Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH:6]2[O:10][B:9]([OH:11])[C:8]3[CH:12]=[C:13]([NH:16]C(=O)C4C=CC=CC=4C(F)(F)F)[CH:14]=[CH:15][C:7]2=3)[CH2:5][CH2:4]CC1.[F:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1.[CH2:39]([Mg]Br)C(C)C>>[F:29][C:30]1[CH:38]=[CH:37][C:33]([C:34]([NH:16][C:13]2[CH:14]=[CH:15][C:7]3[CH:6]([CH2:1][CH:5]([CH3:4])[CH3:39])[O:10][B:9]([OH:11])[C:8]=3[CH:12]=2)=[O:35])=[CH:32][CH:31]=1
Reactant: CC(C)C[Mg]Br
Reactant: O=C(Nc1ccc2c(c1)B(O)OC2C1CCCC1)c1ccccc1C(F)(F)F
Reactant: O=C(Cl)c1ccc(F)cc1
Product: CC(C)CC1OB(O)c2cc(NC(=O)c3ccc(F)cc3)ccc21

Procedure:
The title compound was prepared using a procedure similar to that of N-(3-cyclopentyl-1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-2-trifluoromethyl-benzamide with 4-fluorobenzoyl chloride replacing 2-trifluoromethylbenzoyl chloride, and with isobutyl magnesium bromide replacing cyclopentyl magnesium bromide. Data: LCMS (M/Z): 328 (M+H); 1H NMR (DMSO-d6) δ: 10.25 (s, 1H), 9.11 (s, 1H), 8.07 (d, J=1.9 Hz, 1H), 7.98-8.04 (m, 2H), 7.71 (dd, J=8.2, 2.0 Hz, 1H), 7.29-7.37 (m, 3H), 5.11 (dd, J=9.8, 3.1 Hz, 1H), 1.81-1.93 (m, 1H), 1.65 (ddd, J=13.9, 9.0, 3.2 Hz, 1H), 1.27 (ddd, J=14.1, 9.7, 4.7 Hz, 1H), 0.98 (d, J=6.5 Hz, 3H), 0.89 (d, J=6.7 Hz, 3H).
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[N:9]1[C:17]2[C:12](=[N:13][CH:14]=[CH:15][CH:16]=2)[S:11][C:10]=1[NH2:18].Cl[C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([OH:30])[CH:28]=2)[N:23]=[CH:22][N:21]=1>>[CH3:8][C:7]1[C:2]([O:30][C:27]2[CH:28]=[C:29]3[C:24](=[CH:25][CH:26]=2)[N:23]=[CH:22][N:21]=[C:20]3[NH:18][C:10]2[S:11][C:12]3[C:17]([N:9]=2)=[CH:16][CH:15]=[CH:14][N:13]=3)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Oc1ccc2ncnc(Cl)c2c1
Reactant: Nc1nc2cccnc2s1
Reactant: Cc1cccnc1Cl
Product: Cc1cccnc1Oc1ccc2ncnc(Nc3nc4cccnc4s3)c2c1

Procedure:
The compound of Example 83 was manufactured by the same method as in Example 22, by a similar method thereto or by a combination of such a method with a conventional method using 2-chloro-3-methylpyridine, thiazolo[5,4-b]pyridin-2-yl-amine and 4-chloro-6-hydroxy-quinazoline.
Reaction SMILES: CS(O)(=O)=[O:3].[Cl:6][CH2:7][C@@H:8]([O:12][Si](C)(C)C)[CH2:9][C:10]#N.[C:17]([O:21][C:22](=[O:25])[CH2:23]Br)([CH3:20])([CH3:19])[CH3:18].Cl>[Zn].O1CCCC1>[C:17]([O:21][C:22](=[O:25])[CH2:23][C:10](=[O:3])[CH2:9][C@H:8]([OH:12])[CH2:7][Cl:6])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CS(=O)(=O)O
Reactant: C[Si](C)(C)O[C@H](CCl)CC#N
Agent: Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC(=O)C[C@H](O)CCl
Temperature: 0 °C
Yield: 87 %

Procedure:
Zinc dust (690 mg), tetrahydrofuran (4.0 mL), and methanesulfonic acid (10 mg) were introduced into a reaction vessel and the mixture was stirred under reflux. To the mixture was added (S)-4-chloro-3-trimethylsilanyloxybutyronitrile (1.00 g) and subsequently t-butylbromoacetate (2.04 g) over 1 hour. The mixture was stirred under reflux for 30 minutes, and cooled to 0° C. Aqueous 3 N hydrochloric acid solution was added dropwise until the acidity of the reaction solution became pH 4, and the reaction solution was stirred for 3 hours. After the completion of reaction, tetrahydrofuran was distilled off under reduced pressure, and the residue was extracted with ethyl acetate and purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=⅓, v/v) to give the title compound in a yield of 87% (1.07 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([NH2:11])[CH:5]=1)([O-:3])=[O:2].[C:12](O)(=O)[CH2:13][CH2:14][CH2:15][CH3:16]>P(Cl)(Cl)(Cl)=O>[CH2:13]([C:12]1[NH:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=2[N:11]=1)[CH2:14][CH2:15][CH3:16]
Reactant: Nc1ccc([N+](=O)[O-])cc1N
Reactant: CCCCC(=O)O
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCc1nc2cc([N+](=O)[O-])ccc2[nH]1

Procedure:
11.5 g (0.075 mol) of 4-nitro-o-phenylenediamine are introduced in portions at ambient temperature into a mixture of 8.66 g (0.085 mol) of valeric acid and 120 ml of phosphorus oxychloride. The mixture is then heated for 3 hours under reflux. The reaction mixture is separated in 1.5 kg of iced water, rendered alkaline using concentrated ammonia and extracted three times using 500 ml of ethyl acetate. The organic phase is separated off, dried using magnesium sulphate and rotary evaporated. The oily residue is purified over a silica gel column (grain size: 0.063-0.2 mm, eluting agent: methylene chloride/0-2% ethanol). The homogeneous fractions are evaporated to dryness.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=1>>[C:13]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:14]=[CH:15][CH:16]=[C:11]([N:9]2[CH:10]=[C:6]([C:4]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=3)=[O:5])[N:7]=[CH:8]2)[CH:12]=1
Reactant: Fc1cccc(Br)c1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3ccccc3)c2)cn1
Product: O=C(c1cccc(F)c1)c1cn(-c2cccc(-c3ccccc3)c2)cn1

Procedure:
This compound was prepared by method C using compound 12a and 1-bromo-3-fluorobenzene. HRMS (ESI+): m/z=343.1231 [M+H]
Reaction SMILES: FC1C=C(C[C@H](NC(=O)CN2C3CCCCC=3C(C(F)(F)F)=N2)C2N(C3C=CC(OC)=CC=3)C=CN=2)C=C(F)C=1.Cl.[Cl:42][C:43]1[CH:48]=[CH:47][C:46]([C:49]2[O:50][C:51]([CH:54]([NH2:64])[CH2:55][C:56]3[CH:61]=[C:60]([F:62])[CH:59]=[C:58]([F:63])[CH:57]=3)=[CH:52][N:53]=2)=[CH:45][CH:44]=1.[OH:65][C:66]1[CH:67]=[C:68]2[C:72](=[CH:73][CH:74]=1)[NH:71][CH:70]=[C:69]2[CH2:75][C:76](O)=[O:77]>>[Cl:42][C:43]1[CH:48]=[CH:47][C:46]([C:49]2[O:50][C:51]([CH:54]([NH:64][C:76](=[O:77])[CH2:75][C:69]3[C:68]4[C:72](=[CH:73][CH:74]=[C:66]([OH:65])[CH:67]=4)[NH:71][CH:70]=3)[CH2:55][C:56]3[CH:61]=[C:60]([F:62])[CH:59]=[C:58]([F:63])[CH:57]=3)=[CH:52][N:53]=2)=[CH:45][CH:44]=1
Reactant: O=C(O)Cc1c[nH]c2ccc(O)cc12
Reactant: NC(Cc1cc(F)cc(F)c1)c1cnc(-c2ccc(Cl)cc2)o1
Agent: COc1ccc(-n2ccnc2[C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)(F)F)c3c2CCCC3)cc1
Agent: Cl
Product: O=C(Cc1c[nH]c2ccc(O)cc12)NC(Cc1cc(F)cc(F)c1)c1cnc(-c2ccc(Cl)cc2)o1

Procedure:
The title compound was prepared according to the method presented for the synthesis of compound 5F of Example 5 utilizing 19E and 2-(5-hydroxy-1H-indol-3-yl)acetic acid. 1H NMR (400 MHz, CDCl3) δ 8.06 (s, 1H), 7.81 (d, J=8.3 Hz, 2H), 7.41 (d, J=8.5 Hz, 2H), 7.27 (m, 1H), 7.08 (s, 1H), 6.87-6.76 (m, 2H), 6.60 (m, 1H), 6.47 (d, J=6.0 Hz, 2H), 6.30 (s, 1H), 5.26 (d, J=7.9 Hz, 1H), 3.67 (s, 2H), 3.08-2.93 (m, 2H). MS (m/z) 508.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH2:7][C:6](F)([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5](F)([C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:4][C:3]=1[F:26].CC(C1C=CC(O)=CC=1)(C1C=CC(O)=CC=1)C.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C>[F:1][C:2]1[CH2:7][CH:6]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]([C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:4][C:3]=1[F:26]
Reactant: O=C(c1ccccc1)C1(F)CC(F)=C(F)CC1(F)C(=O)c1ccccc1
Agent: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: Cc1ccccc1
Product: O=C(c1ccccc1)C1CC(F)=C(F)CC1C(=O)c1ccccc1
Temperature: 130 °C

Procedure:
The synthesis of polycyclohexenepolyetherketone 28 was conducted in a three-neck flask equipped with a nitrogen inlet, Dean-Stark and condenser. A detailed synthetic procedure for its synthesis is as follows: The flask was charged with the monomer difluoro-4,5-difluoro-4,5-dibenzoylcyclohexene 3 (7.65 mmol, 2.48 g) and bisphenol (BPA) (7.65 mmol, 1.74 g) in N,N-dimethylacetamide (15 mL). Toluene (15 mL) was added, followed by anhydrous potassium carbonate (22.9 mmol, 3.2 g). The reaction mixture was then heated until toluene began to reflux. An optimum reflux temperature range was reached at 130° C. Toluene was periodically removed from the Dean-Stark trap to replace with dry toluene to ensure dehydration. The reaction mixture was maintained at 130° C. for 1-2 h at which point the viscosity increased enormously. The reaction mixture seemed to reach near completion or completion by the dramatic increase in viscosity and was then cooled, a few drops of acetic acid was added, and then diluted with toluene. The polymer solution was coagulated in a large amount of methanol, filtered, and washed with methanol. The white fibrous polymer 28 was redissolved in chloroform, hot filtered through Celite, reprecipitated into a large volume of methanol, filtered and dried in vacuo at 80° C. for 24 h. The yield was essentially quantitative.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10](=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1.C1C=CC=CC=1.[CH3:24][CH:25]([N:27]1[C:31]([NH2:32])=[CH:30][CH:29]=[N:28]1)[CH3:26]>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:30]3[CH:29]=[N:28][N:27]([CH:25]([CH3:26])[CH3:24])[C:31]=3[N:32]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(=O)CC(=O)c1ccc(Cl)cc1
Reactant: CC(C)n1nccc1N
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(-c2ccc(Cl)cc2)nc2c1cnn2C(C)C

Procedure:
The title compound was prepared in the same manner as described for intermediate 61 using ethyl 4-(4-chlorophenyl)-2,4-dioxobutanoate (610 mg, 2.397 mmol), benzene (5 mL), 1-(1-methylethyl)-1H-pyrazol-5-amine (300 mg, 2.397 mmol), and acetic acid (4 mL). The crude product was purified by column chromatography (Silica gel, eluent: 0 to 100% EtOAc/hexanes) to give 621 mg (75%) of product. LCMS E-S (M+H)=344.1. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.48-1.57 (m, 3H), 1.64-1.74 (m, 6H), 4.56 (q, J=7.1 Hz, 2H), 5.46 (m, 1H), 7.49-7.55 (m, 2H), 8.15-8.18 (m, 2H), 8.21 (s, 1H), 8.42 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9].C(OC(=O)C)(=O)C.C(O)(=O)C.OS(O)(=O)=O.[N+:38]([O-])([OH:40])=[O:39]>>[Cl:1][C:2]1[CH:17]=[C:16]([C:18]([F:20])([F:19])[F:21])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:13]=[CH:12][C:11]([N+:38]([O-:40])=[O:39])=[C:7]([CH:6]=1)[C:8]([OH:10])=[O:9]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1cccc(Oc2ccc(C(F)(F)F)cc2Cl)c1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C(O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reaction time: 1.5 h
Yield: 80.3 %

Procedure:
3-(2-Chloro-4-trifluoromethylphenoxy)benzoic acid (275.9 g, 0.935 mole), acetic anhydride (276 g, 2.7 mole), glacial acetic acid (276 g, 4.6 mole) and conc. H2SO4 (44 g) were charged into a three-neck 5 liter flask equipped with a mechanical stirrer, thermometer and an addition funnel. Nitric acid (90%, 91.7 g, 1.3 mole) was added at 15°-25° C. over 0.5 hr. The cooling bath was substituted with a water bath and the reaction was stirred for 1.5 hrs. at 30° C. The reaction was quenched with 1250 ml of water (at 30° C.), stirred for 0.25 hr. The resultant yellow precipitate was filtered and washed with 2 liters of water. Recrystallization from toluene (750 ml) afforded 271.6 g of 5-(2-chloro-4-trifluoromethylphenoxy)-2-nitrobenzoic acid; m.p. 120°-121° C.
Reaction SMILES: [CH2:1]([N:8]([CH2:15][C:16]1[C:21](Cl)=[N:20][C:19]([N:23]([CH:25]2[CH2:28][CH2:27][CH2:26]2)[CH3:24])=[CH:18][N:17]=1)[CH2:9][C@@H:10]([OH:14])[CH2:11][O:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].O>CN(C=O)C>[CH2:1]([N:8]1[CH2:15][C:16]2[N:17]=[CH:18][C:19]([N:23]([CH:25]3[CH2:28][CH2:27][CH2:26]3)[CH3:24])=[N:20][C:21]=2[O:14][C@@H:10]([CH2:11][O:12][CH3:13])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC[C@H](O)CN(Cc1ccccc1)Cc1ncc(N(C)C2CCC2)nc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC[C@H]1CN(Cc2ccccc2)Cc2ncc(N(C)C3CCC3)nc2O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.9 %

Procedure:
To a solution of (2R)-1-[benzyl({3-chloro-5-[cyclobutyl(methyl)amino]pyrazin-2-yl}methyl)amino]-3-methoxypropan-2-ol (670 mg) in DMF (10 ml) was added potassium tert-butoxide (223 mg), and the mixture was stirred at room temperature for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient: 10→50% ethyl acetate/hexane) to give the title compound (530 mg, 87%).
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9](=[O:16])[NH:10]2)=[O:4].[CH:17]([NH2:21])([CH2:19][CH3:20])[CH3:18].Cl>C(O)C>[CH:17]([NH:21][CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9](=[O:16])[NH:10]2)=[O:4])([CH2:19][CH3:20])[CH3:18]
Reactant: CCC(C)N
Reactant: O=C(CCl)c1ccc(O)c2[nH]c(=O)ccc12
Agent: Cl
Solvent: CCO
Product: CCC(C)NCC(=O)c1ccc(O)c2[nH]c(=O)ccc12
Yield: 58.4 %

Procedure:
4.3 g of the 5-chloroacetyl-8-hydroxycarbostyril (IV) obtained in Example 4 or 8 was suspended in 50 ml of ethanol, and 5 g of sec-butylamine was added dropwise to the resulting suspension while stirring followed by stirring at 60° to 65° C. for 5 hours. After cooling, the resulting mixture was adjusted to a pH of 3 with concentrated hydrochloric acid. The precipitated crystals were filtered, washed with acetone and recrystallized from methanol-ethanol (1:1 by volume) to obtain 2.9 g of 5-sec-butylaminoacetyl-8-hydroxycarbostyril (II) hydrochloride having a melting point of 289° - 291° C. (with decomposition) as pale yellow crystals.
Reaction SMILES: [BH4-].[Na+].Cl.[CH2:4]([N:11]1[CH2:16][CH2:15][CH:14]([C:17](OCC)=[O:18])[C:13](=[O:22])[CH2:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O>CO>[CH2:4]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][OH:18])[CH:13]([OH:22])[CH2:12]1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CCOC(=O)C1CCN(Cc2ccccc2)CC1=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OCC1CCN(Cc2ccccc2)CC1O
Reaction time: 0.25 h

Procedure:
Sodium borohydride (40 g) was added in portions to a stirred solution of ethyl N-benzyl-3-oxopiperidine-4-carboxylate hydrochloride in methanol (500 mL), over 2 h. Water (300 mL) was added slowly, the mixture stirred for 15 min, and then the organics were evaporated. The resulting residue was partitioned between DCM and water (×3), the combined organic layers dried over anhydrous sodium sulfate, and the solvent evaporated to give the product as a cis trans mixture, used in the next step without further purification.
Reaction SMILES: C(OC)(=O)[CH2:2][C:3](OC)=[O:4].CC[O-].[Na+].[O:14]1[CH2:18][CH2:17][CH:16]([C:19]2[CH:23]=[C:22]([CH:24]=[CH:25][C:26](=[O:28])[CH3:27])[O:21][N:20]=2)[CH2:15]1>CO>[OH:4][C:3]1[CH2:2][CH:24]([C:22]2[O:21][N:20]=[C:19]([CH:16]3[CH2:17][CH2:18][O:14][CH2:15]3)[CH:23]=2)[CH2:25][C:26](=[O:28])[CH:27]=1
Reactant: COC(=O)CC(=O)OC
Reactant: CC(=O)C=Cc1cc(C2CCOC2)no1
Agent: CC[O-]
Agent: [Na+]
Solvent: CO
Product: O=C1C=C(O)CC(c2cc(C3CCOC3)no2)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
10.6 g of dimethyl malonate in 300 ml of methanol were initially taken, and 14.4 g of a 30% strength sodium ethylate solution in methanol were added at room temperature. Thereafter, 16.0 g of 4-[tetrahydrofur-3-ylisoxazol-5-yl]-3-buten-2-one were added and the mixture was stirred for 1 day at 25° C. The residue which remained after the solvent had been removed was taken up in 10% strength sodium hydroxide solution and stirred for 24 hours at 25° C. The sodium hydroxide phase was washed with methyl tert-butyl ether, acidified to pH 2 with concentrated hydrochloric acid and then heated at 85° C. for 2 hours. The solid formed was filtered off, washed with water and dried 12.3 g of a beige solid of melting point 142°-144° C. were obtained
Reaction SMILES: C[O-].[Na+].C([S:7][C@@H:8]1[CH2:12][N:11]([CH3:13])[C@H:10]([C:14]([N:16]2[CH2:20][CH2:19][C@H:18]([NH:21][C:22](=[O:41])[CH2:23][NH:24][C:25]([NH:27][C:28]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=3)=[O:29])=[NH:26])[CH2:17]2)=[O:15])[CH2:9]1)(=O)C.Cl>CO>[SH:7][C@@H:8]1[CH2:12][N:11]([CH3:13])[C@H:10]([C:14]([N:16]2[CH2:20][CH2:19][C@H:18]([NH:21][C:22](=[O:41])[CH2:23][NH:24][C:25]([NH:27][C:28]([O:30][CH2:31][C:32]3[CH:33]=[CH:34][C:35]([N+:38]([O-:40])=[O:39])=[CH:36][CH:37]=3)=[O:29])=[NH:26])[CH2:17]2)=[O:15])[CH2:9]1
Reactant: CC(=O)S[C@H]1C[C@@H](C(=O)N2CC[C@H](NC(=O)CNC(=N)NC(=O)OCc3ccc([N+](=O)[O-])cc3)C2)N(C)C1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CN1C[C@@H](S)C[C@H]1C(=O)N1CC[C@H](NC(=O)CNC(=N)NC(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Yield: 58.2 %

Procedure:
A solution of 28% sodium methylate in methanol (0.5 ml) was added to a solution of (2S,4S)-4-acetylthio-1-methyl-2-[(3S)-3-[2-[3-(4-nitrobenzyloxycarbonyl)guanidino]acetylamino]pyrrolidin-1-ylcarbonyl]pyrrolidine (1.5 g) in methanol (30 ml) and stirred at room temperature for I hour. At the end of this time, to the resulting mixture was added 1N hydrochloric acid (2.73 ml) and concentrated in vacuo. The resulting residue was chromatographed on a reverse phase column (Cosmosil 75C18PREP (trade mark) manufactured by Nacalai tesque Inc.) using a mixture of acetonitrile and water as the eluant. The fractions containing the desired product were combined and concentrated in vacuo. The residue was powdered in a mixture of ethyl acetate and isopropyl ether. Powdery (2S,4S)-4-mercapto-1-methyl-2-[(3S)-3[2-[3-(4-nitrobenzyloxycarbonyl)guanidino]acetylamino]pyrrolidin-1-yl-carbonyl]pyrrolidine (806 mg) was obtained by filtration.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:4]=[C:5]([CH:9]([NH:11][C:12](=[O:17])[CH2:13][CH:14](C)C)[CH3:10])[C:6](=[O:8])[N:7]=1.[NH2:25][C:26]1[NH:27][N:28]([CH2:36][C:37]2[CH:42]=CC=C[CH:38]=2)[CH:29]([CH:33]([NH2:35])[CH3:34])[C:30](=[O:32])[N:31]=1.C(OC(=O)CC(C)C)(=O)CC(C)C>>[NH2:1][C:2]1[N:3]([CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:4]=[C:5]([CH:9]([NH:11][C:12](=[O:17])[CH:13]([CH3:14])[CH3:26])[CH3:10])[C:6](=[O:8])[N:7]=1.[NH2:25][C:26]1[NH:27][N:28]2[C:36]([CH:37]([CH3:42])[CH3:38])=[N:35][C:33]([CH3:34])=[C:29]2[C:30](=[O:32])[N:31]=1
Reactant: CC(C)CC(=O)NC(C)c1nn(Cc2ccccc2)c(N)nc1=O
Reactant: CC(N)C1C(=O)N=C(N)NN1Cc1ccccc1
Agent: CC(C)CC(=O)OC(=O)CC(C)C
Product: CC(C)C(=O)NC(C)c1nn(Cc2ccccc2)c(N)nc1=O
Product: Cc1nc(C(C)C)n2[nH]c(N)nc(=O)c12

Procedure:
In a similar way N-[1-(3-Amino-2-benzyl-2,5-dihydro-5-oxo-as-triazin-6-yl)ethyl]isovaleramide m.p. 149.5° was prepared from 3-amino-1-benzyl-6(1-aminoethyl)-as-triazin-5-one and isovaleric anhydride.
Reaction SMILES: Br[C:2]1[C:11]2[N:10]=[CH:9][C:8](=[O:12])[NH:7][C:6]=2[N:5]=[C:4]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=2[F:22])[N:3]=1.[NH2:23][CH:24]([CH2:27][OH:28])[CH2:25][OH:26]>>[Cl:21][C:17]1[C:16]([F:22])=[C:15]([CH2:14][S:13][C:4]2[N:3]=[C:2]([NH:23][CH:24]([CH2:27][OH:28])[CH2:25][OH:26])[C:11]3[N:10]=[CH:9][C:8](=[O:12])[NH:7][C:6]=3[N:5]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: O=c1cnc2c(Br)nc(SCc3cccc(Cl)c3F)nc2[nH]1
Reactant: NC(CO)CO
Product: O=c1cnc2c(NC(CO)CO)nc(SCc3cccc(Cl)c3F)nc2[nH]1
Yield: 66.3 %

Procedure:
The titled compound (51 mg) was prepared by the method of Example 6, step (f) using the product from Example 6, step (e) (75 mg) and 2-amino-1,3-propanediol (37 mg).
Reaction SMILES: [C:1]1(C)C=CC=CC=1.[Na].[CH:9]1([N:15]2[C:20](=[O:21])[N:19]=[C:18]([S:22][CH3:23])[NH:17][C:16]2=[O:24])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.S(OC)(OC)(=O)=O.[OH-].[Na+]>O>[CH3:1][N:19]1[C:18]([S:22][CH3:23])=[N:17][C:16](=[O:24])[N:15]([CH:9]2[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]2)[C:20]1=[O:21]
Reactant: CSc1nc(=O)n(C2CCCCC2)c(=O)[nH]1
Reactant: Cc1ccccc1
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: COS(=O)(=O)OC
Solvent: O
Product: CSc1nc(=O)n(C2CCCCC2)c(=O)n1C

Procedure:
This toluene slurry of 3-cyclohexyl-6-methylthio-s-triazine-2,4(1H,3H)-dione sodium salt is then agitated with 650 parts of water for 0.15 hrs. The aqueous layer is separated and reacted at 25°-30° during 0.25 hrs with 57 parts of dimethyl sulfate. After the dimethyl sulfate is added, the pH of the reaction is maintained at pH 9-9.5 by addition of a total of 7.5 parts of 50% aqueous sodium hydroxide. The total reaction time is 1.8 hrs at which time filtration and drying gives 70 parts of white 1-methyl-3-cyclohexyl-6-methylthio-s-triazine-2,4(1H,3H)-dione, m.p. 137°-139°.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6](B(O)O)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[NH2:13][C:14]1[C:23]2[C:18](=[C:19](Br)[C:20]([CH3:25])=[CH:21][C:22]=2[F:24])[N:17]=[N:16][C:15]=1[C:27]([NH2:29])=[O:28]>>[NH2:13][C:14]1[C:23]2[C:18](=[C:19]([C:6]3[CH:5]=[C:4]4[C:9](=[CH:8][CH:7]=3)[NH:1][N:2]=[CH:3]4)[C:20]([CH3:25])=[CH:21][C:22]=2[F:24])[N:17]=[N:16][C:15]=1[C:27]([NH2:29])=[O:28]
Reactant: Cc1cc(F)c2c(N)c(C(N)=O)nnc2c1Br
Reactant: OB(O)c1ccc2[nH]ncc2c1
Product: Cc1cc(F)c2c(N)c(C(N)=O)nnc2c1-c1ccc2[nH]ncc2c1

Procedure:
The title compound was prepared in a manner similar to EXAMPLE 1 using (1H-indazol-5-yl)boronic acid and 4-amino-8-bromo-5-fluoro-7-methylcinnoline-3-carboxamide. 1H NMR (400 MHz, CD3OD) δ ppm 2.28 (s, 3 H), 7.19-7.30 (m, 1 H), 7.35 (d, J=16 Hz, 1H), 7.59-7.70 (m, 2 H), 8.07 (s, 1 H); ESI-MS m/z [M+H]+ 337.2.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][C@H:9]([CH3:14])[C:10]([CH3:13])([OH:12])[CH3:11])[C:5]([I:15])=[CH:4][N:3]=1.[O:16]1[CH:21]=[CH:20][CH2:19][CH2:18][CH2:17]1.S(C1C=CC(C)=CC=1)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([O:8][C@H:9]([CH3:14])[C:10]([CH3:11])([O:12][CH:17]2[CH2:18][CH2:19][CH2:20][CH2:21][O:16]2)[CH3:13])[C:5]([I:15])=[CH:4][N:3]=1
Reactant: C[C@@H](Oc1nc(Cl)ncc1I)C(C)(C)O
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: C[C@@H](Oc1nc(Cl)ncc1I)C(C)(C)OC1CCCCO1
Temperature: 25 °C
Reaction time: 22 h
Yield: 89 %

Procedure:
A solution of 4.96 g (14.5 mmol) of (R)-3-(2-chloro-5-iodopyrimidin-4-yloxy)-2-methylbutan-2-ol in 30 ml of DCM was admixed with 2.64 ml (29.0 mmol) of dihydropyrane and 0.36 g (1.5 mmol) of pyridinium tosylate and stirred for 22 hours at room temperature. The mixture was diluted with DCM and washed with saturated sodium hydrogen carbonate solution. The organic phase was dried (Na2SO4), filtered and concentrated by evaporation. The resulting residue was purified chromatographically (hexane/ethyl acetate 4:1). This gave 5.50 g (12.9 mmol; yield: 89%) of the diastereomer mixture.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:20]2[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[C:14](=[O:15])[NH:13][C:12]([CH3:16])=[N:11][C:10]=1[CH2:17][CH2:18][CH3:19].Br[CH2:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[CH3:32][C:31]([CH3:34])([CH3:33])[C:30](=[O:35])[CH2:29][N:13]1[C:14](=[O:15])[C:9]([CH2:8][C:7]2[CH:6]=[CH:5][C:4]([C:20]3[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:3][C:2]=2[F:1])=[C:10]([CH2:17][CH2:18][CH3:19])[N:11]=[C:12]1[CH3:16]
Reactant: CC(C)(C)C(=O)CBr
Reactant: CCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCc1nc(C)n(CC(=O)C(C)(C)C)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 25.8 %

Procedure:
A mixture of 3′-fluoro-4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (2.04 g), 1-bromo-3,3-dimethylbutan-2-one (1.53 g), potassium carbonate (1.59 g) and N,N-dimethylformamide (30 mL) was stirred at room temperature for 4 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.67 g, 26%).