Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NC([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([O:14][CH2:15][C:16]1[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=1)=[CH:9][CH:8]=2)CC.[CH2:26]([O:33][C:34](Cl)=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1(C)C=CC=CC=1>[CH2:26]([O:33][C:34]([NH:6][CH2:5][CH2:13][CH2:12][C:13]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:14][CH2:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]=3)[CH:11]=2)[NH:6][CH:5]=1)=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCC(N)c1cc2cc(OCc3ccc4ccccc4n3)ccc2[nH]1
Solvent: Cc1ccccc1
Product: O=C(NCCCc1c[nH]c2ccc(OCc3ccc4ccccc4n3)cc12)OCc1ccccc1
Temperature: 100 °C

Procedure:
A mixture of 1-aminopropyl-5-(2-quinolylmethoxy)-indole (1.0 g) and benzyloxycarbonyl chloride (1.0 ml) in toluene was heated at 100° C. for 15 minutes. The cooled solution was concentrated in vacuo and the resultant product purified by chromatographed on silica gel using 30%-ethyl acetate in n-hexanes as eluent to yield 1-(3-(benzyloxycarbonylamino-n-propyl)-5-(2-quinolylmethoxy)-indole (0.27 g), m.p. 109°-111° C.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C([Sn]([C:25]#[N:26])(CCCC)CCCC)CCC.O.[Cl-].[NH4+].[NH4+].[NH4+].[NH4+].[Cl-].[Cl-].[Cl-]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.ClC(Cl)C>[C:25]([C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1)#[N:26]
Reactant: CCCC[Sn](C#N)(CCCC)CCCC
Reactant: O=C1Cc2ccc(Br)cc2N1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(Cl)Cl
Solvent: O
Product: N#Cc1ccc2c(c1)NC(=O)C2
Reaction time: 6 h
Yield: 30.2 %

Procedure:
6-Bromo-1,3-dihydro-indol-2-one (0.621 g, 2.93 mmol), tributyltin cyanide 1.11 g, 3.5 mmol), tetraammonium chloride hydrate (0.97 g, 5.9 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.21 g, 0.3 mmol) and tetrakis (triphenylphosphine)palladium(0) (0.342 g, 0.3 mmol) were treated with dichloroethane (100 mL) and the reaction refluxed for 16 h under nitrogen with stirring. A further addition of tetrakis (triphenylphosphine)palladium(0) (0.23 g, 0.2 mmol) was made and reflux continued a further 6 h. A third addition of tetrakis (triphenylphosphine)palladium(0) (0.345 9, 0.3 mmol) was made and the reaction returned to reflux for 16 h. On cooling the reaction solution was washed twice with an aqueous solution of potassium fluoride (50 mL) and the organic phase dried over magnesium sulfate, filtered and evaporated to dryness. The product was subjected to chromatography on silica gel using dichloromethane to give 140 mg of 6-cyano-1,3-dihydro-indol-2-one contaminated with triphenylphosphine oxide. A second chromatographic purification chromatography on silica gel using dichloromethane gave 61 mg of pure 6-cyano-1,3-dihydro-indol-2-one; 1H-NMR (DMSO-d6): δ10.64 (bs, 1H), 7.37 (s, 2H), 7.10 (s, 1H), 3.56 (s, 2H). Mass spectrum (negative ion electrospray): m/z=157 (M−1, 100%).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH:10]([NH:11]C=O)[C:4]=2[CH:3]=1.[ClH:14]>>[ClH:14].[Br:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH:10]([NH2:11])[C:4]=2[CH:3]=1
Reactant: O=CNC1CCCc2sc(Br)cc21
Agent: Cl
Product: NC1CCCc2sc(Br)cc21

Procedure:
Acid hydrolysis of 2-bromo-N-formyl-4,5,6,7-tetrahydrobenzo[b]thien-4-amine (Example 35) with 1 N hydrochloric acid after refluxing for 1 hour and evaporating to dryness affords 2-bromo-4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine hydrochloride.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][N:5]=[C:6]([C:12]1([O:17][CH2:16][CH2:15][O:14]1)[CH3:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH3:18]C(C)([O-])C.[K+]>CN(C)C=O>[CH:3]1([O:4][N:5]=[C:6]([C:12]2([O:17][CH2:16][CH2:15][O:14]2)[CH3:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:18][CH2:2]1
Reactant: CC(C)(C)[O-]
Reactant: CCOC(=O)C(=NOCCBr)C1(C)OCCO1
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(=NOC1CC1)C1(C)OCCO1
Temperature: 0 °C

Procedure:
To a solution of ethyl 2-(2-bromoethoxyimino)-3,3-ethylenedioxybutyrate (syn isomer)(50 g) in N,N-dimethylformamide (100 ml) was portionwise added potassium tert-butoxide (21 g) under -10° C. and the resulted mixture was allowed to be stirred under ice-cooling for 20 minutes. The mixture was poured into ice-water (400 ml) and extracted with methylene chloride (200 ml). The extract was washed with water (200 ml×3) and saturated aqueous solution of sodium chloride (400 ml) successively, dried over magnesium sulfate, and added methylene iodide (16.2 ml). To the solution was dropwise added a 35% (W/W) solution of diethylzinc in cyclohexane (55 ml) under reflux during 40 minutes under nitrogen. atmosphere. After refluxed for 18 hours, the mixture was poured into ice-water (400 ml) and adjusted to pH 40 with 1N hydrochloric acid. The organic layer was separated, washed with an aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride successively, dried over magnesium sulfate, and concentrated in vacuo. The residue was subjected to column chromatography on silica gel (50 g) using diisopropyl ether as an eluent to give ethyl 2-cyclopropyloxyimino-3,3-ethylenedioxybutyrate (syn isomer)(l5 g), the physical data of which were identical to those of the compound prepared in Preparation 10.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:8]([CH2:9]Br)=[CH:7][C:6]([N+:11]([O-:13])=[O:12])=[N:5]1.[F:14][CH:15]([F:18])[CH2:16][NH2:17].CS(C)=O>O>[F:14][CH:15]([F:18])[CH2:16][N:17]1[CH2:2][CH2:3][N:4]2[N:5]=[C:6]([N+:11]([O-:13])=[O:12])[CH:7]=[C:8]2[CH2:9]1
Reactant: NCC(F)F
Reactant: O=[N+]([O-])c1cc(CBr)n(CCBr)n1
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])c1cc2n(n1)CCN(CC(F)F)C2
Temperature: 120 °C
Yield: 79.9 %

Procedure:
A sealed tube equipped with a magnetic stirrer was charged with 1-(2-bromoethyl)-5-(bromomethyl)-3-nitro-1H-pyrazole 124c (632 mg, 2.0 mmol), 2,2-difluoroethanamine (486 mg, 6.0 mmol), and DMSO (5 mL). It was heated at 120° C. for 2 h. The mixture was cooled to room temperature and diluted with water (20 mL). The resulting mixture was extracted with ethyl acetate (3×20 mL). The combiner organic layer was dried and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica-gel column chromatography eluting with 50:1 dichloromethane/methanol to afford 135a (371 mg, 80%) as a yellow solid. MS-ESI: [M+H]+ 233.2
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:16])[C:11]([OH:15])([CH3:14])[CH2:12][OH:13])=[CH:5][C:4]=1[C:17]([F:20])([F:19])[F:18])#[N:2].[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>N1C=CC=CC=1.ClCCl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:16])[C:11]([OH:15])([CH3:14])[CH2:12][O:13][S:27]([C:24]2[CH:25]=[CH:26][C:21]([CH3:31])=[CH:22][CH:23]=2)(=[O:29])=[O:28])=[CH:5][C:4]=1[C:17]([F:19])([F:18])[F:20])#[N:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(O)(CO)C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC(C)(O)C(=O)Nc2ccc(C#N)c(C(F)(F)F)c2)cc1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
A solution of 5 g (17.35 mol) of N-[4-cyano-3-trifluoromethyl-phenyl]-2,3-dihydroxy-2-methyl-propionamide in 50 ml of dry pyridine was cooled to 0° C. and 10 g (52.45 mmol) of p-toluenesulfonyl chloride was added in small portions. The mixture was stirred at 0° C. for 5 h, then diluted with 200 ml of dichloromethane, washed three times with 50 ml of saturated aqueous sodium hydrogen carbonate, twice with 50 ml of 10% aqueous hydrochloric acid and 50 ml of brine. The organic layer was dried over sodium sulfate and concentrated in vacuum. The residue was crystallized from a 1:5 mixture of ethyl acetate/petroleum ether, which has a boiling range of 40–70° C.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([CH3:11])[C:6](=O)[CH2:7][O:8][CH3:9])C.C(O)(=O)C.[CH:17]([NH2:19])=[NH:18].C[O-].[Na+].[Na].Cl>CO.O>[CH3:9][O:8][CH2:7][C:6]1[C:5]([CH3:11])=[C:4]([OH:3])[N:19]=[CH:17][N:18]=1
Reactant: CCOC(=O)C(C)C(=O)COC
Reactant: N=CN
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: COCc1ncnc(O)c1C
Reaction time: 23 h

Procedure:
2-Methyl-3-keto-4-methoxybutyric acid ethyl ester (60 g) and formamidine acetate (39.06 g) were dissolved in methanol (150 ml) and treated, under nitrogen, with a sodium methoxide solution, prepared from sodium (17.42 g) and methanol (225 ml). The mixture was stirred at 50° for 23 hours, stripped, water added and the pH lowered to 7 (HCl). The solution was extracted with chloroform, extracts dried (MgSO4) and stripped to a residue, which was triturated with diethyl ether to give 4-methoxymethyl-5-methyl-6-hydroxypyrimidine, 38.72 g, m.p. 139°-140°.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].F[C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[C:8]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([CH3:24])[CH:18]=1)=[N:9][CH:10]=[N:11]2>>[NH2:4][CH2:3][CH2:1][O:2][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[C:8]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([CH3:24])[CH:18]=1)=[N:9][CH:10]=[N:11]2
Reactant: Cc1cc(Nc2ncnc3cccc(F)c23)ccc1O
Reactant: NCCO
Product: Cc1cc(Nc2ncnc3cccc(OCCN)c23)ccc1O
Yield: 23 %

Procedure:
The procedure described in Example 3 (preparation of starting materials) was repeated using ethanolamine and 4-[(5-fluoroquinazolin-4-yl)amino]-2-methylphenol (obtained as described in Example 3, preparation of starting materials) to give 4-{[5-(2-aminoethoxy)quinazolin-4-yl]amino}-2-methylphenol as a grey solid in 23% yield; NMR spectrum (DMSO-d6) 2.14 (s, 3H), 3.09 (d, 2H), 3.28 (s, 2H), 4.25 (t, 2H), 6.77 (d, 1H), 7.08 (d, 1H), 7.28 (d, 1H), 7.46 (dd, 1H), 7.55 (d, 1H), 7.66 (t, 1H), 8.40 (s, 1H), 10.31 (s, 1H); Mass spectrum MH+ 311.
Reaction SMILES: CN1CCN(C2C=CC(NC3C4N(N=CN=4)C(C4C=C(C(N)=O)SC=4)=CN=3)=CC=2)CC1.[Br:32][C:33]1[N:38]2[N:39]=[CH:40][N:41]=[C:37]2[C:36](Br)=[N:35][CH:34]=1.[F:43][C:44]1[CH:49]=[C:48]([N:50]2[CH2:55][CH2:54][O:53][CH2:52][CH2:51]2)[CH:47]=[CH:46][C:45]=1[NH2:56].CCN(C(C)C)C(C)C.N12CCN(CC1)CC2>CC(O)C>[Br:32][C:33]1[N:38]2[N:39]=[CH:40][N:41]=[C:37]2[C:36]([NH:56][C:45]2[CH:46]=[CH:47][C:48]([N:50]3[CH2:51][CH2:52][O:53][CH2:54][CH2:55]3)=[CH:49][C:44]=2[F:43])=[N:35][CH:34]=1
Reactant: Nc1ccc(N2CCOCC2)cc1F
Reactant: Brc1ncc(Br)n2ncnc12
Agent: C1CN2CCN1CC2
Agent: CN1CCN(c2ccc(Nc3ncc(-c4csc(C(N)=O)c4)n4ncnc34)cc2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Fc1cc(N2CCOCC2)ccc1Nc1ncc(Br)n2ncnc12

Procedure:
This compound may be prepared using methods as described for Compound 6, step 1, using 5,8-dibromo-[1,2,4]triazolo[1,5-a]pyrazine (0.105 g, 0.89 mmol), 2-fluoro-4-morpholin-4-yl-phenylamine (93 mg, 0.474 mmol), DIPEA (0.123 mL, 0.706 mmol) and 1,4-diazabicyclo[2.2.2]octane (53 mg, 0.472 mmol) in 2-propanol (2 mL). The reaction mixture is partitioned between DCM and 10% citric acid (aq) solution, the organic layer is separated and washed with 10% citric acid solution, water and brine, dried over MgSO4, filtered and concentrated in vacuo. The title compound is isolated as a pale red solid (77 mg, 42%) and used in the next step without further purification. LCMS: Rt 3.48 min (89%).
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].O.[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16]([OH:19])(=[O:18])=[O:17])=[CH:12][CH:11]=1.[N+:21]([C:24]1[CH:31]=[CH:30][C:27]([CH2:28]O)=[CH:26][CH:25]=1)([O-:23])=[O:22]>C1C=CC=CC=1>[C:10]1([CH3:20])[CH:11]=[CH:12][C:13]([S:16]([OH:19])(=[O:17])=[O:18])=[CH:14][CH:15]=1.[N+:21]([C:24]1[CH:31]=[CH:30][C:27]([CH2:28][O:4][C:3](=[O:5])[C@@H:2]2[CH2:6][CH2:7][CH2:8][NH:1]2)=[CH:26][CH:25]=1)([O-:23])=[O:22]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: O=[N+]([O-])c1ccc(CO)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)[C@@H]1CCCN1
Yield: 118.3 %

Procedure:
A mixture solution of 5.0 g of L-proline, 9.91 g of p-toluenesulfonic acid monohydrate and 6.65 g of p-nitrobenzyl alcohol in 100 ml of benzene was refluxed for 2 days by using Dean-Stark trap. After reaction, the solvent was removed under reduced pressure and the resulting residue was washed with diethyl ether to give 21.7 g of L-proline p-nitrobenzyl ester p-toluenesulfonic acid salt as oil. Then, a mixture solution of 12.17 g of Boc-glycine and 13.32 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide.hydrochloride in 150 ml of ethylene chloride was stirred for 25 minutes under ice-cooling at nitrogen atmosphere. To this reaction mixture was added a solution of 29.36 g of the compound obtained above in 100 ml ethylene chloride and the reaction mixture was stirred overnight at room temperature. After reaction, the reaction mixture was washed with 10% citric acid aqueous solution, 4% sodium bicarbonate aqueous solution and saline, and dried over magnesium sulfate. The solvent was removed under reduced pressure and the resulting residue was purified by silica gel column chromatography (chloroform-methanol) to give 8.00 g of [N-(t-butoxycarbonyl)glycyl]L-proline p-nitrobenzyl ester [Compound (22)].
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[Li]CCCC.CN(CCN(C)C)C.[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][CH:33]([CH:36]=[O:37])[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>C1COCC1>[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][CH:33]([CH:36]([OH:37])[C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=2)[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: COc1ccc(Br)cc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(C(O)C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 47.4 %

Procedure:
To a solution of 4-bromoanisole (5.00 g, 26.70 mmol) in THF (100 mL) at −78° C. was added n-BuLi (1.9M in hexanes, 14 mL, 26.7 mmol). After the solution was stirred at −78° C. for 45 minutes, TMEDA (4.03 mL, 26.7 mmol) was added followed by a solution of 4-formyl-piperidine-1-carboxylic acid tert-butyl ester (4.76 g, 22.3 mmol) in THF (20 mL), and the mixture was stirred at −78° C. for 1 hour. The reaction was quenched with saturated aqueous NH4Cl and after work-up and purification gave 4-[hydroxy-(4-methoxy-phenyl)-methyl]-piperidine-1-carboxylic acid tert-butyl ester (3.40 g, 47%) as a white foam.
Reaction SMILES: [Cl-].[NH4+].O.C(O)(C)C.[C:8]([O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-])=O)[CH:24]=1)(=[O:12])[C:9]([CH3:11])=[CH2:10]>C(OCC)(=O)C>[C:8]([O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH2:29])[CH:24]=1)(=[O:12])[C:9]([CH3:11])=[CH2:10]
Reactant: C=C(C)C(=O)OCCOCCOCCOc1cccc([N+](=O)[O-])c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(C)O
Solvent: CCOC(C)=O
Solvent: O
Product: C=C(C)C(=O)OCCOCCOCCOc1cccc(N)c1
Temperature: 75 °C

Procedure:
A mixture of 25 g of reduced iron, 1 g of ammonium chloride, 50 ml of water, and 250 ml of isopropyl alcohol was raised to a temperature of 75° C. with stirring and after adding dropwise an ethyl acetate solution of the compound (1-B) to the aqueous solution (the mixture) over a period of one hour, the resultant mixture was further stirred for 2 hours. After removing insoluble matters from the reaction mixture by filtration, 200 ml of ethyl acetate and 500 ml of water were added to the reaction mixture and the ethyl acetate layer was extracted. The ethyl acetate layer was concentrated and the residue was purified by silica gel column chromatography using chloroform as a developing solvent to provide 15.3 g of 2-(2-(2-(3-aminophenoxy)ethoxy)ethoxy)ethyl methacrylate (1-C).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].Br[CH2:6][C:7](=O)/[C:8](=[N:33]/[O:34][CH3:35])/[C:9]([NH:11][CH:12]1[C:31](=[O:32])[N:14]2[C:15]([C:28]([OH:30])=[O:29])=[C:16]([CH2:19][S:20][C:21]([C:23]3[O:24][CH:25]=[CH:26][CH:27]=3)=[O:22])[CH2:17][S:18][C@H:13]12)=[O:10].O1CCCC1.C(=O)(O)[O-].[Na+]>O.C(Cl)Cl>[CH3:35][O:34]/[N:33]=[C:8](\[C:9]([NH:11][C@@H:12]1[C:31](=[O:32])[N:14]2[C:15]([C:28]([OH:30])=[O:29])=[C:16]([CH2:19][S:20][C:21]([C:23]3[O:24][CH:25]=[CH:26][CH:27]=3)=[O:22])[CH2:17][S:18][C@H:13]12)=[O:10])/[C:7]1[N:1]=[C:2]([NH2:4])[S:3][CH:6]=1
Reactant: CO/N=C(/C(=O)CBr)C(=O)NC1C(=O)N2C(C(=O)O)=C(CSC(=O)c3ccco3)CS[C@H]12
Reactant: NC(N)=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CSC(=O)c3ccco3)CS[C@H]12)c1csc(N)n1
Temperature: 7.5 °C
Reaction time: 2 h

Procedure:
25.0 g (0.3289 moles) of thiourea was dissolved in 160 ml of demineralised water. This solution was added to a mixture containing 7-[4-bromo-2(Z)-methoxyimino-3-oxobutyramido]-3-[[(2-furanylcarbonyl)thio]methyl]-3-cephem-4-carboxylic acid in methylene chloride, as obtained from Step C 240 ml of tetrahydrofuran (THF) over a period of 30 mins. The reaction mixture was stirred for 2 hrs at 5-10° C. The pH of the solution was adjusted to 5.0 with aqueous sodium bicarbonate solution.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@H:11]([S:13][C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][C@H:9]1[CH2:33][OH:34])=O)(C)(C)C.[CH2:35](Br)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[CH2:35]([O:34][CH2:33][C@@H:9]1[CH2:10][C@@H:11]([S:13][C:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:12][NH:8]1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CO
Reactant: BrCc1ccccc1
Product: c1ccc(COC[C@@H]2C[C@@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)CN2)cc1

Procedure:
In analogy: The reaction of (2S,4R)-2-hydroxymethyl-4-tritylsulfanyl-pyrrolidine-1-carboxylic acid tert-butyl ester with benzylbromide gave (2S,4R)-2-benzyloxymethyl-4-tritylsulfanyl-pyrrolidine, MS: 466 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:26][C@H:25]([CH2:27][O:28]CC4C=CC(Cl)=CC=4Cl)[C@@H:14]([O:15]CC4C=CC(Cl)=CC=4Cl)[C@@:12]3([CH2:38][CH3:39])[OH:13])[C:4]=2[N:5]=[CH:6][N:7]=1.B(Cl)(Cl)Cl>ClCCl>[Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:26][C@H:25]([CH2:27][OH:28])[C@@H:14]([OH:15])[C@@:12]3([CH2:38][CH3:39])[OH:13])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CC[C@@]1(O)[C@H](OCc2ccc(Cl)cc2Cl)[C@@H](COCc2ccc(Cl)cc2Cl)O[C@H]1n1ccc2c(Cl)ncnc21
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: CC[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1ccc2c(Cl)ncnc21
Temperature: -78 °C
Reaction time: 1 h
Yield: 79.3 %

Procedure:
To a solution of the compound from Step B (307 mg, 0.45 mmol) in dichloromethane (8 mL) was added boron trichloride (1M in dichloromethane) (4.50 mL, 4.50 mmol) at −78° C. The mixture was stirred at −78° C. for 1 h, then at −10° C. for 3 h. The reaction was quenched by addition of methanol/dichloromethane (1:1) (10 mL), stirred at −15° C. for 30 min, and neutralized by addition of aqueous ammonium hydroxide. The mixture was evaporated in vacuo and the resulting oil purified on silica gel using methanol/dichloromethane (1:9) as eluent. Fractions containing the product were pooled and evaporated in vacuo to give the desired product (112 mg) as a colorless foam.
Reaction SMILES: [C:1]([C:3]1[C:8](Br)=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].[C:10]1([CH3:19])[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C(O)C>[C:1]([C:3]1[C:8]([C:13]2[CH:14]=[CH:15][C:10]([CH3:19])=[CH:11][CH:12]=2)=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2]
Reactant: N#Cc1ncccc1Br
Reactant: Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1ccc(-c2cccnc2C#N)cc1
Yield: 34 %

Procedure:
Under nitrogen, 13.91 g (76 mmol) of 2-cyano-3-bromopyridine from step 2 and 11.41 g (84 mmol) of 4-tolylboronic acid from step 3 were treated with 2.65 g (2.3 mmol) of tetrakis (triphenylphosphine)palladium zero, 155 mL of toluene, 60 mL of ethanol, and 77 mL of 2M aqueous sodium carbonate. The reaction mixture was heated to reflux and vigorously stirred overnight. The product crystallized from the reaction mixture after several days at ambient temperature. Filtration provided 5.02 g (34%) of 2-cyano-3-(4-tolyl)pyridine as a colorless solid: mp 136°-138° C.; NMR (CDCl3) δ2.44 (s, 3H), 7.34 (d, J=8 Hz, 2H), 7.47 (d, J=8 Hz, 2H), 7.56 (dd, J=8 and 5 Hz, 1H), 7.85 (dd, J=8 and 2 Hz, 1H), 8.68 (dd, J=5 and 2 Hz, 1H); MS (70 eV) m/e (rel intensity) 194 (100).
Reaction SMILES: C([O:5][C:6](=[O:25])[CH:7]([C:15]1[CH:20]=[C:19]([F:21])[C:18]([C:22]#[N:23])=[CH:17][C:16]=1[F:24])C(OC(C)(C)C)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:22]([C:18]1[C:19]([F:21])=[CH:20][C:15]([CH2:7][C:6]([OH:25])=[O:5])=[C:16]([F:24])[CH:17]=1)#[N:23]
Reactant: CC(C)(C)OC(=O)C(C(=O)OC(C)(C)C)c1cc(F)c(C#N)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cc(F)c(CC(=O)O)cc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 89.6 %

Procedure:
To the di-tert-butyl(4-cyano-2,5-difluorophenyl)propanedioate (10.0 g, 28.3 mmol) in dichloromethane (30 mL) was added triflouroacetic acid (10 mL) and the mixture stirred for 12 h at room temperature. The solution was concentrated under reduced pressure and chased with toluene (2×) to give the crude product as a yellowish oil (5 g, 90%, 85% purity as indicated by NMR). The residue was used in the next step without further purification. 1H NMR (500 MHz, CDCl3) δ 7.31 (dd, J=3, J=2 Hz, 1H), 7.21 (dd, J=5.8, J=5.8 Hz, 1H), 3.67 (s, 2H). LC-MS (IE, m/z): 198 [M+1]+.
Reaction SMILES: [C:1]([NH:4][C:5]([C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=1)([CH3:7])[CH3:6])(=[O:3])[CH3:2].S(=O)(=O)(O)O.[CH3:22]O>>[C:1]([NH:4][C:5]([C:8]1[CH:9]=[CH:10][C:11]([C:12]([O:14][CH3:22])=[O:13])=[CH:15][CH:16]=1)([CH3:7])[CH3:6])(=[O:3])[CH3:2]
Reactant: CO
Reactant: CC(=O)NC(C)(C)c1ccc(C(=O)O)cc1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(C(C)(C)NC(C)=O)cc1

Procedure:
A suspension of 4-(1-acetamido-1-methylethyl)benzoic acid (73.4 g) and sulfuric acid (0.7 ml) in methanol (370 ml) was refluxed for 16 hr. The solvent was evaporated and 10% aqueous sodium hydrogencarbonate (500 ml) was added and the mixture was extracted with ethyl acetate (500 ml). The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was recrystallized from ethyl acetate-isopropyl ether to give the title compound (39.0 g) as pale-yellow crystals, m.p.=165-167° C.