Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=2)[C:10]2[C:5](=[CH:6][C:7]([O:30][CH3:31])=[C:8]([O:28][CH3:29])[CH:9]=2)[N:4]=1.[CH2:32]([NH:34][CH2:35][CH3:36])[CH3:33].CO>O>[CH2:32]([N:34]([CH2:2][C:3]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=2)[C:10]2[C:5](=[CH:6][C:7]([O:30][CH3:31])=[C:8]([O:28][CH3:29])[CH:9]=2)[N:4]=1)[CH2:35][CH3:36])[CH3:33]
Reactant: CCOC(=O)c1c(CCl)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Reactant: CCNCC
Solvent: O
Solvent: CO
Product: CCOC(=O)c1c(CN(CC)CC)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 11.8 %

Procedure:
A mixture of ethyl 2-chloromethyl-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinoline-3-carboxylate (4.0 g), diethylamine (1.28 g) and methanol (45 ml) was stirred at room temperature for 4 days. The reaction mixture was poured into water and extracted with dichloromethane. The dichloromethane layer was washed with water and dried over magnesium sulfate, and the solvent was evaporated. The residue was subjected to column chromatography on silica gel. The fractions eluted with ethyl acetate gave ethyl 2-(N,N-diethylaminomethyl)-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinoline-3-carboxylate (0.51 g, 18%). This compound was recrystallized from ethyl acetate-hexane. Colorless prisms, mp. 130°-131° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C@@H:6]1[CH2:10][C@@H:9]([NH:11][C:12]([C:14]2[S:15][C:16]([Cl:19])=[CH:17][CH:18]=2)=[O:13])[CH2:8][NH:7]1)=[O:5].BrC([C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]2=[O:37])=[CH:27][C:26]=1[F:38])C(N)=O>CN(C=O)C>[CH3:2][O:3][C:4]([C@@H:6]1[CH2:10][C@@H:9]([NH:11][C:12]([C:14]2[S:15][C:16]([Cl:19])=[CH:17][CH:18]=2)=[O:13])[CH2:8][N:7]1[CH2:14][C:12](=[O:13])[NH:11][C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]2=[O:37])=[CH:27][C:26]=1[F:38])=[O:5]
Reactant: NC(=O)C(Br)c1ccc(-n2ccccc2=O)cc1F
Reactant: COC(=O)[C@@H]1C[C@@H](NC(=O)c2ccc(Cl)s2)CN1
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1C[C@@H](NC(=O)c2ccc(Cl)s2)CN1CC(=O)Nc1ccc(-n2ccccc2=O)cc1F

Procedure:
11.4 Using general procedure A with DMF as solvent (2S,4R)-4-[(5-chloro-thiophene-2-carbonyl)-amino]-pyrrolidine-2-carboxylic acid methyl ester hydrochloride was reacted with 2-bromo-[2-fluoro-4-(2-oxo-pyridin-1-yl)-phenyl]-acetamide to give (2S,4R)-4-[(5-chloro-thiophene-2-carbonyl)-amino]-1-{[2-fluoro-4-(2-oxo-pyridin-1-yl)-phenylcarbamoyl]-methyl}-pyrrolidine-2-carboxylic acid methyl ester. White solid. MS 533.2 ([M+H]+)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[B:8]([OH:10])[OH:9].[C:11](Cl)(=[O:14])[CH:12]=[CH2:13]>>[C:11]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[B:8]([OH:10])[OH:9])(=[O:14])[CH:12]=[CH2:13]
Reactant: Nc1ccccc1B(O)O
Reactant: C=CC(=O)Cl
Product: C=CC(=O)Nc1ccccc1B(O)O

Procedure:
2-Acrylamido-phenylboronic acid (“2-APB”) was synthesised by reacting 2-aminophenylboronic acid with an excess of acryloyl chloride in an aqueous alkaline solution. The product was extracted in acetone and dried using a rotary evaporator. The structure of 2-APB was confirmed using NMR. The purity was shown to be greater than 90%.
Reaction SMILES: [CH3:1][O-:2].[Na+].[NH2:4][C:5]1[C:6]([F:29])=[CH:7][C:8]([F:28])=[C:9]([N:11]2[C:20]3[C:15](=[CH:16][C:17]([F:23])=[C:18](F)[C:19]=3[CH3:21])[C:14](=[O:24])[C:13]([C:25]([OH:27])=[O:26])=[CH:12]2)[CH:10]=1>C(O)(=O)C.CO>[NH2:4][C:5]1[C:6]([F:29])=[CH:7][C:8]([F:28])=[C:9]([N:11]2[C:20]3[C:15](=[CH:16][C:17]([F:23])=[C:18]([O:2][CH3:1])[C:19]=3[CH3:21])[C:14](=[O:24])[C:13]([C:25]([OH:27])=[O:26])=[CH:12]2)[CH:10]=1
Reactant: Cc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)cc3F)c12
Reactant: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1c(F)cc2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)cc3F)c2c1C
Temperature: 40 °C
Reaction time: 48 h
Yield: 80.2 %

Procedure:
Methanol (500 mg) and sodium methoxide (28% methanol solution; 200 mg) were added to 1-(5-amino-2,4-difluorophenyl)-6,7-difluoro-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (350 mg), and the mixture was heated and stirred at 40° C. for 2 days. Acetic acid (2 drops) was added to the reaction mixture to collect solids by filtration. The solids were washed with ethanol and dried to obtain the title compound (290 mg) as a pale yellow powder.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:48]=[CH:47][C:12]([CH2:13][C@H:14]([NH:35][C:36](=[O:46])[O:37][C@H:38]2[C@H:45]3[C@H:41]([O:42][CH2:43][CH2:44]3)[O:40][CH2:39]2)[C@H:15]([OH:34])[CH2:16][N:17]([CH2:30][CH:31]([CH3:33])[CH3:32])[S:18]([C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][CH:22]=2)(=[O:20])=[O:19])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(O)C.[Pt]>[NH2:27][C:24]1[CH:23]=[CH:22][C:21]([S:18]([N:17]([CH2:30][CH:31]([CH3:33])[CH3:32])[CH2:16][C@@H:15]([OH:34])[C@@H:14]([NH:35][C:36](=[O:46])[O:37][C@H:38]2[C@H:45]3[C@H:41]([O:42][CH2:43][CH2:44]3)[O:40][CH2:39]2)[CH2:13][C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:48][CH:47]=2)(=[O:19])=[O:20])=[CH:26][CH:25]=1
Reactant: [H][H]
Reactant: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)O[C@@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Pt]
Solvent: CCO
Product: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)O[C@@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc(N)cc1
Yield: 52.7 %

Procedure:
To a stirred solution of (3S,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-1-[4-(benzyloxy)benzyl]-2-hydroxy-3-{isobutyl[(4-nitrophenyl)sulfonyl]amino}propylcarbamate (0.20 g, 0.29 mmol) in 3 mL of ethanol was added 64 mg of platinum (on activated-carbon, 3%. Pt). The mixture was stirred under an atmospheric pressure of hydrogen for 12 hours. The catalyst was filtered, and the solvent was removed under reduced pressure. The residue was purified on silica gel using ethyl acetate-hexanes (4:1) as eluent to provide 0.10 g (52%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([OH:11])[C:3]=1[CH:4]=[O:5].[CH3:12][C@@H:13](O)[CH2:14][CH:15]=[CH2:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.CCOCC>[F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([O:11][C@H:15]([CH2:14][CH:13]=[CH2:12])[CH3:16])[C:3]=1[CH:4]=[O:5]
Reactant: C=CC[C@@H](C)O
Reactant: O=Cc1c(O)cc(F)cc1F
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CC[C@H](C)Oc1cc(F)cc(F)c1C=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 23.7 %

Procedure:
To a solution of 2,4-difluoro-6-hydroxybenzaldehyde (1.0 g, 6.33 mmol) in THF (14 ml) were added (R)-(−)-pent-4-en-2-ol (1.090 g, 12.65 mmol) and triphenylphosphine (2.157 g, 8.22 mmol). To this mixture was added dropwise DIAD (1.599 ml, 8.22 mmol) (exotherm) and stirred at rt. After 20 h, the mixture was diluted with Et2O and washed with 1N NaOH followed by water (3×'s) then brine, dried (Na2SO4), filtered and concentrated. The crude was purified by flash chromatography (Biotage; 0%-50% EtOAc/hexane; 10 CV) to give (S)-2,4-difluoro-6-(pent-4-en-2-yloxy)benzaldehyde (0.3394 g, 1.500 mmol, 23.72% yield) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ: 10.33 (s, 1H), 6.67-6.32 (m, 2H), 6.04-5.63 (m, 1H), 5.32-5.00 (m, 2H), 4.66-4.40 (m, 1H), 2.68-2.28 (m, 2H), 1.41 (d, J=6.1 Hz, 3H).
Reaction SMILES: [C:1]([NH:4][CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].[O-]CC.[Na+].[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:24]Br>C(O)C>[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:24][CH2:2][C:1]([NH:4][CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[O:3]
Reactant: Clc1ccc(CBr)cc1Cl
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(NC(=O)CCc1ccc(Cl)c(Cl)c1)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Diethyl acetamidomalonate (48.2 g) was dissolved in ethanol (250 ml) containing sodium ethoxide (10.2 g) and stirred at room temperature for 0.5 hours before adding 3,4-dichlorobenzyl bromide and heating at reflux for 3.5 hours. After cooling, the title compound was collected by filtration and dried under reduced pressure(36.73 g).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[S:10]([NH2:13])(=[O:12])=[O:11].[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[O:23])=[CH:17][CH:16]=1>>[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:13][S:10]([C:2]2[O:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[CH:3]=2)(=[O:11])=[O:12])=[O:23])=[CH:17][CH:16]=1
Reactant: NS(=O)(=O)c1cc2ccccc2o1
Reactant: Cc1ccc(N=C=O)cc1
Product: Cc1ccc(NC(=O)NS(=O)(=O)c2cc3ccccc3o2)cc1
Yield: 63.7 %

Procedure:
2-Benzofuransulfonamide (7.6 mmol), prepared as described in Example 2, was reacted with 4-methylphenylisocyanate (7.6 mmol) as described in Example 2 to obtain 1.6 g of the title product as a solid.
Reaction SMILES: OCC[N:4]1[C:8]2[CH:9]=[C:10]([CH3:14])[C:11]([CH3:13])=[CH:12][C:7]=2[N:6]=[CH:5]1.[NH+]1C=CC=CC=1.C([CH2:23][CH2:24][O:25][P:26](=[O:29])([O-:28])[O-:27])#N.[NH+]1C=CC=CC=1>N1C=CC=CC=1.O>[CH3:14][C:10]1[C:11]([CH3:13])=[CH:12][C:7]2[N:6]=[C:5]([CH2:23][CH2:24][O:25][P:26](=[O:27])([OH:29])[OH:28])[NH:4][C:8]=2[CH:9]=1
Reactant: Cc1cc2ncn(CCO)c2cc1C
Reactant: N#CCCOP(=O)([O-])[O-]
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: c1ccncc1
Product: Cc1cc2nc(CCOP(=O)(O)O)[nH]c2cc1C
Reaction time: 48 h

Procedure:
A 0.19 g amount of the crude 1-(2-hydroxyethyl)-5,6-dimethylbenzimidazole and 2 ml of 2-cyanoethylphosphoric acid pyridinium salt solution (1 mmol/ml) were dissolved in 20 ml of dry pyridine, and the solution was concentrated to dryness under a reduced pressure. This process was repeated twice more, and further, the dried material was thoroughly dried by a vacuum pump, dissolved in 20 ml of dry pyridine, 1.67 g of dicyclohexylcarbodiimide was added thereto, and the mixture was stored at room temperature for 2 days. After an addition of water to the product, the mixture was concentrated to dryness under a reduced pressure, followed by an addition of 40 ml of an aqueous LiOH solution (0.5 N) to carry out the reaction at 100° C. for 45 minutes. The reaction mixture was filtered to give a filtrate, which was diluted with water, adjusted to a pH of 2.5 to 3, and then the mixture was applied to an ion exchange column (Dowex 50 (hydrogen ion form)). Elution was effected successively with water and 2 N pyridine, and the fractions eluted with the latter were concentrated to dryness under a reduced pressure to give 0.27 g of crude 2-(5,6-dimethylbenzimidazolyl)ethylphosphoric acid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])[N:5]=[C:4]([NH:13][CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:3]=1.[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[CH3:10][C:9]([NH:8][C:6]1[N:5]=[C:4]([NH:13][CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:3]=[C:2]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[N:7]=1)([CH3:12])[CH3:11]
Reactant: C1CNCCN1
Reactant: CC(C)(C)CNc1cc(Cl)nc(NC(C)(C)C)n1
Product: CC(C)(C)CNc1cc(N2CCNCC2)nc(NC(C)(C)C)n1
Yield: 86 %

Procedure:
The reaction of 6-chloro-2-(1,1-dimethylethylamino)-4-(2,2-dimethylpropylamino)pyrimidine with piperazine as described in Example 5 gives the title compound in a yield of 86.0%, m.p.:120°-124° C.
Reaction SMILES: [C:1]([C:3]1[CH:50]=[CH:49][C:6]2[N:7]([CH2:36][C:37]3[C:46]4[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=4)[CH:40]=[CH:39][C:38]=3[O:47][CH3:48])[C:8](=[O:35])[C@@H:9]([NH:21][C:22](=[O:34])[C@@H:23]([N:25](C)[C:26](=O)OC(C)(C)C)[CH3:24])[C@H:10]([CH3:20])[N:11]([C:12]([CH:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[O:13])[C:5]=2[CH:4]=1)#[N:2].[ClH:51]>O1CCOCC1.CCOCC>[ClH:51].[C:1]([C:3]1[CH:50]=[CH:49][C:6]2[N:7]([CH2:36][C:37]3[C:46]4[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=4)[CH:40]=[CH:39][C:38]=3[O:47][CH3:48])[C:8](=[O:35])[C@@H:9]([NH:21][C:22](=[O:34])[C@@H:23]([NH:25][CH3:26])[CH3:24])[C@H:10]([CH3:20])[N:11]([C:12]([CH:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[O:13])[C:5]=2[CH:4]=1)#[N:2]
Reactant: COc1ccc2ccccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)[C@H](C)N(C(=O)C2CCOCC2)c2cc(C#N)ccc21
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CN[C@@H](C)C(=O)N[C@@H]1C(=O)N(Cc2c(OC)ccc3ccccc23)c2ccc(C#N)cc2N(C(=O)C2CCOCC2)[C@H]1C
Yield: 84 %

Procedure:
A rt solution of tert-butyl(S)-1-((3S,4S)-7-cyano-1-((2-methoxynaphthalen-1-yl)methyl)-4-methyl-2-oxo-5-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (75 mg, 110 μmol) in 4 M HCl in dioxane (548 μl) was stirred for 1 h. The reaction was diluted with Et2O and the solids were collected by vacuum filtration, taken up in MeCN—H2O, and lyophilized to provide (S)-N-((3S,4S)-7-cyano-1-((2-methoxynaphthalen-1-yl)methyl)-4-methyl-2-oxo-5-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-2-(methylamino)propanamide hydrochloride (57.0 mg, 84% yield) as a white solid. MS m/z 584 (MH)+.
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].C(=O)([O-])[O-].[Ca+2].[NH2:10][C:11]1[S:12][C:13]([CH3:22])=[C:14]([CH3:21])[C:15]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17]>C(Cl)(Cl)Cl.O.C(Cl)(Cl)Cl>[N:10]([C:11]1[S:12][C:13]([CH3:22])=[C:14]([CH3:21])[C:15]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:1]=[S:2]
Reactant: CCOC(=O)c1c(N)sc(C)c1C
Reactant: S=C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1c(N=C=S)sc(C)c1C
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 95.1 %

Procedure:
To a mixture of thiophosgene (5.10 mL, 7.64 mmol) and calcium carbonate (1.05 g, 10.54 mmol) in CHCl3/H2O (½ by volume, 6 mL) was added dropwise a solution of ethyl 2-amino-4,5-dimethylthiophene-3-carboxylate (1.05 g, 5.27 mmol) in CHCl3 (7 mL) at 0° C. over a period of 1 h. The reaction mixture was the stirred for 2.5 h at 0° C., washed with water (3×). The organic layer was dried over MgSO4, filtered and concentrated to give the title compound (1.21 g, 100%). 1H NMR (400 MHz, DMSO-d6) δ1.32 (t, 3H, J=7.1 Hz), 2.19 (s, 3H), 2.30 (s, 3H), 4.28 (q, 2H, J=7.1 Hz).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][CH2:11][C:12]([F:15])([F:14])[F:13])=[N:8][CH:9]=1)([O-:3])=[O:2].[C:16](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C=O)C>[CH3:16][N:10]([C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=1)[CH2:11][C:12]([F:15])([F:13])[F:14]
Reactant: O=[N+]([O-])c1ccc(NCC(F)(F)F)nc1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN(CC(F)(F)F)c1ccc([N+](=O)[O-])cn1
Temperature: 50 °C
Yield: 110.4 %

Procedure:
A mixture of (5-nitro-pyridin-2-yl)-(2,2,2-trifluoro-ethyl)-amine (230 mg, 1.04 mmol), cesium carbonate (730 mg, 2.07 mmol) and iodomethane (0.59 mL, 4.18 mmol) in DMF (4 mL) was heated in a sealed tube at 50° C. for 3 hr. The reaction mixture was evaporated to dryness and the crude was partitioned between methylene chloride and water. The organic layer was dried over magnesium sulfate, filtered and concentrated to give methyl-(5-nitro-pyridin-2-yl)-(2,2,2-trifluoro-ethyl)-amine (270 mg, crude) as a brown solid, which was directly used in the next step reaction without further purification. LCMS calcd for C8H8F3N3O2 (m/e) 235, obsd 236 (M+H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([CH2:14][OH:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:25]N(C)P(=O)(N(C)C)N(C)C.CI>O>[CH2:1]([N:8]1[CH2:9][CH2:10][C:11]([CH2:14][O:15][CH3:25])([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Reactant: OCC1(Nc2ccccc2)CCN(Cc2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: COCC1(Nc2ccccc2)CCN(Cc2ccccc2)CC1

Procedure:
A mixture of 72.5 g of 1-benzyl-4-anilino-4-piperidinemethanol, 11 g of sodium hydride (50% in mineral oil) and 427 g of hexamethylphosphoric triamide is stirred. Then 33 g of methyl iodide is added dropwise to the reaction mixture and the mixture is stirred overnight. The mixture is added to 2500 ml of water, extracted with six 500 ml portions of toluene, dried over anhydrous sodium sulfate and flash evaporated to give an oil. The oil is purified in a Waters Associates Prep LC/System 500, using a PrepPAK-500/SILICA column (40% ethyl acetate in hexane) to give 1-benzyl-4-methoxymethyl-4-anilinopiperidine.
Reaction SMILES: Cl.Cl[CH:3]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[Cl:17])[CH2:4][N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1.[O:18]([CH2:22][CH3:23])[C:19]([S-:21])=[S:20].[K+]>C(O)C>[Cl:17][C:11]1[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:10]=1[CH:3]([S:21][C:19]([O:18][CH2:22][CH3:23])=[S:20])[CH2:4][N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1
Reactant: Clc1ccc(C(Cl)Cn2ccnc2)c(Cl)c1
Reactant: CCOC(=S)[S-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: CCOC(=S)SC(Cn1ccnc1)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Twenty grams of 1-(β, 2,4-trichlorophenethyl)imidazole hydrochloride was added to 300 milliliters (ml) of absolute ethanol and 25 grams of anhydrous potassium ethyl xanthate. The mixture was stirred at room temperature for about 3 days until the reaction was complete as indicated by thin layer chromatography. The solvent was removed, water added and the product extracted with ether. The extracts were washed with water, dried over magnesium sulfate and the ether evaporated. The resulting oil was purified by chromatography on silicia gel eluting with 15% acetone in dichloromethane. The resulting oil was then dissolved in ether and an ethereal solution of oxalic acid was added dropwise until precipitation was complete. Recrystallization of the precipitate from acetone provides the oxalate salt of 1-[2,4-dichloro-β-(ethoxythiocarbonylthio)phenethyl]imidazole as a white solid having a melting point of 122.5°-124° C. (foaming).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][NH2:9])[CH:5]=[CH:6][CH:7]=1.[CH:10](=O)[CH2:11][CH2:12][CH3:13]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[CH2:8][NH:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCC=O
Reactant: NCc1cccc(Cl)c1
Product: CCCCNCc1cccc(Cl)c1
Yield: 31.6 %

Procedure:
Following a procedure analogous to that for the synthesis of Example 106, (3-chlorophenyl)methanamine (750 mg, 5.30 mmol) and butyraldehyde (480 μL, 5.30 mmol) were converted to the title compound (331 mg, 32%). 1H NMR (CDCl3) δ 7.64-7.55 (m, 2H), 7.44-7.33 (m, 2H), 4.02 (s, 2H), 2.84-2.72 (m, 2H), 1.84 (td, J=7.8, 15.8 Hz, 2H), 1.38 (sxt, J=7.5 Hz, 2H), 0.91 (t, J=7.4 Hz, 3H); MS(ESI+) m/z 198.1 (M+H)+.
Reaction SMILES: [C:1]1([C@H:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][CH2:9][NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19].C1(C)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:22][CH:21]([O:20][C:18]([N:8]1[CH2:9][CH2:10][C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C@@H:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:19])[CH3:23]
Reactant: CC(C)OC(=O)Cl
Reactant: c1ccc([C@@H]2NCCc3ccccc32)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)OC(=O)N1CCc2ccccc2[C@@H]1c1ccccc1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
A 15.00 g portion of (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline and 9.22 g of isopropyl chloroformate were added to a mixture of 75 ml of toluene, 10.43 g of potassium carbonate and 45 ml of water and stirred at 20° C. for 2 hours, and then the organic layer was washed with 50 ml of water. The thus obtained organic layer was concentrated under a reduced pressure and then dried to obtain 21.71 g of (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid propan-2-yl ester (1H-NMR (DMSO-d6, tetramethylsilane internal standard, 80° C.): δ 1.18 (3H, d, J=6.4 Hz), 1.22 (3H, d, J=6.4 Hz), 2.73-2.93 (2H, m), 3.25-3.34 (1H, m), 3.83-3.92 (1H, m), 4.80-4.91 (1H, m), 6.22 (1H, s), 7.06-7.33 (9H, m), mass spectrum: m/z=296 [M +H]+ (FAB)).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][C:11]2([O:13][CH2:12]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].B(F)(F)[F:17].CCOCC>[OH-].[Na+]>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][C:11]([F:17])([CH2:12][OH:13])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: FB(F)F
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CO2
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(F)(CO)CC1
Reaction time: 1 h

Procedure:
A mixed solution of 6-aza-1-oxaspiro[2.5]octane-6-carboxylic acid tert-butyl ester (10.0 g, 46.9 mmol) in benzene-ether (2:1) (750 mL) was cooled to 0° C., and after adding BF3.OEt2 (29.6 mL, 234 mmol) to the solution, it was stirred 1 hour. The reaction mixture was poured into ice-cooled 1N NaOH (500 ml) and stirred. After extraction with AcOEt (500 ml×3 times), the extract was washed with water and then with saturated brine, and finally dried over anhydrous MgSO4. The solvent was distilled off, and the crude product was purified by silica gel column chromatography (30% AcOEt/hexane) to obtain 4-fluoro-4-(hydroxymethyl)piperidinecarboxylic acid tert-butyl ester. The compound was identified by 1H-NMR. The yield was 4.26 g (39%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH2:20])[N:3]=1.B([C:24]1[CH:35]=[CH:34][C:27]([CH2:28][C@@H:29]([C:31]([OH:33])=[O:32])[NH2:30])=[CH:26][CH:25]=1)(O)O.C(#N)C.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[NH2:30][CH:29]([CH2:28][C:27]1[CH:34]=[CH:35][C:24]([C:2]2[N:3]=[C:4]([NH2:20])[N:5]=[C:6]([O:8][CH:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:10]([F:13])([F:12])[F:11])[N:7]=2)=[CH:25][CH:26]=1)[C:31]([OH:33])=[O:32]
Reactant: N[C@@H](Cc1ccc(B(O)O)cc1)C(=O)O
Reactant: Nc1nc(Cl)nc(OC(c2ccccc2)C(F)(F)F)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Nc1nc(OC(c2ccccc2)C(F)(F)F)nc(-c2ccc(CC(N)C(=O)O)cc2)n1
Temperature: 150 °C
Yield: 7.4 %

Procedure:
A microwave vial was charged with 4-chloro-6-[2,2,2-trifluoro-1-phenyl-ethoxy]-[1,3,5]triazine-2-ylamine (33 mg, 0.1 mmol), 4-borono-L-phenylalanine (31 mg, 0.15 mmol), 1 ml of actonitrile, and 0.7 ml of water. Aqueous sodium carbonate (0.3 ml, 1M) was added to above solution followed by 5 mol percent dichlorobis(triphenylphosphine)-palladium(II). The reaction vessel was sealed and heated to 150° C. for 5 minutes by microwave. After cooling, the reaction mixture was evaporated to dryness. The residue was dissolved in 2.5 ml of methanol, was then purified with Prep-LC to give 3.2 mg 2-amino-3-{4-[4-amino-6-(1-phenyl-2,2,2-trifluoro-ethoxy]-[1,3,5]triazin-2-yl]-phenyl)-propionic acid. 1H NMR (300 MHz, CD3OD) δ 8.22 (d, J=8.20 Hz, 2H), 7.52 (m, 2 H), 7.33 (m, 5H) 6.62 (m, 1H), 4.19 (t, 1 H), 3.1-3.33 (m, 2 H).
Reaction SMILES: [NH:1]1[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Cl[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]>C(OCC)C>[C:11]([N:1]1[CH2:3][CH2:2]1)([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]
Reactant: C1CN1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Product: O=C(OCc1ccccc1)N1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred, distilled aziridine solution (500 m, 0.1 mol) in a round-bottom flask cooling with an ice bath, three equivalents of potassium carbonate was added. After all of the solid dissolved, benzyl chloroformate (1.5 equivalents) in ethyl ether (150 mL) was added over 2 h. The solution was stirred overnight and warmed to room temperature, and the aqueous phase was extracted with methylene chloride (5×30 mL). The organic phases were combined and passed through a flash silica gel pad and concentrated to afford the Cbz-aziridine as colorless thick oil, yield: 7.2 g, 81%.