ccccc2[nH]1)C1CCNCC1
Reactant: COc1cc(C(=O)N2CCC(CCS(C)(=O)=O)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Agent: I
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(=O)c4nc5ccccc5[nH]4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of Example 6.6.2 using 1-(3,4,5-trimethoxy-benzoyl)-3-(3,4-dichloro-phenyl)-3-(2-methanesulfonyl-ethyl)-pyrrolidine and 4-(1 H-benzoimidazole-2-carbonyl)-piperidine hydroiodide salt to give the title compound: Rf=0.35 (silica gel, 10% methanol/ethyl acetate containing 0.1% concentrated aqueous ammonia solution).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]2[S:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[CH2:9][CH:8]([N:17]3[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][OH:26])[CH2:19][CH2:18]3)[C:7]=2[CH:27]=1.[C:28](Cl)(=[O:44])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43].O.[OH-].[NH4+]>C(Cl)(Cl)Cl.C1C=CC=CC=1>[CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]2[S:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[CH2:9][CH:8]([N:17]3[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][CH2:25][O:26][C:28](=[O:44])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:21][CH2:22]3)[C:7]=2[CH:27]=1
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: CSc1ccc2c(c1)C(N1CCN(CCCO)CC1)Cc1ccccc1S2
Agent: [NH4+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: c1ccccc1
Product: CCCCCCCCCCCCCCCC(=O)OCCCN1CCN(C2Cc3ccccc3Sc3ccc(SC)cc32)CC1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of 14.0 grams of 8-methylthio-10-[4-(3-hydroxypropyl)piperazino]-10,11-dihydrodibenzo[b,f]thiepin in a mixture of 20 milliliters of chloroform and 60 milliliters of benzene was added 19.2 grams of palmitoyl chloride (hexadecanoyl chloride) and the mixture was allowed to stand at room temperature overnight. Thereafter the mixture was heated at a temperature of 60°C for a period of 2 hours. After cooling, the mixture was added to 100 milliliters of water containing 10 milliliters of concentrated aqueous ammonium hydroxide solution, and the mixture was extracted with benzene. The extract was then washed with water, dried over anhydrous potassium carbonate, and the solvent was evaporated therefrom. The residue which included the desired ester was dissolved as completely as possible in benzene and the solution was subjected to chromatographic separation in an alumina column which was then eluted with benzene. From the benzene extract, 14.4 grams of pure 8-methylthio-10-[4-(3-hexadecanoyloxypropyl)piperazino]-10,11-dihydrodibenzo[b,f]thiepin was recovered. The palmitic acid with which the product was contaminated was substantially completely adsorbed on the alumina column. The crude base was converted into the crystalline di(hydrogen maleate) in accordance with the general procedure described in the foregoing Examples. The yield of the salt which, after recrystallization from acetone, had a melting point of 126°-127°C, was 14.4 grams. The pure base was recovered in the form of a colorless viscous liquid by subsequent treatment of the salt with a dilute aqueous ammonium hydroxide solution and extraction with benzene.
Reaction SMILES: [C:1]([C:5]1[CH:25]=[CH:24][C:8]2[NH:9][C:10]([C@@H:12]([NH:16]C(=O)OC(C)(C)C)[C@H:13]([OH:15])[CH3:14])=[N:11][C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:16][C@H:12]([C:10]1[NH:9][C:8]2[CH:24]=[CH:25][C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])=[CH:6][C:7]=2[N:11]=1)[C@H:13]([OH:15])[CH3:14]
Reactant: C[C@@H](O)[C@H](NC(=O)OC(C)(C)C)c1nc2cc(C(C)(C)C)ccc2[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](O)[C@H](N)c1nc2cc(C(C)(C)C)ccc2[nH]1
Temperature: 25 °C
Yield: 28.1 %

Procedure:
To tert-butyl [(1R,2R)-1-(5-tert-butyl-1H-benzimidazol-2-yl)-2-hydroxypropyl]-carbamate (105 mg, 0.302 mmol) was added DCM (5 mL) followed by TFA (700 μL) at 0° C. The reaction was allowed to warm to room temperature for 4 hours before cooling back to 0° C. and quenching with saturated aqueous NaHCO3 solution (20 mL). The mixture was extracted with DCM, the organic layer collected, dried over MgSO4 and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with DCM:MeOH:NH3 (80:20:2) to afford the title compound (21 mg, 28%).
Reaction SMILES: [CH2:1]([O:3][C@H:4]1[CH2:21][C@@H:20]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[O:19][C:6]2([CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]2)[CH2:5]1)[CH3:2].FC(F)(F)C(O)=O>C(Cl)Cl.[OH-].[Na+]>[CH2:1]([O:3][C@H:4]1[CH2:21][C@@H:20]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[O:19][C:6]2([CH2:7][CH2:8][NH:9][CH2:10][CH2:11]2)[CH2:5]1)[CH3:2]
Reactant: CCO[C@H]1C[C@@H](c2ccc(F)cc2)OC2(CCN(C(=O)OC(C)(C)C)CC2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCO[C@H]1C[C@@H](c2ccc(F)cc2)OC2(CCNCC2)C1
Reaction time: 1 h
Yield: 136.3 %

Procedure:
To a solution of tert-butyl cis-8-ethoxy-10-(4-fluorophenyl)-11-oxa-3-azaspiro[5.5]undecane-3-carboxylate (510 mg, 1.30 mmol) in CH2Cl2 (1 mL) was added a 1:1 solution of trifluoroacetic acid (1 mL) in CH2Cl2 (1 mL). After 1 hour, the reaction mixture was diluted with aqueous 1 N NaOH (50 mL) and extracted with ethyl acetate (2×50 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to provide cis-8-ethoxy-10-(4-fluorophenyl)-11-oxa-3-azaspiro[5.5]undecane (520 mg). 1H NMR (400 MHz, CDCl3) δ 7.46-7.31 (m, 2H), 7.10-6.98 (m, 2H), 4.54 (d, J=11.8 Hz, 1H), 3.76 (ddd, J=15.7, 11.3, 4.4 Hz, 1H), 3.66-3.46 (m, 2H), 3.09 (dt, J=13.9, 7.0 Hz, 1H), 2.99-2.76 (m, 3H), 2.69-2.21 (m, 2H), 2.17-2.00 (m, 2H), 1.79-1.64 (m, 1H), 1.64-1.49 (m, 1H), 1.50-1.24 (m, 2H), 1.24-1.12 (m, 3H). ESI-MS m/z calc. 293.18, found 294.5 (M+1)+; Retention time: 0.97 minutes (3 minute run).
Reaction SMILES: Br[C:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[S:4][C:3]=1[CH3:11].[CH2:12]([CH:14]([C:17]1[C:18]2[N:19]([C:24](I)=[C:25]([CH3:27])[N:26]=2)[N:20]=[C:21]([CH3:23])[CH:22]=1)[CH2:15][CH3:16])[CH3:13]>C1COCC1.[Zn]>[CH2:12]([CH:14]([C:17]1[C:18]2[N:19]([C:24]([C:2]3[C:6]4=[N:7][CH:8]=[CH:9][CH:10]=[C:5]4[S:4][C:3]=3[CH3:11])=[C:25]([CH3:27])[N:26]=2)[N:20]=[C:21]([CH3:23])[CH:22]=1)[CH2:15][CH3:16])[CH3:13]
Reactant: Cc1sc2cccnc2c1Br
Reactant: CCC(CC)c1cc(C)nn2c(I)c(C)nc12
Agent: [Zn]
Solvent: C1CCOC1
Product: CCC(CC)c1cc(C)nn2c(-c3c(C)sc4cccnc34)c(C)nc12
Yield: 9.2 %

Procedure:
380 mg of 3-Bromo-2-methyl-thieno[3,2-b]pyridine (1.66 mmol) is placed into the vial with 3.56 ml of Reiki Zn, suspension in THF (2.50 mmol) and capped and heated at 100C for 2 h. The excess Zinc is allowed to settle down and the solution is transferred to the vial containing 250 mg of 8-(1-ethyl-propyl)-3-iodo-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.72 mmol) and 48 mg of PdCl2(pddf) (0.06 mmol) in 2 ml of dry THF. The vial is capped by Teflon cap and heated at 80C for overnight. The reaction mixture is quenched by sat.NH4Claq. and extracted by CH2Cl2, dried over Na2SO4 and evaporated. The crude product is applied onto a silica-gel chromatography column (Hexane: AcOEt: 2 M NH3 in MeOH=20:4:1) to give 24.2 mg of the title compound. Yield 9.2%. mass spectrum (m/e): 365 (M+1); 1H-NMR (CDCl3): 8.66 (dd, 1H, J=4.7 Hz, 1.4 Hz), 8.16 (dd, 1H, J=8.1 Hz, 1.4 Hz), 7.25 (dd, 1H, J=8.1 Hz, 4.7 Hz), 6.68 (s, 1H), 3.43 (m, 1H), 2.50 (s, 3H), 2.47 (s, 3H), 2.46 (s, 3H), 1.88 (m, 4H), 0.93 (m, 6H) ppm.
Reaction SMILES: [O:1]=[S:2]1(=[O:17])[CH2:7][CH2:6][N:5]([C:8]2[C:14]([F:15])=[CH:13][C:11]([NH2:12])=[CH:10][C:9]=2[F:16])[CH2:4][CH2:3]1.[O-]S(C(F)(F)F)(=O)=O.[Li+].[O:27]1[CH2:33][C@@H:28]1[C:29]([O:31][CH3:32])=[O:30]>C(#N)C>[O:17]=[S:2]1(=[O:1])[CH2:7][CH2:6][N:5]([C:8]2[C:14]([F:15])=[CH:13][C:11]([NH:12][CH2:33][C@@H:28]([OH:27])[C:29]([O:31][CH3:32])=[O:30])=[CH:10][C:9]=2[F:16])[CH2:4][CH2:3]1
Reactant: COC(=O)[C@H]1CO1
Reactant: Nc1cc(F)c(N2CCS(=O)(=O)CC2)c(F)c1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Li+]
Solvent: CC#N
Product: COC(=O)[C@H](O)CNc1cc(F)c(N2CCS(=O)(=O)CC2)c(F)c1
Temperature: 70 °C
Reaction time: 7 h
Yield: 56.5 %

Procedure:
A solution of 4-(1,1-dioxidothiomorpholin-4-yl)-3,5-difluoroaniline (EXAMPLE 15, Step 3, 1.30 g, 5.0 mmol) in acetonitrile (7.5 mL) is treated with lithium triflate (0.60 g, 5.0 mmol) and methyl (2R)-2,3-epoxypropanoate (0.51 g, 0.46 mL, 5.0 mmol) and heated to 70° C. for 2 h. At this time an additional amount (1.5 mmol each) of the two reagents is added and the mixture stirred for another 7 h at 70° C. The reaction mixture is then cooled to room temperature, concentrated, and purified by column chromatography (50→60% ethyl acetate-hexane) to provide the title compound (1.03 g, 57%), MS (m/z): [M+H]+=365; 1H NMR (300 MHz, CDCl3): δ 3.04 (d, 1H), 3.15 (m, 4H), 3.31-3.46 (m, 2H), 3.47-3.56 (m, 4H), 3.83 (s, 3H), 4.20 (t, 1H), 4.40 (m, 1H), 6.17 (d, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([N:18]3[CH2:23][C@H:22]([CH3:24])[NH:21][C@H:20]([CH3:25])[CH2:19]3)[CH:15]=[CH:14][C:13]=2[O:26][CH3:27])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[S:28]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29]1.CC(C)([O-])C.[K+].C1(C)C=CC=CC=1>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:25][C@H:20]1[NH:21][C@@H:22]([CH3:24])[CH2:23][N:18]([C:16]2[CH:15]=[CH:14][C:13]([O:26][CH3:27])=[C:12]([NH:11][S:8]([C:5]3[CH:6]=[CH:7][C:2]([C:30]4[CH:31]=[CH:32][S:28][CH:29]=4)=[CH:3][CH:4]=3)(=[O:10])=[O:9])[CH:17]=2)[CH2:19]1
Reactant: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(Br)cc1
Reactant: OB(O)c1ccsc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: COCCOC
Product: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(-c2ccsc2)cc1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 4-bromo-N-[5-(cis-3,5-dimethyl-1-piperazinyl)-2-(methyloxy)phenyl]benzenesulfonamide (E106) (200 mg, 0.44 mmol) and 3-thienylboronic acid (113 mg, 0.88 mmol) in DME (3 ml) was added potassium tert-butoxide (445 mg, 3.97 mmol) and tetrakis(triphenylphosphine)palladium(0) (30.5 mg, 0.03 mmol) in water (1 ml) and the resulting mixture stirred in a microwave (set at high absorbance) at 100° C. for 30 minutes. 2-3 ml of toluene added and solvent evaporated, the residue dissolved in methanol and added to a preconditioned (methanol) SCX cartridge eluting with methanol (×3), ammonia (1M in methanol (×2)) and then ammonia (2M in methanol (×3)), followed by by mass directed autoprep HPLC followed by trituration with diethyl ether to afford the title compound (E119). MS (AP+) m/e 458 [M+H]+.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:16].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25](Cl)=[O:26])=[CH:20][C:19]=1[F:28]>>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]([NH:1][N:2]2[N:11]=[C:10]([C:12]([F:15])([F:13])[F:14])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:16])=[O:26])=[CH:20][C:19]=1[F:28]
Reactant: Nn1nc(C(F)(F)F)c2ccccc2c1=O
Reactant: O=C(Cl)Cc1ccc(Cl)c(F)c1
Product: O=C(Cc1ccc(Cl)c(F)c1)Nn1nc(C(F)(F)F)c2ccccc2c1=O

Procedure:
The product of Example 11B and 2-(4-chloro-3-fluorophenyl)acetyl chloride were treated using a method similar to that described in Example 1C to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 11.92-11.95 (bs, 1H), 8.43 (d, J=8.3 Hz, 1H), 8.11-8.17 (m, 1H), 7.99-8.08 (m, 2H), 7.58 (t, J=8.1 Hz, 1H), 7.43 (dd, J=10.5, 1.9 Hz, 1H), 7.25 (dd, J=8.3, 1.9 Hz, 1H), 3.79 (s, 2H); MS (ESI) m/z 400 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[CH2:23][OH:24])=[CH:17][CH:16]=1>[O-2].[O-2].[Mn+4]>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([CH:21]=[CH:22][CH:23]=[O:24])=[CH:19][CH:20]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCc1ccc(/C=C/CO)cc1
Agent: [Mn+4]
Agent: [O-2]
Product: Cc1oc(-c2ccccc2)nc1CCc1ccc(C=CC=O)cc1

Procedure:
(E)-3-[4-[2-(5-Methyl-2-phenyl-4-oxazolyl)ethyl]phenyl]-2-propenol was oxidized with activated manganese dioxide in the same manner as in Reference Example 25 to yield 4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethyl]cinnamaldehyde, which was then recrystallized from ethyl acetate-hexane to yield colorless prisms having a melting point of 99°-100° C.
Reaction SMILES: [CH2:1]([NH:8][C@H:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[C:17](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+].Cl>ClCCCl>[CH2:1]([N:8]([CH3:17])[C@H:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: O[C@@H]1CCC[C@@H]1NCc1ccccc1
Agent: C=O
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCCl
Product: CN(Cc1ccccc1)[C@H]1CCC[C@H]1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.5 %

Procedure:
Under a nitrogen atmosphere, to a mixture of (1R,2S)-2-(benzylamino)cyclopentanol (1.36 g), 1,2-dichloroethane (34 mL), and a 37% aqueous formaldehyde solution (1.73 mL) was added sodium triacetoxyborohydride (4.52 g), followed by stirring at room temperature overnight. To the reactant was added a saturated aqueous sodium hydrogen carbonate solution, and then acidified by the addition of 1 M hydrochloric acid. The aqueous phase was washed with ethyl acetate. The water phase was basified with a 1 M aqueous sodium hydroxide solution, and then chloroform was added thereto, followed by liquid separation. The organic phase was washed with saturated brine and dried over anhydrous magnesium sulfate. The mixture was filtered and then the filtrate was concentrated under reduced pressure to obtain (1R,2S)-2-[benzyl(methyl)amino]cyclopentanol (1.38 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.Br[C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([NH2:17])=[O:16].C([O-])([O-])=O.[K+].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CCO.CCOC(C)=O.Cl[Pd]Cl>[OH:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:20]=[CH:19][CH:18]=[C:14]([C:15]([NH2:17])=[O:16])[CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: OB(O)c1cccc(O)c1
Reactant: NC(=O)c1cccc(Br)c1
Agent: Cl[Pd]Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: NC(=O)c1cccc(-c2cccc(O)c2)c1
Temperature: 22.5 °C
Reaction time: 4 h
Yield: 84.6 %

Procedure:
A 50 L reactor was charged with 3-hydroxyphenylboronic acid (1.776 kg, 12.88 mol, 1.05 eq), 3-bromobenzamide (2.453 kg, 12.26 mol, 1.0 eq), tetrabutylammonium bromide (0.198 kg, 0.61 mol, 0.05 eq), PdCl2 (0.011 kg, 0.061 mol, 0.005 eq), and EtOH (9.689 kg). To the reaction mixture at 20-25° C., with moderate stirring, was added a slurry of K2CO3 (3.390 kg, 24.53 mol, 2 eq) in EtOH (4.84 kg). The K2CO3 container was rinsed with EtOH (4.84 kg) into the reactor. The reaction mixture was stirred at 20-25° C. for approximately 3-5 hours and monitored by thin layer chromatography (TLC) (hexanes:EtOAc 6:4). After the reaction was judged to be complete, 10% aq. HCl was added to the reaction mixture until the pH reached 1-2. Additional 10% aq. HCl was added, resulting in a final pH less than 1. The solution was agitated for approximately 35 minutes at 20-25° C. Approximately 12 liters of the solution was drained off and set aside. The remaining reaction mixture was diluted with EtOAc and washed with water (0.17 mL of EtOAc was added per mL of solution, and 0.294 mL of water per mL of solution). The organic phases were combined and concentrated in vacuo. Once the organic phases were reduced in volume to about 9 L, the mixture was transfered to reactor and 32 L of water was added. The temperature of the mixture was adjusted to 0-5° C., and it was agitated for 30 minutes. The product precipitated from the mixture and was filtered. The filter cake was washed with water from the reactor and dried at ambient temperature for about 18 hours, yielding 2.212 Kg (85%) of a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH2:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[C:5]([N:16]=O)=[C:4]([NH2:18])[N:3]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+].N>O>[NH2:1][C:2]1[N:7]=[C:6]([O:8][CH2:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[C:5]([NH2:16])=[C:4]([NH2:18])[N:3]=1
Reactant: Nc1nc(N)c(N=O)c(OCC2CCCCC2)n1
Agent: N
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Product: Nc1nc(N)c(N)c(OCC2CCCCC2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a strirred suspension of 2,6-diamino-5-nitroso-4-cyclohexylmethoxypyrimidine (0.10 g, 0.4 mmol) in water (5 ml) at 50° C. was added sodium dithionite (0.16 g, 0.92 mmol) in portions over a period of 5 h. The reaction mixture was allowed to cool to room temperature and stirred at ambient temperature overnight. The pH of the solution was adjusted to 7 with aqueous ammonia solution (2 ml), and the resulting fine yellow precipitate was collected by filtration and washed with water. The product was purified by recrystallisation from water (0.06 9, 60%), m.p. 154° C.; (Found: C, 55.50; H, 7.95; N, 29.34% C11H19N5O requires C, 55.69; H, 8.02; N, 29.53%); δH (200 MHz, d6-DMSO) 1.02-1.39 (5H, m, C6H11), 1.71-1.89 (6H, m, C6H11), 3.22 (2H, br s, NH2), 4.03 (2H, d, OCH2, J=6.53 Hz), 5.32 (2H, br s, NH2), 5.71 (2H, br s, NH2); m/z (+EI) 237 (M+, 84%), 155 (MH+-C7H13, 100), 124 (MH+-C7H13O, 15).
Reaction SMILES: O1CCOCC1.[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12](OB(O)O)=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:26]1[CH:27]=[CH:28][C:29]([N+:33]([O-:35])=[O:34])=[C:30]([CH:32]=1)[NH2:31]>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)C(C)(C)C)(C)(C)C.C(Cl)(Cl)Cl.C(OCC)C>[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:26]2[CH:27]=[CH:28][C:29]([N+:33]([O-:35])=[O:34])=[C:30]([CH:32]=2)[NH2:31])=[CH:11][CH:10]=1
Reactant: COc1ccc(OB(O)O)cc1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: COc1ccc(-c2ccc([N+](=O)[O-])c(N)c2)cc1
Temperature: 85 °C
Reaction time: 0.17 h
Yield: 102.4 %

Procedure:
Under an argon stream, a dioxane solution (10 ml) of tris-t-butylphosphine (240 mg) was added to a mixture of p-methoxyphenyl boric acid (4.364 g), tris(dibenzylideneacetone)dipalladium (452 mg), cesium carbonate (10.561 g), 5-chloro-2-nitroaniline (4505 mg) and dioxane (50 ml), followed by 2 hours and 10 minutes of heating at 85° C. After cooling to room temperature on standing, diethyl ether (500 ml) and chloroform (500 ml) were added thereto. After insoluble matter was removed by filtration, the filtrate was concentrated to obtain an aimed compound, 5-(4′-methoxyphenyl)-2-nitroaniline (6.5 g).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[CH:20][C:21]([CH2:24]OS(C)(=O)=O)=[N:22][CH:23]=3)=[C:14]([F:30])[CH:13]=2)[CH2:7]1)(=[O:3])[CH3:2].[O:31]1[CH:35]=[C:34]([CH2:36][NH2:37])[CH:33]=[N:32]1>CN(C=O)C>[F:30][C:14]1[CH:13]=[C:12]([N:8]2[CH2:7][CH:6]([CH2:5][NH:4][C:1](=[O:3])[CH3:2])[O:10][C:9]2=[O:11])[CH:17]=[CH:16][C:15]=1[C:18]1[CH:23]=[N:22][C:21]([CH2:24][NH:37][CH2:36][C:34]2[CH:33]=[N:32][O:31][CH:35]=2)=[CH:20][CH:19]=1
Reactant: NCc1cnoc1
Reactant: CC(=O)NCC1CN(c2ccc(-c3ccc(COS(C)(=O)=O)nc3)c(F)c2)C(=O)O1
Solvent: CN(C)C=O
Product: CC(=O)NCC1CN(c2ccc(-c3ccc(CNCc4cnoc4)nc3)c(F)c2)C(=O)O1
Temperature: 60 °C
Reaction time: 6 h
Yield: 10 %

Procedure:
A solution of the methanesulfonic acid 5-{4-[5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenyl}-pyridin-2-ylmethyl ester 106 (220 mg, 0.5 mmol) in DMF (4.0 mL) was treated with C-isoxazol-4-yl-methylamine (68 mg, 0.5 mmol, 1.0 equiv) at room temperature, and the resulting reaction mixture was warmed to 60° C. and stirred for 6 hours. When TLC and MS showed the reaction to be complete, the reaction mixture was concentrated in vacuo, and the residue was directly purified by column chromatography (0–5% MeOH/CH2Cl2 gradient elution) to afford the desired N-{3-[3-Fluoro-4-(6-{[(isoxazol-4-ylmethyl)-amino]-methyl}-pyridin-3-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide 4252 (22 mg, 10%) as off-white solids. LCMS (EI): 440 (M++H).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:13])=[C:4]([NH2:12])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[C:14]([O:19]CC)(=S)[C:15]([NH2:17])=O>C(O)CCC>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]2[C:3]=1[N:13]=[C:15]([NH2:17])[C:14](=[O:19])[NH:12]2
Reactant: Nc1cc(C(F)(F)F)cc(Br)c1N
Reactant: CCOC(=S)C(N)=O
Solvent: CCCCO
Product: Nc1nc2c(Br)cc(C(F)(F)F)cc2[nH]c1=O
Temperature: 25 °C
Yield: 27.1 %

Procedure:
An adaptation of the method of Burrell et al., J. Chem. Soc. Perkin I. 2707 (1973), was used. A mixture of 3-bromo-5-trifluoromethyl-1,2-phenylenediamine (384 mg, 1.50 mmol; Maybridge Co.) and ethyl thiooxamate (220 mg, 1.70 mmol; Aldrich Co.) in 4 mL of 1-butanol was heated to reflux. The resulting solution was stirred under reflux for 6 h. The resulting suspension was cooled to 25 ° C. A pale yellow precipitate appeared. The mixture was vacuum filtered and the solid was washed with EtOH (5×2 mL) and dried in vacuum at 60° C. overnight to yield 125 mg (27.1%) of 5-bromo-7-trifluoromethyl-3-aminoquinoxalin-2(1H)-one (tentatively named as this since the regiochemistry is not sure) as a pale yellow solid of a new compound: mp dec.>267° C. 1H NMR (300 MHz, DMSO-d6) δ 7.680 (s, 1H, H-7), 7.495 (s, 1H, H-5). LRMS: 307 (M+, 100%), 280 (50%).