Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](/[C:36]1[N:37]=[C:38]([NH:41][C:42]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[S:39][CH:40]=1)\[C:5]([NH:7][CH:8]1[C:34](=[O:35])[N:10]2[C:11]([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:12](CI)[CH2:13][S:14](=[O:15])[C@H:9]12)=[O:6].Br.[OH:62][C:63]1[CH:64]=[C:65]2[C:69](=[CH:70][CH:71]=1)[CH2:68][NH:67][CH2:66]2.C(N(CC)CC)C>CN(C)C=O>[CH3:1][O:2]/[N:3]=[C:4](/[C:36]1[N:37]=[C:38]([NH:41][C:42]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)([C:55]2[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=2)[C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)[S:39][CH:40]=1)\[C:5]([NH:7][CH:8]1[C:34](=[O:35])[N:10]2[C:11]([C:18]([O:20][CH:21]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[O:19])=[C:12]([N:67]3[CH2:66][C:65]4[C:69](=[CH:70][CH:71]=[C:63]([OH:62])[CH:64]=4)[CH2:68]3)[CH2:13][S:14](=[O:15])[C@H:9]12)=[O:6]
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CI)CS(=O)[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: Oc1ccc2c(c1)CNC2
Agent: Br
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(N3Cc4ccc(O)cc4C3)CS(=O)[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.2 %

Procedure:
2.4 g (2.53 mmol) of the powder obtained in Example 1 (B) was dissolved in 20 ml of N,N-dimethylformamide, and 0.77 g (3.56 mmol) of 5-hydroxyisoindoline hydrobromide and 0.6 ml (4.3 mmol) of triethylamine were added thereto. The mixture was stirred at room temperature for 1 hour. The dimethylformamide was distilled off under reduced pressure. The residue was subjected to silica gel flush column chromatography (ethyl acetate/n-hexane =3/1 to 1/0) to obtain 2.1 g (yield: 87%) of the above-identified compound.
Reaction SMILES: [C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][C:4]([NH:7][C:8](=[O:22])[N:9]([C@H:11]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:12]([OH:14])=O)[CH3:10])=[CH:3][CH:2]=1.[CH2:29]([N:31]([CH2:34]C)[CH2:32]C)[CH3:30].C[NH:37][C@@H](CC1C=CC=CC=1)C(O)=O.C1(C2C=CC=CC=2)C=CC(N=C=O)=CC=1>C1COCC1.CC(C)=O.O>[C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][C:4]([NH:7][C:8](=[O:22])[N:9]([C@H:11]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:12]([NH:37][CH2:30][CH2:29][N:31]([CH3:34])[CH3:32])=[O:14])[CH3:10])=[CH:3][CH:2]=1
Reactant: CCN(CC)CC
Reactant: CN[C@@H](Cc1ccccc1)C(=O)O
Reactant: CN(C(=O)Nc1ccc(-c2ccccc2)cc1)[C@H](Cc1ccccc1)C(=O)O
Agent: O=C=Nc1ccc(-c2ccccc2)cc1
Solvent: CC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CN(C)CCNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)Nc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 24 %

Procedure:
(R)-2-(3-Biphenyl-4-yl-1-methyl-ureido)-3-phenyl-propionic acid. Triethylamine (0.17 g, 1.68 mmol) was added to a suspension of (S)-2-methylamino-3-phenyl-propionic acid (0.2 g, 1.12 mmol) in 1:1 acetone/H2O (80 mL). Once the (S)-2-methylamino-3-phenyl-propionic acid dissolved, 4-biphenylyl isocyanate (0.228 g, 1.17 mmol) was added as a solution in THF (1.5 mL) at 0° C. As the mixture was warmed to rt, solids crashed out of solution. The mixture was stirred for 7 h at rt, and then the solvents were removed. After acidifying with 1 N HCl (10 mL) to bring the pH to 2, the reaction mixture was filtered, and the aqueous filtrate was extracted with EtOAc (3×40 mL). The combined organic layers were washed with brine and dried (MgSO4), and the solvent was removed. Column chromatography using [5–20% (1% NH4OH/MeOH)/CH2Cl2] afforded 0.1 g (24%) of the desired product. MS (electrospray): mass calculated for C23H22N2O3, 374.16; m/z found, 375.1 [M+H]+, 397.1 [M+Na]+. 1H NMR (400 MHz, CD3OD): 7.63–7.59 (m, 4H), 7.45–7.41 (m, 2H), 7.36–7.29 (m, 4H), 7.23–7.21 (m, 2H), 7.04–7.01 (m, 2H), 4.48 (t, J=4.1 Hz, 1H), 3.37–3.33 (m, 1H), 3.25 (dd, J=14.4, 3.8 Hz, 1H), 3.10 (s, 3H).
Reaction SMILES: [C:1]1([C:7]([CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[OH:10])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClCCO[CH2:21][CH2:22]Cl.[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>CCOCC>[N:24]1([CH2:21][CH2:22][O:8][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: ClCCOCCCl
Reactant: C1CCNCC1
Reactant: O=C(c1ccccc1)C(O)c1ccccc1
Solvent: CCOCC
Product: O=C(c1ccccc1)C(OCCN1CCCCC1)c1ccccc1

Procedure:
With stirring, 27 g (0.1 mole) of benzoin-2-chloroethyl ether and 68 g (0.8 mole) of piperidine are kept for 6 hours at 110° C. After cooling, the product is taken up in ether and the ether layer is washed with water, dried over Na2SO4 and concentrated. The residual oil is taken up in hexane and the crystals obtained are recrystallised from hexane. Melting point: 53° C.
Reaction SMILES: Cl[C:2](=[O:13])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10].[Br:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[C:17]([N+:22]([O-:24])=[O:23])[CH:16]=1.C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C>[Br:14][C:15]1[CH:21]=[CH:20][C:18]([NH:19][C:2](=[O:13])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:17]([N+:22]([O-:24])=[O:23])[CH:16]=1
Reactant: Nc1ccc(Br)cc1[N+](=O)[O-]
Reactant: COC(=O)CCCCCCC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)CCCCCCC(=O)Nc1ccc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.2 %

Procedure:
To a solution of methyl 8-chloro-8-oxooctanoate (229 mg, 1.11 mmol) in DMF at 0° C. was added a solution of 4-bromo-2-nitroaniline (200 mg, 0.922 mmol) and triethylamine (0.37 mL, 2.77 mmol) in DMF drop-wise. The reaction was stirred overnight at room temperature, diluted with ethyl acetate and washed with 1 N HCl, saturated sodium bicarbonate solution and brine. The separated organic layer was concentrated and purified by biotage column chromatography to give methyl 8-(4-bromo-2-nitrophenylamino)-8-oxooctanoate (290 mg)
Reaction SMILES: [CH3:1][C:2]1[S:10][C:9]2[C:8](=[O:11])[N:7]3[CH:12]=[C:13]([C:16]([NH2:18])=O)[CH:14]=[CH:15][C:6]3=[N:5][C:4]=2[CH:3]=1.P(Cl)(Cl)(Cl)=O.C(Cl)(Cl)Cl>N1C=CC=CC=1>[CH3:1][C:2]1[S:10][C:9]2[C:8](=[O:11])[N:7]3[CH:12]=[C:13]([C:16]#[N:18])[CH:14]=[CH:15][C:6]3=[N:5][C:4]=2[CH:3]=1
Reactant: Cc1cc2nc3ccc(C(N)=O)cn3c(=O)c2s1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc2nc3ccc(C#N)cn3c(=O)c2s1

Procedure:
2-Methyl-10-oxo-10H-pyrido[1,2-a]thieno[3,2-d]pyrimidine-7-carboxamide (Example 44), 0.6 g (0.0023 mol), in 10 ml of pyridine, 25 ml of phosphorus oxychloride and 25 ml of chloroform is refluxed on a steam bath for three hours. The solvents are evaporated in vacuo and the residue is treated with 100 ml of ice water. The resulting precipitate is filtered to give 0.5 g of 2-methyl-10-oxo-10H-pyrido[1,2-a]thieno[3,2-d]pyrimidine-7-carbonitrile; mp 258°-259° C. after recrystallization from methanol.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[C:9](=[O:11])[CH3:10].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH:20]1[CH2:22][CH2:21]1>CC(C)=O>[CH:20]1([CH2:19][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=2[C:9](=[O:11])[CH3:10])[CH2:22][CH2:21]1
Reactant: CC(=O)c1c(O)cccc1O
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)c1c(O)cccc1OCC1CC1
Temperature: 50 °C
Reaction time: 48 h
Yield: 83.2 %

Procedure:
To a stirred solution of 1-(2,6-dihydroxyphenyl)ethanone (50.0 g, 328 mmol) in acetone (1000 mL) were added potassium carbonate (227 g, 1643 mmol) and (bromomethyl)cyclopropane (35.1 mL, 361 mmol). The mixture was stirred at 50° C. for 2 days. The reaction mixture was filtrated on Celite®, and then the filtrate was concentrated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate. The separated organic phase was washed with water and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was suspended in hexane. Then the suspension was stirred at 80° C. for 30 min. The solution was filtered and the filtrate was allowed to cool to room temperature. The resulting white solid was collected by filtration, washed with hexane, and dried under reduced pressure to give 1-{2-[(cyclopropylmethyl)oxy]-6-hydroxyphenyl} ethanone as a pale yellow solid (56.3 g, yield; 83%).
Reaction SMILES: [N:1]1[C:10]2[CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][CH2:6][C:5]=2[CH:4]=[C:3]([C:18]([O:20][CH3:21])=[O:19])[CH:2]=1.[ClH:22]>>[ClH:22].[N:1]1[C:10]2[CH2:9][NH:8][CH2:7][CH2:6][C:5]=2[CH:4]=[C:3]([C:18]([O:20][CH3:21])=[O:19])[CH:2]=1
Reactant: COC(=O)c1cnc2c(c1)CCN(C(=O)OC(C)(C)C)C2
Agent: Cl
Product: COC(=O)c1cnc2c(c1)CCNC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 119.5 %

Procedure:
A round-bottom flask containing 7-tert-butyl 3-methyl 5,6-dihydro-1,7-naphthyridine-3,7-(8H)-dicarboxylate (0.470 g, 1.61 mmol) and hydrochloric acid (6.03 mL, 24.1 mmol, 4.0 M in 1,4-dioxane) was stirred at rt for 1 h. The solution was then completely evaporated to yield methyl 5,6,7,8-tetrahydro-1,7-naphthyridine-3-carboxylate hydrochloride (0.440 g, 100%). LC-MS: (FA) ES+ 193; 1H NMR (Methanol-d4, 400 MHz) δ 9.26 (s, 1 H), 8.87 (s, 1 H), 4.83 (s, 2 H), 4.03 (s, 3 H), 3.69 (m, 2 H), 3.43 (t, J=5.5 Hz, 2 H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[Cl-].[F:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16][Zn+]>C1COCC1.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>[F:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: Fc1ccccc1C[Zn+]
Reactant: COC(=O)c1ccnc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1CCOC1
Product: COC(=O)c1ccnc(Cc2ccccc2F)c1
Temperature: 60 °C
Reaction time: 18 h
Yield: 72.9 %

Procedure:
Methyl 2-chloroisonicotinate (5.2 g, 30.31 mmol) and Pd(PPh3)4 (0.700 g, 0.61 mmol) were dissolved under nitrogen in THF (100 mL) and (2-fluorobenzyl)zinc(II) chloride (0.5 M in THF) (90 mL, 45.00 mmol) was added and the brown solution was stirred at 60° C. for 18 h. The reaction was quenched by addition of methanol (50.0 mL). The solution was diluted with EtOAc, washed with NH4Cl (aq) and dried over Na2SO4, then evaporated. The compound was purified in 2 runs via Biotage, SNAP 340 g KP-SIL, eluent isocratic heptane/ethyl acetate 8:2 for 2 CV, then linear gradient heptane/ethyl acetate 8:2 to 5:5 over 5 CV to give methyl 2-(2-fluorobenzyl)isonicotinate (5.42 g, 73%) as a yellow oil. 1H NMR (400 MHz, cdcl3) 3.92 (s, 3H), 4.25 (s, 2H), 7.00-7.13 (m, 2H), 7.18-7.30 (m, 2H), 7.64-7.74 (m, 2H), 8.69 (d, 1H). MS m/z 246 (M+H)+
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH3:15][N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=2)[NH2:25])[CH2:18][CH2:17]1.C(N(CC)CC)C.C(OCC)C>CN1C(=O)CCC1>[N+:12]([C:3]1[CH:4]=[C:5]([CH2:8][C:9]([OH:11])=[O:10])[CH:6]=[CH:7][C:2]=1[NH:25][C:24]1[CH:26]=[CH:27][CH:28]=[C:22]([N:19]2[CH2:18][CH2:17][N:16]([CH3:15])[CH2:21][CH2:20]2)[CH:23]=1)([O-:14])=[O:13]
Reactant: CN1CCN(c2cccc(N)c2)CC1
Reactant: O=C(O)Cc1ccc(F)c([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: CN1CCCC1=O
Product: CN1CCN(c2cccc(Nc3ccc(CC(=O)O)cc3[N+](=O)[O-])c2)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 29.1 %

Procedure:
To a suspension of 1i (3.0 g, 15.1 mmol) in anhydrous NMP (2 ml) was added 2c (2.88 g, 15.1 mmol) and triethylamine (2.1 ml, 30.2 mmol). The mixture was stirred at 80° C. under a stream of nitrogen overnight. The cooled mixture was poured into a mixture of diethyl ether and petroleum ether (100 ml, 1:1 v/v) resulting in separation of an oily lower phase. The mixture was decanted and the oil was dissolved in dichloromethane and eluted through silica gel with a mixture of dichloromethane and methanol (4:1 v/v) to yield 3-nitro-4-(3-(4-methylpiperazin-1-yl)phenylamino)-phenylacetic acid (1.63 g, 29%). This acid (0.64 g, 1.73 mmol) was dissolved in methanol and concentrated hydrochloric acid (0.2 ml) was added. The mixture was heated to reflux for 4 days. The solvent was removed under reduced pressure and the residue was purified by column-chromatography on silica gel using a mixture of dichloromethane, methanol and aqueous ammonia (90:10:1 v/v/v) as the eluent to leave the ester (0.47 g, 71%) as a red oil. This oil was hydrogenated in methanol at ambient pressure using Pd (5% on activated carbon) as the catalyst to yield the corresponding diamine (0.38 g). This diamine was treated with triethyl orthoformate (0.35 ml, 2.14 mmol) and a catalytic amount of pTSA in THF (5 ml) at 80° C. for 30 min. The solvent was evaporated and the residue was partitioned between aqueous sodium hydroxide (1 M) and ethyl acetate. The organic phase was dried over sodium sulfate, concentrated and eluted through a silica gel column with a mixture of dichloromethane, methanol and aqueous ammonia (90:10:1 v/v/v). The product precipitated as the hydrochloride by addition of a solution of anhydrous hydrogen chloride in diethyl ether to the eluate. Yield of 4l1: 0.2 g (41%). M.p. 140-142° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][CH:7]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:8]2=[O:12])=[CH:4][C:3]=1[O:18][CH3:19].N#N.CC(C)([O-])C.[K+].[CH2:28](I)[CH2:29][CH2:30][CH3:31]>C1C=CC=CC=1.C(O)(C)(C)C.O>[CH2:28]([C:7]1([CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:6][C:5]2[C:9](=[C:10]([Cl:11])[C:2]([Cl:1])=[C:3]([O:18][CH3:19])[CH:4]=2)[C:8]1=[O:12])[CH2:29][CH2:30][CH3:31]
Reactant: COc1cc2c(c(Cl)c1Cl)C(=O)C(C1CCCC1)C2
Reactant: CCCCI
Agent: CC(C)(C)[O-]
Agent: N#N
Agent: [K+]
Solvent: c1ccccc1
Solvent: CC(C)(C)O
Solvent: O
Product: CCCCC1(C2CCCC2)Cc2cc(OC)c(Cl)c(Cl)c2C1=O

Procedure:
A solution of 6,7-dichloro-2-cyclopentyl-2,3-dihydro-5-methoxy-1H-inden-1-one (7.2 g) in benzene (70 ml) was heated at reflux in a N2 atmosphere and treated over a 5 minute period with a solution of potassium t-butoxide (4.2 g) in t-butanol (70 ml). The solution was refluxed for 3/4 hour, treated with butyl iodide (11 ml), refluxed for an additional 3/4 hour, cooled, treated with water (50 ml) and the organic solvents were distilled at reduced pressure. The aqueous slurry was extracted with ether washed with water, dried over MgSO4 and evaporated at reduced pressure. Treatment of the residue with hexane (100 ml) gave 6.9 g of 2-butyl-6,7-dichloro-2-cyclopentyl-2,3-dihydro-5-methoxy-1H-inden-1-one, m.p. 122°-123° C.
Reaction SMILES: [CH:1]1([NH:8][C:9]2[O:10][CH2:11][C:12]3[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][C:13]=3[N:14]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:20]1([S:26](Cl)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH:1]1([NH:8][C:9]2[O:10][CH2:11][C:12]3[CH:18]=[C:17]([NH:19][S:26]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)(=[O:28])=[O:27])[CH:16]=[CH:15][C:13]=3[N:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: Nc1ccc2c(c1)COC(NC1CCCCCC1)=N2
Reactant: O=S(=O)(Cl)c1ccccc1
Product: O=S(=O)(Nc1ccc2c(c1)COC(NC1CCCCCC1)=N2)c1ccccc1
Yield: 5.5 %

Procedure:
Prepared from N2-cycloheptyl-4H-benzo[d][1,3]oxazine-2,6-diamine (example 92) (200 mg, 0.77 mmol) and benzenesulfonyl chloride (136 mg, 0.77 mmol) according to the procedure described for example 27. Obtained the title compound as a white foam (17 mg, 5.5%), MS (ISP) m/e=400.3 [(M+H)+].
Reaction SMILES: [NH:1]([C:71]([O:73][C:74]([CH3:77])([CH3:76])[CH3:75])=[O:72])[C@H:2]([C:8]([NH:10][C@H:11]([C:29]([N:31]1[CH2:70][CH2:69][CH2:68][C@H:32]1[C:33]([NH:35][C@H:36]([C:38]([NH:40][C@H:41]([C:58]([O:60]CC1C=CC=CC=1)=[O:59])[CH2:42][CH2:43][CH2:44][CH2:45][NH:46][C:47]([O:49][CH2:50][C:51]1[CH:57]=[CH:56][CH:55]=[CH:54][C:52]=1[Cl:53])=[O:48])=[O:39])[CH3:37])=[O:34])=[O:30])[CH2:12][CH2:13][CH2:14][NH:15][C:16](=[NH:28])[NH:17][S:18]([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6].[OH-].[Na+].C(Cl)(Cl)Cl.CO>CO>[NH:1]([C:71]([O:73][C:74]([CH3:75])([CH3:77])[CH3:76])=[O:72])[C@H:2]([C:8]([NH:10][C@H:11]([C:29]([N:31]1[CH2:70][CH2:69][CH2:68][C@H:32]1[C:33]([NH:35][C@H:36]([C:38]([NH:40][C@H:41]([C:58]([OH:60])=[O:59])[CH2:42][CH2:43][CH2:44][CH2:45][NH:46][C:47]([O:49][CH2:50][C:51]1[CH:57]=[CH:56][CH:55]=[CH:54][C:52]=1[Cl:53])=[O:48])=[O:39])[CH3:37])=[O:34])=[O:30])[CH2:12][CH2:13][CH2:14][NH:15][C:16](=[NH:28])[NH:17][S:18]([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6]
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)[C@H](CCC(N)=O)NC(=O)OC(C)(C)C)C(=O)N2CCC[C@H]2C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCNC(=O)OCc2ccccc2Cl)C(=O)OCc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)[C@H](CCC(N)=O)NC(=O)OC(C)(C)C)C(=O)N2CCC[C@H]2C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCNC(=O)OCc2ccccc2Cl)C(=O)O)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
At 0° C. to the solution of 770 mg (0.694 mmol) of Boc-Gln-Arg(Tos)-Pro-Ala-Lys(ClZ)-OBzl (SEQ ID NO: 16) in 18 ml of methanol 5 ml of the solution of NaOH in methanol (2 mol/L) were added. The reaction mixture was stirred at 0° C. for 2 h and TLC (chloroform/methanol, 15:1) indicated complete disappearance of Boc-Gln-Arg(Tos)-Pro-Ala-Lys(ClZ)-OBzl (SEQ ID NO: 16). The reaction mixture was neutralized to pH 7 and evaporated at room temperature to remove methanol. The residue was acidified to pH 1–2 with hydrochloric acid (2 mol/L) to provide 610 mg (86%) of the title compound as a colorless powder.
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]1[S:12][C@@H:11]([CH2:13]O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:35].CCCCCC>C(OCC)C>[C:1]([O:5][C:6]([C@@H:8]1[S:12][C@@H:11]([CH2:13][Cl:35])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)[C@H]1CC[C@H](CO)S1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: CCOCC
Product: CC(C)(C)OC(=O)[C@H]1CC[C@H](CCl)S1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of trans-5-tert-butoxycarbonyl-2-hydroxymethyltetrahydrothiophene (compound No. 1-5, 5.0 g) in anhydrous diethylether (80 ml), triphenylphosphine (9.7 g) and carbon tetrachloride (5.7 g) are added under nitrogen atmosphere and the mixture is stirred for 2 hours at room temperature. n-Hexane (200 ml) is added to the mixture and filtrated. The filtrate is concentrated in vacuo. The oily residue is purified by a silica gel column chromatography to give trans-5-tert-butoxycarbonyl-2-chloromethyltetrahydrothiophene.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([O:11][CH2:12][C@H:13]([OH:21])[CH2:14][N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[CH:7][C:5]=2[N:6]=1.[CH2:22](Br)[CH:23]=[CH2:24].C(=O)([O-])[O-].[K+].[K+].ClCCl>CC(C)=O.CO>[CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([O:11][CH2:12][C@H:13]([OH:21])[CH2:14][N:15]3[CH2:16][CH2:17][N:18]([CH2:24][CH:23]=[CH2:22])[CH2:19][CH2:20]3)=[CH:7][C:5]=2[N:6]=1
Reactant: C=CCBr
Reactant: Cc1nc2cc(OC[C@H](O)CN3CCNCC3)ccc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Solvent: CC(C)=O
Product: C=CCN1CCN(C[C@@H](O)COc2ccc3sc(C)nc3c2)CC1
Reaction time: 5 h
Yield: 43.2 %

Procedure:
To a solution of (2R)-1-(2-methylbenzothiazol-5-yloxy)-3-piperazin-1-yl-propan-2-ol (300 mg, 1.0 mmol) in acetone (10 ml) was added allyl bromide (0.130 ml, 1.5 mmol) and potasium carbonate (280 mg, 2.0 mmol). The solution was heated to reflux and stirred for 5 hours. Thin layer chromatography (10:1 dichloromethane:methanol) showed formation of product. The solution was cooled and filtered. The filtrate was concentrated under reduced pressure, and the residue purified by preparative chromatography (10:1 dichloromethane:methanol) to yield (2R)-1-(2-methylbenzothiazol-5-yloxy)-3-(4-prop-2-enylpiperazinyl)propan-2-ol (150 mg, M+1=348.2)
Reaction SMILES: S([O:5][CH2:6][CH2:7][N:8]1[C:12]([NH2:13])=[C:11]([NH2:14])[CH:10]=[N:9]1)(O)(=O)=O.[C:15]([O:19][C:20]([NH:22][CH2:23][CH2:24][C@H:25]([OH:29])[C:26](O)=[O:27])=[O:21])([CH3:18])([CH3:17])[CH3:16].C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>O>[NH2:13][C:12]1[N:8]([CH2:7][CH2:6][OH:5])[N:9]=[CH:10][C:11]=1[NH:14][C:26](=[O:27])[C@@H:25]([OH:29])[CH2:24][CH2:23][NH:22][C:20](=[O:21])[O:19][C:15]([CH3:16])([CH3:17])[CH3:18]
Reactant: Nc1cnn(CCOS(=O)(=O)O)c1N
Reactant: CC(C)(C)OC(=O)NCC[C@H](O)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCC[C@H](O)C(=O)Nc1cnn(CCO)c1N
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(4,5-diamino-1H-pyrazol-1-yl)ethanol sulfate (2 g) and (2S)-4-[(tert-butoxycarbonyl)amino]-2-hydroxybutanoic acid (1.92 g) in water (8 ml) were added triethylamine (2.32 ml) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.76 g), and the mixture was stirred at room temperature for 3 hours. The whole mixture was extracted with ethyl acetate-tetrahydrofuran (1:1) and the solvent was evaporated under reduced pressure to give a crude product of tert-butyl ((3S)-4-{[5-amino-1-(2-hydroxyethyl)-1H-pyrazol-4-yl]amino}-3-hydroxy-4-oxobutyl)carbamate. The obtained crude product was used for Preparation 38 without further purification.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].[H-].[Na+].Br[CH2:10][C:11]1[CH:16]=[C:15]([C:17]2[C:22]([Cl:23])=[CH:21][C:20]([C:24]([F:27])([F:26])[F:25])=[CH:19][N:18]=2)[N:14]2[N:28]=[CH:29][N:30]=[C:13]2[N:12]=1.Cl>O1CCCC1>[Cl:23][C:22]1[C:17]([C:15]2[N:14]3[N:28]=[CH:29][N:30]=[C:13]3[N:12]=[C:11]([CH2:10][O:4][CH2:3][C:2]([F:6])([F:5])[F:1])[CH:16]=2)=[N:18][CH:19]=[C:20]([C:24]([F:26])([F:25])[F:27])[CH:21]=1
Reactant: OCC(F)(F)F
Reactant: FC(F)(F)c1cnc(-c2cc(CBr)nc3ncnn23)c(Cl)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: FC(F)(F)COCc1cc(-c2ncc(C(F)(F)F)cc2Cl)n2ncnc2n1
Reaction time: 0.08 h
Yield: 30.8 %

Procedure:
230 mg of 2,2,2-trifluoroethanol was added to a tetrahydrofuran (dehydrated) 8 mL solution of 33 mg of 60% sodium hydride, followed by stirring for 5 minutes, and 300 mg of 5-bromomethyl-7-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidine was added at room temperature, followed by stirring for 5 minutes. After completion of the reaction, 1N hydrochloric acid was added to make it acidic, followed by extraction with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/1) to obtain 97 mg of the desired product.