Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClCCCC(OC(=O)C)CCCCC.ClCCCC(OC(=O)C)C(C)(C)CCCC.C([O:34][CH:35]([C:55](C)(C)[CH2:56][CH2:57][CH2:58][CH3:59])[CH2:36][CH2:37][CH2:38][N:39]([CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][C:50]([O:52]CC)=[O:51])[S:40]([CH3:43])(=[O:42])=[O:41])(=O)C>>[OH:34][C@H:35]([CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])[C:36]#[C:37][CH2:38][N:39]([CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][C:50]([OH:52])=[O:51])[S:40]([CH3:43])(=[O:41])=[O:42]
Reactant: CCCCC(C)(C)C(CCCN(CCCCCCC(=O)OCC)S(C)(=O)=O)OC(C)=O
Agent: CCCCC(C)(C)C(CCCCl)OC(C)=O
Agent: CCCCCC(CCCCl)OC(C)=O
Product: CCCCC[C@@H](O)C#CCN(CCCCCCC(=O)O)S(C)(=O)=O

Procedure:
The synthesis of this compound is carried out as described in Example 1 except that, in Step A, the 1-chloro-4-acetoxynonane is replaced by an equimolar amount of 1-chloro-4-acetoxy-5,5-dimethylnonane (Example G). The product of Step A is thus ethyl 7-[N-(4-acetoxy-5,5-dimethylnonyl)methanesulfonamido]heptanoate. The subsequent step yields 7-[N-(4-hydroxy-5,5-dimethylnonyl)methanesulfonamido]heptanoic acid (B).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[S:10][C:9]([Sn](CCCC)(CCCC)CCCC)=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.I[C:25]1[CH:26]=[N:27][N:28]([CH2:30][CH2:31][N:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:29]=1.[As](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].[Cu]I>[Cl:1][C:2]1[C:3]2[S:10][C:9]([C:25]3[CH:26]=[N:27][N:28]([CH2:30][CH2:31][N:32]4[CH2:36][CH2:35][CH2:34][CH2:33]4)[CH:29]=3)=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Ic1cnn(CCN2CCCC2)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc2ncnc(Cl)c2s1
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Product: Clc1ncnc2cc(-c3cnn(CCN4CCCC4)c3)sc12
Temperature: 80 °C

Procedure:
Compound 52.1 (22.58 mmol) and 4-iodo-1-(2-pyrrolidin-1-yl-ethyl)-1H-pyrazole (22.32 mmol) was dissolved in DMF and degassed with nitrogen. To this was added Pd2(dba)3 (0.23 mmol), Ph3As (0.46 mmol) and CuI (1.16 mmol). The reaction mixture was heated at 80° C. for 6 hours, concentrated to dryness and purified by flash column chromatography on silica gel (10% MeOH in dichloromethane) to provide 4-chloro-6-[1-(2-pyrrolidin-1-yl-ethyl)-1H-pyrazol-4-yl]-thieno[3,2-d]pyrimidine (compound 52.2).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH2:8].[C:9](O)(=O)[CH3:10].[OH-].[NH4+]>O>[CH3:9][C:10]1[NH:8][C:7]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=2[N:1]=1
Reactant: CC(=O)O
Reactant: Nc1ccncc1N
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: Cc1nc2cnccc2[nH]1
Temperature: 125 °C

Procedure:
A mixture of 5 g of 3,4-diaminopyridine, 3.9 ml of acetic acid and 50 ml of polyphosphoric acid was heated to 125° C. for 2 hours. The reaction mixture was poured into water and the pH adjusted to 8 with ammonium hydroxide. The product was extracted with methanol-chloroform (1:1) and the extracts dried over sodium sulfate and concentrated to dryness. Extraction of the residue with 50 ml of hot ethanol gave 3.98 g of product.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][C:10](=[O:38])[NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:21][CH2:20][C@@H:19]([C:22]([C:35](=[O:37])[NH2:36])([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:18]1)C)(C)(C)C.Cl.C(O)(C(F)(F)F)=O>C(Cl)Cl.O1CCOCC1>[CH3:6][NH:7][CH2:9][C:10]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:21][CH2:20][C@@H:19]([C:22]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:35]([NH2:36])=[O:37])[CH2:18]1)=[O:38]
Reactant: CN(CC(=O)NCCCCCN1CC[C@@H](C(C(N)=O)(c2ccccc2)c2ccccc2)C1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: CNCC(=O)NCCCCCN1CC[C@@H](C(C(N)=O)(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.7 %

Procedure:
To a stirred solution of ({5-[(S)-3-(carbamoyldiphenylmethyl)pyrrolidin-1-yl]pentylcarbamoyl}methyl)methylcarbamic acid tert-butyl ester (23.47 g, 43.7 mmol) in DCM (60 mL) was added 4 N HCl in dioxane (100 mL). The reaction mixture was stirred at room temperature for 2 hours and then concentrated to dryness. The residue was dissolved in water (100 mL) and this solution was washed with DCM (4×60 mL). The aqueous phase was then made basic with 20% aqueous potassium carbonate and extracted with DCM (4×60 mL). The combined organic phase was dried over magnesium sulfate, filtered and concentrated. The residue was then dissolved in water (50 mL) containing TFA (2.5 eq) and purified by HPLC to obtain 17.5 g of the title compound as a bis(trifluoroacetate) salt. MS m/z [M+H+] calc'd for C26H36N4O2 437.3; found 437.5.
Reaction SMILES: [CH3:1][N:2]([C@@H:4]1[C:22](=[O:23])[C:21]([C:24]([NH2:26])=[O:25])=[C:20]([OH:27])[C@:19]2([OH:28])[C@H:5]1[CH2:6][C@H:7]1[C:16]([C:17]2=[O:18])=[C:15]([OH:29])[C:14]2[C:9](=[C:10](I)[CH:11]=[CH:12][C:13]=2[OH:30])[CH2:8]1)[CH3:3]>CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:1][N:2]([C@@H:4]1[C:22](=[O:23])[C:21]([C:24]([NH2:26])=[O:25])=[C:20]([OH:27])[C@:19]2([OH:28])[C@H:5]1[CH2:6][C@H:7]1[C:16]([C:17]2=[O:18])=[C:15]([OH:29])[C:14]2[C:9](=[C:10]([C:4]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:5]=3)[CH:11]=[CH:12][C:13]=2[OH:30])[CH2:8]1)[CH3:3]
Reactant: CN(C)[C@@H]1C(=O)C(C(N)=O)=C(O)[C@@]2(O)C(=O)C3=C(O)c4c(O)ccc(I)c4C[C@H]3C[C@@H]12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: CN(C)[C@@H]1C(=O)C(C(N)=O)=C(O)[C@@]2(O)C(=O)C3=C(O)c4c(O)ccc(-c5ccccc5)c4C[C@H]3C[C@@H]12
Temperature: 25 °C
Reaction time: 2 h
Yield: 42 %

Procedure:
7-iodosancycline, 150 mg (0.28 mM), Pd(OAc)2 and 10 mL of Me0H are added to a flask with a stir bar and the system degassed 3× using argon. Na2CO3 (87 mg, 0.8 mM) dissolved in water and argon degassed is added via syringe is added along with phenylboronic acid (68 mg, 0.55 mM) in Me0H that was also degassed. The reaction was followed by HPLC for 2 hours and cooled to room temperature. The solution was filtered, and dried to produce a crude mixture. The solid was dissolved in dimethylformamide and injected onto a preparative HPLC system using C18 reverse-phase silica. The fraction at 36-38 minutes was isolated, and the solvent removed in vacuo to yield the product plus salts. The salts were removed before extraction into 50:25:25 water:butanol:ethyl acetate and dried in vacuo. This solid was dissolved in Me0H and the HCl salt made by bubbling in HCl gas. The solvent was removed to produce the product, substantially free of positional isomers, in 42% yield as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@H:14]([NH2:16])[CH3:15])[N:5]=[C:4]([CH3:17])[C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19].[OH:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27](O)=[O:28]>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@H:14]([NH:16][C:27](=[O:28])[C:26]2[CH:30]=[CH:31][CH:32]=[C:24]([OH:23])[CH:25]=2)[CH3:15])[N:5]=[C:4]([CH3:17])[C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)c1c(C)nc2cccc(OC[C@@H](C)N)c2c1N
Reactant: O=C(O)c1cccc(O)c1
Product: CCOC(=O)c1c(C)nc2cccc(OC[C@@H](C)NC(=O)c3cccc(O)c3)c2c1N

Procedure:
Prepared as in Example 24a from (R)-ethyl 4-amino-5-(2-aminopropoxy)-2-methylquinoline-3-carboxylate (Example 86b) and 3-hydroxybenzoic acid as brown solid (36%). MS 424 (MH+).
Reaction SMILES: [NH4+]=[S:2].[Si:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[N:31]=[C:30]([CH3:32])[O:29][N:28]=3)=[CH:23][CH:22]=2)[C:18]#[N:19])=[CH:13][C:12]=1[O:33][CH3:34])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].C1COCC1.O>CO.C(OCC)(=O)C>[Si:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]3[N:31]=[C:30]([CH3:32])[O:29][N:28]=3)=[CH:25][CH:26]=2)[C:18]([NH2:19])=[S:2])=[CH:13][C:12]=1[O:33][CH3:34])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:4])[CH3:5]
Reactant: COc1cc(C(C#N)Nc2ccc(-c3noc(C)n3)cc2)ccc1O[Si](C)(C)C(C)(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cc(C(Nc2ccc(-c3noc(C)n3)cc2)C(N)=S)ccc1O[Si](C)(C)C(C)(C)C

Procedure:
After adding 32 ml of a 20% aqueous solution of ammonium sulfide to a solution of 8.45 g of (4-t-butyldimethylsilanyloxy-3-methoxyphenyl)-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]acetonitrile in 300 ml of a methanol:THF=2:1 mixed solvent, the mixture was stirred at room temperature for 23 hours. Water was added to the reaction mixture and extraction was performed with ethyl acetate. After washing the organic layer with saturated brine, it was dried over anhydrous sodium sulfate. The desiccating agent was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (8.26 g) as a crude product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:13][CH2:14][C:15]2[C:24]([F:25])=[CH:23][C:18]([C:19]([O:21]C)=[O:20])=[C:17]([F:26])[CH:16]=2)[CH:5]=[N:6][C:7]=1[O:8][CH2:9][CH:10]([CH3:12])[CH3:11].[OH-].[Li+]>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([O:13][CH2:14][C:15]2[C:24]([F:25])=[CH:23][C:18]([C:19]([OH:21])=[O:20])=[C:17]([F:26])[CH:16]=2)[CH:5]=[N:6][C:7]=1[O:8][CH2:9][CH:10]([CH3:12])[CH3:11]
Reactant: COC(=O)c1cc(F)c(COc2cnc(OCC(C)C)c(Cl)c2)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)COc1ncc(OCc2cc(F)c(C(=O)O)cc2F)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.2 %

Procedure:
To a solution of methyl 4-((5-chloro-6-isobutoxypyridin-3-yloxy)methyl)-2,5-difluorobenzoate (Preparation 4, 623 mg, 1.6 mmol) in THF (10 mL) was added lithium hydroxide (1.8 mL of a 1 M solution in water) and the mixture stirred at room temperature under nitrogen for 18 hours. The solvent was evaporated in vacuo to give the title compound (352 mg, 59%) as a pale yellow solid and was used directly in the next step.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[SH:11].Cl[CH2:13][CH2:14][CH2:15][CH2:16][OH:17].C(N(CC)CC)C.O>CC(C)=O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11][CH2:13][CH2:14][CH2:15][CH2:16][OH:17]
Reactant: OCCCCCl
Reactant: Sc1ccc2ccccc2c1
Solvent: CC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: OCCCCSc1ccc2ccccc2c1
Yield: 70.5 %

Procedure:
20 g of 2-naphthalene thiol was dissolved in 100 ml of acetone, and 13.39 g of 4-chloro-1-butanol and 25.04 g of triethylamine were added dropwise. The mixture was reacted for 12 hours at room temperature while stirring and poured into 100 ml of water. The reaction mixture was extracted three times with 50 ml of ethyl acetate. The resulting organic layer was washed three times with 50 ml of 10 wt % sodium carbonate aqueous solution and three times with 50 ml of 5 wt % oxalic-acid aqueous solution. The separated water layer was repeatedly washed with distilled water until pH 7. The organic layer was dried using 3 g of magnesium sulfate. After removing magnesium sulfate by filtration, the solvent was evaporated using a rotary evaporator to obtain 20.2 g of 4-(naphthalen-2-ylsulfanyl)butan-1-ol as a highly viscous oily liquid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12](=O)[N:13]=1.[NH:19]([C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)[NH2:20]>CC1CCCO1.C(O)(=O)CC>[CH:16]1[CH:17]=[CH:18][C:10]([OH:9])=[C:11]([C:12]2[N:13]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[OH:1])[N:19]([C:21]3[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=3)[N:20]=2)[CH:15]=1
Reactant: O=c1nc(-c2ccccc2O)oc2ccccc12
Reactant: NNc1ccc(C(=O)O)cc1
Solvent: CC1CCCO1
Solvent: CCC(=O)O
Product: O=C(O)c1ccc(-n2nc(-c3ccccc3O)nc2-c2ccccc2O)cc1
Temperature: 98 °C
Yield: 50.4 %

Procedure:
A suspension of 0.7 g (2.92 mmol) of 2-(2-hydroxyphenyl)benz[e][1,3]oxazin-4-one and 0.52 g (3.44 mmol) of 4-hydrazinobenzoic acid in 8 ml of 2-methyltetrahydrofuran and 5 ml of propionic acid is heated to its boiling point and maintained at this temperature (98° C.) for 2 hours. After completion of the reaction, the mixture is cooled and filtered. The product is washed with 2-methyltetrahydrofuran. After drying, 0.55 g of raw deferasirox is obtained, i.e. 50% of the theory, with an HPLC purity of 95.3% and a melting temperature of 255 to 262° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[C:7]([CH:11]([NH:14][C:15]([C:17]2[C:18]3[CH:25]=[N:24][N:23]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)[C:19]=3[CH:20]=[N:21][CH:22]=2)=[O:16])[CH2:12][CH3:13])[O:8][C:9]=1[CH3:10])=O.[NH3:33].CO>>[C:3]([C:5]1[N:6]=[C:7]([CH:11]([NH:14][C:15]([C:17]2[C:18]3[CH:25]=[N:24][N:23]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)[C:19]=3[CH:20]=[N:21][CH:22]=2)=[O:16])[CH2:12][CH3:13])[O:8][C:9]=1[CH3:10])(=[O:2])[NH2:33]
Reactant: CCC(NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)c1nc(C(=O)OC)c(C)o1
Reactant: N
Solvent: CO
Product: CCC(NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)c1nc(C(N)=O)c(C)o1
Temperature: 90 °C
Reaction time: 34 h

Procedure:
A mixture of 2-(1-{[1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carbonyl]-amino}-propyl)-5-methyl-oxazole-4-carboxylic acid methyl ester (40 mg, 0.091 mmol) in a 7 M solution of ammonia in methanol (525 μL, 3.66 mmol) was stirred at 90° C. in a sealed tube. After 34 hours, the reaction was cooled to room temperature, vented, opened and concentrated. The resulting residue was purified by silica gel chromatography eluting with a gradient of 0-10% methanol in methylene chloride to afford the title compound as white solid. MS m/z 423.89 (MH+).
Reaction SMILES: C1COCC1.[CH:6]([CH:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[CH2:19][CH2:18][CH:17]([CH:20]=[O:21])[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)=[CH2:7].[BH4-].[Na+].[Cl-].[NH4+]>C(OCC)(=O)C.O.C(O)C>[CH:6]([C@H:8]1[CH2:13][CH2:12][C@H:11]([C@H:14]2[CH2:19][CH2:18][C@H:17]([CH2:20][OH:21])[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)=[CH2:7]
Reactant: C=CC1CCC(C2CCC(C=O)CC2)CC1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: C=C[C@H]1CC[C@H]([C@H]2CC[C@H](CO)CC2)CC1
Temperature: -10 °C

Procedure:
A THF (180 mL) solution of 60.1 g of a nearly colorless solid obtained in (3-3) was added dropwise in an ethanol (120 mL) solution of 1.65 g of sodium borohydride under stirring at −10° C. while stirring the inner temperature. After raising the temperature to room temperature and stirring for 2 hours, water, ethyl acetate and an aqueous ammonium chloride aqueous were added, thereby terminating the reaction. The saturated saline was added to the reacted solution, and the organic layer was separated, and then the aqueous layer was extracted with ethyl acetate (twice). The combined organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by column chromatography to obtain 15.4 g of trans-4-(trans-4-vinylcyclohexyl)cyclohexylmethanol as a white solid.
Reaction SMILES: C(NCC)C.[CH2:6]([N:8](CC)[C:9]([C:11]1[CH:12]=[CH:13][C:14]2[C:15](=[O:25])[C:16]3[C:21]([O:22][C:23]=2[CH:24]=1)=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:10])[CH3:7].C([NH-])C>>[CH2:6]([NH:8][C:9]([C:11]1[CH:12]=[CH:13][C:14]2[C:15](=[O:25])[C:16]3[C:21]([O:22][C:23]=2[CH:24]=1)=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:10])[CH3:7]
Reactant: CCN(CC)C(=O)c1ccc2c(=O)c3ccccc3oc2c1
Agent: CC[NH-]
Solvent: CCNCC
Product: CCNC(=O)c1ccc2c(=O)c3ccccc3oc2c1

Procedure:
Following Procedure 6, substituting ethylamine for diethylamine, compound 6a was converted into its monoethyl amide. MS m/z (MH+) 267.9.
Reaction SMILES: S([O-])([O-])(=O)=O.[Zr+4:6].S([O-])([O-])(=O)=O.S([O-])([O-])(=O)=O.[NH4+].[NH4+].[P:19](=[O:23])([OH:22])([OH:21])[OH:20].[OH-].[Na+]>O>[P:19]([O-:23])([O-:22])([O-:21])=[O:20].[Zr+4:6].[P:19]([O-:23])([O-:22])([O-:21])=[O:20].[P:19]([O-:23])([O-:22])([O-:21])=[O:20].[P:19]([O-:23])([O-:22])([O-:21])=[O:20].[Zr+4:6].[Zr+4:6]
Reactant: O=P(O)(O)O
Agent: [Zr+4]
Agent: O=S(=O)([O-])[O-]
Agent: [NH4+]
Solvent: O
Product: O=P([O-])([O-])[O-]
Temperature: 120 °C

Procedure:
Zirconium sulfate (0.12 mol), ammonium sulfate (0.04 mol), phosphoric acid (0.18 mol) and sodium hydroxide (0.018 mol) under mixing were added to pure water (40 g) to prepare a homogeneous aqueous solution. This reaction mixture was heated for 4 hours under saturated water vapor pressure at 120° C., and the precipitate was subjected to filtration, washing with water and drying to obtain a zirconium phosphate salt having a network structure. This was added to an aqueous silver nitrate solution containing a given amount of silver ion and stirred at 60° C. for 10 hours. Then, the slurry was filtrated, and the residue was sufficiently washed with pure water, heated and dried at 110° C. overnight and fired at 900° C. for 4 hours to obtain a microbicide having the following composition (Sample No. 11).
Reaction SMILES: C(N(CC)CC)C.Br[C:9]1[C:10]([CH3:23])=[C:11]([CH3:22])[C:12]2[O:16][C:15]([CH2:18][Br:19])([CH3:17])[CH2:14][C:13]=2[C:20]=1[CH3:21]>C(O)C.[C].[Pd]>[Br:19][CH2:18][C:15]1([CH3:17])[CH2:14][C:13]2[C:20]([CH3:21])=[CH:9][C:10]([CH3:23])=[C:11]([CH3:22])[C:12]=2[O:16]1
Reactant: Cc1c(C)c2c(c(C)c1Br)CC(C)(CBr)O2
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cc(C)c2c(c1C)OC(C)(CBr)C2
Yield: 92.2 %

Procedure:
Triethylamine (5.0 ml, 35.6 mmol) was added to a solution of 5-bromo-2-bromomethyl-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran (12.4 g, 35.6 mmol) in ethanol (100 ml). Catalytic hydrogenation decomposition reaction was carried out on 5% palladium carbon under a hydrogen atmosphere. After the completion of the reaction, the catalyst was filtered and the filtrate was concentrated. The residue was dissolved in isopropyl ether, washed with water, dried and the solvent was distilled off. The residue was crystallized from methanol to obtain the desired compound (8.84 g, yield: 92.2%), m.p. 39°-40° C.
Reaction SMILES: FC(F)(F)S(O)(=O)=O.[Cl:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[F:17].[I:18]N1C(=O)CCC1=O>>[Cl:9][C:10]1[CH:15]=[C:14]([F:16])[C:13]([I:18])=[CH:12][C:11]=1[F:17]
Reactant: Fc1ccc(F)c(Cl)c1
Reactant: O=C1CCC(=O)N1I
Agent: O=S(=O)(O)C(F)(F)F
Product: Fc1cc(I)c(F)cc1Cl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 77.5 %

Procedure:
Trifluoromethanesulfonic acid (9.9 mL, 110 mmol) was added to 2-chloro-1,4-difluorobenzene (2.2 g, 15 mmol) at room temperature and then cooled to 0° C. N-Iodosuccinimide (3.16 g, 14.1 mmol) was then added in multiple portions. After 10 minutes, the reaction mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction mixture was poured over ice-water and extracted with hexane. The organic layer was washed with saturated Na2SO4, dried and concentrated. The crude product was purified by silica gel chromatography (100% hexanes) to give 1-chloro-2,5-difluoro-4-iodobenzene (3.0 g, 74%). 1H NMR (400 MHz, CDCl3) δ 7.52 (dd, J=5.4, 7.8, 1H), 7.17-7.08 (m, 1H).
Reaction SMILES: C(O)(C(F)(F)F)=O.[S:8]1[CH:12]=[CH:11][C:10]([C@H:13]2[C@H:22]3[CH2:23][CH2:24][N:25]([C:26]([O:28]C(C)(C)C)=O)[C@H:21]3[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[NH:14]2)=[CH:9]1.[OH-].[Na+].[C:35]([NH:43][C:44]1[CH:52]=[CH:51][CH:50]=[CH:49][C:45]=1C(O)=O)(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(N(CC)CC)C.CCOC(OC(OCC)=O)=O>O>[S:8]1[CH:12]=[CH:11][C:10]([C@H:13]2[C@H:22]3[CH2:23][CH2:24][N:25]([C:26]([C:45]4[CH:49]=[CH:50][CH:51]=[CH:52][C:44]=4[NH:43][C:35](=[O:42])[C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)=[O:28])[C@H:21]3[C:20]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[NH:14]2)=[CH:9]1
Reactant: O=C(Nc1ccccc1C(=O)O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]2[C@H](c3ccsc3)Nc3ccccc3[C@@H]21
Agent: CCOC(=O)OC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1C(=O)N1CC[C@@H]2[C@H](c3ccsc3)Nc3ccccc3[C@@H]21)c1ccccc1
Temperature: 25 °C
Reaction time: 0.05 h
Yield: 43.1 %

Procedure:
TFA (2 ml) was added to tert-butyl (3aR*,4R*,9bR*)-4-(3-thienyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-carboxylate (219 mg, 0.61 mmol), and the mixture was stirred at room temperature for 3 min. Ice was added to the reaction solution, and the mixture was basified with 8N aqueous sodium hydroxide solution and extracted with ethyl acetate. The extract was washed with saturated brine, dried (over anhydrous MgSO4), and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in tetrahydrofuran (3 ml), 2-(benzoylamino)benzoic acid (162 mg, 0.67 mmol) and triethylamine (124 mg, 1.2 mmol) were added. DEPC (99 mg, 0.61 mmol) was added at 0° C. and the mixture was stirred at room temperature for 30 min. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with 6% aqueous sodium hydrogen carbonate solution and saturated brine, dried (over anhydrous MgSO4), and the solvent was evaporated under reduced pressure. The residue was subjected to column chromatography using silica gel (30 g), and eluted with hexane-ethyl acetate (9:1-3:1, v/v) to give the title compound (126 mg, 43%) as colorless crystals.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([OH:43])=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:47][O:48][CH2:49][CH:50]1[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:35][CH2:36][CH:37]([CH2:40][C:41]([N:53]4[CH2:54][CH2:55][CH:50]([CH2:49][O:48][CH3:47])[CH2:51][CH2:52]4)=[O:43])[CH2:38][CH2:39]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COCC1CCNCC1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)N2CCC(COC)CC2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with 4-(methoxymethyl)piperidine (Alfa) to give the title product. LC-MS (ES+) 776 [(M+H)+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH:11][C:12]2[CH:17]=[C:16]([C:18]3[CH:45]=[CH:44][C:21]4[N:22](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[CH:23]=[N:24][C:20]=4[CH:19]=3)[N:15]=[C:14]([O:46][CH3:47])[N:13]=2)=[CH:5][CH:4]=1.FC(F)(F)C(O)=O.O.CO>C(Cl)Cl>[NH:22]1[C:21]2[CH:44]=[CH:45][C:18]([C:16]3[N:15]=[C:14]([O:46][CH3:47])[N:13]=[C:12]([NH:11][CH2:10][CH2:9][C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=4)[CH:17]=3)=[CH:19][C:20]=2[N:24]=[CH:23]1
Reactant: COc1ccc(CCNc2cc(-c3ccc4c(c3)ncn4C(c3ccccc3)(c3ccccc3)c3ccccc3)nc(OC)n2)cc1
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CCNc2cc(-c3ccc4[nH]cnc4c3)nc(OC)n2)cc1
Temperature: 25 °C
Yield: 49.4 %

Procedure:
A mixture of [2-(4-methoxy-phenyl)-ethyl]-[2-methoxy-6-(1-trityl-1H-benzoimidazol-5-yl)-pyrimidin-4-yl]-amine [300 mg, 0.485 mmol, Intermediate (28)], DCM (5 mL), trifluoroacetic acid (2 mL) and water (5%) is stirred at ambient temperature. The reaction mixture is concentrated by rotary evaporator to remove the solvent. The residue is taken up in saturated sodium bicarbonate solution and this solution is extracted with ethyl acetate. The extract is dried over magnesium sulfate, filtered and concentrated to provide a solid, which is subjected to flash column chromatography on silica gel eluting with 5% MeOH in DCM to afford [6-(1H-benzoimidazol-5-yl)-2-methoxy-pyrimidin-4-yl]-[2-(4-methoxy-phenyl)-ethyl]-amine [90 mg, 49%, Example 14(a)]. LCMS: RT=4.73 minutes, MS: 376 (M+H). IC50=2.7 nM