Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:15]1([CH3:31])[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH:22]1[C:27]([O:29][CH3:30])=[O:28].C(=O)([O-])O.[Na+]>CN(C)C=O>[CH2:7]([N:24]1[CH2:25][CH2:26][CH:21]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH3:31])[CH:22]([C:27]([O:29][CH3:30])=[O:28])[CH2:23]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)C1CNCCC1c1ccccc1C
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C1CN(Cc2ccccc2)CCC1c1ccccc1C
Temperature: 70 °C
Reaction time: 1.5 h

Procedure:
540 mg of potassium carbonate and 0.25 mL of benzyl bromide were added to N,N-dimethylformamide (7 mL) solution of 453 mg of methyl (3RS,4SR)-4-o-tolyl-piperidine-3-carboxylate obtained in Production Example 31, and stirred at 70° C. for 1.5 hours. Then, this was restored to room temperature, aqueous saturated sodium hydrogencarbonate solution was added thereto and extracted with ether. The ether layer was washed with saturated saline water, and dried with anhydrous sodium sulfate, and the solvent was evaporated off under reduced pressure. The residue was separated and purified through silica gel column chroamtography (hexane/ethyl acetate=9/1) to obtain 463 mg of methyl (3RS,4SR)-1-benzyl-4-o-tolyl-piperidine-3-carboxylate. The compound was processed in the same manner as in Production Example 33-1 to obtain 360 mg of the entitled compound.
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:11][C:12](=[O:22])[C:13]2[CH:18]=[C:17]([F:19])[C:16](F)=[CH:15][C:14]=2[F:21])=[C:4]([C:7]([O:9]C)=[O:8])[S:5][CH:6]=1.[CH3:23][OH:24].[OH-].[Na+].Cl>C1COCC1>[F:21][C:14]1[CH:15]=[C:16]([O:24][CH3:23])[C:17]([F:19])=[CH:18][C:13]=1[C:12]([NH:11][C:3]1[C:2]([CH3:1])=[CH:6][S:5][C:4]=1[C:7]([OH:9])=[O:8])=[O:22]
Reactant: CO
Reactant: COC(=O)c1scc(C)c1NC(=O)c1cc(F)c(F)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc(F)c(C(=O)Nc2c(C)csc2C(=O)O)cc1F
Temperature: 70 °C

Procedure:
After a mixture of methyl 4-methyl-3-[(2,4,5-trifluorobenzoyl)amino]thiophene-2-carboxylate, MeOH, THF and 1M NaOH aq was stirred at 70° C., 1M of hydrochloric acid aq was added and the extracted solid was filtered to give 3-[(2,5-difluoro-4-methoxybenzoyl)amino]-4-methythiophene-2-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].Cl[C:12]1[C:13]2[C:26]([CH3:27])=[C:25]([CH3:28])[S:24][C:14]=2[N:15]=[C:16]([C:18]2[CH:23]=[N:22][CH:21]=[CH:20][N:19]=2)[N:17]=1>>[N:19]1[CH:20]=[CH:21][N:22]=[CH:23][C:18]=1[C:16]1[N:17]=[C:12]([NH:6][CH2:5][C:4]2[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=2)[C:13]2[C:26]([CH3:27])=[C:25]([CH3:28])[S:24][C:14]=2[N:15]=1
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: Cc1sc2nc(-c3cnccn3)nc(Cl)c2c1C
Product: Cc1sc2nc(-c3cnccn3)nc(NCc3ccc(Cl)c(Cl)c3)c2c1C

Procedure:
With the procedure of Example 1, the reaction of 3,4-dichlorobenzylamine with 4-chloro-2-(pyrazin-2-yl)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyrazin-2-yl)-4-(3,4-dichlorobenzylamino)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: C1(C2[C:5](=CC=CC=2)[CH:4]([O:11][C:12](=[O:35])[CH2:13][CH2:14][CH2:15][CH2:16][CH:17]2[S:34][C@H:20]3[CH2:21][C@@H:22]([OH:33])[C@H:23](/[CH:24]=[CH:25]/[C@@H:26]([OH:32])[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C@H:19]3[CH2:18]2)O1)=O.[OH:36]C1C2C(=CC=CC=2)C(=O)O1>>[OH:36][CH2:5][CH2:4][O:11][C:12](=[O:35])[CH2:13][CH2:14][CH2:15][CH2:16][CH:17]1[S:34][C@H:20]2[CH2:21][C@@H:22]([OH:33])[C@H:23](/[CH:24]=[CH:25]/[C@@H:26]([OH:32])[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C@H:19]2[CH2:18]1
Reactant: O=C1OC(O)c2ccccc21
Reactant: CCCCC[C@H](O)/C=C/[C@@H]1[C@H]2CC(CCCCC(=O)OC3OC(=O)c4ccccc43)S[C@H]2C[C@H]1O
Product: CCCCC[C@H](O)/C=C/[C@@H]1[C@H]2CC(CCCCC(=O)OCCO)S[C@H]2C[C@H]1O

Procedure:
(13E)-(6RS,9α,11α,15S)-6,9-Epithio-11,15-dihydroxyprost-13-enoic acid phthalid-3-yl ester from 3-hydroxyphthalide.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH:4]([NH:7][CH:8]([P:17](=[O:24])([O:21]CC)[O:18]CC)[P:9](=[O:16])([O:13]CC)[O:10]CC)[CH2:3][CH2:2]1>Cl>[S:1]1[CH2:6][CH2:5][CH:4]([NH:7][CH:8]([P:17](=[O:18])([OH:21])[OH:24])[P:9](=[O:10])([OH:16])[OH:13])[CH2:3][CH2:2]1
Reactant: CCOP(=O)(OCC)C(NC1CCSCC1)P(=O)(OCC)OCC
Agent: Cl
Product: O=P(O)(O)C(NC1CCSCC1)P(=O)(O)O
Yield: 65.2 %

Procedure:
1.7 g of tetraethyl (tetrahydro-2H-thiopyran-4-yl)aminomethylenebis(phosphonate) was dissolved in 20 ml of concentrated hydrochloric acid and heated under reflux for 2.5 hours. After cooling, the reaction solution was concentrated under reduced pressure to eliminate hydrochloric acid, 30 ml of purified water was added to the residue and then the mixture was again concentrated under reduced pressure. The obtained pale yellow solid was recrystallized from water-methanol to give 0.8 g of (tetrahydro-2H-thiopyran-4-yl)aminomethylenebis(phosphonic acid) as colorless crystals in the form of needle.
Reaction SMILES: [C:1]([NH:9][CH:10]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C@H:11]([S:14]CC1C=CC(OC)=CC=1)[CH:12]=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:31][C@H:32]([C:34]([N:36]1[CH2:47][CH2:46][CH2:45][C@H:37]1[C:38]([O:40]C(C)(C)C)=[O:39])=[O:35])[CH3:33].C(O)C.C([BH3-])#N.[Na+]>O1CCCC1>[C:1]([NH:9][C@@H:10]([CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH:11]([SH:14])[CH2:12][NH:31][C@H:32]([C:34]([N:36]1[CH2:47][CH2:46][CH2:45][C@H:37]1[C:38]([OH:40])=[O:39])=[O:35])[CH3:33])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CS[C@H](C=O)C(Cc2ccccc2)NC(=O)c2ccccc2)cc1
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: C[C@H](NCC(S)[C@H](Cc1ccccc1)NC(=O)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 2.5 h

Procedure:
A mixture of (S)-β-(benzoylamino)-α-[[(4-methoxyphenyl)methyl]thio]-benzenebutanal (isomer A) (0.45 g., 1.07 mmole), L-alanyl-L-proline, 1,1-dimethylethyl ester (0.78 g., 3.21 mmole), and crushed 3A° molecular sieves (2 g.) in tetrahydrofuran (5 ml.) and absolute ethanol (5 ml.) is stirred at room temperature under argon. After 2.5 hours, sodium cyanoborohydride (0.20 g., 3 eq.) is added and stirring continued for 15 hours. The reaction mixture is filtered to remove the sieves and the filtrate is diluted with ethyl acetate and washed with water, 1N hydrochloric acid (twice), 1N sodium bicarbonate, and brine. After drying over anhydrous MgSO4, the solvent is removed to give the desired product, as a mixture of diastereomers, as a pale yellow oil. TLC (silica gel, benzene:acetone, 4:1) isomer A at Rf =0.30 and isomer B at Rf =0.13. Flash chromatography (silica gel LPS-1; benzene:acetone, 7:3) affords impure product (isomer A). Repeated flash chromatography (silica gel LPS-1; ethyl acetate:benzene, 6:4) gives 0.20 g. of 1-[N-[(3S)-3-(benzoylamino)- 2-[[(4-methoxyphenyl)methyl]thio]-4-phenylbutyl]L-alanyl]-L-proline, 1,1-dimethylethyl ester (isomer A) as a nearly colorless oil.
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH2:9][N:8](C(OCC2C=CC=CC=2)=O)[CH2:7][CH2:6]1)[CH:2]([CH3:4])[CH3:3]>C(O)C.[C].[Pd]>[CH2:1]([N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CN1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)CN1CCNCC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 112.9 %

Procedure:
The resulting benzyl 4-isobutylpiperazin-1-carboxylate (1.05 g) was dissolved in 35 mL of ethanol, 10% palladium-carbon (750 mg) was added thereto, and the reaction mixture was stirred at room temperature under hydrogen atmosphere (1 atm) for 12 hours. The palladium-carbon was removed by filtration, and the filtrate was evaporated to give the title compound (610 mg) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH3:13])=[CH:11][NH:10][C:9]=2[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:4][CH:3]=1.[H-].[Na+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C>[CH2:21]([N:10]1[CH:11]=[C:12]([CH3:13])[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[C:9]1[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1[nH]cc(C)c1-c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(-c2ccc(F)cc2)c(C)cn1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 86.5 %

Procedure:
A solution of ethyl 3-(4-fluorophenyl)-4-methyl-1H-pyrrole-2-carboxylate (5.5 g, 22.26 mmol) in DMF (12 mL) was added to a mixture of 60% NaH (1.1 g, 33.39 mmol) in dry DMF (20 mL) at 0° C. under a N2 atmosphere and the mixture was stirred for 15 min. Benzyl bromide (2.9 mL, 24.49 mmol) was added and it was stirred at 80° C. for 12 h. The reaction mixture was cooled to 0° C., quenched with brine (20 mL), diluted with water (50 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with water (75 mL) and brine (75 mL), dried (Na2SO4) and concentrated under reduced pressure to afford the desired product (6.5 g, 87%) as brown color solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[CH2:14][CH2:15][C:16](OC)=[O:17])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[CH2:14][CH2:15][CH2:16][OH:17])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: COC(=O)CCc1cnoc1-c1cc(Cl)cc(Cl)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Product: OCCCc1cnoc1-c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.9 %

Procedure:
To a solution of methyl 3-[5-(3,5-dichlorophenyl)-4-isoxazolyl]propionate (2.25 g) in tetrahydrofuran (30 ml) was gently added diisobutylaluminum hydride (1.0 M hexane solution, 20 ml) at 0° C., and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and 3-[5-(3,5-dichlorophenyl)-4-isoxazolyl]propan-1-ol (1.65 g, yield 81%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio). NMR (CDCl3) δ: 1.83–2.00 (2H, m), 2.72–2.86 (2H, m), 3.68–3.80 (2H, m), 7.43 (1H, t, J=1.8 Hz), 7.64 (2H, d, J=1.8 Hz), 8.24 (1H, s).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=O)=[N:2]1.Cl.[CH:14]([N:17]1[CH2:22][CH2:21][CH:20]([NH2:23])[CH2:19][CH2:18]1)([CH3:16])[CH3:15].C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.O>CN(C=O)C.CCN(CC)CC>[CH:14]([N:17]1[CH2:22][CH2:21][CH:20]([NH:23][C:10]([C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][N:2]=2)=[O:12])[CH2:19][CH2:18]1)([CH3:16])[CH3:15]
Reactant: CC(C)N1CCC(N)CC1
Reactant: O=C(O)c1n[nH]c2ccccc12
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)N1CCC(NC(=O)c2n[nH]c3ccccc23)CC1
Reaction time: 16 h

Procedure:
To a solution of 300 mg 1H-Indazole-3-carboxylic acid in 3 mL DMF and 1 mL NEt3, 398 mg 1-Isopropyl-piperidin-4-ylamine hydrochloride and 471 mg BOP-Cl were added at RT and the mixture was stirred for 16 h. After the addition of 5 mL water the mixture was filtered through a chem elut® cartridge by elution with ethyl acetate and then concentrated under reduced pressure. The residue was directly subjected to the subsequent alkylation reaction without further purification. Yield: 340 mg.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8](F)[CH:9]=1)[C:5]#[N:6].[CH3:11][O-:12].[Na+]>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:12][CH3:11])[CH:9]=1)[C:5]#[N:6]
Reactant: C[O-]
Reactant: N#Cc1cc(F)cc(F)c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(F)cc(C#N)c1
Yield: 35.5 %

Procedure:
In a 250 ml round bottom flask equipped with stir bar added 3,5-Difluorobenzonitrile (4.2 g, 30.4 mmol), sodium methoxide (10.4 ml, 45.6 mmol, 25% methanol) and dimethylformamide (40 ml). Stirred the resulting reaction mixture at room temperature, overnight. The reaction mixture was concentrated in-vacuo and residue was dissolved in dichloromethane (200 ml). The organic phase was washed sequentially with water (150 ml) and brine (150 ml), dried. (sodium sulfate) and concentrated in-vacuo. The crude residue was purified on silica gel using 10% diethyl ether in hexanes to isolate 3-Fluoro-5-methoxybenzonitrile (1.63 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:15](OC)=[O:16])[C:5]([NH:9][CH2:10][C:11](OC)=[O:12])=[N:6][C:7]=1[Cl:8].[BH4-].[K+].[Cl-].[Li+].P([O-])(O)(O)=O.[K+]>O1CCCC1.ClCCl.O>[Cl:1][C:2]1[N:3]=[C:4]([CH2:15][OH:16])[C:5]([NH:9][CH2:10][CH2:11][OH:12])=[N:6][C:7]=1[Cl:8]
Reactant: COC(=O)CNc1nc(Cl)c(Cl)nc1C(=O)OC
Agent: O=P([O-])(O)O
Agent: [BH4-]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: OCCNc1nc(Cl)c(Cl)nc1CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.1 %

Procedure:
In 2.5 ml of tetrahydrofuran there was dissolved methyl [(5,6-dichloro-3-(methoxycarbonyl)pyrazinyl)amino]acetate (50 mg), prepared as in Step B above, after which potassium borohydride (22 mg; 0.0012 Mol) and lithium chloride (18 mg) were added. The reaction mixture was stirred overnight at room temperature. An additional 44 mg of potassium borohydride and 36 mg of lithium chloride were then added, and the reaction mixture was stirred at room temperature for 6 hours. Water (1 ml) was added, and the reaction mixture was cooled and stirred for 15 minutes, after which potassium dihydrogen phosphate (653 mg; 0.0048 Mol) was added. The solvent was blown off under nitrogen, and the residue was taken up in dichloromethane and filtered. The precipitate was washed twice with dichloromethane and once with ethyl acetate. The combined filtrates were concentrated under vacuum to give the title compound (32 mg).
Reaction SMILES: [C:1]1([CH3:14])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:8]([NH2:13])=[CH:9][N:10]=[N:11][CH:12]=1.[CH3:15]CCCCCC.C(OCC)(=O)C>>[CH3:15][NH:13][C:8]1[C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[CH3:14])=[CH:12][N:11]=[N:10][CH:9]=1
Reactant: CCCCCCC
Reactant: Cc1ccccc1-c1cnncc1N
Solvent: CCOC(C)=O
Product: CNc1cnncc1-c1ccccc1C

Procedure:
The title compound was prepared in analogy to example 8, intermediate a, from 5-o-tolyl-pyridazin-4-ylamine and using a gradient of n-heptane:ethyl acetate (100:0 to 40:60) for the chromatographic purification. Light yellow solid (71%). MS (EI): m/z=199 ([M]).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10](Cl)=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:13][C@H:14]([C:16]([OH:18])=[O:17])[CH3:15].[OH-].[Na+]>O>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:13][C@H:14]([C:16]([OH:18])=[O:17])[CH3:15])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=C(Cl)Cc1cc(F)cc(F)c1
Reactant: C[C@H](N)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
3,5-Difluorophenylacetyl chloride was added dropwise to a 0° C. solution of L-alanine (Aldrich) (16.7 g, 0.187 mol) in 2 N sodium hydroxide (215 mL, 0.43 mol). The reaction was stirred for 1 h at 0° C. and then overnight at room temperature. The reaction was diluted with water (100 mL), then extracted with ethyl acetate (3×150 mL). The organic layer was then washed with brine (200 mL), dried over MgSO4, and rotoevaporated at reduced pressure to a residue. Recrystallization of the residue from ethyl acetate/hexanes afforded the desired product (34.5 g, 82% yield).
Reaction SMILES: [CH2:1]([CH2:11][N:12]([CH2:17][C:18]([O-:20])=[O:19])[CH2:13][C:14]([OH:16])=[O:15])[N:2]([CH2:7][C:8]([OH:10])=[O:9])[CH2:3][C:4]([O-:6])=[O:5].[Na+].[Na+].[OH-].[Na+].C(N(CC([O-])=O)CC([O-])=O)CN(CC([O-])=O)CC([O-])=O.[Na+].[Na+].[Na+].[Na+]>O>[CH2:1]([N:2]([CH2:7][C:8]([OH:10])=[O:9])[CH2:3][C:4]([OH:6])=[O:5])[CH2:11][N:12]([CH2:17][C:18]([OH:20])=[O:19])[CH2:13][C:14]([OH:16])=[O:15]
Reactant: O=C([O-])CN(CCN(CC(=O)[O-])CC(=O)O)CC(=O)O
Agent: O=C([O-])CN(CCN(CC(=O)[O-])CC(=O)[O-])CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O

Procedure:
Disodium edetate (3.6 g) and 0.8 g of sodium hydroxide were dissolved in 170 mL of water. Polyethylene glycol 3350 (213 g) was added to this solution and dissolved. The sodium hydroxide facilitates the dissolution of the disodium edetate in the aqueous polyethylene glycol, through formation of the tetrasodium salt of EDTA. The polyethylene glycol solution was added to the drug-resin complex suspension and mixed well. The resulting mixture was dried in a fluid bed dryer by passing warm air through the wet polyethylene glycol treated drug resin complex at a sufficient velocity to suspend the material being dried. The inlet air temperature was 25 to 50C. and the mixture was dried to a moisture content of 6 to 10% by weight. This drying resulted in an EDTA concentration of about 0.36% by weight.
Reaction SMILES: Br[C:2]1[C:19]2[C:10](=[CH:11][C:12]3[C:17](C=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2.[C:20]1([CH3:26])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)(O)[O-].[Na+].C1(B(O)O)C=CC=CC=1>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.O.C(O)C>[C:20]1([C:26]2[C:19]3[C:10](=[CH:9][C:8]4[C:3]([CH:2]=3)=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:11]=[C:12]3[C:17]=2[CH:16]=[CH:15][CH:14]=[CH:13]3)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Cc1ccccc1
Reactant: Brc1c2ccccc2cc2cc3ccccc3cc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: OB(O)c1ccccc1
Solvent: CCO
Solvent: O
Product: c1ccc(-c2c3ccccc3cc3cc4ccccc4cc23)cc1
Temperature: 75 °C
Reaction time: 15 h
Yield: 93 %

Procedure:
In a 100-ml round-bottomed flask equipped with a magnetic stirrer, were added 1.0 g (3.26 mmol) of 5-bromonaphthacene, 23 mg (0.0326 mmol) of dichlorobis(triphenylphosphine)palladium(II) catalyst and 12 ml of toluene. A solution containing 0.69 g (6.51 mmol) of sodium bicarbonate in 4 ml of water was added to the flask. The mixture was degassed via nitrogen purge for 10 minutes. A solution of 0.417 g (3.42 mmol) of phenylboronic acid in 12 ml of ethanol was then added to the flask, and the reaction mixture was heated to 75° C. and stirred overnight for 15 hours. The resulting reaction mixture contained yellow and white solids that were dissolved by the addition of toluene and water. The mixture was transferred to a 100-ml separatory funnel and the aqueous layer was extracted three times with 15 ml of toluene. After the toluene layer was back-extracted once with distilled water, it was stirred over sodium sulfate for one hour and filtered. Charcoal (2 g) was added to the toluene layer and stirred for a minimum of 2 hours. The charcoal was filtered off and the solvent was removed by rotary evaporation. The product was dried at room temperature under vacuum (product sublimed at higher temperatures). 5-Phenylnaphthacene was obtained in 93% yield (0.92 g) and used without further purification.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[Cl:11][C:12]1[N:17]=[C:16]([CH3:18])[N:15]=[C:14]([O:19][CH2:20][CH2:21][O:22][CH:23]2[CH:28]([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][CH2:38][O:39][CH2:40][C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=4[O:47][CH3:48])=[CH:31][CH:30]=3)[CH2:27][CH2:26][N:25]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:24]2)[C:13]=1[CH2:56][C:57](OC)=[O:58].CO.Cl>O1CCCC1>[Cl:11][C:12]1[N:17]=[C:16]([CH3:18])[N:15]=[C:14]([O:19][CH2:20][CH2:21][O:22][CH:23]2[CH:28]([C:29]3[CH:30]=[CH:31][C:32]([O:35][CH2:36][CH2:37][CH2:38][O:39][CH2:40][C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=4[O:47][CH3:48])=[CH:33][CH:34]=3)[CH2:27][CH2:26][N:25]([C:49]([O:51][C:52]([CH3:55])([CH3:53])[CH3:54])=[O:50])[CH2:24]2)[C:13]=1[CH2:56][CH2:57][OH:58]
Reactant: COC(=O)Cc1c(Cl)nc(C)nc1OCCOC1CN(C(=O)OC(C)(C)C)CCC1c1ccc(OCCCOCc2ccccc2OC)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOc2nc(C)nc(Cl)c2CCO)cc1
Temperature: -40 °C
Reaction time: 0.17 h

Procedure:
4.8 ml of diisobutylaluminium hydride (1.5M in toluene) are added dropwise at −70° C. over 10 minutes to the solution of 1.74 g of tert-butyl 3-[2-(6-chloro-5-methoxycarbonylmethyl-2-methylpyrimidin-4-yloxy)ethoxy]-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate in 20 ml of tetrahydrofuran. The reaction mixture is warmed slowly to −40° C. over 3 hours, admixed with 0.4 ml of methanol and subsequently warmed to room temperature. The reaction solution is admixed with 20 ml of 0.5N HCl and stirred vigorously over 10 minutes. The reaction mixture is extracted with tert-butyl methyl ether (2×). The combined organic phases are washed successively with 1M sodium potassium tartrate solution and brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a colourless oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.35 (2:1 EtOAc-heptane); Rt=5.75.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[C:6](=[N:12]O)[CH2:5]2.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[NH2:12][CH:6]1[CH2:5][C:4]2[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=2)[CH:7]1[OH:11]
Reactant: O=C1C(=NO)Cc2cc(F)ccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: NC1Cc2cc(F)ccc2C1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46 %

Procedure:
The product obtained in Step A dissolved in 70 ml of tetrahydrofuran is added dropwise, in the course of 30 minutes, to a suspension of 2.67 g of lithium aluminium hydride in 15 ml of tetrahydrofuran. After stirring for 30 minutes at ambient temperature and then after 12 hours at reflux of the solvent, the reaction mixture is cooled and then carefully hydrolysed using, in succession, 1.9 ml of water, 1.5 ml of 20% sodium hydroxide solution and then 6.7 ml of water. The solution is subsequently stirred for 3 hours at ambient temperature and then filtered, rinsed with tetrahydrofuran and evaporated to dryness. Chromatography on silica gel (dichloromethane/methanol/ammonium hydroxide: 95/5/0.5) allows the expected product to be isolated in the proportion of 54% of the cis product and 46% of the trans product.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([C:10]([OH:12])=O)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[NH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18].C1N=CN(C(N2C=NC=C2)=O)C=1>O1CCCC1>[OH:18][CH2:17][CH2:16][CH2:15][CH2:14][NH:13][C:10]([C:7]1[CH:8]=[CH:9][C:4]2[N:3]=[CH:2][S:1][C:5]=2[CH:6]=1)=[O:12]
Reactant: O=C(O)c1ccc2ncsc2c1
Reactant: NCCCCO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(NCCCCO)c1ccc2ncsc2c1
Reaction time: 0.5 h

Procedure:
2.69 g (15 mmol) of benzothiazole-6-carboxylic acid is dissolved in a mixture of 1.34 g (15 mmol) 4-amino-butan-1-ol and 70 mL dry tetrahydrofuran. 2.43 g (15 mmol) of CDI is added after stirring for 30 minutes and then stirred for another hour. The mixture is concentrated in vacuum. The resulting residue is suspended in dichloromethane, water is added, and the organic phase is separated. The aqueous phase is extracted with dichloromethane twice. The combined organic phases are dried over sodium sulfate and concentrated in vacuum.