Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:13]OS(C)(=O)=O)[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C-:19]#[N:20].[Na+].O>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:13][C:19]#[N:20])[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: [C-]#N
Reactant: CS(=O)(=O)OCC1(c2ccc(Cl)cc2)CCCC1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCC1(c2ccc(Cl)cc2)CCCC1
Temperature: 130 °C
Reaction time: 4 h
Yield: 77 %

Procedure:
To a stirred solution of methanesulfonic acid 1-(4-chlorophenyl)-cyclopentylmethyl ester (320) (14 g, 48.48 mmol) in dimethyl sulfoxide (50 mL) were added KI (805 mg, 4.85 mmol) and NaCN (3.6 g, 72.72 mmol) and stirred for 130° C. for 4 h. After completion of reaction, cold water (200 mL) was added. After extraction with ethyl acetate (3×100 mL), the combined organic parts were washed with saturated ferrous sulphate solution (2×100 mL), water (2×100 mL) and brine (100 mL) and dried and concentrated. The crude product was purified by CombiFlash column (10-20% ethyl acetate in hexane was used as eluent) to get [1-(4-chlorophenyl)-cyclopentyl]-acetonitrile (321) (8.2 g, 77%) as a light yellow liquid.
Reaction SMILES: N[C@H:2]([C:7]([OH:9])=[O:8])[C@H:3]([CH2:5][CH3:6])[CH3:4].NC(N)=O.[ClH:14]>[N+]([O-])(O)=O>[Cl:14][C@@H:2]([CH:3]([CH3:4])[CH2:5][CH3:6])[C:7]([OH:9])=[O:8]
Reactant: Cl
Reactant: CC[C@H](C)[C@H](N)C(=O)O
Agent: NC(N)=O
Solvent: O=[N+]([O-])O
Product: CCC(C)[C@H](Cl)C(=O)O
Temperature: 80 °C

Procedure:
To 20 g (0.150 moles) of L-(+)-isoleucine and 2 g of urea, 60 mL concentrated HCl and 30 mL concentrated HNO3 are added at room temperature. The mixture is subsequently heated for 1 hour at 80° C. and then for 1 hour at 50° C. on a water bath (complete dissolution of the acid with heavy foaming). After cooling, the solution is extracted with ether several times, the ether extract is washed with water and dried over calcium chloride, the solvent is distilled off in a rotary evaporator and the residue is fractionated under vacuum.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2[N:12]=[CH:11][C:10]([C:13](=O)[CH3:14])=[CH:9][C:8]=2[CH3:16])[CH:6]=1.[CH3:17][C:18]([S@:21]([NH2:23])=[O:22])([CH3:20])[CH3:19]>>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2[N:12]=[CH:11][C:10]([CH:13]([NH:23][S@@:21]([C:18]([CH3:20])([CH3:19])[CH3:17])=[O:22])[CH3:14])=[CH:9][C:8]=2[CH3:16])[CH:6]=1
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(=O)c1cnc(-n2cc(Cl)cn2)c(C)c1
Product: Cc1cc(C(C)N[S@](=O)C(C)(C)C)cnc1-n1cc(Cl)cn1
Yield: 57 %

Procedure:
The title compound is prepared in 57% yield (1.08 g, colorless amorphous) from 1-(6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)ethanone (1.30 g, 5.52 mmol, Step-4) and (R)-2-methylpropane-2-sulfinamide (1.00 g, 8.27 mmol) in a similar manner to Step-4 of Amine-1.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][C:6]([OH:8])=O)[CH3:2].C[Mg]Br.[CH3:13][S:14][C:15]1[N:20]=[C:19]([Cl:21])[C:18](C(Cl)=O)=[CH:17][N:16]=1.Cl>O1CCCC1.CCOCC>[CH2:1]([O:3][C:4](=[O:9])[CH2:5][C:6]([C:18]1[C:19]([Cl:21])=[N:20][C:15]([S:14][CH3:13])=[N:16][CH:17]=1)=[O:8])[CH3:2]
Reactant: CSc1ncc(C(=O)Cl)c(Cl)n1
Reactant: CCOC(=O)CC(=O)O
Agent: C[Mg]Br
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)c1cnc(SC)nc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.5 %

Procedure:
A solution of malonic acid monoethyl ester (12.3 g) dissolved in tetrahydrofuran (80 ml) was cooled with ice, and then, to the resulting solution, a solution of methylmagnesium bromide (3M) in ether (64 ml) was added dropwise. After the resultant mixture was stirred for 20 minutes, a solution of 2-methylthio-4-chloropyrimidine-5-carbonylchloride (8.6 g) dissolved in tetrahydrofuran (100 ml) was added dropwise to the mixture, which was then stirred for two hours at a room temperature. This reaction mixture was poured into ice water, and then, concentrated hydrochloric acid was added to the resulting solution so that pH might be adjusted to be 5-6, and the solution was subsequently extracted with ethyl acetate. The obtained extract was dried over anhydrous sodium sulfate, and solvent was distilled off under reduced pressure. Then, purification was conducted by silica gel column chromatography (eluent: chloroform), and thus, 3-(2-methylthio-4-chloropyrimidin-5-yl)-3-oxopropionic acid ethyl ester (8.0 g) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[N:14]=[C:15]([NH:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)[S:16][CH:17]=3)[CH:10]=[N:9]2)=[CH:5][CH:4]=1.[Cl:27]N1C(=O)CCC1=O>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[N:14]=[C:15]([NH:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)[S:16][C:17]=3[Cl:27])[CH:10]=[N:9]2)=[CH:25][CH:26]=1
Reactant: COc1ccc(Cn2cc(-c3csc(Nc4ccccn4)n3)cn2)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(Cn2cc(-c3nc(Nc4ccccn4)sc3Cl)cn2)cc1
Yield: 84.1 %

Procedure:
According to Scheme 4 Step 1 Method A: A solution of N-(4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)thiazol-2-yl)pyridin-2-amine (1.38 mmol, 500 mg) and N-chlorosuccinimide (1.38 mmol, 184 mg) in DMF (3 mL) was stirred for 1 hour at 50° C. The reaction mixture was diluted with AcOEt (250 mL) and the organic phase was washed with a saturated solution of Na2CO3. The organic phase was dried over MgSO4, was filtered and was concentrated to yield N-(4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-5-chlorothiazol-2-yl)pyridin-2-amine (1.16 mmol, 460 mg, 84%) as a beige solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:12]=2[C:13]#[N:14])=[CH:4][CH:3]=1.[CH2:19]([O:21][CH2:22]OCC)[CH3:20].CN(C)C=O.P(Cl)(Cl)(Cl)=O.[OH-].[Na+]>C(#N)C.O.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([CH2:22][O:21][CH2:19][CH3:20])[C:10]([C:15]([F:18])([F:16])[F:17])=[CH:11][C:12]=2[C:13]#[N:14])=[CH:6][CH:7]=1
Reactant: CCOCOCC
Reactant: N#Cc1cc(C(F)(F)F)[nH]c1-c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: Cc1ccccc1
Product: CCOCn1c(C(F)(F)F)cc(C#N)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
A stirred mixture of 2-(p-chlorophenyl)-5-(trifluoromethyl)pyrrole-3-carbonitrile (13.5 g, 0.05 mole), diethoxymethane (7.8 g, 0.075 mole) and dimethylformamide (5.5 g, 0.075 mole) in acetonitrile, under N2, is treated with phosphorous oxychloride (11.5 g, 0.075 mole) over a 0.25 hour period at 39°-45° C., heated at 39°-45° C. for 0.75 hour and treated dropwise with triethylmine (10.1 g, 0.10 mole) at 45°-55° C. over a 0.5 hour period. The reaction mixture is diluted with water, stirred for 16 hours at 25° C. and concentrated in vacuo to give a crude product. The crude material is stirred at reflux temperature with a mixture of toluene and dilute aqueous NaOH and cooled to room temperature. The phases are separated and the organic phase is concentrated in vacuo to give the title product as a solid, mp 83°-84.5° C., 13.1 g, 80 % yield, identified by mass spectral analysis.
Reaction SMILES: [CH3:1][O-:2].[Mg+2].C[O-].[F:6][C:7]1[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=1.C=O>CO.C1(C)C=CC=CC=1>[F:6][C:7]1[CH:12]=[CH:11][C:10]([CH:1]=[O:2])=[C:9]([OH:13])[CH:8]=1
Reactant: C[O-]
Reactant: Oc1cccc(F)c1
Agent: C=O
Agent: [Mg+2]
Solvent: Cc1ccccc1
Solvent: CO
Product: O=Cc1ccc(F)cc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.2 %

Procedure:
Magnesium methoxide (13 g, 150 mmol, 6% in methanol) in methanol (50 mL) was treated with 3-fluorophenol (22.4 g, 200 mmol). The solution was heated to reflux and approximately half the methanol distilled off. Toluene (300 mL) was added and the reaction mixture was heated with azeotropic removal of solvent until the temperature of the distillate reached 95° C. A slurry of paraformaldehyde powder (22 g, 720 mmol) in toluene (20 mL) was added in small portions over 1 hour to the reaction with concurrent removal of volatile materials by distillation. The mixture was stirred was at 95° C. for 1 hour, cooled to 25° C., quenched by slow addition to 10% sulfuric acid and stirred at 30-40° C. for 2 hours. The layers were separated and the aqueous portion extracted with toluene (2×50 mL). The organic layers were combined, washed with 10% sulfuric acid, washed with water, dried with sodium sulfate, filtered and the solvent was evaporated. The resulting yellow oil was purified by flash chromatography over silica gel eluting with hexane:ethyl acetate (5:1) to provide 9.7 g of the title compound as a white solid.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([O:11][CH3:12])=[O:10])[CH2:5][CH2:4]1.[Cl:13][CH2:14][CH2:15][CH2:16][C:17](Cl)=[O:18].C(N(CC)CC)C>ClCCl>[Cl:13][CH2:14][CH2:15][CH2:16][C:17]([NH:2][C@H:3]1[CH2:4][CH2:5][C@H:6]([C:9]([O:11][CH3:12])=[O:10])[CH2:7][CH2:8]1)=[O:18]
Reactant: COC(=O)[C@H]1CC[C@H](N)CC1
Reactant: O=C(Cl)CCCCl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H]1CC[C@H](NC(=O)CCCCl)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Methyl trans-4-aminocyclohexanecarboxylate hydrochloride (45.31 g) is suspended in dichloromethane (1000 ml), thereto is added 4-chlorobutyryl chloride (31.5 ml) under ice-cooling and to the mixture is added dropwise a solution of triethylamine (81.5 ml) in dichloromethane (80 ml). The reaction solution is warmed to room temperature, stirred for 3 hours and the reaction solution is concentrated under reduced pressure. To the resulting residue are poured ethyl acetate and 5% hydrochloric acid, and the organic layer is separated, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer is dried over sodium sulfate and treated with activated carbon, and the filtrate is concentrated under reduced pressure. The resulting residue is suspended in diisopropyl ether, filtered to collect the precipitates, dried to give methyl trans-4-(4-chlorobutyrylamino)cyclohexanecarboxylate (38.81 g).
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:46]/[O:47][C:48]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])([CH3:50])[CH3:49])/[C:27]([NH:29][CH:30]2[C:44](=[O:45])[N:32]3[C:33]([C:41]([OH:43])=[O:42])=[C:34]([CH2:37]SC#N)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:58]([NH:61]C(C)C)(C)[CH3:59].C1(C)C=CC=CC=1.C(O)(=O)C>CC#N.CCOCC>[CH2:58]([NH:61][CH2:37][C:34]1[CH2:35][S:36][C@@H:31]2[CH:30]([NH:29][C:27](=[O:28])/[C:26](/[C:24]3[N:25]=[C:21]([NH:20][C:1]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=4)[S:22][CH:23]=3)=[N:46]\[O:47][C:48]([C:51]([O:53][C:54]([CH3:56])([CH3:55])[CH3:57])=[O:52])([CH3:49])[CH3:50])[C:44](=[O:45])[N:32]2[C:33]=1[C:41]([OH:43])=[O:42])[CH3:59]
Reactant: CC(C)(C)OC(=O)C(C)(C)O/N=C(\C(=O)NC1C(=O)N2C(C(=O)O)=C(CSC#N)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: CC(C)NC(C)C
Solvent: CC(=O)O
Solvent: CC#N
Solvent: Cc1ccccc1
Product: CCNCC1=C(C(=O)O)N2C(=O)C(NC(=O)/C(=N\OC(C)(C)C(=O)OC(C)(C)C)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Yield: 92.4 %

Procedure:
7-[2-(2-tritylaminothiazol-4-yl)-2((Z)-1-t-butoxycarbonyl-1-methylethoxyimino)acetamido]-3-cyanothiomethylceph-3-em-4-carboxylic acid (10 g) was dissolved in CH3CN (100 ml) and treated, quickly, dropwise at room temperature, with a mixture of 1,3,5-THT (4.2 g, 4.6 ml) and diisopropylamine (3.1 g, 4.1 ml). After 15 min at room temperature the solution was poured into a mixture of toluene (500 ml) and glacial acetic acid (50 ml) and extracted several times with brine. The organic phase was dried over MgSO4, filtered through celite and evaporated to give a foam. Trituration of the foam with ether gave 3-ethylaminomethyl-7-[2-(2-tritylamino-thiazol-4-yl)-2((Z)-1-t-butoxycarbonyl-1-methylethoxy-imino)-acetamido]ceph-3-em-4-carboxylic acid as a granular solid (9.08 g, 92% yield) NMR (200 MHzd6DMSO+CD3COOD): 1.17(t,3H); 1.32(s,9H); 1.39(s,3H); 1.40(s,3H); 2.96 (q,2H); 3.54(d,1H); 3.59(d,1H); 3.65(d,1H); 3.86(d,1H); 5.08(d,1H); 5.69(d,1H); 6.68(s,1H); 7.1-7.4(m,15H).
Reaction SMILES: Cl.[Cl:2][C:3]1[N:4]=[C:5]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]2[CH3:18])[C:6]2[CH2:11][NH:10][CH2:9][C:7]=2[N:8]=1.[CH3:19][C:20]([CH:23]=O)([CH3:22])[CH3:21].C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.C(OCC)(=O)C.O>[Cl:2][C:3]1[N:4]=[C:5]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]2[CH3:18])[C:6]2[CH2:11][N:10]([CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:9][C:7]=2[N:8]=1
Reactant: CC(C)(C)C=O
Reactant: C[C@H]1COCCN1c1nc(Cl)nc2c1CNC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@H]1COCCN1c1nc(Cl)nc2c1CN(CC(C)(C)C)C2
Reaction time: 8 h

Procedure:
(S)-4-(2-chloro-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)-3-methylmorpholine hydrochloride (intermediate 6) (163 mg, 0.56 mmol) was stirred in THF (2 mL) with pivaldehyde (0.124 mL, 1.12 mmol) and triethylamine (0.234 mL, 1.68 mmol). After 1 h sodium triacetoxyborohydride (237 mg, 1.12 mmol) was added and the reaction was stirred overnight. Water and ethyl acetate were added. The organic layer was washed (brine) and concentrated in vacuo to give an orange oil, which was used crude.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([Cl:15])[C:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[N:6][CH:7]=1.[C:16]([Zn]C#N)#[N:17].N#N.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>CN(C=O)C.[Zn].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]>[Cl:15][C:4]1[C:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[N:6][CH:7]=[C:2]([C:16]#[N:17])[CH:3]=1
Reactant: CC(C)(C)OC(=O)c1ncc(Br)cc1Cl
Reactant: N#C[Zn]C#N
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: N#N
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1ncc(C#N)cc1Cl
Temperature: 95 °C

Procedure:
A mixture of tert-butyl 5-bromo-3-chloropicolinate (12 g, 41.0 mmol), dicyanozinc (3.37 g, 28.7 mmol), and zinc (0.375 g, 5.74 mmol) were suspended in DMF (82 ml) in round bottom flak. The suspension was purged with N2 and finally Pd2(dba)3 (1.878 g, 2.051 mmol), tri-tert-butylphosphine (6.2 ml, 6.15 mmol) and neat tri-tert-butylphosphine (300 mg), was added under the Ar. The r×n mixture was heated to 95° C. for 3 h. Then another 2.8 g of Pd2(dba)3 and 1.2 g of neat P ligand were added. 3.5 h later, it was cooled to RT and black precipitate was filtered out by filtration. The filtrate was diluted with 150 ml of MTBE. The organic layer was washed with 100 ml of water and brine. It was dried on MgSO4 and concentrated which was carried over to next step directly. MS m/z=261.0/263.0 (M+Na).
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH3:17])[N:15]=2)[C:10](=[O:18])[C:9]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:8]1)=[O:6])([CH3:3])[CH3:2].[CH2:24]([Mg]Br)[CH3:25].[Cl-].[NH4+]>C1COCC1.[Cu]I>[CH:1]([O:4][C:5]([N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH3:17])[N:15]=2)[C:10](=[O:18])[CH:9]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:8]1[CH2:24][CH3:25])=[O:6])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cn(C(=O)OC(C)C)c2nc(C)ccc2c1=O
Reactant: CC[Mg]Br
Agent: [Cu]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)C1C(=O)c2ccc(C)nc2N(C(=O)OC(C)C)C1CC
Temperature: -78 °C
Yield: 54 %

Procedure:
Mix 7-methyl-4-oxo-4H-[1,8]naphthyridine-1,3-dicarboxylic acid 3-ethyl ester 1-isopropyl ester (1.21 g, 3.80 mmol) and copper(I) iodide (1.59 g, 8.36 mmol) in THF (75 ml). Cool the mixture to −78° C. Inject ethyl magnesium bromide (3.0 M in diethyl ether, 7.60 ml) and stir for 2 h. Warm up to −20° C. and keep the reaction at that temperature for 3 h. Pour the reaction mixture into saturated ammonium chloride solution (100 ml). Extract with ethyl acetate (3×100 ml). Combine the organic layers, dry over sodium sulfate, filter and concentrate. Purify using silica gel column chromatography (gradient eluent, 0-60% ethyl acetate in hexane) to provide 2-ethyl-7-methyl-4-oxo-3,4-dihydro-2H-[1,8]naphthyridine-1,3-dicarboxylic acid 3-ethyl ester 1-isopropyl ester (0.715 g, 54%). MS (ES+): 349 (M+H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]([NH2:16])=[O:15])[O:11][N:10]=2)=[CH:5][CH:4]=1.[F:17][C:18]([F:28])([F:27])[O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[OH:26].C([O-])([O-])=O.[K+].[K+]>CC#N>[F:17][C:18]([F:27])([F:28])[O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]([NH2:16])=[O:15])[O:11][N:10]=2)=[CH:5][CH:4]=1
Reactant: Oc1ccccc1OC(F)(F)F
Reactant: NC(=O)c1cc(-c2ccc(CBr)cc2)no1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: NC(=O)c1cc(-c2ccc(COc3ccccc3OC(F)(F)F)cc2)no1
Temperature: 90 °C
Yield: 74.1 %

Procedure:
To a mixture of 3-(4-bromomethyl-phenyl)-isoxazole-5-carboxylic acid amide (which may be prepared as described in Preparation of Intermediate 14; 30 mg, 0.107 mmol) in CH3CN (2 mL) were added 2-trifluoromethoxyphenol (25 μL, 0.187 mmol) and K2CO3 (30 mg, 0.22 mmol). The mixture was heated at 90° C. for 16 h and then evaporated to dryness. The residue was purified by chromatography (66-75% EtOAc/hexanes) to give 3-[4-(2-trifluoromethoxy-phenoxymethyl)-phenyl]-isoxazole-5-carboxylic acid amide (30 mg, 74%) as a white powder. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.39 (br. s., 1H), 8.01 (br. s., 1H), 7.94 (d, J=8.4 Hz, 2H), 7.54-7.63 (m, 3H), 7.26-7.41 (m, 3H), 6.97-7.07 (m, 1H), 5.29 (s, 2H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:30]=[CH:29][C:6]([NH:7]/[C:8](=[C:15]2\[C:16](=[O:28])[NH:17][C:18]3[C:23]\2=[CH:22][CH:21]=[C:20]([C:24]([O:26][CH3:27])=[O:25])[CH:19]=3)/[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[CH3:31][S:32](Cl)(=[O:34])=[O:33].C(N(CC)CC)C>>[CH3:31][S:32]([NH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([NH:7]/[C:8](=[C:15]2\[C:16](=[O:28])[NH:17][C:18]3[C:23]\2=[CH:22][CH:21]=[C:20]([C:24]([O:26][CH3:27])=[O:25])[CH:19]=3)/[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:29][CH:30]=1)(=[O:34])=[O:33]
Reactant: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CN)cc1)c1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CNS(C)(=O)=O)cc1)c1ccccc1

Procedure:
Prepared from 3-Z-[1-(4-aminomethyl-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone and methanesulphonyl chloride/triethylamine Rf value: 0.7 (silica gel, methylene chloride/methanol=5:1) C25H23N3O5S
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][CH2:16][C@H:8]3[C:7](=[O:17])[NH:6][C:5]=2[CH:4]=1.Cl.Cl.[CH:20]1([NH:23][C:24](=[O:38])[C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)=[C:27]([CH3:37])[CH:26]=2)[CH2:22][CH2:21]1.[I-].C(C[P+](C)(C)C)#N.C(N(CC)C(C)C)(C)C>C(#N)CC>[CH:20]1([NH:23][C:24](=[O:38])[C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH2:32][CH2:33][N:34]([CH2:2][C:3]4[CH:12]=[N:11][C:10]5[N:9]6[CH2:13][CH2:14][CH2:15][CH2:16][C@H:8]6[C:7](=[O:17])[NH:6][C:5]=5[CH:4]=4)[CH2:35][CH2:36]3)=[C:27]([CH3:37])[CH:26]=2)[CH2:22][CH2:21]1
Reactant: Cc1cc(C(=O)NC2CC2)ccc1N1CCNCC1
Reactant: O=C1Nc2cc(CO)cnc2N2CCCC[C@@H]12
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)NC2CC2)ccc1N1CCN(Cc2cnc3c(c2)NC(=O)[C@@H]2CCCCN32)CC1
Temperature: 90 °C
Yield: 24.9 %

Procedure:
(S)-3-(hydroxymethyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one (100 mg, 0.429 mmol), N-cyclopropyl-3-methyl-4-(piperazin-1-yl)benzamide dihydrochloride (143 mg, 0.430 mmol), (cyanomethyl)trimethylphosphonium iodide (167 mg, 0.686 mmol) and N,N-diisopropylethylamine (374 μl, 2.143 mmol) were suspended in Propiononitrile (Volume: 1287 μl) and heated in a closed vial at 90° C. for 4 h. The reaction mixture became a dark brown solution. It was cooled to room temperature and purified using HPLC (NH4HCO3 buffered, 20-70% ACN in water). The fractions were concentrated in vacuo and the resulting solid was recrystallized from MeCN (20 mL), filtered off, washed with water (2 mL) and dried in vacuum to afford (S)-N-cyclopropyl-3-methyl-4-(4-((6-oxo-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide (50.7 mg, 0.107 mmol, 24.92% yield) as a light brown solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.49-0.59 (m, 2 H) 0.60-0.71 (m, 2 H) 1.33-1.57 (m, 3 H) 1.64 (d, J=12.88 Hz, 1 H) 1.85 (d, J=12.63 Hz, 1 H) 2.04 (d, J=12.88 Hz, 1 H) 2.25 (s, 3 H) 2.42-2.56 (m, 4 H) 2.60 (td, J=12.63, 2.78 Hz, 1 H) 2.76-2.93 (m, 5 H) 3.38 (s, 2 H) 3.84 (dd, J=11.37, 2.78 Hz, 1 H) 4.50 (d, J=13.14 Hz, 1 H) 6.98 (d, J=2.02 Hz, 1 H) 7.00 (d, J=8.34 Hz, 1 H) 7.56-7.63 (m, 2 H) 7.66 (d, J=2.02 Hz, 1 H) 8.22 (d, J=4.29 Hz, 1 H) 10.49 (s, 1 H); [M+H] calc'd for C27H34N6O2, 475; found, 475.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:23]2[CH2:27][C@H:26]([CH2:28][NH:29][C:30](=[O:32])[CH3:31])[O:25][C:24]2=[O:33])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[N:17]=2)=[O:14])[N:10]=[CH:9]1.[C:34](OC(=O)C)(=[O:36])[CH3:35]>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([N:23]2[CH2:27][C@H:26]([CH2:28][NH:29][C:30](=[O:32])[CH3:31])[O:25][C:24]2=[O:33])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:34](=[O:36])[CH3:35])[N:17]=2)=[O:14])[N:10]=[CH:9]1
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)NC[C@H]1CN(c2ccc(-n3cnc(C(=O)Nc4cccc(N)n4)c3)c(F)c2)C(=O)O1
Solvent: c1ccncc1
Product: CC(=O)NC[C@H]1CN(c2ccc(-n3cnc(C(=O)Nc4cccc(NC(C)=O)n4)c3)c(F)c2)C(=O)O1
Reaction time: 60 h

Procedure:
N-[(5S)-3-(3-Fluoro-4-(4-(6-aminopyridin-2-ylaminocarbonyl)imidazol-1-yl)phenyl)-2-oxooxazolidin-5-ylmethyl]acetamide (70 mg, 0.15 mM) was dissolved in pyridine (3 ml) and treated with acetic anhydride (0.5 ml). After standing 60 hours at ambient temperature, solvent was evaporated, and the residue triturated with water (10 ml). Filtration gave the title product (47 mg).
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[CH2:9]([N:16]1[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CCCCCCC.CS(C)=O>[CH2:9]([N:16]1[CH2:21][CH2:20][C:19]2([O:22][CH2:4]2)[CH2:18][CH2:17]1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: C[S+](C)(C)=O
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCCCCCC
Product: c1ccc(CN2CCC3(CC2)CO3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium hydride (55% suspension in mineral oil, 1.57 g, 35 mmol) was washed with heptane, dried in the stream of nitrogen and suspended in dry DMSO (10 ml). A solution of trimethylsulfoxonium iodide (4.8 g, 22 mmol) in DMSO (45 ml) was added dropwise under nitrogen. After stirring for 20 min a solution of 1-benzylpiperidin-4-one (3.78 g, 20 mmol) was added dropwise. The mixture was stirred overnight at room temperature, then poured over ice (200 g), and extracted with dichloromethane (2×200 ml). The combined extracts were washed with water (3×100 ml) and dried over Na2SO4. The solvent was removed i. vacuo. The residue was dissolved in diethyl ether, and the insoluble material was removed by filtration. Evaporation of solven afforded pale-yellow oil (2.95 g, 73%).