Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:3]([O:5][C@@H:6]1[CH:11]2[CH2:12][CH2:13][N:8]([CH2:9][CH2:10]2)[CH2:7]1)=[O:4].C(N(CC)CC)C.[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(Cl)Cl>[C:27]([NH:1][CH:2]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:3]([O:5][C@@H:6]1[CH:11]2[CH2:10][CH2:9][N:8]([CH2:13][CH2:12]2)[CH2:7]1)=[O:4])(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 50.5 %

Procedure:
To a solution of (R)-quinuclidin-3-yl 2-amino-2-phenylacetate (I30) (100 mg, 0.38 mmol) in DCM (4 ml) and triethylamine (0.08 ml, 0.58 mmol), was added benzoyl chloride (58.0 μl, 0.50 mmol). The reaction was stirred at RT for 1.5 hours, and then the volatiles were evaporated. The crude was purified by flash chromatography (DCM/MeOH/NH4OH=95/5/0.3) to obtain (R)-quinuclidin-3-yl 2-benzamido-2-phenylacetate (70 mg; 50% yield).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6]4=[C:7]([C:17](=[O:27])[C:18]([CH2:20][C:21]5[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=5)=[CH:19][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([OH:16])[CH:10]=3.Cl.Cl[CH2:30][C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1>>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6]4=[C:7]([C:17](=[O:27])[C:18]([CH2:20][C:21]5[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=5)=[CH:19][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([O:16][CH2:30][C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1)[CH:10]=3
Reactant: ClCc1cccnc1
Reactant: O=c1c(Cc2cccnc2)cn2c3c(cc(O)cc13)Sc1ccc(Br)cc1-2
Agent: Cl
Product: O=c1c(Cc2cccnc2)cn2c3c(cc(OCc4cccnc4)cc13)Sc1ccc(Br)cc1-2
Yield: 38.6 %

Procedure:
According to Example 34, the compound (300 mg) produced in Example 37 was reacted with 3-chloromethylpyridine hydrochloride (142 mg) to obtain the title compound (140 mg; 46%).
Reaction SMILES: ICC(F)(F)F.ClC1C=CC(CBr)=C(F)C=1.N1C2C(=CC=CN=2)C=C1.COC1C=C2C(=NC=1)NC=C2.CCC1N=C(CC2C=CC(OC)=CC=2)OC1.[Cl:53][C:54]1[CH:83]=[CH:82][C:57]([CH2:58][O:59][C:60]2[C:61]([O:79][CH2:80][CH3:81])=[C:62]([C:66]([C:68]3[C:76]4[C:71](=[N:72][CH:73]=[C:74](OC)[CH:75]=4)[NH:70][CH:69]=3)=O)[CH:63]=[CH:64][CH:65]=2)=[C:56](F)[CH:55]=1>>[Cl:53][C:54]1[CH:55]=[CH:56][C:57]([CH2:58][O:59][C:60]2[C:61]([O:79][CH2:80][CH3:81])=[C:62]([CH:63]=[CH:64][CH:65]=2)[CH2:66][C:68]2[C:76]3[C:71](=[N:72][CH:73]=[CH:74][CH:75]=3)[NH:70][CH:69]=2)=[CH:82][CH:83]=1
Reactant: CCOc1c(OCc2ccc(Cl)cc2F)cccc1C(=O)c1c[nH]c2ncc(OC)cc12
Agent: CCC1COC(Cc2ccc(OC)cc2)=N1
Agent: COc1cnc2[nH]ccc2c1
Agent: FC(F)(F)CI
Product: CCOc1c(Cc2c[nH]c3ncccc23)cccc1OCc1ccc(Cl)cc1

Procedure:
were prepared following the protocol of Scheme 71, substituting iodoethane with iodomethane in Step 3 to provide P-1891, or substituting iodoethane with 2-iodo-1,1,1-trifluoroethane in Step 3 to provide P-2076, or substituting 4-chlorobenzyl bromide 557 with 4-chloro-2-fluoro-benzyl bromide in Step 1 and 7-azaindole 94 with 5-methoxy-7-azaindole in Step 4 to provide P-2016. MS(ESI) [M+H+]+=393.4 (P-1891), 461.08 (P-2076), and 455.2 (P-2016).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[OH:21][CH2:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH2:25][NH:26][CH2:27]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[OH:21][CH2:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH2:25][N:26]([C:11]1[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5][N:4]3[CH:1]3[CH2:2][CH2:3]3)=[CH:9][C:10]=1[F:16])[CH2:27]2
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: OCc1cccc2c1CNC2
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3Cc4cccc(CO)c4C3)c(F)cc2c1=O
Yield: 41.3 %

Procedure:
283 mg of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 179 mg of 4-hydroxymethylisoindoline, 304 mg of DBU, and 2 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 170 mg of the target compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[CH3:10][Si:11]([C:14]#[CH:15])([CH3:13])[CH3:12].N1C=CC=CC=1>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.[Cu]I.CCCCCC.C(OCC)(=O)C>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:15]#[C:14][Si:11]([CH3:13])([CH3:12])[CH3:10])=[CH:3][CH:4]=1
Reactant: COc1ccc(Br)cc1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: c1ccncc1
Product: COc1ccc(C#C[Si](C)(C)C)cc1
Temperature: 60 °C
Yield: 65 %

Procedure:
p-Bromoanisole(3.74 g, 20 mmol), tetrakis(triphenylphosphine)palladium (1.16 g, 1 mmol) and CuI (0.381 g, 2 mmol) were placed in a 100 mL three neck round bottom flask, equipped with a pressure equalizing addition funnel and a reflux condenser which was connected to a vacuum line. The third neck of the flask was sealed with a rubber septum. The apparatus was purged with nitrogen three times. Pyridine, (30 mL) was added and the mixture was stirred until it became a single clear phase. Trimethylsilyl-acetylene (1.96 g, 20 mmol) and 20 mL of pyridine were placed in the addition funnel and the solution was added dropwise to the reaction mixture at 45° C. The reaction mixture was heated to 60° C. The progress of the reaction was monitored by TLC (silica gel with hexane/ethyl acetate). When the reaction was complete, it was extracted with ether. The organic solution was dried over anhydrous magnesium sulfate, filtered and the volatile solvents removed by evaporation under reduced pressure. The residue was purified by column chromatography (silica gel with hexane/ethyl acetate). In this way, 2.66g, 65% yield, was obtained. 1H NMR δ: 7.39(d, 2H, J=8.75 Hz), 6.80(d, 2H, J=8.75 Hz), 3.78(s, 3H), 0.23(s, 9H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:17]([C:18](=[O:33])[NH:19][C@H:20]([C:25]([O:27][CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)=[O:26])[CH2:21][CH:22]([CH3:24])[CH3:23])[CH2:16][C:15]2[C:10](=[CH:11][C:12]([N+:34]([O-])=O)=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCOC(C)=O.[Pd].[C]>[C:1]([O:5][C:6]([N:8]1[C@H:17]([C:18](=[O:33])[NH:19][C@H:20]([C:25]([O:27][CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32]2)=[O:26])[CH2:21][CH:22]([CH3:24])[CH3:23])[CH2:16][C:15]2[C:10](=[CH:11][C:12]([NH2:34])=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)C[C@H](NC(=O)[C@@H]1Cc2ccc([N+](=O)[O-])cc2CN1C(=O)OC(C)(C)C)C(=O)OC1CCCC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)C[C@H](NC(=O)[C@@H]1Cc2ccc(N)cc2CN1C(=O)OC(C)(C)C)C(=O)OC1CCCC1
Reaction time: 16 h

Procedure:
(S)-3-((S)-1-Cyclopentyloxycarbonyl-3-methyl-butylcarbamoyl)-7-nitro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (3.14 g, 6.24 mmol) and Pd/carbon (0.4 g) were suspended in EtOAc (20 ml). The reaction was stirred under a hydrogen atmosphere (balloon pressure) for 16 h. The solution was filtered through a pad of celite and the solvent removed. The crude product (3.04 g) was used in the next step without further purification. LCMS purity 83%, m/z 474 [M++H]+
Reaction SMILES: F[C:2]1[C:3]([CH3:15])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12](=[O:14])[CH3:13])[CH:8]=[CH:7][CH:6]=2.[CH3:16][C:17]([NH2:25])([CH2:19][CH2:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH3:18].C(N(C(C)C)C(C)C)C>CN1C(=O)CCC1.C(Cl)Cl>[CH3:15][C:3]1[C:2]([NH:25][C:17]([CH3:18])([CH2:19][CH2:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH3:16])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:12](=[O:14])[CH3:13])[N:4]=1
Reactant: CC(=O)c1cccc2nc(C)c(F)nc12
Reactant: CC(C)(N)CCS(C)(=O)=O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)c1cccc2nc(C)c(NC(C)(C)CCS(C)(=O)=O)nc12
Yield: 100.1 %

Procedure:
A solution of 1-(3-fluoro-2-methylquinoxalin-5-yl)ethanone (126g, 300 mg, 1.469 mmol), 2-methyl-4-(methylsulfonyl)butan-2-amine (338b, 486 mg, 2.94 mmol), and N-ethyl-N-isopropylpropan-2-amine (1.02 mL, 5.88 mmol) in NMP (2.94 mL) was stirred at 120° C. for 16 h when product and a small amount of hydrolysis were observed via lcms. The reaction mixture was diluted with DCM (150 mL), added to a separatory funnel, and washed with saturated aq. NaHCO3 (3×100 mL); the organic layer was separated, dried over Na2SO4, and concentrated. The crude product was adsorbed onto silica and was purified via automated flash chromatography (silica gel) with 100% DCM to 2% 2 M NH3 in MeOH/DCM to give 1-(2-methyl-3-((2-methyl-4-(methylsulfonyl)butan-2-yl)amino)quinoxalin-5-yl)ethanone (338c, 513 mg, 1.47 mmol, 100% yield) as a red oil contaminated with NMP. 1H NMR (400 MHz, CDCl3) δ ppm 1.56 (s, 6H) 2.56 (s, 3H) 2.62-2.68 (m, 2H) 2.78 (s, 3H) 2.83 (s, 3H) 2.94-3.01 (m, 2H) 4.82 (s, 1H) 7.40 (dd, J=8.12, 7.34 Hz, 1H) 7.70 (dd, J=7.34, 1.47 Hz, 1H) 7.92 (dd, J=8.12, 1.47 Hz, 1H). MS (ESI, pos. ion) m/z: 350.2 (M+1).
Reaction SMILES: [Br:1]Br.[C:3]([C:11]1[C:12](=[O:21])[N:13]([CH3:20])[C:14](=[O:19])[N:15]([CH3:18])[C:16]=1[CH3:17])(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl.CCOC(C)=O>[C:3]([C:11]1[C:12](=[O:21])[N:13]([CH3:20])[C:14](=[O:19])[N:15]([CH3:18])[C:16]=1[CH2:17][Br:1])(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Cc1c(C(=O)c2ccccc2)c(=O)n(C)c(=O)n1C
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: Cn1c(CBr)c(C(=O)c2ccccc2)c(=O)n(C)c1=O
Temperature: 55 °C
Reaction time: 0.5 h

Procedure:
Bromine (0.497 mL, 9.68 mmol) was added to a solution of 5-benzoyl-1,3,6-trimethyl pyrimidine-2,4(1H,3H)-dione (step 2) (2.5 g, 9.68 mmol) in chloroform (50 mL) with stirring under nitrogen. The mixture was heated to 55° C. for 2 h. A further portion of bromine (0.25 mL, 0.5 equiv) was added and heating continued at 55° C. for a further 30 min. The mixture was cooled to RT, diluted with CHCl3 (50 mL) and poured into saturated sodium thiosulfate solution (150 mL). The layers were separated and the aqueous phase was extracted with CHCl3 (50 mL). The combined organics were washed with water (50 mL), brine (50 mL), dried (Na2SO4) and filtered under reduced pressure. The solvent was evaporated under reduced pressure to afford a pale yellow solid. This solid was dissolved in hot EtOAc (50 mL) and slowly evaporated until crystallisation was observed. The resulting white solid was collected by reduced pressure filtration and washed with cold EtOAc (10 mL) and dried in air. The compound was further dried under vacuum at 50° C. for 2 h. The title product was isolated as white micro needles.
Reaction SMILES: [OH:1]O.[F:3][C:4]1[C:9]([F:10])=[C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH:7]=[CH:6][C:5]=1[C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>C(OCC)C>[F:3][C:4]1[C:9]([F:10])=[C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH:7]=[CH:6][C:5]=1[C:20]1[CH:25]=[CH:24][C:23]([OH:1])=[CH:22][CH:21]=1
Reactant: OO
Reactant: CCCCCCCCOc1ccc(-c2ccc(B(O)O)cc2)c(F)c1F
Solvent: CCOCC
Product: CCCCCCCCOc1ccc(-c2ccc(O)cc2)c(F)c1F

Procedure:
10% hydrogen peroxide (10.5 ml, 0.023 mol) was added dropwise to a stirred, refluxing solution of 2,3 -difluoro-4 -octoxybiphenyl-4'-yl-boronic acid (10) (2.9g, 8.0 mmol), in diethyl ether (40 ml). The stirred mixture was heated under reflux until tic showed the reaction to be complete. The ether layer was separated and the aqueous layer extracted with ether. The combined ethereal layers were washed with water and dried. The solvent was removed. The crude product was purified by flash chromatography (silica gel/petroleum fraction (bp 40°-60° C.) - ethyl acetate, 2:1) to give a white solid which was recrystallised from pentane/ethyl acetate mixtures.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7])#[CH:2].[CH3:12][S-:13].[Na+]>ClCCl>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([S:13][CH3:12])=[O:7])#[CH:2]
Reactant: C[S-]
Reactant: C#Cc1cccc(C(=O)Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: C#Cc1cccc(C(=O)SC)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Air in a 20 ml Schlenk tube was replaced by Ar gas and 1.02 g (7 mmol) of m-ethynylbenzoic acid and 5 g (42 mmol) of thionyl chloride were added to the tube and the mixture was stirred at 50° C. for 2 hours and then excess thionyl chloride was removed by distillation under reduced pressure to obtain m-ethynylbenzoyl chloride. To the m-ethynylbenzoyl chloride obtained was added 7 ml of dichloromethane and the resultant mixture was ice-cooled. Then, 515 mg (7.35 mmol) of sodium methanethiolate was added to the mixture and the mixture was stirred at room temperature for 3 hours. After completion of the stirring, dichloromethane was removed by distillation under reduced pressure and 35 ml of water was added to the resultant residue. The mixture was extracted with 35 ml of ethyl acetate and the extract was dried over magnesium sulfate and the solvent was removed by distillation under reduced pressure using an evaporator. The resultant crude reaction product was purified by column chromatography (Hexane/AcOEt=10/1) using silica gel to obtain 0.49 g of S-methyl 3-ethynyl-thiobenzoate which is a desired product as yellow solid. (Yield: 40%)
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)[C:9](=[O:25])[N:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[CH:22]=[CH:23][NH:24][C:17]=23)[CH2:12][CH2:11]1)(C)(C)C.Cl>C(Cl)Cl.O1CCOCC1>[NH2:7][CH:8]([CH2:26][C:27]1[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=1)[C:9]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[CH:22]=[CH:23][NH:24][C:17]=23)[CH2:12][CH2:11]1)=[O:25]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ccnc3cc[nH]c23)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: NC(Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ccnc3cc[nH]c23)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of {1-(4-chlorobenzyl)-2-oxo-2-[4-(1H-pyrrolo[3,2-b]pyridin-7-yl)-piperazin-1-yl]-ethyl}-carbamic acid tert-butyl ester in DCM (4 mL) was added HCl in Dioxane (4M, 1 mL). The mixture was stirred at room temperature for 4 hours. The solvent removed to afford the product 2-Amino-3-(4-chlorophenyl)-1-[4-(1H-pyrrolo[3,2-b]pyridin-7-yl)-piperazin-1-yl]-propan-1-one quantitatively. MS (ESI+) [M+H]+ 384.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[CH:16][C:5]=2[S:6][C:7]=1[C:8]([N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)=[O:9].[Cu][C:25]#[N:26].O>CN(C)C=O>[CH3:21][O:20][C:18]1[C:17]([O:22][CH3:23])=[CH:16][C:5]2[S:6][C:7]([C:8]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)=[O:9])=[C:3]([CH3:2])[C:4]=2[C:19]=1[C:25]#[N:26]
Reactant: COc1cc2sc(C(=O)N3CCOCC3)c(CBr)c2cc1OC
Reactant: N#C[Cu]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2sc(C(=O)N3CCOCC3)c(C)c2c(C#N)c1OC

Procedure:
(4-Bromo-5,6-dimethoxy-3-methyl-benzo[b]thiophen-2-yl)-morpholin-4-yl-methanone (0.42 g) from Example 33 and copper(I) cyanide (2.0 g) in N,N-dimethylformamide (8 ml) were irradiated in a microwave oven at 150° C. for 1.5 hours. To the mixture water was added and the product was extracted into ethyl acetate. Ethyl acetate was dried and evaporated to dryness.
Reaction SMILES: [I-].CS[C:4]1[S:5][CH2:6][C@@H:7]2[CH2:16][C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH2:9][N+:8]=12.[NH2:17][C:18]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:19]=1[CH:20]=[C:21]([CH2:28][O:29][CH2:30][CH3:31])[N:22]=[CH:23]2>N1C=CC=CC=1>[CH2:30]([O:29][CH2:28][C:21]1[N:22]=[CH:23][C:24]2[C:19]([CH:20]=1)=[C:18]([N:17]=[C:4]1[N:8]3[CH2:9][C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=4[CH2:16][C@H:7]3[CH2:6][S:5]1)[CH:27]=[CH:26][CH:25]=2)[CH3:31]
Reactant: CSC1=[N+]2Cc3ccccc3C[C@H]2CS1
Reactant: CCOCc1cc2c(N)cccc2cn1
Agent: [I-]
Solvent: c1ccncc1
Product: CCOCc1cc2c(N=C3SC[C@@H]4Cc5ccccc5CN34)cccc2cn1
Temperature: 20 °C
Reaction time: 24 h
Yield: 67.4 %

Procedure:
(S)-3-Methylthio-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinolinium iodide (7.2 g) is added to a solution of 5-amino-3-ethoxymethylisoquinoline (4.1 g) in pyridine (150 cc). The suspension is stirred for 24 hours at a temperature of about 20° C. The insoluble material gradually dissolves. The solution is concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 60° C. The residue is dissolved in a mixture of methylene chloride (100 cc) and N sodium hydroxide solution (100 cc). The organic phase is decanted, washed with water (50 cc), dried over magnesium sulphate and filtered and the filtrate is evaporated to dryness at 40° C. under reduced pressure (20 mm Hg; 2.7 kPa). The residue is recrystallised from isopropyl alcohol (80 cc). (S)-3-[(3-Ethoxymethylisoquinol-5-yl)imino]-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinoline (5.2 g) is thus obtained in the form of a pale yellow solid melting at 88° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([O:29][C:30]2[CH:35]=[CH:34][C:33]([S:36]([CH3:39])(=[O:38])=[O:37])=[CH:32][CH:31]=2)[CH:12]=[C:13]2[C:17]=1[NH:16][C:15]([C:18]1[S:19][CH:20]([CH2:23][C:24](OCC)=[O:25])[CH2:21][N:22]=1)=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Li+].Cl.C(OCC)(=O)C>O1CCCC1.CCCCCC>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([O:29][C:30]2[CH:31]=[CH:32][C:33]([S:36]([CH3:39])(=[O:38])=[O:37])=[CH:34][CH:35]=2)[CH:12]=[C:13]2[C:17]=1[NH:16][C:15]([C:18]1[S:19][CH:20]([CH2:23][CH2:24][OH:25])[CH2:21][N:22]=1)=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)cc4)cc(OCc4ccccc4)c3[nH]2)S1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(Oc2cc(OCc3ccccc3)c3[nH]c(C4=NCC(CCO)S4)cc3c2)cc1
Temperature: 25 °C
Reaction time: 13 h
Yield: 12 %

Procedure:
Ethyl (2-{7-(benzyloxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetate (470 mg) was dissolved in tetrahydrofuran (8 mL), lithium borohydride (100 mg) was added, and the mixture was stirred at room temperature for 13 hr. 1M Hydrochloric acid was added to the reaction mixture, and the mixture was subjected to extraction with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, filtrated, and concentrated under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (ethyl acetate:hexane=30:70 to 100:0, volume ratio), and the obtained yellow oil was crystallized from ethanol. The obtained crystals were recrystallized from ethanol to give the title compound (52 mg, yield 12%) as colorless crystals. melting point 97-98° C. MS 523 (MH+).
Reaction SMILES: [NH2:1][C@@H:2]1[C:34](=[O:35])[N:4]2[C:5]([C:18]([O:20][CH:21]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])=[C:6]([S:9]/[CH:10]=[CH:11]\[C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[CH2:7][S:8][C@H:3]12.C[Si](C)(C)NC(=O)C.[C:44]1([CH2:50][C:51](Cl)=[O:52])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.O>O1CCCC1.C(OCC)(=O)C>[C:44]1([CH2:50][C:51]([NH:1][C@@H:2]2[C:34](=[O:35])[N:4]3[C:5]([C:18]([O:20][CH:21]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[O:19])=[C:6]([S:9]/[CH:10]=[CH:11]\[C:12]4[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=4)[CH2:7][S:8][C@H:3]23)=[O:52])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(S/C=C\c3cccnc3)CS[C@H]12
Reactant: O=C(Cl)Cc1ccccc1
Agent: CC(=O)N[Si](C)(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(S/C=C\c3cccnc3)CS[C@H]12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of benzhydryl 7β-amino-3-[(Z)-2-(3-pyridyl)vinylthio]-3-cephem-4-carboxylate (500 mg) in tetrahydrofuran (12.5 ml) was added N-trimethylsilylacetamide (550 mg), and stirred at room temperature for 20 minutes. To the solution was added dropwise a solution of phenyl acetyl chloride (146 μl) above at -20° C. for 2 minutes. The mixture was stirred at -20~-15° C. for 50 minutes. To the reaction mixture were added water (50 ml), ethyl acetate (50 ml) and tetrahydrofuran (15 ml). The organic layer was separated, washed with water and saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was triturated with ethyl acetate to give benzhydryl 7β-(2-phenylacetamido)-3-[(Z)-2-(3-pyridyl)vinylthio]-3-cephem-4-carboxylate (532 mg).
Reaction SMILES: Cl[C:2]1[C:15]2[C:14](=O)[C:13]3[C:8](=[CH:9][C:10]([O:17][CH3:18])=[CH:11][CH:12]=3)[S:7][C:6]=2[C:5]([CH3:19])=[CH:4][CH:3]=1.[CH2:20]([N:22]([CH2:27][CH3:28])[CH2:23][CH2:24][NH:25][NH2:26])[CH3:21]>>[CH2:20]([N:22]([CH2:27][CH3:28])[CH2:23][CH2:24][N:25]1[C:2]2[CH:3]=[CH:4][C:5]([CH3:19])=[C:6]3[S:7][C:8]4[CH:9]=[C:10]([O:17][CH3:18])[CH:11]=[CH:12][C:13]=4[C:14]([C:15]=23)=[N:26]1)[CH3:21]
Reactant: COc1ccc2c(=O)c3c(Cl)ccc(C)c3sc2c1
Reactant: CCN(CC)CCNN
Product: CCN(CC)CCn1nc2c3c(c(C)ccc31)Sc1cc(OC)ccc1-2

Procedure:
By the condensation of 1-chloro-6-methoxy-4-methyl-9-thioxanthenone with 2-(diethylamino)ethylhydrazine was obtained 2-(2-(diethylamino)ethyl)-8-methoxy-5-methyl-2H(1)benzothiopyrano[4,3,2-cd]indazole. To 0.18g. of this base in acetone (3 ml.) was added 30% aqueous hydrogen peroxide (0.22 ml.). After standing at room temperature for 90 hours the solution was evaporated under reduced pressure. The solid residue gave crystals m.p. 132° - 133° (decomp.) from acetone which consisted of 2-(2-(diethylamino)ethyl)-8-methoxy-5-methyl-2H(1)benzothiopyrano[4,3,2-cd]indazole N-oxide 1.75 hydrate.
Reaction SMILES: Cl[C:2]1C=C(Cl)C=C(Cl)C=1O.C([Zn]CC)C.C(I)I.[CH2:19]=[C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][C:28]=2[O:30][CH2:31][O:32][CH3:33])[O:23][CH2:22][CH2:21]1>C(Cl)Cl.CCCCCC>[CH3:33][O:32][CH2:31][O:30][C:28]1[CH:27]=[CH:26][CH:25]=[C:24]2[O:23][CH2:22][CH2:21][C:20]3([CH2:2][CH2:19]3)[C:29]=12
Reactant: C=C1CCOc2cccc(OCOC)c21
Reactant: Oc1c(Cl)cc(Cl)cc1Cl
Agent: CC[Zn]CC
Solvent: ICI
Solvent: CCCCCC
Solvent: ClCCl
Product: COCOc1cccc2c1C1(CCO2)CC1
Reaction time: 0.25 h
Yield: 80.4 %

Procedure:
To a solution of 2,4,6-trichlorophenol (307 mg, 1.557 mmol) in 12.0 mL of DCM, at −40° C., 1M solution in hexane of diethylzinc (1.557 mL, 1.557 mmol) was added. After stirring at that temperature for 15 minutes, CH2I2 (0.126 mL, 1.557 mmol) was added. After stirring for additional 15 minutes, 4-methylidene-5-{[(methyloxy)methyl]oxy}-3,4-dihydro-2H-chromene (169 mg, 0.819 mmol) dissolved in 3.0 mL of DCM was added. The cold bath was removed and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with DCM, washed with a 10% aqueous solution of HCl 2 times, then with an aqueous saturated solution of NaHCO3 2 times, an aqueous saturated solution of Na2SO3 2 times and brine (2 times). The organic layer was then dried over Na2OS4, filtered and evaporated and the residue was purified by flash chromatography (Biotage SP1) on silica gel using cyclohexane/ethyl acetate from 100:0 to 95:5. Collected residue was dissolved in DCM and washed (two times) with KOH (30% aq sol). The organic layer was dried over sodium sulphate, filtered and evaporated to afford the title compound (145 mg).