Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:30])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:29])[CH:16]([CH:25]([CH2:27][CH3:28])[CH3:26])[NH:17]C(OC(C)(C)C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:31].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:31].[CH2:1]([O:8][C:9](=[O:30])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:29])[CH:16]([CH:25]([CH2:27][CH3:28])[CH3:26])[NH2:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(C)C(NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Product: CCC(C)C(N)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 90 %

Procedure:
N-t-butyloxycarbonyl-D,L-isoleucyl-L-proline benzyl ester (13 g) was dissolved in ethyl acetate (34 ml), and 15% HCl/ethyl acetate solution (25 ml) was added dropwisely upon cooled. After the completion of addition, the resulting mixture was allowed to warm up naturally to room temperature to react for 4 h, and then concentrated under reduced pressure to remove the reaction liquid, and the oil was recrystallized with isopropanol/n-hexane to give 4.5 g white solid (90%), with the content being 94% (HPLC, mobile phase 1, method 2).
Reaction SMILES: [C:1]([C:4]1[C:25]([N+:26]([O-:28])=[O:27])=[CH:24][C:7]([O:8][CH2:9][C:10]2([NH:13][C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])[CH2:12][CH2:11]2)=[C:6]([O:29][CH3:30])[CH:5]=1)(=[O:3])[CH3:2].CO[CH:33](OC)[N:34]([CH3:36])[CH3:35]>CN(C=O)C.O>[CH3:33][N:34]([CH3:36])[CH:35]=[CH:2][C:1]([C:4]1[C:25]([N+:26]([O-:28])=[O:27])=[CH:24][C:7]([O:8][CH2:9][C:10]2([NH:13][C:14]([O:16][CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:15])[CH2:12][CH2:11]2)=[C:6]([O:29][CH3:30])[CH:5]=1)=[O:3]
Reactant: COC(OC)N(C)C
Reactant: COc1cc(C(C)=O)c([N+](=O)[O-])cc1OCC1(NC(=O)OCc2ccccc2)CC1
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C(=O)C=CN(C)C)c([N+](=O)[O-])cc1OCC1(NC(=O)OCc2ccccc2)CC1
Temperature: 100 °C
Reaction time: 2 h
Yield: 98.7 %

Procedure:
A mixture of the compound of Example 2 (1.7 g, 4.1 mmol) and N,N-dimethylformamide dimethylacetal (0.9 g, 8.2 mmol) in DMF (6 mL) was stirred at 100° C. for 2 h. After cooling at room temperature, the reaction mixture was diluted with water (30 mL) and extracted with AcOEt (3×50 mL). The combined organic phases were washed with brine (2×50 mL), dried and evaporated to give 1-[(4-(3-dimethylaminopropenoyl)-2-methoxy-5-nitrophenoxy)methyl]-N-benzyloxycarbonyl-1-aminocyclopropane (1.9 g, yield: 95%) as a yellow solid.
Reaction SMILES: [CH2:1]([N:4]1[C:9]2[CH:10]=[C:11]([C:14](=[O:25])[CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=3[Cl:24])[CH:12]=[CH:13][C:8]=2[O:7][CH2:6][C:5]1=[O:26])[CH:2]=[CH2:3].[CH3:27]I>C(O)C>[CH2:1]([N:4]1[C:9]2[CH:10]=[C:11]([C:14](=[O:25])[CH:15]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=3[Cl:24])[CH3:27])[CH:12]=[CH:13][C:8]=2[O:7][CH2:6][C:5]1=[O:26])[CH:2]=[CH2:3]
Reactant: C=CCN1C(=O)COc2ccc(C(=O)Cc3ccc(OC)cc3Cl)cc21
Reactant: CI
Solvent: CCO
Product: C=CCN1C(=O)COc2ccc(C(=O)C(C)c3ccc(OC)cc3Cl)cc21

Procedure:
In analogy to Example 56, step 2, 4-allyl-6-[2-(2-chloro-4-methoxy-phenyl)-acetyl]-4H-benzo[1,4]oxazin-3-one (8.9 g) was reacted with methyl iodide at r.t. for 2 h. The crude product was treated with ethanol (25 ml), filtered and dried under high vacuum to give the title compound (7.2 g) as a light yellow solid. MS (m/e)=386.2 [M+H+].
Reaction SMILES: C[Al](C)C.[O:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]1[O:11][NH2:12].[CH2:13]([O:20][C@H:21]([C:39](OC)=[O:40])[C@@H:22]([CH2:35][CH:36]([CH3:38])[CH3:37])[C:23]([NH:25][N:26]([CH2:31][CH:32]([CH3:34])[CH3:33])[S:27]([CH3:30])(=[O:29])=[O:28])=[O:24])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:13]([O:20][C@H:21]([C:39](=[O:40])[NH:12][O:11][CH:6]1[CH2:7][CH2:8][CH2:9][CH2:10][O:5]1)[C@@H:22]([CH2:35][CH:36]([CH3:38])[CH3:37])[C:23]([NH:25][N:26]([CH2:31][CH:32]([CH3:33])[CH3:34])[S:27]([CH3:30])(=[O:28])=[O:29])=[O:24])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: NOC1CCCCO1
Reactant: COC(=O)[C@@H](OCc1ccccc1)[C@@H](CC(C)C)C(=O)NN(CC(C)C)S(C)(=O)=O
Agent: C[Al](C)C
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)C[C@@H](C(=O)NN(CC(C)C)S(C)(=O)=O)[C@H](OCc1ccccc1)C(=O)NOC1CCCCO1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 29.8 %

Procedure:
0.530 ml of a 2M solution of trimethylaluminium in toluene was added to a solution of 0.124 g of O-(tetrahydro-2H-pyran-2(RS)-yl)-hydroxylamine in 5 ml of dry toluene at 0° C. under a nitrogen atmosphere. The mixture was stirred at 0° C. for 0.5 hours and then 0.335 g of 2(R)-[(S)-(benzyloxy)(methoxycarbonyl)methyl]-2′-isobutyl-2′-(methanesulphonyl)-4-methylvalerohydrazide was added in one portion. The mixture was then left to warm to room temperature overnight. The mixture was diluted with ethyl acetate and washed in succession with 2M aqueous hydrochloric acid and 5% aqueous sodium hydrogen carbonate solution and then dried over anhydrous magnesium sulphate. The solvent was evaporated and the residue was triturated with hexane/diethyl ether (2:1) to give 0.119 g of 2(R)-[(S)-(benzyloxy)-[(tetrahydro-2(RS)-pyranyloxy)-carbamoyl]methyl]-2′-isobutyl-2′-(methanesulphonyl)-4-methylvalerohydrazide in the form of a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:16](=O)[CH3:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:6]=[CH:7][CH:8]=1.Cl.[CH3:20][O:21][C:22]1[CH:32]=[CH:31][C:25]([CH2:26][S:27][C:28](=[NH:30])[NH2:29])=[CH:24][CH:23]=1.C([O-])(=O)C.[Na+]>CN(C)C=O.CCOCC>[CH3:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([CH2:26][S:27][C:28]2[NH:30][C:16]([CH3:17])=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)[N:29]=2)=[CH:31][CH:32]=1
Reactant: CCOC(=O)C(=Cc1cccc(OC)c1)C(C)=O
Reactant: COc1ccc(CSC(=N)N)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)C1=C(C)NC(SCc2ccc(OC)cc2)=NC1c1cccc(OC)c1
Reaction time: 4 h

Procedure:
A mixture of 2-[(3-methoxyphenyl)methylene]-3-oxobutanoic acid, ethyl ester (2.0 g., 8 mmole), S-(4-methoxybenzyl)thiopseudourea, hydrochloride (1.87 g., 8 mmole), and sodium acetate (0.67 g., 8 mmole) in dimethylformamide (10 ml.) is stirred at 70° for 4 hours. The cooled mixture is diluted with ether and washed with water, sodium bicarbonate, and brine. The dried solution is evaporated to give 2.85 g. of an impure oil. Flash chromatography using ethyl acetate:hexanes (1:3) gives 2.0 g. of 1,4-dihydro-2-[[(4-methoxyphenyl)methyl]thio]-4-(3-methoxyphenyl)- 6-methyl-5-pyrimidinedicarboxylic acid, ethyl ester as an oil.
Reaction SMILES: C[N:2]([CH2:4][C:5]1[N:9](C(CCCCCC)C(O)=O)[C:8]2[CH:20]=[CH:21][C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[N:31]=NNN=3)=[CH:23][C:7]=2[N:6]=1)[CH3:3].N1C[CH2:38][CH2:37][CH2:36]1>C1COCC1>[C:30]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:22]1[CH:21]=[CH:20][C:8]2[NH:9][C:5]([CH2:4][N:2]3[CH2:3][CH2:38][CH2:37][CH2:36]3)=[N:6][C:7]=2[CH:23]=1)#[N:31]
Reactant: CCCCCCC(C(=O)O)n1c(CN(C)C)nc2cc(-c3ccccc3-c3nn[nH]n3)ccc21
Reactant: C1CCNC1
Solvent: C1CCOC1
Product: N#Cc1ccccc1-c1ccc2[nH]c(CN3CCCC3)nc2c1
Temperature: 25 °C
Yield: 84.6 %

Procedure:
2-Chloromethyl-5-2-cyanophenyl)-1H-benzimidazole (2.28 mmoles, 0.54 g--see Example 35) and pyrrolidine (5.26 mole, 0.375 g.) were dissolved in THF and stirred at room temperature. The solvents were removed in vacuo. The residue was dissolved in ethyl acetate, washed with water, and concentrated to yield 0.583 g of 5-(2-Cyanophenyl)-2-(1-pyrrolidinomethyl)-1H-benzimidazole.
Reaction SMILES: C(NC(C)C)(C)C.[Li].[CH2:9]([O:16][C:17]1[CH2:22][CH2:21][CH2:20][C:19](=[O:23])[CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH2:24]1[O:34][C:27]2([CH2:32][CH2:31][C:30](=[O:33])[CH2:29][CH2:28]2)[O:26][CH2:25]1.[Cl-].[NH4+]>O1CCCC1.ClCCl>[CH2:9]([O:16][C:17]1[CH2:22][CH2:21][CH:20]([C:30]2([OH:33])[CH2:31][CH2:32][C:27]3([O:34][CH2:24][CH2:25][O:26]3)[CH2:28][CH2:29]2)[C:19](=[O:23])[CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C1C=C(OCc2ccccc2)CCC1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [Cl-]
Agent: [Li]
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C1C=C(OCc2ccccc2)CCC1C1(O)CCC2(CC1)OCCO2
Temperature: -78 °C
Reaction time: 0.58 h
Yield: 88.5 %

Procedure:
To a round-bottomed flask was added anhydrous tetrahydrofuran (600 ml) and diisopropylamine (38.1 ml). The stirred solution was cooled to −78° C. and nbutyl lithium (113.4 ml, 2.4 M in cyclohexanes) was added dropwise via syringe in 20 ml portions. The resulting yellow solution was stirred for 35 min at −78° C., then 3-benzyloxy-2-cyclohexen-1-one (50.0 g) was added as a solution in anhydrous tetrahydrofuran (100 ml). The solution was stirred for 1 hr prior to the addition of cyclohexane-1,4-dione monoethylene ketal (38.7 g) as a solution in anhydrous tetrahydrofuran (100 ml). The solution was stirred for 2 hr at −78° C., then allowed to warm slowly to room temperature over 1 hr. Saturated aqueous ammonium chloride (80 ml) was added, followed by dichloromethane (700 ml), and the mixture was stirred until no solids remained. The layers were separated and the aqueous phase extracted with dichloromethane (2×100 ml). The combined organic layers were washed with brine (50 ml), dried over magnesium sulfate, then concentrated in vacuo. Trituration of the resulting solid with methanol afforded the title compound (78.4 g, 88%). m/z (ES+) 359 (M+H+).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[C:11]([C:13]([OH:15])=O)[CH:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:47][O:48][C:49]1[C:50]2[N:63]=[C:62]([NH2:64])[S:61][C:51]=2[C:52]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)=[N:53][CH:54]=1>C1COCC1>[CH3:47][O:48][C:49]1[C:50]2[N:63]=[C:62]([NH:64][C:13](=[O:15])[C:11]3[CH:10]=[CH:9][N:8]=[C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)[CH:12]=3)[S:61][C:51]=2[C:52]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)=[N:53][CH:54]=1
Reactant: COc1cnc(-c2ccccc2)c2sc(N)nc12
Reactant: O=C(O)c1ccnc(N2CCOCC2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COc1cnc(-c2ccccc2)c2sc(NC(=O)c3ccnc(N4CCOCC4)c3)nc12

Procedure:
From 2-(4-morpholinyl)-4-pyridinecarboxylic acid, HATU and N-methylmorpholine in THF, then treatment with 7-methoxy-4-phenyl-thiazolo[5,4-c]pyridin-2-ylamine. ES-MS m/e (%): 448 (M+H+, 100).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][C@@H:3]([C:7]([OH:9])=[O:8])[CH2:2]1.Cl[C:11]1[N:16]=[CH:15][C:14]([B:17]([OH:19])[OH:18])=[CH:13][N:12]=1>>[B:17]([C:14]1[CH:13]=[N:12][C:11]([N:1]2[CH2:6][CH2:5][O:4][C@@H:3]([C:7]([OH:9])=[O:8])[CH2:2]2)=[N:16][CH:15]=1)([OH:19])[OH:18]
Reactant: O=C(O)[C@H]1CNCCO1
Reactant: OB(O)c1cnc(Cl)nc1
Product: O=C(O)[C@H]1CN(c2ncc(B(O)O)cn2)CCO1

Procedure:
The title compound was prepared from (2R)-morpholine-2-carboxylic acid and (2-chloropyrimidin-5-yl)boronic acid in accordance with General Method C.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:5][CH:4]([C:6]([OH:8])=[O:7])[CH2:3]1.[H-].[Na+].CN(C)C=O.[CH2:16](I)[CH2:17][CH3:18]>C(OCC)(=O)C>[CH2:1]=[C:2]1[CH2:5][CH:4]([C:6]([O:8][CH2:16][CH2:17][CH3:18])=[O:7])[CH2:3]1
Reactant: CCCI
Reactant: C=C1CC(C(=O)O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=C1CC(C(=O)OCCC)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 66 %

Procedure:
A mixture of 3-methylidenecyclobutanecarboxylic acid (18 g), sodium hydride (6.9 g) and N,N-dimethylformamide (300 mL) was stirred at room temperature for 10 min, propyl iodide (17 mL) was added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by distillation (45-50° C., 2 mmHg) to give the title compound as a colorless oil (16 g, 66%).
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]2[C:6](=O)[C:7]3[C:8]([CH2:13][CH2:14][C:4]=2[CH:3]=1)=[N:9][CH:10]=[CH:11][CH:12]=3.[CH3:18][Mg]Br.[Cl-].[NH4+]>O1CCCC1>[F:1][C:2]1[CH:17]=[CH:16][C:5]2[C:6](=[CH2:18])[C:7]3[C:8]([CH2:13][CH2:14][C:4]=2[CH:3]=1)=[N:9][CH:10]=[CH:11][CH:12]=3
Reactant: C[Mg]Br
Reactant: O=C1c2ccc(F)cc2CCc2ncccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=C1c2ccc(F)cc2CCc2ncccc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Chill a mixture of 8-fluoro-10,11-dihydro-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one (1.3 g, 5.7 mmol) and dry tetrahydrofuran (50 mL) to 0° C. Treat this mixture with methyl magnesium bromide(3.0M solution in diethyl ether, 5.7 mL, 17.2 mmol). Remove cooling and stir the admixture at room temperature for 15 min. Quench the reaction, while cooling with an ice-water bath, by adding saturated aqueous ammonium chloride solution (50 mL). Separate the layers and extract the aqueous layer with methylene chloride (2×50 mL). Dry the combined organic layers with magnesium sulfate, filter and concentrate to provide the intermediate product as a thick crude oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[OH:9])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH:19]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:20]([O:22][CH3:23])=[O:21]>CN(C=O)C.[Cl-].[Na+].O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[O:9][CH:19]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:20]([O:22][CH3:23])=[O:21])=[CH:4][CH:3]=1
Reactant: OC(c1ccc(Br)cc1)c1ccccn1
Reactant: COC(=O)C(Br)CC(C)C
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(CC(C)C)OC(c1ccc(Br)cc1)c1ccccn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (4-bromophenyl)(pyridin-2-yl)methanol from step 1 (720 mg, 2.73 mmol) in DMF (14 mL) at 0° C., was added sodium hydride portionwise (69 mg, 2.87 mmol). The mixture was stirred 30 minutes before the methyl 2-bromo-4-methylpentanoate was slowly added (469 μL, 2.87 mmol). The reaction was allowed to warm to room temperature and was aged for 3 hours more. The mixture was then poured into brine and extracted 3 times with ethyl acetate. The combined organic extracts were dried and concentrated and the crude product obtained was chromatographed on silica gel using 50% ethyl acetate in hexanes to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:14])=O>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:14])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cccc(Cl)c1Cl
Product: O=C(Cl)c1cccc(Cl)c1Cl

Procedure:
A mixture of 2,3-dichlorobenzoic acid (39.4 g 0.2M) and thionyl chloride (100 mls) was heated to reflux for 21/2 hours. The cooled solution was evaporated down in vacuo and distilled under nitrogen. Yield 35.5 g (85%), b.p. 146°-148° C. at 31 mm of mercury pressure.
Reaction SMILES: [OH:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Cl:14]C1C=C(C(O)=O)C(O)=CC=1.O>C(O)(=O)C>[Cl:14][C:8]1[CH:7]=[C:3]([C:4]([OH:6])=[O:5])[C:2]([OH:1])=[C:10]([N+:11]([O-:13])=[O:12])[CH:9]=1
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1O
Reactant: O=C(O)c1cc(Cl)ccc1O
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1cc(Cl)cc([N+](=O)[O-])c1O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The following procedure demonstrates the preparation of compound 1 with X=5-Cl, with comparable procedures being useful for obtaining related compounds having different X substituents. A solution suspension of 10 g of 5-chlorosalicylic acid in 50 mL glacial acetic acid was cooled in an ice bath until the solvent began to freeze. The bath was exchanged to a room temperature water bath and 4.47 g of 90% fuming nitric acid (1:1 equivalent) in 3 mL glacial acetic acid was added dropwise. After addition was complete, the mixture was stirred for 150 minutes at room temperature (R.T.) in the water bath. It was then poured into 120 mL of ice and water and stirred in an ice bath for 30 minutes. The precipitated solid was collected by filtration and air-dried overnight.
Reaction SMILES: C(O[C:4]([CH:6]1[CH2:11][NH:10][C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[O:7]1)=[O:5])C.[C:16]([O:20][C:21](=[O:24])[CH2:22][NH2:23])([CH3:19])([CH3:18])[CH3:17]>C1(C)C=CC=CC=1>[C:16]([O:20][C:21]([CH2:22][NH:23][C:4]([CH:6]1[CH2:11][NH:10][C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[O:7]1)=[O:5])=[O:24])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)CN
Reactant: CCOC(=O)C1CNc2ccccc2O1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)CNC(=O)C1CNc2ccccc2O1
Reaction time: 5 h

Procedure:
1.0 g of 2(R,S)-ethoxycarbonyl-3,4-dihydro-2H-1,4-benzoxazine and 1.2 g of glycine-tert-butyl ester are heated at 80° C. in 10 ml of toluene. After 5 h, the mixture is evaporated and pure 2(R,S)-(tert-butoxycarbonylmethylaminocarbonyl)-3,4-dihydro-2H-1,4-benzoxazine is isolated by means of FC over 100 g of silica gel (mobile phase Z): Rf (Z)=0.38.
Reaction SMILES: O[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH2:7][CH:6]([C:12]([OH:14])=[O:13])[CH2:5]2.C1C=CC(C(O)C(N)C(O)=O)=CC=1.N[C@H](C(O)=O)CC1C=CC=CC=1>>[NH:8]1[C:9]2[C:4](=[CH:3][CH:2]=[CH:11][CH:10]=2)[CH2:5][CH:6]([C:12]([OH:14])=[O:13])[CH2:7]1
Reactant: O=C(O)C1CNc2ccc(O)cc2C1
Agent: NC(C(=O)O)C(O)c1ccccc1
Agent: N[C@@H](Cc1ccccc1)C(=O)O
Product: O=C(O)C1CNc2ccccc2C1
Yield: 95 %

Procedure:
That same document describes the preparation of (-)-6-hydroxy-1,2,3,4-tetrahydroquinoline-3-carboxylic acid with an optical purity of 100% and a yield of 95%, from m-tyrosine in accordance with the same method. However, where L-phenylalanine is used as the starting material, it is not possible to obtain a (-)-1,2,3,4-tetrahydroquinoline-3-carboxylic acid with 100% optical purity.
Reaction SMILES: C([O:8][C:9]1[C:10]([C:22](O)=O)=[N:11][CH:12]=[N:13][C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)C1C=CC=CC=1.[NH2:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[NH2:34])[C:29]#[N:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[OH:8][C:9]1[C:10]([C:22]2[NH:34][C:33]3[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][C:26]=3[N:25]=2)=[N:11][CH:12]=[N:13][C:14]=1[C:15]1[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=1
Reactant: N#Cc1ccc(N)c(N)c1
Reactant: Cc1ccc(-c2ncnc(C(=O)O)c2OCc2ccccc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ncnc(-c3nc4cc(C#N)ccc4[nH]3)c2O)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 5-(benzyloxy)-6-p-tolylpyrimidine-4-carboxylic acid P72 (80 mg, 0.25 mmol) in DMF (3 mL) was added 3,4-diaminobenzonitrile (40 mg, 0.30 mmol), HATU (124 mg, 0.33 mmol) and diisopropylethylamine (48 mg, 0.37 mmol). The reaction mixture was stirred at room temperature for 18 hours. The organic solvent was evaporated under reduced pressure. Ethyl acetate and 1 N hydrochloric acid were added. The organic layer was washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate. The organic solvent was evaporated under reduced pressure. The intermediate was purified by flash column chromatography. The intermediate was dissolved in acetic acid (5 mL) and heated in a microwave reactor at 160° C. for 1 hour. The organic solvent was evaporated under reduced pressure. Trifluoroacetic acid (5 mL) was added and the solution was heated in a microwave reactor at 120° C. for 30 minutes. The organic solvent was evaporated under reduced pressure. The crude product was purified by RP-HPLC to afford the desired 2-(5-hydroxy-6-p-tolylpyrimidin-4-yl)-1H-benzo[d]imidazole-5-carbonitrile P73 (16 mg, 0.049 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[N:11]=[C:10]([CH2:21][CH2:22][CH:23]=[N:24][OH:25])[CH:9]=2)=[CH:4][CH:3]=1.CN(C1C=CC(N=NC2C=CC(S(O)(=O)=O)=CC=2)=CC=1)C.[BH3-]C#N.[Na+].Cl>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[N:11]=[C:10]([CH2:21][CH2:22][CH2:23][NH:24][OH:25])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc(-n2nc(CCC=NO)cc2-c2ccc(Cl)cc2)cc1
Agent: CN(C)c1ccc(N=Nc2ccc(S(=O)(=O)O)cc2)cc1
Agent: Cl
Agent: [BH3-]C#N
Solvent: CO
Product: COc1ccc(-n2nc(CCCNO)cc2-c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of the oxime 26 (2.70 g, 7.59 mM) in MeOH (50 ml), containing methyl orange (2 mg) as as indicator, was added a solution of NaBH3CN (0.52 g, 8.4 mM) in MeOH (20 ml), and a solution of 2N HCl, simultaneously, at such a rate to maintain a pH of 3 to 4. The reaction was stirred for 3 hours at room temperature, acidified to pH 1 and concentrated in vacuo. The residue was diluted with H2O (100 ml), adjusted to pH 8.5 with 5N NaOH, and extracted with EtOAc. The extracts were combined, dried (Na2SO4), filtered and concentrated in vacuo. The residue was chromatographed on Merck Silica Gel 60 (90 g, 230-400 mesh) with EtOAc:MeOH (9:1) as eluent. Crystallization from Et2O afforded pure 38 (1.64 g, 60%) as a white solid, mp=91°-93°. MS, m/e 357(M+).
Reaction SMILES: C(C1N=C(N2CCC(F)(F)C2)C2C(=NN(CC)N=2)N=1)(C)(C)C.[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:40][C:39]([F:42])([F:41])[C:38]([F:44])([F:43])[CH2:37]2)[C:30]2[N:35]=[N:34][NH:33][C:31]=2[N:32]=1)([CH3:26])([CH3:25])[CH3:24].Br[CH2:46][C:47]1[C:51]([CH3:52])=[N:50][O:49][N:48]=1>>[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:40][C:39]([F:41])([F:42])[C:38]([F:43])([F:44])[CH2:37]2)[C:30]2[C:31](=[N:33][N:34]([CH2:46][C:47]3[C:51]([CH3:52])=[N:50][O:49][N:48]=3)[N:35]=2)[N:32]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: Cc1nonc1CBr
Reactant: CC(C)(C)c1nc(N2CC(F)(F)C(F)(F)C2)c2nn[nH]c2n1
Agent: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Product: Cc1nonc1Cn1nc2nc(C(C)(C)C)nc(N3CC(F)(F)C(F)(F)C3)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-Butyl-7-(3,3,4,4-tetrafluoro-pyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3-(bromomethyl)-4-methyl-1,2,5-oxadiazole and isolated as light yellow gum. MS (m/e): 415.3 (MH+).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([CH2:16][CH3:17])=[C:11]([CH2:13][CH2:14][Cl:15])[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2].Cl.[F:19][C:20]1[CH:21]=[CH:22][C:23]2[C:27]([CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[CH:26][S:25][C:24]=2[CH:34]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O.C1(C)C=CC=CC=1.O>[ClH:15].[C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([CH2:16][CH3:17])=[C:11]([CH2:13][CH2:14][N:31]3[CH2:32][CH2:33][CH:28]([C:27]4[C:23]5[CH:22]=[CH:21][C:20]([F:19])=[CH:34][C:24]=5[S:25][CH:26]=4)[CH2:29][CH2:30]3)[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: Fc1ccc2c(C3CCNCC3)csc2c1
Reactant: CCc1c(CCCl)sc2c1CCN(C(C)=O)C2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: CCc1c(CCN2CCC(c3csc4cc(F)ccc34)CC2)sc2c1CCN(C(C)=O)C2
Temperature: 70 °C
Reaction time: 7 h
Yield: 34.5 %

Procedure:
A mixture of 0.7 g of 6-acetyl-2-(2-chloroethyl)-3-ethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine, 0.7 g of 4-(6-fluorobenzo(b)thiophen-3-yl)piperidine hydrochloride, 1.8 g of potassium carbonate and 0.6 g of potassium iodide in 25 ml of dimethylformamide and 25 ml of toluene was stirred at 70° C. for 7 hours and poured into water. The toluene layer was washed with water, dried over magnesium and concentrated. The residue was purified by column chromatography on a silica gel and dissolved in ethanol to convert hydrochloride thereof, and then recrystallized from methanol to give 0.45 g of 6-acetyl-3-ethyl-2-(2-(4-(6-fluorobenzo-(b)thiophen-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine hydrochloride, m.p. 240° C. (decomposition).