Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1(Br)[O:9][C@H:8]([CH2:10][OH:11])[C@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].[CH3:13][CH:14]([CH2:16][CH2:17][CH2:18][C@H:19]([C@@H:21]1[C@:39]2([CH3:40])[C@H:24]([C@H:25]3[C@H:36]([CH2:37][CH2:38]2)[C@:34]2([CH3:35])[C:28]([CH2:29][C@H:30]([CH2:32][CH2:33]2)[OH:31])=[CH:27][CH2:26]3)[CH2:23][CH2:22]1)[CH3:20])[CH3:15]>ClCCl.FC(F)(F)S([O-])(=O)=O.[Ag+]>[C@@H:1]1([CH2:15][CH:14]([CH2:16][CH2:17][CH2:18][C@H:19]([C@@H:21]2[C@:39]3([CH3:40])[C@H:24]([C@H:25]4[C@H:36]([CH2:37][CH2:38]3)[C@:34]3([CH3:35])[C:28]([CH2:29][C@H:30]([CH2:32][CH2:33]3)[OH:31])=[CH:27][CH2:26]4)[CH2:23][CH2:22]2)[CH3:20])[CH3:13])[O:9][C@H:8]([CH2:10][OH:11])[C@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: OC[C@H]1OC(Br)[C@H](O)[C@@H](O)[C@H]1O
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClCCl
Product: CC(CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C)C[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O

Procedure:
Compound 4 (see FIG. 12) was prepared from galactose 1 that was treated with pivaloyl chloride in pyridine. Instead of the expected penta-pivaloyl derivative, the partially pivaloylated compound 2 was obtained in good yield and high purity without the need of chromatographic purification. The free hydroxyl group in compound 2 was protected by an acetyl group (→3). This was followed by treatment with hydrogen bromide in acetic acid to provide the galactosyl bromide 4. Bromide 4 was coupled with cholesterol 5 under promotion by silver trifluoromethanesulfonate in dichloromethane to provide the desired β-galactosyl-cholesterol 6 in a stereoselective manner (see FIG. 13). The β-anomeric configuration was demonstrated by 1-H NMR spectroscopy. The O-protecting groups were subsequently removed by treatment with sodium methoxide in a mixture of anhydrous dichloromethane and methanol to provide the cholesteryl β-D-galactopyranoside 7 as an amorphous solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C@@H:8]([C:10](=[O:15])N(OC)C)[CH3:9])([CH3:4])([CH3:3])[CH3:2].[CH2:17]([Mg]Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1>[C:1]([O:5][C:6](=[O:16])[NH:7][C@H:8]([CH3:9])[C:10](=[O:15])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cl[Mg]Cc1ccccc1
Reactant: CON(C)C(=O)[C@@H](C)NC(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: C[C@@H](NC(=O)OC(C)(C)C)C(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 103.9 %

Procedure:
In a round-bottomed flask, [(R)-1-(methoxy-methyl-carbamoyl)-ethyl]-carbamic acid tert-butyl ester (300 mg, 1.29 mmol) was dissolved in THF (8 ml). The solution was cooled to −16° C. (NaCl/ice bath) and benzylmagnesium chloride (1.0 M in diethyl ether, 3.8 ml, 3.8 mmol) was added dropwise. After the addition, the reaction mixture was allowed to warm slowly to room temperature and stirred for 5.5 h. The reaction mixture was quenched with saturated aqueous NH4Cl and extracted with EtOAc (2×). The combined organic layers were washed with water and brine then dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over silica gel with EtOAc/hexanes (gradient 0-20% EtOAc) to afford 353 mg (99%) of ((R)-1-methyl-2-oxo-3-phenyl-propyl)-carbamic acid tert-butyl ester as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:11]([Cl:12])=[C:10]2[C:5]([C:6](=[O:25])[C:7]([C:20]([O:22]CC)=[O:21])=[CH:8][N:9]2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:4][N:3]=1.O.S(=O)(=O)(O)O>C(O)(=O)C>[Cl:1][C:2]1[C:11]([Cl:12])=[C:10]2[C:5]([C:6](=[O:25])[C:7]([C:20]([OH:22])=[O:21])=[CH:8][N:9]2[C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)=[CH:4][N:3]=1
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2)c2c(Cl)c(Cl)ncc2c1=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1cn(-c2ccc(F)cc2)c2c(Cl)c(Cl)ncc2c1=O
Temperature: 0 °C

Procedure:
3.3 g (0.0087 mol) of ethyl 7,8-dichloro-1-(4-fluorophenyl)-1,4-dihydro-4-oxo-1,6-naphthyridine-3-carboxylate are heated at reflux in a mixture of 11.5 ml of acetic acid, 11.5 ml of water and 1.15 ml of concentrated sulphuric acid for two hours. The cooled mixture is put into ice-water, the product is isolated and washed with water.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C@@H:12](O)[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].[NH:19]=[N+:20]=[N-:21].C(P(CCCC)CCCC)CCC.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C(=O)=O>C1(C)C=CC=CC=1.C1COCC1>[N:19]([C@@H:12]([C:6]1[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=1)[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])=[N+:20]=[N-:21]
Reactant: CCOc1cc([C@@H](O)CS(C)(=O)=O)ccc1OC
Reactant: [N-]=[N+]=N
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: CCCCP(CCCC)CCCC
Agent: O=C=O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOc1cc([C@@H](CS(C)(=O)=O)N=[N+]=[N-])ccc1OC
Reaction time: 16 h
Yield: 81 %

Procedure:
A mixture of (R)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanol (0.94 g, 3.4 mmol) in toluene (280 mL) and THF (20 mL) was sparged with nitrogen for 15 min, and then a ˜1.1 M solution of hydrazoic acid in toluene (13.8 mL, ˜15 mmol) was added. The flask was cooled in a dry ice-acetone bath. When the internal temperature reached <−60° C., tributylphosphine (1.7 mL, 6.9 mmol), and then diisopropyl azodicarboxylate (1.6 mL, 7.9 mmol) were added. The cooling bath was charged with dry ice for the next 4 h in order to maintain the reaction temperature at <−60° C., and then the temperature was allowed to gradually rise. After 16 h, the internal temperature had climbed to −2° C. Then, silica gel (20 g) was added and the resulting slurry was evaporated. The residue was chromatographed on a silica gel column, using a hexanes-EtOAc gradient. After pooling and evaporating the appropriate fractions, the residue was triturated with heptane (25 mL) and the slurry was filtered. Solids were dried under vacuum, to provide (S)-4-(1-azido-2-(methylsulfonyl)ethyl)-2-ethoxy-1-methoxybenzene as a white solid (0.84 g, 81% yield); HPLC (Hypersil BDS C8, 5.0 μm, 250×4.6 mm, 1.5 mL/min, 278 nm, 90/10 gradient to 80/20 0.1% aqueous TFA/MeOH over 10 min then gradient to 10/90 0.1% aqueous TFA/MeOH over the next 15 min): 17.77 (99.9%); 1H NMR (DMSO-d6) δ 1.33 (t, 3H), 2.99 (s, 3H), 3.55 (dd, J=4.0, 14.7 Hz, 1H), 3.77 (s, 3H), 3.90 (dd, J=9.6, 14.7 Hz, 1H), 3.98-4.13 (m, 2H), 5.01-5.21 (m, 1H), 6.90-7.05 (m, 2H), 7.08 (s, 1H).
Reaction SMILES: C(O[C:9]1[CH:26]=[CH:25][C:12]2[CH:13]=[C:14]([C:17]3[CH:22]=[CH:21][C:20](OC)=[CH:19][CH:18]=3)[CH2:15][O:16][C:11]=2[CH:10]=1)C1C=CC=CC=1.[O:27]1C2C(=CC=CC=2)C(O)CC1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCOCC1>[O:16]1[C:11]2[C:12](=[CH:25][CH:26]=[CH:9][CH:10]=2)[C:13](=[O:27])[C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:15]1
Reactant: COc1ccc(C2=Cc3ccc(OCc4ccccc4)cc3OC2)cc1
Reactant: OC1CCOc2ccccc21
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Product: O=c1c(-c2ccccc2)coc2ccccc12

Procedure:
Using the general procedure of hydroboration-oxidation, compound 1 was converted into a chroman-4-ol (compound 4) at a yield of 60%. Compound 4 was treated with 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) in refluxing 1,4-dioxane to undergo oxidation-dehydrogenation to give an isoflavone (compound 5) at a yield of 78%. After the deprotection of compound 5 with AlCl3/EtSH, daidzein (compound 6a) was produced at a yield of 92%. On the other hand, compound 5 could be selectively debenzylated with Pearlman's reagent to give formononetin (compound 6b) at a yield of 94%,
Reaction SMILES: [CH3:1][O:2][C:3]1[S:4][CH:5]=[C:6]([O:8][CH3:9])[N:7]=1.C1(N(C)[CH:17]=[O:18])C=CC=CC=1.P(Cl)(Cl)(Cl)=O.C(Cl)(Cl)=O.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>ClCCl>[CH3:1][O:2][C:3]1[S:4][C:5]([CH:17]=[O:18])=[C:6]([O:8][CH3:9])[N:7]=1
Reactant: CN(C=O)c1ccccc1
Reactant: COc1csc(OC)n1
Agent: O=C(Cl)Cl
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: COc1nc(OC)c(C=O)s1

Procedure:
To a stirred solution of 2,4-dimethoxythiazole (0.01 mol), which may be prepared as described in Step (a) above, in dichloromethane is added N-phenyl-N-methylformamide (0.01 mol) and phosphorous oxychloride (POCl3, 0.01 mol), or optionally phosgene or trifluoromethanesulfonic acid anhydride instead of POCl3, and the mixture is stirred. Reaction progress may be followed by TLC or HPLC. When a sufficient amount of the desired product is formed, the mixture is partitioned between ethyl acetate and water. The organic layer is washed with brine, dried over sodium sulfate, and rotary evaporated to give 2,4-dimethoxythiazole-5-carboxaldehyde, which may be purified, if needed or desired, by chromatography on silica gel or crystallization.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH:3]=[CH2:4].[CH3:6][S:7](Cl)(=[O:9])=[O:8].Cl.C(N(CC)CC)C>O1CCCC1.C(N(CC)CC)C>[CH3:6][S:7]([O:5][CH2:1][CH2:2][CH:3]=[CH2:4])(=[O:9])=[O:8]
Reactant: C=CCCO
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CCCOS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
A four-necked flask (11) was charged with 3-buten-1-ol (72 g), dry tetrahydrofuran (400 ml), and methanesulfonyl chloride (126 g), and the mixture was subjected to a nitrogen stream. After sufficiently cooling the flask with ice water, triethylamine (111 g) was slowly added dropwise to the flask from a dropping funnel After the dropwise addition, the mixture was stirred for about 30 minutes while cooling the flask with ice water, and then stirred at room temperature for about 4 hours. After completion of the reaction, 100 ml of tetrahydrofuran was added to the mixture, and salts (triethylamine hydrochloride) produced by the reaction were filtered off Most of the tetrahydrofuran was evaporated from the filtrate using an evaporator. After the addition of 200 ml of diethyl ether to the residue, the mixture was sequentially washed with 5% hydrochloric acid, a saturated sodium bicarbonate aqueous solution, and a saturated sodium chloride solution, and dried over anhydrous magnesium sulfate, and magnesium sulfate was filtered off Diethyl ether was evaporated from the filtrate using an evaporator to obtain 126 g of 4-methanesulfonyloxy-1-butene (hereinafter referred to as “mesylate”) as a yellowish brown oil (yield: 84%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]2[C:14]([OH:15])=[C:13]([C:16]([OH:18])=O)[CH:12]=[N:11][C:10]=12)=[O:5])[CH3:2].Cl.[O:20]=[C:21]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:23]2([CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[O:22]1>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]2[C:14]([OH:15])=[C:13]([C:16]([N:26]3[CH2:27][CH2:28][C:23]4([C:29]5[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=5)[C:21](=[O:20])[O:22]4)[CH2:24][CH2:25]3)=[O:18])[CH:12]=[N:11][C:10]=12)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnn2c(O)c(C(=O)O)cnc12
Reactant: O=C1OC2(CCNCC2)c2ccccc21
Agent: Cl
Product: CCOC(=O)c1cnn2c(O)c(C(=O)N3CCC4(CC3)OC(=O)c3ccccc34)cnc12
Yield: 89 %

Procedure:
In the same manner as in Example 1, step 2 and using 3-ethoxycarbonyl-7-hydroxypyrazolo[1,5-a]pyrimidine-6-carboxylic acid (0.436 g, 1.74 mmol) obtained in Example 19, step 2 and 3-oxo-3H-spiro[isobenzofuran-1,4′-piperidine]hydrochloride (Journal of Organic Chemistry, 1976, vol. 15, item 2628, 0.500 g, 2.09 mmol), the title compound (0.680 g, 89%) was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[O:14][CH2:13]3)=[C:6]([OH:20])[C:5]=1[O:21][CH3:22])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:29](Br)[CH2:30][CH3:31]>C(#N)C>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[O:14][CH2:13]3)=[C:6]([O:20][CH2:29][CH2:30][CH3:31])[C:5]=1[O:21][CH3:22])[CH3:2]
Reactant: CCCBr
Reactant: CCOc1ccc(-c2ccc3c(c2)COC3=O)c(O)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCOc1c(-c2ccc3c(c2)COC3=O)ccc(OCC)c1OC
Temperature: 70 °C
Yield: 22 %

Procedure:
To a stirring solution of 5-(4-ethoxy-2-hydroxy-3-methoxyphenyl)isobenzofuran-1(3H)-one (80 mg, 0.266 mmol) in acetonitrile was added potassium carbonate (110 mg, 0.798 mmol) and propyl bromide (130 mg, 1.066 mmol) and the resultant reaction mixture was heated to 70° C. for 2 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure. Purification of the residue by flash column chromatography (silica gel, 0-25% ethyl acetate in pet ether) afforded the title compound as a solid (20 mg, 22%).
Reaction SMILES: [CH:1]1([C:5]2([C:8]3[N:13]=[C:12]4[S:14][C:15]([C:17]5[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][C:18]=5[F:25])=[N:16][C:11]4=[CH:10][CH:9]=3)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.Cl.[NH:27]1[CH2:30][CH:29]([C:31]([O:33][CH3:34])=[O:32])[CH2:28]1>>[CH:1]1([C:5]2([C:8]3[N:13]=[C:12]4[S:14][C:15]([C:17]5[CH:24]=[CH:23][C:20]([CH2:21][N:27]6[CH2:30][CH:29]([C:31]([O:33][CH3:34])=[O:32])[CH2:28]6)=[CH:19][C:18]=5[F:25])=[N:16][C:11]4=[CH:10][CH:9]=3)[CH2:6][CH2:7]2)[CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)C1CNC1
Reactant: O=Cc1ccc(-c2nc3ccc(C4(C5CCC5)CC4)nc3s2)c(F)c1
Agent: Cl
Product: COC(=O)C1CN(Cc2ccc(-c3nc4ccc(C5(C6CCC6)CC5)nc4s3)c(F)c2)C1

Procedure:
Reaction of 4-(5-(1-cyclobutylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)-3-fluorobenzaldehyde (66.2 mg, 0.188 mmol) and methyl azetidine-3-carboxylate hydrochloride (42.7 mg, 0.282 mmol) according to Reference R and the general procedure for reductive amination to give methyl 1-(4-(5-(1-cyclobutylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)-3-fluorobenzyl)azetidine-3-carboxylate as a white solid. MS (ESI) m/z: Calculated: 451.2; Observed: 451.9 (M++1).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[C:7](B(O)O)=[CH:6][NH:5][N:4]=1.Br[C:14]1[N:19]=[C:18]2[S:20][C:21]([NH:23][C:24](=[O:35])[C:25]3[CH:30]=[CH:29][C:28]([C:31]([OH:34])([CH3:33])[CH3:32])=[CH:27][CH:26]=3)=[N:22][C:17]2=[CH:16][CH:15]=1>>[OH:34][C:31]([C:28]1[CH:27]=[CH:26][C:25]([C:24]([NH:23][C:21]2[S:20][C:18]3[C:17]([N:22]=2)=[CH:16][CH:15]=[C:14]([C:7]2[C:3]([C:2]([F:12])([F:11])[F:1])=[N:4][NH:5][CH:6]=2)[N:19]=3)=[O:35])=[CH:30][CH:29]=1)([CH3:32])[CH3:33]
Reactant: OB(O)c1c[nH]nc1C(F)(F)F
Reactant: CC(C)(O)c1ccc(C(=O)Nc2nc3ccc(Br)nc3s2)cc1
Product: CC(C)(O)c1ccc(C(=O)Nc2nc3ccc(-c4c[nH]nc4C(F)(F)F)nc3s2)cc1
Yield: 7 %

Procedure:
The titled compound (yield=7%) was prepared using a procedure analogous to that described in connection with 10 (Example 10) except 3-(trifluoromethyl)-1H-pyrazol-4-ylboronic acid and 1D (Example 1) were used as starting materials. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.47 (s, 6H) 7.67 (d, J=8.34 Hz, 2H) 7.76 (d, J=8.34 Hz, 1H) 8.11 (d, J=8.34 Hz, 2H) 8.20 (d, J=8.59 Hz, 1H) 8.57 (s, 1H) 12.97 (s, 1H) 13.88 (br. s., 1H); ESI-MS: m/z 448.0 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]2=[N:12][N:13]=[CH:14][N:4]2[N:3]=1.[NH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>COCCO>[N:20]1([CH2:19][CH2:18][CH2:17][CH2:16][NH:15][C:2]2[C:11]3[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=3[C:5]3=[N:12][N:13]=[CH:14][N:4]3[N:3]=2)[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: Clc1nn2cnnc2c2c1CCCC2
Reactant: NCCCCN1CCCC1
Solvent: COCCO
Product: c1nnc2c3c(c(NCCCCN4CCCC4)nn12)CCCC3
Temperature: 0 °C

Procedure:
A solution of 9.1 g of 6-chloro-7,8,9,10-tetrahydro-1,2,4-triazolo[3,4-a]phthalazine and 17.7 g of 1-(4-aminobutyl)pyrrolidine in 50 ml of 2-methoxyethanol was heated at reflux for 16 hours. The reaction mixture was then poured into ice water and the tan solid which formed was separated by filtration and recrystallized from toluene to give 6-[4-(1-pyrrolidinyl)butylamino]-7,8,9,10-tetrahydro-1,2,4-triazolo[3,4-a]phthalazine melting at about 158.5°-160° C.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[ClH:4].[Cl:5][CH2:6][CH2:7][CH:8]1[CH2:12][N:11]([CH2:13][CH3:14])[C:10](=[NH:15])[N:9]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)C>[ClH:5].[ClH:4].[CH2:13]([N:11]1[CH2:12][CH:8]([CH2:7][CH2:6][N:2]([CH3:3])[CH3:1])[N:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:10]1[NH2:15])[CH3:14]
Reactant: CCN1CC(CCCl)N(c2ccccc2)C1=N
Reactant: CNC
Agent: Cl
Solvent: CCO
Product: CCN1CC(CCN(C)C)N(c2ccccc2)C1N

Procedure:
To a 9.4 g (0.21 mole) of dimethylamine in 200 ml ethanol was added 20 g (0.0695 mole) of 4-(2-chloroethyl)-1-ethyl-2-imino-3-phenylimidazolidine hydrochloride and the solution heated at 100° C. in a steel bomb for 18 hours. The contents were concentrated on the rotary evaporator and the resulting residue partitioned between chloroform and dilute NaOH. The chloroform solution was concentrated and the residue dissolved in isobutyl methyl ketone which was acidified with ethereal HCl. The resulting crystals were recrystallized from isopropanol-isobutyl methyl ketone. Yield 7.8 g (37.8%); m.p. 252°-254° C.
Reaction SMILES: [CH3:1][C:2]1[C:14]([O:15][CH3:16])=[C:13]([CH3:17])[C:5]([CH2:6][S:7][C:8]2[NH:9][CH:10]=[CH:11][N:12]=2)=[C:4]([NH:18][CH2:19][CH2:20][O:21][CH3:22])[CH:3]=1.ClC1C=CC=C(C(OO)=[O:31])C=1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl.CO>[CH3:1][C:2]1[C:14]([O:15][CH3:16])=[C:13]([CH3:17])[C:5]([CH2:6][S:7]([C:8]2[NH:12][CH:11]=[CH:10][N:9]=2)=[O:31])=[C:4]([NH:18][CH2:19][CH2:20][O:21][CH3:22])[CH:3]=1
Reactant: COCCNc1cc(C)c(OC)c(C)c1CSc1ncc[nH]1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COCCNc1cc(C)c(OC)c(C)c1CS(=O)c1ncc[nH]1
Yield: 37.3 %

Procedure:
2.00 g (6.2 mmol) of 2-[4,6-dimethyl-5-methoxy-2-(2-methoxyethylamino)benzylthio]imidazole was dissolved in a mixture of 20 ml of chloroform and 2 ml of methanol. To the resulting solution was added 1.27 g of 85 % m-chloroperbenzoic acid under chilling with NaCl-ice for a period of 20 min. After the reaction was completed, chloroform and 5 % aqueous sodium carbonate were added. The organic portion was collected and washed twice with 20 ml of 0.05 N aqueous sodium hydroxide. The resulting mixture was then subject to extraction with 30 ml of 1 N aqueous sodium hydroxide. The aqueous portion was collected and washed with chloroform. To the washed solution was added 45 ml of 1 N aqueous ammonium chloride. The deposited oily product was extracted with dichloromethane. The dichloromethane portion was collected and dried over anhydrous sodium sulfate. Dichloromethane was distilled off and then the residue was crystallized from ether/hexane to give 0.78 g of the desired compound as a pale brown crystalline powder. (Yield: 37 %)
Reaction SMILES: [CH3:1][NH:2][C@H:3]([C:7]([NH:9][C@H:10]([C:14]([N:16]([C@@H:18]([C@@H:57]([CH3:60])[CH2:58][CH3:59])[C@H:19]([O:55][CH3:56])[CH2:20][C:21]([N:23]1[CH2:27][CH2:26][CH2:25][C@H:24]1[C@H:28]([O:53][CH3:54])[C@@H:29]([CH3:52])[C:30]([NH:32][C@@H:33]([CH2:42][C:43]1[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[NH:45][CH:44]=1)[C:34]([N:36]1[CH2:41][CH2:40][CH2:39][CH2:38][O:37]1)=[O:35])=[O:31])=[O:22])[CH3:17])=[O:15])[CH:11]([CH3:13])[CH3:12])=[O:8])[CH:4]([CH3:6])[CH3:5].[CH:61]([C:63]1[CH:71]=[CH:70][C:66]([C:67]([OH:69])=[O:68])=[CH:65][CH:64]=1)=O>>[C:67]([C:66]1[CH:70]=[CH:71][C:63]([CH2:61][N:2]([CH3:1])[C@H:3]([C:7]([NH:9][C@H:10]([C:14]([N:16]([C@@H:18]([C@@H:57]([CH3:60])[CH2:58][CH3:59])[C@H:19]([O:55][CH3:56])[CH2:20][C:21]([N:23]2[CH2:27][CH2:26][CH2:25][C@H:24]2[C@H:28]([O:53][CH3:54])[C@@H:29]([CH3:52])[C:30]([NH:32][C@@H:33]([CH2:42][C:43]2[C:51]3[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=3)[NH:45][CH:44]=2)[C:34]([N:36]2[CH2:41][CH2:40][CH2:39][CH2:38][O:37]2)=[O:35])=[O:31])=[O:22])[CH3:17])=[O:15])[CH:11]([CH3:12])[CH3:13])=[O:8])[CH:4]([CH3:5])[CH3:6])=[CH:64][CH:65]=1)([OH:69])=[O:68]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N1CCCCO1)OC)N(C)C(=O)[C@@H](NC(=O)[C@@H](NC)C(C)C)C(C)C
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N1CCCCO1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)Cc1ccc(C(=O)O)cc1)C(C)C

Procedure:
First, in analogy to the preparation of Intermediate 183, Intermediate 192 was reacted with 4-formylbenzoic acid with borane-pyridine complex to give N-(4-carboxybenzyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(2S)-3-(1H-indol-3-yl)-1-(1,2-oxazinan-2-yl)-1-oxopropan-2-yl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide. This compound was then used, in analogy to Intermediate 210, to generate 11 mg (68% of theory) of the title compound.
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:11][CH:10]=2)C(=O)C2=CC=CC=C12.O.NN>CO>[NH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)CCc1ccc(CCCN2C(=O)c3ccccc3C2=O)cc1
Agent: NN
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)CCc1ccc(CCCN)cc1
Temperature: 25 °C
Yield: 89.8 %

Procedure:
With 6.88 g (17.5 mmols) of t-butyl 3-[4-(3-phthalimidopropyl)phenyl]propionate were admixed 1.10 ml (22.8 mmols) of hydrazine hydrate and 50 ml of methanol. The mixture was refluxed for 1 hour, cooled to room temperature and then concentrated. The concentrate was dissolved in 200 ml of 1 mol dm-3NaOH, followed by extraction with ether. The extract was dried over K2CO3 and concentrated to give 4.14 g (yield 90%) of t-butyl 3-[4-(3-aminopropyl)phenyl]propionate in the form of an oil.
Reaction SMILES: [S:1](Cl)([CH3:4])(=[O:3])=[O:2].[O:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[CH2:11][OH:12].C(N(CC)CC)C>O1CCCC1>[CH3:4][S:1]([O:12][CH2:11][CH:7]1[CH2:8][CH2:9][CH2:10][O:6]1)(=[O:3])=[O:2]
Reactant: CS(=O)(=O)Cl
Reactant: OCC1CCCO1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)OCC1CCCO1
Reaction time: 2 h

Procedure:
Mesyl chloride (6.17 g) was dropwise added to a solution of 5.0 g of (tetrahydro-2furanyl)methanol, 2.18 g of triethylamine and 30 ml of tetrahydrofuran under ice-cooling over 30 minutes, followed by stirring at the same temperature for 2 hours. After the completion of reaction, the insolubles were filtered, and the filtrate was then concentrated under a reduced pressure to obtain (tetrahydro-2-furanyl)methyl methanesulfonate as an oil.
Reaction SMILES: [CH2:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]1=[O:13])[CH:2]=[CH2:3].[Cl-].[OH-].[Na+].Br[CH2:18][CH2:19][CH2:20][Cl:21]>O>[Cl:21][CH2:20][CH2:19][CH2:18][N:6]1[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:4]([CH2:1][CH:2]=[CH2:3])[C:5]1=[O:13]
Reactant: C=CCn1c(=O)[nH]c2ccccc21
Reactant: ClCCCBr
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=CCn1c(=O)n(CCCCl)c2ccccc21
Reaction time: 5 h
Yield: 84 %

Procedure:
To a stirred and heated mixture of 17.5 parts of 1,3-dihydro-1-(2-propenyl)-2H-benzimidazol-2-one, 5 parts of N,N,N-triethylbenzenemethanaminimum chloride and 150 parts of a sodium hydroxide solution 60% are added dropwise 20.5 parts of 1-bromo-3-chloropropane at 60° C. Upon completion, stirring at 60° C is continued for 5 hours. The reaction mixture is cooled, water is added and the product is extracted with trichloromethane. The extract is dried, filtered and evaporated, yielding 21 parts (84%) of 1-(3-chloropropyl)-1,3-dihydro-3-(2-propenyl)-2H-benzimidazol-2-one as a residue.