Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[C:13][C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20]CC)=[O:19])=[CH:16][CH:15]=3)[CH:10]=2)[N:5]=[C:4]([S:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:3]1.[Li+].[OH-].CC1(C)C2C(=CC=C(C#CC3C=CC(C(O)=O)=CC=3)C=2)N=C(OC(C)C)C1>C1COCC1.CCO>[CH3:1][C:2]1([CH3:33])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[C:13][C:14]3[CH:15]=[CH:16][C:17]([C:18]([OH:20])=[O:19])=[CH:23][CH:24]=3)[CH:10]=2)[N:5]=[C:4]([S:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:3]1
Reactant: CCCCCCCSC1=Nc2ccc(C#Cc3ccc(C(=O)OCC)cc3)cc2C(C)(C)C1
Agent: CC(C)OC1=Nc2ccc(C#Cc3ccc(C(=O)O)cc3)cc2C(C)(C)C1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCCCCCSC1=Nc2ccc(C#Cc3ccc(C(=O)O)cc3)cc2C(C)(C)C1

Procedure:
0.0647 g (0.140 mmol) of ethyl 4-[(4,4-dimethyl-2-heptylthio-3,4-dihydro-6-quinolinyl)ethynyl]benzoate (Compound 10) in 2 ml of THF, 1 ml of EtOH was reacted with 2 ml of 1N LiOH substantially in accordance with the procedure used for the preparation of 4-[(4,4-dimethyl-2-iso-propoxy-3,4-dihydro-6-quinolinyl)ethynyl]benzoic acid (Compound 11). Purification by recrystallization in acetonitrile yielded the title compound as a yellow powder.
Reaction SMILES: CO[C:3](=[O:20])[CH2:4][NH:5][CH2:6][CH2:7][NH:8][C:9]([C:11]1[C:16]([NH2:17])=[N:15][C:14]([NH2:18])=[C:13]([Cl:19])[N:12]=1)=[O:10].[CH2:21]([NH2:24])[CH2:22][NH2:23]>>[NH2:17][C:16]1[C:11]([C:9]([NH:8][CH2:7][CH2:6][NH:5][CH2:4][C:3]([NH:23][CH2:22][CH2:21][NH2:24])=[O:20])=[O:10])=[N:12][C:13]([Cl:19])=[C:14]([NH2:18])[N:15]=1
Reactant: NCCN
Reactant: COC(=O)CNCCNC(=O)c1nc(Cl)c(N)nc1N
Product: NCCNC(=O)CNCCNC(=O)c1nc(Cl)c(N)nc1N
Yield: 100 %

Procedure:
A solution of 7.45 g (24.6 mmol) of N-[2-[[(3,5-diamino-6-chloropyrazinyl)carbonyl]amino]ethyl]glycine methyl ester and 22.48 ml (373.9 mmol) of ethylenediamine was stirred at ambient temperature for two days. The excess diamine was evaporated. There was obtained 8.14 g (24.6 mmol, 100%) of 3,5-diamino-N-[2-[[2-[(2-aminoethyl)amino]2-oxoethyl]amino]ethyl]-6-chloropyrazinecarboxamide as a yellow solid: Rf=0.28, Solvent System A.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:12][C:13]([F:32])([F:31])[C:14]1([CH2:17][CH:18]([C:21]2[CH:22]=[N:23][C:24]([C:27]([F:30])([F:29])[F:28])=[N:25][CH:26]=2)[CH2:19][NH2:20])[CH2:16][CH2:15]1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:20][CH2:19][CH:18]([C:21]1[CH:22]=[N:23][C:24]([C:27]([F:30])([F:29])[F:28])=[N:25][CH:26]=1)[CH2:17][C:14]1([C:13]([F:12])([F:31])[F:32])[CH2:16][CH2:15]1)=[O:6]
Reactant: NCC(CC1(C(F)(F)F)CC1)c1cnc(C(F)(F)F)nc1
Reactant: O=C(O)c1cccc(Cl)c1Cl
Product: O=C(NCC(CC1(C(F)(F)F)CC1)c1cnc(C(F)(F)F)nc1)c1cccc(Cl)c1Cl

Procedure:
From 2,3-dichlorobenzoic acid and 3-(1-(trifluoromethyl)cyclopropyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)propan-1-amine. LCMS (MH+): m/z=486.1, tR (minutes, Method F)=2.77
Reaction SMILES: CC1C=CC(S(O)(=O)=O)=CC=1.[NH2:12][C@H:13]1[CH:16]([C:17]#[N:18])[NH:15][C:14]1=[O:19].N1C=CC=CC=1.[C:26]1([CH2:32][C:33](Cl)=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(Cl)Cl.O>[C:17]([C@H:16]1[NH:15][C:14](=[O:19])[C@H:13]1[NH:12][C:33](=[O:34])[CH2:32][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)#[N:18]
Reactant: N#CC1NC(=O)[C@H]1N
Reactant: O=C(Cl)Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: N#C[C@H]1NC(=O)[C@H]1NC(=O)Cc1ccccc1
Temperature: 25 °C

Procedure:
In 100 ml of methylene chloride were dissolved under ice-cooling 5 g of p-toluenesulfonate of (3S, 4RS)-3-amino-4-cyano-2-azetidinone and 4.2 g of pyridine. To the solution was added 3 g of phenylacetyl chloride. The mixture was stirred at room temperature (about 25° C.) for ten minutes, which was shaken with water. The organic layer was separated and dried on anhydrous magnesium sulfate, then concentrated under reduced pressure. The concentrate was purified on a silicagel column chromatography [ethyl acetate:n-hexane (2:1)] to yield 1.16 g of (3S, 4S)-4-cyano-3-phenylacetamido-2-azetidinone (A) and subsequently 0.84 g of a corresponding (3S, 4R)-derivative (B).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[I:8][CH2:9][CH3:10]>>[I-:8].[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N+:3]=1[CH2:9][CH3:10]
Reactant: Nc1ccccn1
Reactant: CCI
Product: CC[n+]1ccccc1N
Product: [I-]

Procedure:
In a 1 L three-necked flask fitted with a reflux condenser were placed 28.2 g of 2-aminopyridine and 60.8 g of iodoethane, and the mixture was stirred under reflux for 2 hours. The reaction mixture was stirred at room temperature for another hour, and the resulting precipitate was filtered under reduced pressure and washed with ethyl acetate (50 ml×2). The residue was dried at room temperature for 3 hours.
Reaction SMILES: [CH2:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[CH2:4][CH:3]=[CH:2]1.CCN(CC)CC.Cl[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>C(Cl)Cl>[CH2:4]1[C:5]2([CH2:10][CH2:9][N:8]([C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])[CH2:7][CH2:6]2)[CH2:1][CH:2]=[CH:3]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C1=CCC2(C1)CCNCC2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCC2(CC=CC2)CC1
Reaction time: 1 h
Yield: 70.9 %

Procedure:
To a solution of 8-azaspiro[4.5]dec-2-ene (2.74 g, 20 mmol) in Et3N (4.2 mL, 30 mmol) and DCM (100 mL) at 0° C. was added dropwise benzyl chloroformate (3.4 mL, 24 mmol). After 1 h, the solution was partitioned between H2O-DCM and the aqueous phase was extracted several times with DCM. The combined organic fractions were dried (Na2SO4), concentrated and purified via column chromatography (silica, 10% EtOAc in hexanes) yielding the title compound (3.85 g, 71%) as a yellow oil: LCMS (ES) m/e 272 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:23](O)=[O:24])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([Br:22])[CH:16]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][C:32]=1[N:33]1[CH2:38][C@H:37]([C:39]([F:42])([F:41])[F:40])[CH2:36][C@H:35]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[CH2:34]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:22][C:17]1[CH:16]=[C:15]2[C:20]([CH:21]=[C:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:13]([C:23]([NH:26][C:27]3[CH:28]=[N:29][CH:30]=[CH:31][C:32]=3[N:33]3[CH2:38][C@H:37]([C:39]([F:41])([F:40])[F:42])[CH2:36][C@H:35]([NH:43][C:44]([O:45][C:46]([CH3:47])([CH3:49])[CH3:48])=[O:50])[CH2:34]3)=[O:24])=[N:14]2)=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](C(F)(F)F)CN(c2ccncc2N)C1
Reactant: O=C(Nc1cc2ccc(Br)cc2nc1C(=O)O)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](C(F)(F)F)CN(c2ccncc2NC(=O)c2nc3cc(Br)ccc3cc2NC(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.1 %

Procedure:
To a mixture of 3-{[(benzyloxy)carbonyl]amino}-7-bromoquinoline-2-carboxylic acid (0.50 g, 1.2 mmol), tert-butyl [(3S,5R)-1-(3-aminopyridin-4-yl)-5-(trifluoromethyl)piperidin-3-yl]carbamate (0.45 g, 1.2 mmol) and HATU (1.2 g, 3.1 mmol) in DMF (4.9 mL), DIPEA (0.65 mL, 3.7 mmol) was added. The mixture was stirred at room temperature for 2 h, then quenched with 50 mL of EtOAc and 30 mL of 1 M NaOH. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organics were concentrated under reduced pressure. The residue was purified by flash chromatography on a 40 g silica gel column, eluting with 0-100% EtOAc in hexanes, to give the sub-title compound (0.492 g, 53%). LCMS calc. for C34H35BrF3N6O5 [M+H]+: m/z=743.2. found: 743.3.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].Cl[C:13]1[C:14]2[C:27]([CH3:28])=[CH:26][S:25][C:15]=2[N:16]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[N:18]=1>>[N:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:17]1[N:18]=[C:13]([NH:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:14]2[C:27]([CH3:28])=[CH:26][S:25][C:15]=2[N:16]=1
Reactant: Cc1csc2nc(-c3ccccn3)nc(Cl)c12
Reactant: NCc1cccc([N+](=O)[O-])c1
Product: Cc1csc2nc(-c3ccccn3)nc(NCc3cccc([N+](=O)[O-])c3)c12

Procedure:
With the procedure of Example 1, the reaction of 3-nitrobenzylamine with 4-chloro-2-(pyridin-2-yl)-5-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-(3-nitrobenzylamino)-5-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Mg].BrCCBr.Br[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:15][N:16]1[C:22]2[CH:23]=[CH:24][N:25]=[CH:26][C:21]=2[N:20]=[CH:19][C:18]2=[CH:27][CH:28]=[CH:29][N:17]12.[Cl-].[NH4+]>C(OCC)C.O1CCCC1>[CH3:15][N:16]1[C:22]2[CH:23]=[CH:24][N:25]=[CH:26][C:21]=2[NH:20][CH:19]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:18]2=[CH:27][CH:28]=[CH:29][N:17]12
Reactant: BrCCc1ccccc1
Reactant: CN1c2ccncc2N=Cc2cccn21
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: BrCCBr
Solvent: C1CCOC1
Solvent: CCOCC
Product: CN1c2ccncc2NC(CCc2ccccc2)c2cccn21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 2.8 g of magnesium turnings in 20 ml of diethyl ether and 20 ml of tetrahydrofuran was added 1 ml of 1,2-dibromoethane followed by 13.94 ml of 2-bromoethylbenzene (dropwise). After initiating the reaction with external heat, the mixture was stirred at room temperature for one hour and then treated, dropwise, with a solution of 10.0 g of 5-methyl-5H-pyrido[3,4-f]-pyrrolo[1,2-b][1,2,5]triazepine in 100 ml of tetrahydrofuran. The reaction mixture was then stirred at room temperature for two hours, poured into an iced ammonium chloride solution, stirred for five minutes, and extracted with ethyl acetate. The organic layer was washed with water followed by a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The concentrate was purified by means of high pressure liquid chromatography (silica gel; elution with ethyl acetate). Flash chromatography of the resultant oil (silica gel; elution with 10% methanol/dichloromethane) afforded a solid which was recrystallized from diethyl ether/ethyl acetate (10:1) to yield 1.25 g of 10,11-dihydro-5-methyl-10-(2-phenylethyl)-5H-pyrido[3,4-f]pyrrolo[1,2-b][1,2,5]triazepine, mp 92°-94° C.
Reaction SMILES: FC(F)(F)C([O-])=O.[N:8]1([C:12]2[NH+:17]=[C:16]([CH2:18][N:19]3[C@@H:23]([CH3:24])[C@@H:22]([C:25]4[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([C:35]([F:38])([F:37])[F:36])[CH:26]=4)[O:21][C:20]3=[O:39])[C:15]([C:40]3[CH:45]=[C:44]([CH2:46][C:47]#[N:48])[CH:43]=[CH:42][C:41]=3[O:49][CH3:50])=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1.Cl.C(N(CC)CC)C.[N-:59]=[N+:60]=[N-:61].[Na+].O>CN1C(=O)CCC1>[N:8]1([C:12]2[N:17]=[C:16]([CH2:18][N:19]3[C@@H:23]([CH3:24])[C@@H:22]([C:25]4[CH:26]=[C:27]([C:35]([F:36])([F:37])[F:38])[CH:28]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:30]=4)[O:21][C:20]3=[O:39])[C:15]([C:40]3[CH:45]=[C:44]([CH2:46][C:47]4[N:59]=[N:60][NH:61][N:48]=4)[CH:43]=[CH:42][C:41]=3[O:49][CH3:50])=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc(CC#N)cc1-c1ccc(N2CCC2)[nH+]c1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Agent: Cl
Agent: O=C([O-])C(F)(F)F
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(Cc2nn[nH]n2)cc1-c1ccc(N2CCC2)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 150 °C
Reaction time: 72 h

Procedure:
A mixture of 6-azetidin-1-yl-2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-3-[5-(cyanomethyl)-2-methoxyphenyl]pyridinium trifluoroacetate (EXAMPLE 256) (15 mg, 0.021 mmol), triethylamine hydrochloride (15 mg, 0.109 mmol), and sodium azide (30 mg, 0.461 mmol) in NMP (2 ml) was stirred at 150° C. under nitrogen for 3 days. Water was added and the mixture extracted 2 times with ethyl acetate. The combined organics were washed with brine, dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by RP HPLC to afford the title compound. Mass spectrum (ESI) 648.3 (M+1). 1H NMR (500 MHz, CD3OD): δ 7.97 (s, 1H); 7.88 (s, 2H); 7.30 (d, J=8.4 Hz, 1H); 7.26 (m, 1H); 7.08 (s, 1H); 7.01 (d, J=8.5 Hz, 1H); 6.34 (d, J=8.4 Hz, 1H); 5.70 (m, 1H); 4.62 (d, J=14.3 Hz, 1H); 4.25 (s, 2H); 4.20 (s, 1H); 4.04 (t, J=7.4 Hz, 4H); 3.86 (br s, 1H); 3.77 (s, 3H); 2.43-2.36 (m, 2H); 0.59 (m, 3H).
Reaction SMILES: [C:1]([O:4][CH:5]1[CH2:9][CH2:8][C:7]([CH:25]([O:27][C:28](=[O:30])[CH3:29])[CH3:26])([C:10]([NH:12][CH2:13][C:14]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:15]=2[OH:24])=[O:11])[CH2:6]1)(=[O:3])[CH3:2].C=O.S(O)([C:36]1C=CC(C)=CC=1)(=O)=O.O>C1(C)C=CC=CC=1>[C:1]([O:4][CH:5]1[CH2:9][CH2:8][C:7]([CH:25]([O:27][C:28](=[O:30])[CH3:29])[CH3:26])([C:10]([N:12]2[CH2:13][C:14]3[CH:19]=[C:18]([C:20]([F:22])([F:21])[F:23])[CH:17]=[CH:16][C:15]=3[O:24][CH2:36]2)=[O:11])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1CCC(C(=O)NCc2cc(C(F)(F)F)ccc2O)(C(C)OC(C)=O)C1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: C=O
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)OC1CCC(C(=O)N2COc3ccc(C(F)(F)F)cc3C2)(C(C)OC(C)=O)C1

Procedure:
3-[1-(Acetyloxy)ethyl]-3-({[2-hydroxy-5-(trifluoromethyl)benzyl]amino}carbonyl)cyclopentyl acetate was combined with paraformaldehyde (ca. 6 g) and TsOH H2O (ca. 100 mg) in 130 mL of toluene. The flask was equipped with a Dean Stark trap and condenser and the reaction mixture was stirred at reflux for 1.5 h. The reaction mixture was filtered to remove remaining paraformaldehyde and the filtrate was concentrated. Purification of the resulting residue was accomplished by MPLC (silica, 65% ethyl acetate/hexanes) to afford 3-[1-(acetyloxy)ethyl]-3-{[6-(trifluoromethyl)-2H-1,3-benzoxazin-3(4H)-yl]carbonyl}cyclopentyl acetate as a mixture of 8 diasteomers.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=[C:10]([C:20]([OH:22])=O)[CH:9]=2)=[CH:4][CH:3]=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.[CH3:55][O:56][C:57]1[CH:61]=[C:60]([CH2:62][NH2:63])[O:59][N:58]=1>CN(C)C=O>[CH3:55][O:56][C:57]1[CH:61]=[C:60]([CH2:62][NH:63][C:20]([C:10]2[CH:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[C:13]([O:14][CH2:15][C:16]([F:19])([F:17])[F:18])=[CH:12][N:11]=2)=[O:22])[O:59][N:58]=1
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)cn1
Reactant: COc1cc(CN)on1
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: COc1cc(CNC(=O)c2cc(-c3ccc(Cl)cc3)c(OCC(F)(F)F)cn2)on1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.1 %

Procedure:
4-(4-Chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (100 mg, 0.3 mmol, example D) was dissolved in dimethylformamide (4 mL). To this stirred solution under argon was added in sequence 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (107 mg, 0.3 mmol), N,N-diisopropyl ethyl amine (0.26 mL, 1.5 mmol) and 3-methoxy-5-isoxazolemethanamine hydrochloride (55 mg, 0.3 mmol). The mixture was shaken for 16 h at room temperature, solvent was removed in vacuo (45° C.) and the residue was digested with dichloromethane (5 mL) and 2N NaOH (1.5 mL) for 5 min. The mixture was absorbed onto 10 g ChemElut (Varian) and eluted with dichloromethane (70 mL). Solvent was evaporated and the brown, oily residue (160 mg) was purified by gradient chromatography on silica with ethyl acetate/n-heptane to give the title compound as a white solid (122 mg, 92%), LC-MS (UV peak area/ESI) 93%, 442.0769 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2([C:22]([OH:24])=[O:23])[CH2:21][CH2:20]2)=[CH:15][CH:14]=1.CC(=CC)C.Cl([O-])=[O:31].[Na+].O.O.P([O-])(O)(O)=O.[Na+]>CC#N.O.C(O)(C)(C)C>[C:22]([C:19]1([C:16]2[CH:17]=[CH:18][C:13]([C:3]3[CH:4]=[C:5]4[C:9](=[CH:10][C:2]=3[Cl:1])[NH:8][CH:7]=[C:6]4[C:11]([OH:31])=[O:12])=[CH:14][CH:15]=2)[CH2:20][CH2:21]1)([OH:24])=[O:23]
Reactant: [O-][Cl+][O-]
Reactant: O=Cc1c[nH]c2cc(Cl)c(-c3ccc(C4(C(=O)O)CC4)cc3)cc12
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: CC#N
Solvent: O
Product: O=C(O)c1c[nH]c2cc(Cl)c(-c3ccc(C4(C(=O)O)CC4)cc3)cc12
Temperature: 0 °C
Yield: 30.4 %

Procedure:
1-[4-(6-chloro-3-formyl-1H-indol-5-yl)phenyl]cyclopropanecarboxylic acid (253 mg, 0.577 mmol) was dissolved in MeCN (6 mL) and warm t-butanol (6 mL). 2-methyl-2-butene (4 mL) was added and the mixture was cooled to 0° C. Sodium chlorite (780 mg, 11.6 mmol) and sodium dihydrogen phosphate dihydrate (1800 mg, 11.54 mmol) were dissolved in water (4 mL). The aqueous solution was added to the organic solution dropwise via addition funnel and the ice bath was removed and the mixture was allowed to warm to room temperature overnight. The reaction was concentrated to remove the organics and extracted with ethyl acetate (20 mL×3). The combined organics were washed with brine (20 mL), dried and concentrated and then purified by reverse phase HPLC to give the title compound (62.4 mg, 30.5% yield) as a white solid. MS (AP+) 377.9 (M+Na)+. 1H NMR (400 MHz, CD3OD) δ 8.02 (s, 1H), 8.00 (s, 1H), 7.57 (s, 1H), 7.40 (m, 4H), 1.61 (m, 2H), 1.27 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[C:15]([CH3:22])[C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([O:13]C)=[C:9]([CH:12]=1)[CH:10]=[O:11].B(Br)(Br)Br.C(OCC)(=O)C.O>ClCCl>[Cl:1][C:2]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[C:15]([CH3:22])[C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([OH:13])=[C:9]([CH:12]=1)[CH:10]=[O:11]
Reactant: COc1ccc(Oc2c(C)cc([N+](=O)[O-])cc2Cl)cc1C=O
Agent: BrB(Br)Br
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: Cc1cc([N+](=O)[O-])cc(Cl)c1Oc1ccc(O)c(C=O)c1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 90.4 %

Procedure:
To a cooled (−78° C.), stirred solution of 5-(2-chloro-6-methyl-4-nitro-phenoxy)-2-methoxy-benzaldehyde (10 g) in dichloromethane (300 mL) was added boron tribromide (23.3 g) dropwise. The reaction was allowed to warm to ambient temperature, stirred for 1.5 h, ice was added to quench the reaction and work up was done with ethyl acetate/water. The organic layer was dried over sodium sulfate, concentrated in vacuo and the resulting oil filtered through a plug of silica gel (eluting with chloroform) to afford 5-(2-chloro-6-methyl-4-nitro-phenoxy)-2-hydroxy-benzaldehyde (8.65 g) as an off-white solid.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[S:13][N:12]=[C:11]([C:14](=[N:32][O:33][CH3:34])[C:15]([NH:17][C@@H:18]2[C:30](=[O:31])[N:20]3[C:21]([C:27]([OH:29])=[O:28])=[C:22]([CH2:25]Cl)[CH2:23][S:24][C@H:19]23)=[O:16])[N:10]=1.[CH3:35][N:36]1[CH2:41][CH2:40][N:39](C(OC(C)(C)C)=O)[CH2:38][CH2:37]1.C(OCC)(=O)C>CN(C)C=O>[NH2:8][C:9]1[S:13][N:12]=[C:11]([C:14](=[N:32][O:33][CH3:34])[C:15]([NH:17][C@@H:18]2[C:30](=[O:31])[N:20]3[C:21]([C:27]([O-:29])=[O:28])=[C:22]([CH2:25][N+:36]4([CH3:35])[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]4)[CH2:23][S:24][C@H:19]23)=[O:16])[N:10]=1
Reactant: CN1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CCl)CS[C@H]12)c1nsc(N)n1
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[N+]3(C)CCNCC3)CS[C@H]12)c1nsc(N)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-chloromethyl-3-cephem-4-carboxylic acid trifluoroacetate (syn isomer) in N,N-dimethylformamide (150 ml) was added 1-methyl-4-tert-butoxycarbonylpiperazine (30 g). After being stirred at room temperature for 30 minutes, the mixture was added dropwise to ethyl acetate (1.5 l). The resulting precipitate was collected by filtration, washed with ethyl acetate and diisopropyl ether. To a solution of the above precipitate in a mixture of methylene chloride (6e ml) and anisole (20 ml) was added dropwise trifluoroacetic acid (40 ml) under ice-cooling. The reaction mixture was stirred at room temperature for 2 hours and added to diisopropyl ether (1.5 l) under stirring. The resultant precipitate was collected by filtration and dissolved in aqueous sodium bicarbonate, and the solution was adjusted to pH 4.0 with hydrochloric acid and subjected to column chromatography on "Diaion HP-20" (Trademark:prepared by Mitsubishi Chemical Industries) with 5% aqueous isopropyl alcohol as an eluent. The eluate was lyophilized to give 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-(1-methyl-1-piperazinio)methyl-3-cephem-4-carboxylate (syn isomer) (12.00 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:31]=[C:32]([NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH:33]=1)[C:12]([C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]([CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:15]=1)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:44]([C:48]1[CH:55]=[CH:54][C:51]([CH2:52]Cl)=[CH:50][CH:49]=1)[CH:45]([CH3:47])[CH3:46].Cl>CN(C)C=O.C(OCC)(=O)C>[CH2:44]([C:48]1[CH:55]=[CH:54][C:51]([CH2:52][N:34]([C:32]2[CH:31]=[C:11]([CH:10]=[C:9]([N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:52][C:51]3[CH:54]=[CH:55][C:48]([CH2:44][CH:45]([CH3:47])[CH3:46])=[CH:49][CH:50]=3)[CH:33]=2)[C:12]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:15]=2)=[O:13])[C:35]([O:37][C:38]([CH3:40])([CH3:39])[CH3:41])=[O:36])=[CH:50][CH:49]=1)[CH:45]([CH3:47])[CH3:46]
Reactant: CCOC(=O)CCCn1cc(C(=O)c2cc(NC(=O)OC(C)(C)C)cc(NC(=O)OC(C)(C)C)c2)c2ccccc21
Reactant: CC(C)Cc1ccc(CCl)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCn1cc(C(=O)c2cc(N(Cc3ccc(CC(C)C)cc3)C(=O)OC(C)(C)C)cc(N(Cc3ccc(CC(C)C)cc3)C(=O)OC(C)(C)C)c2)c2ccccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 170.1 %

Procedure:
A solution of ethyl 4-[3-[3,5-bis(tertbutoxycarbonylamino)benzoyl]indol-1-yl]butyrate (300 mg) in N,N-dimethylformamide (5 ml) was added to a suspension of sodium hydride (60% dispersion in mineral oil, 54 mg) in N,N-dimethylformamide (5 ml ) at 0° C. The mixture was stirred at 0° C. for 30 minutes, and a solution of 4-isobutylbenzyl chloride (38.8 mg) in N,N-dimethylformamide (5 ml) was added at 0° C. The reaction mixture was stirred at 0° C. for 3 hours, and poured into a mixture of 0.1N hydrochloric acid and ethyl acetate. The organic layer was separated, washed with water, aqueous solution of sodium bicarbonate and brine in successively. After dryness over magnesium sulfate and evaporation of the solvent, the residue was chromatographed on silica gel (25 g) eluting with a mixture of ethyl acetate and hexane (1:4) to give ethyl 4-[3-[3,5-bis[N-(4-isobutylbenzyl )-N-tert-butoxycarbonylamino] benzoyl]indol-1-yl]butyrate (155 mg) as an oil.
Reaction SMILES: [ClH:1].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([NH:30]C(=O)[O-])[C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[C:20]4[CH2:27][S:26](=[O:29])(=[O:28])[CH2:25][C:21]=4[N:22]=[CH:23][N:24]=3)[CH2:15][CH2:14]2)=[O:12])=[CH:5][CH:4]=1>O1CCOCC1.C(Cl)Cl>[ClH:2].[ClH:1].[NH2:30][C@H:10]([CH2:9][C:6]1[CH:7]=[CH:8][C:3]([Cl:2])=[CH:4][CH:5]=1)[C:11]([N:13]1[CH2:18][CH2:17][N:16]([C:19]2[C:20]3[CH2:27][S:26](=[O:29])(=[O:28])[CH2:25][C:21]=3[N:22]=[CH:23][N:24]=2)[CH2:15][CH2:14]1)=[O:12]
Reactant: O=C([O-])NC(Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ncnc3c2CS(=O)(=O)C3)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ncnc3c2CS(=O)(=O)C3)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
HCl in dioxane (4M, 2 mL) was added to a solution of 3-(4-chlorophenyl)-1-(4-(6,6-dioxido-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl)piperazin-1-yl)-1-oxopropan-2-ylcarbamate (58 mg, 0.11 mmol) in DCM (10 mL). The mixture was stirred at room temperature for 4 hours, and the solvent was removed to afford (R)-2-amino-3-(4-chlorophenyl)-1-(4-(6,6-dioxido-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one dihydrochloride (47 mg, 100%). LCMS: 436.0 [M+H+] (APCI+).