Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:13][CH2:12][NH:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:21][C:22]1[CH:23]=[C:24]([N:29]2[C:38]3[C:33](=[CH:34][C:35]([F:40])=[C:36](F)[CH:37]=3)[C:32](=[O:41])[N:31]([O:42][CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:30]2=[O:50])[CH:25]=[CH:26][C:27]=1[F:28]>>[Cl:21][C:22]1[CH:23]=[C:24]([N:29]2[C:38]3[C:33](=[CH:34][C:35]([F:40])=[C:36]([N:11]4[CH2:12][CH2:13][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:10]4)[CH:37]=3)[C:32](=[O:41])[N:31]([O:42][CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:30]2=[O:50])[CH:25]=[CH:26][C:27]=1[F:28]
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: O=c1c2cc(F)c(F)cc2n(-c2ccc(F)c(Cl)c2)c(=O)n1OCc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1CCN(c2cc3c(cc2F)c(=O)n(OCc2ccccc2)c(=O)n3-c2ccc(F)c(Cl)c2)C1
Yield: 130.4 %

Procedure:
Using General Method 4, the reaction of 3-t-butoxycarbonylamino-pyrrolidine (0.187 g, 1 mmol), triethylamine (0.14 mL, 1 mmol), and 1-(3-chloro-4-fluorophenyl)-3-benzyloxy-6,7-difluoro-1H-quinazoline-2,4-dione (Example D-1, 0.14 g, 0.32 mmol) provided 0.25 g of the title compound as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:16]=[C:17]([CH:25]=[CH:26][CH:27]=3)[C:18]([NH:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10][CH2:9]2)=[O:7])=[CH:4][C:3]=1[F:30].[F:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[N:38]=[C:39]=[O:40]>ClCCl>[C:21]([NH:20][C:18](=[O:19])[C:17]1[CH:25]=[CH:26][CH:27]=[C:15]([CH2:14][N:11]2[CH2:12][CH2:13][N:8]([C:6](=[O:7])[C:5]3[CH:28]=[CH:29][C:2]([NH:1][C:39]([NH:38][C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=4[F:31])=[O:40])=[C:3]([F:30])[CH:4]=3)[CH2:9][CH2:10]2)[CH:16]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)NC(=O)c1cccc(CN2CCN(C(=O)c3ccc(N)c(F)c3)CC2)c1
Reactant: O=C=Nc1ccccc1F
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1cccc(CN2CCN(C(=O)c3ccc(NC(=O)Nc4ccccc4F)c(F)c3)CC2)c1
Yield: 9 %

Procedure:
3-((4-(4-Amino-3-fluorobenzoyl)piperazin-1-yl)methyl)-N-tert-butylbenzamide (100 mg, 0.242 mmol) and 2-fluorophenylisocyanate (37 mg, 0.267 mmol) were combined and heated in dichloromethane at 100° C. in the microwave for 10 minutes. The solvent was removed under reduced pressure and the residue purified by acidic reverse phase HPLC to afford the title compound (12 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][CH2:17][OH:18].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:16][CH2:17][OH:18])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: OCCOc1ccc(Br)cc1
Temperature: 90 °C
Reaction time: 6 h
Yield: 50.7 %

Procedure:
In DMF (150 ml) was dissolved 4-bromophenol (25 g). To the mixture was added potassium carbonate (30 g) and then was added dropwise 2-bromoethanol (23.5 g), and the mixture was stirred at 90° C. for 6 hours and cooled to room temperature. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (hexane/ethyl acetate=2/1) to give 2-(4-bromophenoxy)-1-ethanol (15.9 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1B(O)O.Br[C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:15]1[CH:21]=[CH:20][CH:19]=[C:17]([NH2:18])[CH:16]=1
Reactant: COc1ccc(B(O)O)c(OC)c1
Reactant: Nc1cccc(Br)c1
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: COCCOC
Product: COc1ccc(-c2cccc(N)c2)c(OC)c1
Temperature: 25 °C
Yield: 74 %

Procedure:
2,4-dimethoxyphenyl boronic acid (0.126 g, 0.693 mmol) and 3-bromoaniline (0.05 mL, 0.462 mmol) were combined in DME (2 mL) in a flame-dried, round-bottom flask. Na2CO3 (2M, 0.485 mL, 0.970 mmol) and Pd(PPh3)4 (0.017 g, 0.014 mmol) were added to the stirred solution. The reaction was refluxed overnight under argon flow, and subsequently cooled to room temperature. The solvent was removed under vacuum and the resulting residue was resuspended in H20 and extracted with CH2Cl2. The organic phase was dried over MgSO4 and concentrated under vacuum. The crude product was purified by silica column chromatography (5-20% EtOAc/hexanes). The purification was monitored by TLC. The solvent was removed under vacuum from fractions containing product, resulting in 0.078 g in 74% yield.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([O:10][CH3:11])=[O:9].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C1C(=O)N([Br:46])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:46][CH2:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1CBr
Temperature: 80 °C

Procedure:
The compound of example 220 (5 g, 0.0184 mol) was dissolved in carbon tetrachloride (125 mL). Benzoyl peroxide (250 mg) and NBS (3.6 g, 0.0202 mol) were added and the reaction mixture was refluxed at 80° C. The reaction mixture was cooled to room temperature and filtered through celite. The filtrate was concentrated to yield crude residue containing 85% mono bromo and 10% dibromo product and 5% starting material. The crude title compound obtained was used directly for preparation of compound of example 222.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.C([O:15][C:16](=O)[CH2:17][S:18][CH3:19])C.C(OCl)(C)(C)C.Cl>C(Cl)Cl.CCOCC.C(N(CC)CC)C>[CH3:19][S:18][CH:17]1[C:3]2[C:2](=[CH:12][CH:11]=[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:4]=2)[NH:1][C:16]1=[O:15]
Reactant: CCOC(=O)CSC
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: CC(C)(C)OCl
Agent: Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1ccc2c(c1)C(SC)C(=O)N2
Temperature: -50 °C
Reaction time: 0.42 h

Procedure:
To a solution of ethyl 4-amino-benzoate (40.0 g) in DCM (900 ml) at −60° C. there is added, dropwise, ethyl(methylsulphanyl)acetate (34.5 ml) under a nitrogen atmosphere. 29.0 g of tBuOCl are then added, dropwise, to the reaction mixture over 25 minutes, maintaining the temperature between −60° C. and −55° C. After stirring for one hour at −50° C., triethylamine (15.4 ml) is added dropwise. The reaction mixture is brought to 0° C. and then aqueous 3M HCl solution (485 ml) is added dropwise. After stirring for 12 hours at ambient temperature, the phases are separated and the organic phase is washed successively with aq. 2M HCl solution, water and then sat. aqueous NaCl solution. The organic phase is dried over sodium sulphate, filtered and evaporated to dryness. The residue obtained is taken up in ether. The crystals obtained are filtered off, washed with ether and dried in vacuo to yield the title product, which is used directly in the next Step.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]2[C@H:12]([CH:13]3[CH2:15][O:14]3)[O:11][C:10]([CH3:17])([CH3:16])[N:9]2[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:25]1([NH2:28])[CH2:27][CH2:26]1>CO>[CH:1]1([CH2:7][C@H:8]2[C@H:12]([C@@H:13]([OH:14])[CH2:15][NH:28][CH:25]3[CH2:27][CH2:26]3)[O:11][C:10]([CH3:17])([CH3:16])[N:9]2[C:18]([O:20][C:21]([CH3:24])([CH3:22])[CH3:23])=[O:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CC1
Reactant: CC(C)(C)OC(=O)N1[C@@H](CC2CCCCC2)[C@H](C2CO2)OC1(C)C
Solvent: CO
Product: CC(C)(C)OC(=O)N1[C@@H](CC2CCCCC2)[C@H]([C@@H](O)CNC2CC2)OC1(C)C
Reaction time: 8 h

Procedure:
A mixture of 733 mg (2.16 mmol) of tert-butyl (4S,5R)-4-(cyclohexylmethyl)-2,2-dimethyl-5-[(RS)-2-oxiranyl]-3-oxazolidinecarboxylate (WO 88/4664) and 2 ml of cyclopropylamine in 15 ml of methanol is stirred at 50° overnight under argon. Thereafter, the reaction mixture is evaporated and, for purification and separation of the epimers, the residue is chromatographed on 100 g of silica gel using a 98:2 mixture of chloroform and methanol as the eluent. There are obtained 185 mg of the less polar tert-butyl (4S,5R)-4-(cyclohexylmethyl)-5-[(S)-2-(cyclopropylamino)-1-hydroxyethyl]-2,2-dimethyl-3-oxazolidinecarboxylate, MS: 397 (M+H)+, and 341 mg of the more polar tert-butyl (4S,5R)-4-(cyclohexylmethyl)-5-[(R)-2-(cyclopropylamino)-1-hydroxyethyl]-2,2-dimethyl-3-oxazolidinecarboxylate, MS: 397 (M+H)+, each as a colourless oil.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2-].[Na+].Br[CH:11]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12]1.CS(C)=[O:25]>O>[CH2:16]([N:13]1[CH2:14][CH2:15][CH:11]([S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:12]1=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrC1CCN(Cc2ccccc2)C1
Reactant: Sc1ccccc1
Reactant: CS(C)=O
Agent: [NH2-]
Agent: [Na+]
Solvent: O
Product: O=C1C(Sc2ccccc2)CCN1Cc1ccccc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
A solution of 55 g (0.5 mole) of thiophenol in 50 ml of dimethylsulfoxide was added dropwise with stirring to 250 ml of dimethylsulfoxide containing 21.5 g (0.55 mole) of sodamide. After stirring the mixture at 40° C. for 1 hr, 120 g (0.05 mole) of 3-bromo-1-benzyl-pyrrolidine (slightly exothermic) was added dropwise. The solution was stirred at 60° C. for 1 hr, diluted with 500 ml of water and extracted with isopropyl ether. The ether phase was dried over sodium sulfate and concentrated, and the residue distilled, b.p. 170°-170° C./5 mm. to give 98 g (73%) of product.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH:8]([CH2:24][CH3:25])[CH2:9][N:10]([N:19]1[CH:23]=[N:22][N:21]=[CH:20]1)[C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1.[OH:26][C:27]1[CH:32]=[CH:31][C:30]([SH:33])=[CH:29][CH:28]=1>CN(C=O)C.C(OCC)(=O)C>[OH:26][C:27]1[CH:32]=[CH:31][C:30]([S:33][CH2:25][CH2:24][CH2:8][CH2:9][N:10]([N:19]2[CH:23]=[N:22][N:21]=[CH:20]2)[C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=2)=[CH:29][CH:28]=1
Reactant: Oc1ccc(S)cc1
Reactant: CCC(Br)CN(c1ccc(C#N)cc1)n1cnnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1ccc(N(CCCCSc2ccc(O)cc2)n2cnnc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Potassium carbonate (500 mg) was added to a solution of 4-[(2-bromo-butyl)-[1,2,4]triazol-4-yl-amino]-benzonitrile (CAB03001, 384 mg, 1.2 mmol) and 4-hydroxy-thiophenol (227 mg, 1.8 mmol) in DMF (20 mL). The mixture was stirred for 18 hours at r.t., diluted with ethyl acetate (100 mL) and extracted with water (two times 30 mL) and brine (30 mL). The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: ethyl acetate, Rf: 0.30). The resulting oil was dissolved in a small amount of ethyl acetate and the product was precipitated by addition of hexane. Yield: 289 mg (66%). 1H-NMR (400 MHz, d6-DMSO) δ=1.48-1.64 (m, 4H) 2.81 (t, J=6.6 Hz, 2H), 3.81 (t, J=6.8 Hz, 2H), 6.62 (d, J=9.0 Hz, 2H), 6.72 (d, J=8.6 Hz, 2H), 7.19 (d, J=9.0 Hz, 2H), 7.72 (d, J=9.0, 2H), 8.94 (s, 2H), 9.56 (s, 1H, —OH). LRMS (FAB+): 366.1 (100, [M+H]+).
Reaction SMILES: C(O)C.[O:4]=[CH:5][C@@H:6]([C@H:8]([C@@H:10]([C@@H:12]([CH2:14][OH:15])[OH:13])[OH:11])[OH:9])[OH:7].[Sn].[CH2:17](Br)[CH:18]=[CH2:19]>O>[CH2:19]([CH:5]([C@@H:6]([C@H:8]([C@@H:10]([C@@H:12]([CH2:14][OH:15])[OH:13])[OH:11])[OH:9])[OH:7])[OH:4])[CH:18]=[CH2:17]
Reactant: C=CCBr
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [Sn]
Solvent: CCO
Solvent: O
Product: C=CCC(O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Temperature: 60 °C

Procedure:
A three liter three-necked round bottom flask, equipped with heating mantle, stirrer, nitrogen inlet, and condensor, was charged with 900 mL of ethanol, 150 mL of water, 180 g (1.00 mole) of D-glucose, 119 g (1.00 mole) of tin powder (−100 mesh), and 121 g (1.00 mole) of allyl bromide. The mixture was stirred and slowly heated at 60° C. The gray suspension was stirred at this temperature for 24 hours, in which time the reaction mixture turned a light yellow color. Heat was removed and the mixture was allowed to cool to room temperature. The reaction was neutralized to pH=7 by adding approximately 200 ml of 5M NaOH aqueous solution. The suspension was filtered to remove solids, and the yellow solution was decolorized with multiple treatments of activated carbon. The activated carbon was removed by filtration, and the solvent was removed by rotary evaporation to isolate a white syrup. Typical yield was 200 g with a threo-erythro ratio of 6:1, based on GC-MS. The 1-allyl sorbitol syrup was used without further purification.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:20]([OH:36])[CH2:21][NH:22][CH:23]2[CH2:31][C:30]3[C:25](=[C:26]([O:34][CH3:35])[CH:27]=[CH:28][C:29]=3[O:32][CH3:33])[CH2:24]2)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)C1C=CC=CC=1.[ClH:37].C(OCC)C>CO.[Pd]>[ClH:37].[OH:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:20]([OH:36])[CH2:21][NH:22][CH:23]2[CH2:31][C:30]3[C:25](=[C:26]([O:34][CH3:35])[CH:27]=[CH:28][C:29]=3[O:32][CH3:33])[CH2:24]2)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2
Reactant: COc1ccc(OC)c2c1CC(NC[C@H](O)c1ccc(OCc3ccccc3)c3[nH]c(=O)ccc13)C2
Agent: [Pd]
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: COc1ccc(OC)c2c1CC(NC[C@H](O)c1ccc(O)c3[nH]c(=O)ccc13)C2
Reaction time: 4 h

Procedure:
(R)-8-Benzyloxy-5-[2-(4,7-dimethoxy-indan-2-ylamino)-1-hydroxy-ethyl]-1H-quinolin-2-one (37 mg, 0.08 mmol) is dissolved in methanol (10 mL) and the compound is deprotected by adding a catalytic amount of 10% palladium on charcoal and placing the solution under an atmosphere of hydrogen. The reaction is shown to be complete by TLC after 4 hours. The catalyst is filtered off, 1M HCl/diethyl ether (1.1 equivalent) is added and the solvent is removed in vacuo. TLC (silica, dichloromethane/methanol 10:1 Rf=0.15). ES+ MS m/e 397 (MH+).
Reaction SMILES: [F:1][C:2]([F:24])([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)[C:3]([NH:5][C:6]1[CH:14]=[C:13](OC)[CH:12]=[CH:11][C:7]=1[C:8]([NH2:10])=[O:9])=[O:4].NC1C=C(OC)C=CC=1C(N)=O.NC1C([F:47])=CC=CC=1C(N)=O>>[F:1][C:2]([F:24])([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)[C:3]([NH:5][C:6]1[C:14]([F:47])=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([NH2:10])=[O:9])=[O:4]
Reactant: COc1ccc(C(N)=O)c(NC(=O)C(F)(F)c2ccc(F)cc2)c1
Reactant: NC(=O)c1cccc(F)c1N
Agent: COc1ccc(C(N)=O)c(N)c1
Product: NC(=O)c1cccc(F)c1NC(=O)C(F)(F)c1ccc(F)cc1

Procedure:
2-(2,2-Difluoro-2-(4-fluorophenyl)acetamido)-3-fluorobenzamide was prepared according to the procedure described in Example 32 for preparation of 2-(2,2-difluoro-2-(4-fluorophenyl)acetamido)-4-methoxybenzamide, substituting 2-amino-4-methoxybenzamide in Example 32 with 2-amino-3-fluorobenzamide. The product was purified on silica gel column using DCM/MeOH as eluent (20%); LC-MS (ESI) m/z 327 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)/[C:5](=[N:12]/[S:13]([C:16]2S[CH:18]=[CH:19][CH:20]=2)(=[O:15])=[O:14])/[CH:4]=[C:3]1[S:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].[Cl:28][C:29]1C=CC(CS(N)(=O)=O)=[CH:31][CH:30]=1>C1COCC1.Cl[Ti](Cl)(Cl)Cl>[Cl:28][C:29]1[CH:18]=[CH:19][C:20]([CH2:16][S:13]([N:12]=[C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2](=[O:1])[C:3]([S:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:4]2)(=[O:14])=[O:15])=[CH:31][CH:30]=1
Reactant: NS(=O)(=O)Cc1ccc(Cl)cc1
Reactant: CCOC(=O)CSC1=C/C(=N\S(=O)(=O)c2cccs2)c2ccccc2C1=O
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: C1CCOC1
Product: CCOC(=O)CSC1=CC(=NS(=O)(=O)Cc2ccc(Cl)cc2)c2ccccc2C1=O

Procedure:
5.2.21 Ethyl 2-(4-(4-chlorobenzylsulfonylimino)-1-oxo-1,4-dihydronaphthalen-2-ylthio)-acetate (8g) was prepared according to the procedure for 8a except using (4-chlorophenyl)methanesulfonamide, TiCl4.2THF and THF as solvent. The title compound 130 mg (56%) was obtained according to the workup procedure for 12a as a yellow solid, m.p.: ° C.
Reaction SMILES: S(=O)(=O)(O)O.C1(CC(O)=[O:14])C=CC=CC=1.[CH:16]1([N:22]=[C:23]=[N:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>N1C=CC=CC=1>[CH:25]1([NH:24][C:23]([NH:22][CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)=[O:14])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: O=C(O)Cc1ccccc1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=S(=O)(O)O
Solvent: c1ccncc1
Product: O=C(NC1CCCCC1)NC1CCCCC1
Reaction time: 0.25 h

Procedure:
A freshly prepared mixture of 26 mg of concentrated sulfuric acid in 2.5 ml of absolute pyridine (suspension of pyridinium sulfate) is added, at 20° C. and while stirring, to a solution of 1.1 g (0.0025 mol) of prednisolone 17-ethyl carbonate and 1.2 g (0.0088 mol) of phenylacetic acid (dried at about 50°-60° C. in vacuo over P2O5 for 5 h.) in 6 ml of absolute pyridine. After stirring for 15 min., 720 mg (0.0035 mol) of N,N'-dicyclohexylcarbodiimide are added. A crystalline precipitate of the N,N'-dicyclohexylurea which has been formed soon appears in the initially clear solution. Stirring is continued until TLC no longer detects starting material and detects the reaction product at RF =0.8 (as a rule, a reaction period of 16 hours; a longer reaction period, e.g. standing or stirring over the weekend, does not impair the reaction result). After this, 0.3 ml of acetic acid are added and the mixture is left to stand for a further 1 h. at 20° C. and then 24-48 h. in a deep-freeze (about -15° C.). The precipitated N,N'-dicyclohexylurea is filtered off and washed with cold pyridine (about -15° C.), and the filtrate is stirred into about 400 ml of a quarter-saturated aqueous solution of sodium chloride; about 5 ml of ethanol are added and the oily-crystalline precipitate is filtered off, washed several times with water and then taken up in about 20 ml of methylene chloride. After drying with sodium sulfate, the solvent is distilled off and the residue is crystallized by adding diethyl ether or diisopropyl ether. 1.1 g of prednisolone 17-ethyl carbonate 21-phenylacetate with a melting point of 179°-183° C. are obtained and can be recrystallized from tertbutanol/diethylether.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:16]([NH:17][C:18](=[O:25])[CH2:19][C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)[C:15](=[O:26])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[CH3:2].C(OC(=O)C)(=O)C>N1C=CC=CC=1>[C:1]([O:4][CH2:5][C:6]1[CH:11]([C:12]([OH:14])=[O:13])[N:10]2[C:15](=[O:26])[C@@H:16]([NH:17][C:18](=[O:25])[CH2:19][C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)[C@H:9]2[S:8][CH:7]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCC1=CS[C@@H]2[C@H](NC(=O)Cc3cccs3)C(=O)N2C1C(=O)O
Reaction time: 0.75 h
Yield: 64.9 %

Procedure:
A solution of 3-acetoxymethyl-7β-(2-thienylacetamido)ceph-3-em-4-carboxylic acid (146.5 g.) in pyridine (600 ml.) was treated with acetic anhydride (45 ml.) and the mixture stirred vigorously at 22° for 45 minutes. The material which crystallised out was isolated by filtration washed with pyridine and ethyl acetate, and dried in vacuo to give the pyridinium salt of the title compound (95.15 g., 54.5%). This pyridinium salt was stirred with water (350 ml.) and ethyl acetate (700 ml.) and 2N-hydrochloric acid (ca 120 ml.) added until all the solid had dissolved. The organic phase was separated, washed with water, dried and evaporated in vacuo to give the title compound (77 g.) as a white solid, m.p. 151°-152.5°, [α]D + 480° 5% sodium carbonate), λmax. 235 nm. (ε 15,200), νmax. 3293 (NH), 1746 (β-lactam), 1722 and 2600 (CO2H), 1722 and 1208 (CH2OCOCH3) and 1660 and 1528 cm.-1 (CONH), τ (D2O - sodium bicarbonate) 2.7 and 3.0 (thienyl, 1-proton t and 2-proton d), 3.62 (C(2) -H, broad s), 4.58 (C(7) -H, d, J 4.5 Hz), 4.69 (C(6) -H, d, J 4.5 Hz), 5.18 (C(4) -H, broad s), 6.15 (CH2CONH, s) and 7.9 (-OCOCH3, s) (CH2OAc obscured by H2O band). (Found: C, 48.3; H, 4.1; N, 7.0; S, 16.2. Calc. for C16H16N2O6S2 : C, 48.4; H, 4.05; N, 7.05; S, 16.15%).
Reaction SMILES: C([O:3][C:4](=[O:47])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[C:14]([C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[CH:16]=2)=[CH:13][C:12]([C:23](=[O:38])[NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:11][C:10]=1[C:39]1[CH:44]=[C:43]([CH3:45])[CH:42]=[C:41]([CH3:46])[CH:40]=1)C.[OH-].[K+]>CO.Cl.O>[CH3:22][C:17]1[CH:16]=[C:15]([C:14]2[CH:13]=[C:12]([C:23](=[O:38])[NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:11]=[C:10]([C:39]3[CH:44]=[C:43]([CH3:45])[CH:42]=[C:41]([CH3:46])[CH:40]=3)[C:9]=2[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:47])=[O:3])[CH:20]=[C:19]([CH3:21])[CH:18]=1
Reactant: CCOC(=O)CCCOc1c(-c2cc(C)cc(C)c2)cc(C(=O)NCCCCCCCc2ccccc2)cc1-c1cc(C)cc(C)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(C)cc(-c2cc(C(=O)NCCCCCCCc3ccccc3)cc(-c3cc(C)cc(C)c3)c2OCCCC(=O)O)c1
Yield: 45.1 %

Procedure:
To a suspension of 4-[3,5,3″,5″-Tetramethyl-5′-(7-phenyl-heptylcarbamoyl)-[1,1′:3′,1″]terphenyl-2′-yloxy]-butyric acid ethyl ester (170 mg, 0.256 mmol) in 4 mL MeOH/1 mL H2O was added solid KOH (12 mg, 0.213 mmol). The reaction mixture was refluxed for 2 d and then the reaction mixture was diluted with 2N HCl and water. The aqueous solution was extracted with EtOAc (3×) and the combined organic extracts were dried over Na2SO4. The solvent was removed in vacuo to give an oil that was flash chromatographed (10% EtOAc:90% Hexanes) on silica gel to yield 70 mg, 43% of the acid as an oily white foam. mp 64-66″C; 1H NMR (DMSO-d6) δ1.29-1.30 (m, 6H); 1.32-1.39 (m, 2H); 1.46-1.48 (m, 4H); 1.86 (t, J=7.47 Hz, 2H); 2.33 (s, 12H); 2.53 (t, J=7.58 Hz, 2H); 3.19-3.31 (m, 4H); 7.01 (s, 2H); 7.12-7.16 (m, 3H); 7.17-7.19 (m, 4H); 7.21-7.24 (m, 2H) 7.71 (s, 2H); 8.48 (t, J=7.00 Hz, 1H); 11.86 (s, 1H); IR 3325, 2925, 2875, 1710, 1630, 1600, 1535, 1450, 1290, 1225, 1210, 850, and 700 cm−1; mass spectrum [(+)APCI], m/z 606 [M+H]+; Anal Calcd. for C40H47NO4: C, 79.30; H, 7.82; N, 2.31; Found: C, 78.65; H, 7.86; N, 1.87.
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[OH:5][C:6]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]1=[O:15]>>[C:1]([CH2:2][CH2:3][N:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]([OH:5])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:7]1=[O:15])#[N:4]
Reactant: C=CC#N
Reactant: O=C1Nc2ccccc2C1(O)c1ccccc1
Product: N#CCCN1C(=O)C(O)(c2ccccc2)c2ccccc21

Procedure:
Reaction of acrylonitrile with 3-hydroxy-3-phenyl-indolin-2-one by a procedure analogous to that of Example 1 gives 1-(2-cyanoethyl)-3-hydroxy-3-phenyl-indolin-2-one Hydrogenation of the 1-(2-cyanoethyl)-3-hydroxy-3-phenyl-indolin-2-one by a procedure analogous to that of Example 2 gives 1-(3-aminopropyl)-3-hydroxy-3-phenyl-indolin-2-one. Cyclodehydration of 1-(3-aminopropyl)-3-hydroxy-3-phenylindolin-2-one by a procedure analogous to that of Example 3 gives 2,3,4,10-tetrahydro-10-phenylpyrimido [1,2-a] indol-10-ol.