Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([CH3:16])=[N:4][N:5]([CH3:15])[C:6]=1[C:7]1[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:8]=1[F:14].C([Li])CCC.[F:22][C:23]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:24]=1[CH:25]=[O:26]>O1CCCC1.[Cl-].[NH4+]>[F:22][C:23]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:24]=1[CH:25]([C:2]1[C:3]([CH3:16])=[N:4][N:5]([CH3:15])[C:6]=1[C:7]1[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:8]=1[F:14])[OH:26]
Reactant: Cc1nn(C)c(-c2c(F)cccc2F)c1Br
Reactant: O=Cc1ccc(F)cc1F
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1nn(C)c(-c2c(F)cccc2F)c1C(O)c1ccc(F)cc1F
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To a mixture of 4-bromo-5-(2,6-difluorophenyl)-1,3-dimethyl-1H-pyrazole (i.e. the product of Step C) (500 mg, 1.7 mmol) in tetrahydrofuran (15 mL) at −78° C. was added dropwise n-butyllithium (2.0 M in hexanes, 0.76 mL, 1.9 mmol). The reaction mixture was stirred at −78° C. for about 20 minutes, and then a solution of 2,4-difluorobenzaldehyde (153 μL, 1.4 mmol) in tetrahydrofuran (1 mL) was added dropwise. After the addition was complete, the reaction mixture was stirred at about −78° C. for about 15 minutes, and then diluted with saturated aqueous ammonium chloride solution (1 mL) and allowed to warm to room temperature. The resulting mixture was poured onto a solid phase extraction tube (Varian Chem Elute®, prepacked with diatomaceous earth) eluting with ethyl acetate (50 mL). The ethyl acetate eluant was concentrated under reduced pressure and the resulting material was purified by MPLC (20 to 50% gradient of ethyl acetate in hexanes as eluant) to provide the title compound, a compound of the present invention, as a solid (560 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([OH:12])[CH:11]=1)[C:5]([NH:7][NH2:8])=[O:6].[N:13]#[C:14]Br.C(=O)(O)[O-].[Na+].CCCCCC>O1CCOCC1>[NH2:13][C:14]1[O:6][C:5]([C:4]2[CH:9]=[C:10]([OH:12])[CH:11]=[C:2]([Br:1])[CH:3]=2)=[N:7][N:8]=1
Reactant: N#CBr
Reactant: NNC(=O)c1cc(O)cc(Br)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCCCCC
Product: Nc1nnc(-c2cc(O)cc(Br)c2)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.3 %

Procedure:
3-Bromo-5-hydroxybenzohydrazide (400 mg, 1.04 mmol) was suspended in 5 ml dioxane. Cyanogen bromide (110 mg, 1.04 mmol) and sodium bicarbonate (4%, 1 ml, 12 mmol) were added and the reaction was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and re-dissolved in ethyl acetate. The organic was washed with water, brine and dried over sodium sulphate, filtered and evaporated under reduced pressure. The oil obtained was precipitate with hexane and filtered to give 126 mg (43% yield) of the title compound. Purity 90%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7](O)=[O:8].ON1C(=O)CCC1=O.Cl.C(N=C=NCCCN(C)C)C.Cl.[CH3:32][NH:33][O:34][CH3:35]>C(#N)C.C(N(CC)CC)C>[CH3:32][N:33]([O:34][CH3:35])[C:7]([C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Br:1])[CH:10]=1)=[O:8]
Reactant: O=C(O)c1cncc(Br)c1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1cncc(Br)c1
Reaction time: 0.5 h
Yield: 61.2 %

Procedure:
To a suspension of 5-bromonicotinic acid (5.0 g) and N-hydroxysuccinimide (4.27 g) in acetonitrile (60 ml) was added 1-ethyl-3—(3′-dimethylaminopropyl)carbodiimide hydrochloride (7.12 g) at room temperature, and the mixture was stirred for 30 minutes. To the reaction mixture were added N,O-dimethyl-hydroxylamine hydrochloride (2.66 g) and triethylamine (10 ml), and the mixture was stirred for 64 hours and concentrated under reduced pressure. To the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified with column chromatography (ethyl acetate/hexane=2:1) to give N-methyl-N-methoxy-5-bromopyridine-3-carboxamide (3.71 g) as pale yellow oil.
Reaction SMILES: [CH:1](=O)[CH3:2].[NH:4]1[CH2:9][CH2:8][CH:7]([NH:10]C(=O)OC(C)(C)C)[CH2:6][CH2:5]1>>[CH2:9]([N:4]1[CH2:2][CH2:1][CH:7]([NH2:10])[CH2:6][CH2:5]1)[CH3:8]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: CC=O
Product: CCN1CCC(N)CC1

Procedure:
Synthesized according to the method of reagent preparation 9 by using acetaldehyde and 1,1-dimethylethyl piperidin-4-ylcarbamate. MS (EI) for C7H16N2: 131 (MH+).
Reaction SMILES: [O:1]=[C:2]1[N:6]2[CH2:7][CH2:8][N:9]([C:11]([NH:13][CH2:14][C:15]3[CH:16]=[C:17]([CH2:21][NH:22]C(=O)OC(C)(C)C)[CH:18]=[CH:19][CH:20]=3)=[O:12])[CH2:10][CH:5]2[C:4]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:3]1.[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45].C(OC(C)C)(C)C>>[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45].[NH2:22][CH2:21][C:17]1[CH:16]=[C:15]([CH2:14][NH:13][C:11]([N:9]2[CH2:8][CH2:7][N:6]3[C:2](=[O:1])[O:3][C:4]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH:5]3[CH2:10]2)=[O:12])[CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)NCc1cccc(CNC(=O)N2CCN3C(=O)OC(c4ccccc4)(c4ccccc4)C3C2)c1
Solvent: CC(C)OC(C)C
Solvent: O=C(O)C(F)(F)F
Product: NCc1cccc(CNC(=O)N2CCN3C(=O)OC(c4ccccc4)(c4ccccc4)C3C2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
To 1,1-dimethylethyl [[3-[[[(tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo[3,4-a]pyrazin-7(1H)-yl)carbonyl]amino]methyl]phenyl]methyl]carbamate (0.12 g, 0.22 mmol) was added trifluoroacetic acid (1.5 mL), and the mixture was stirred at room temperature for 2 hours. To the reaction solution was added diisopropyl ether, the precipitated powder was collected by filtration and dried to obtain the title compound (0.11 g, yield 84%).
Reaction SMILES: [N:1]1([N:7]2[NH:11][CH:10]=[C:9]([C:12]3[N:13]([CH3:20])[C:14]([N+:17]([O-:19])=[O:18])=[CH:15][N:16]=3)[S:8]2)[CH2:6][CH2:5]C[CH2:3][CH2:2]1.[NH:21]1CCNCC1.N1CCCCC1>>[N:1]1([N:7]2[NH:11][CH:10]=[C:9]([C:12]3[N:13]([CH3:20])[C:14]([N+:17]([O-:19])=[O:18])=[CH:15][N:16]=3)[S:8]2)[CH2:6][CH2:5][NH:21][CH2:3][CH2:2]1
Reactant: C1CNCCN1
Reactant: Cn1c([N+](=O)[O-])cnc1C1=CNN(N2CCCCC2)S1
Solvent: C1CCNCC1
Product: Cn1c([N+](=O)[O-])cnc1C1=CNN(N2CCNCC2)S1

Procedure:
The preparation of the subject compound is carried out essentially as described for the 2-piperidino derivative (Example 28), two equivalents of piperazine replacing the piperidine. The crude product is recrystallized from 2-methoxyethanol to yield the pure compound melting at 240°-241° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:42])=[C:5]([C:38]([O:40][CH3:41])=[O:39])[CH:6]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([N+:35]([O-:37])=[O:36])[CH:30]=2)[C:7]=1[C:8]([O:10][CH2:11][C:12]([CH3:28])([CH3:27])[CH2:13][N:14]1[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]1)=[O:9].Cl.C(OC(C)C)(C)C>C(O)C>[CH3:1][C:2]1[NH:3][C:4]([CH3:42])=[C:5]([C:38]([O:40][CH3:41])=[O:39])[CH:6]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([N+:35]([O-:37])=[O:36])[CH:30]=2)[C:7]=1[C:8]([O:10][CH2:11][C:12]([CH3:27])([CH3:28])[CH2:13][N:14]1[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]1)=[O:9]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCC(C)(C)CN2CCN(C(=O)OC(C)(C)C)CC2)C1c1cccc([N+](=O)[O-])c1
Agent: Cl
Solvent: CCO
Solvent: CC(C)OC(C)C
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCC(C)(C)CN2CCNCC2)C1c1cccc([N+](=O)[O-])c1
Reaction time: 1 h
Yield: 43.5 %

Procedure:
9.7 g of 3-[4-(tert-butyloxycarbonyl)-1-piperazinyl]-2,2-dimethylpropyl methyl 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate was dissolved in ethanol and 50 ml of an ethanol solution of 9.9N hydrogen chloride was added under cooling with ice. After stirring the mixed solution for 1 hour under cooling with ice, isopropyl ether was added. The solid which separated was collected by filtration, dissolved in saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The solvent was evaporated under reduced pressure and acetone was added to the residue. The crystal which separated was collected by filtration to give 3.5 g of the subject compound (yield: 43%). The IR and NMR data of the compound thus obtained are as follows: ##STR63##
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[C:18]([O:20][CH3:21])=[O:19].Br[CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.Cl>CN(C=O)C>[CH3:21][O:20][C:18]([C:9]1[CH:10]=[CH:11][C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]=1[O:7][CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:19]
Reactant: COC(=O)c1ccc2ccccc2c1O
Reactant: BrCCOc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2ccccc2c1OCCOc1ccccc1
Yield: 85.1 %

Procedure:
To 22.81 g cesium carbonate and 7.08 g methyl 1-hydroxy-2-naphthoate in 70 ml abs. DMF was added 7.39 g (2-bromo-ethoxy)-benzene and the mixture was reacted for 16 h at 80° C. The reaction was poured unto ice, neutralized with 2 M hydrochloric acid, and extracted with ethyl acetate twice. The combined organic phases were washed with brine, dried over magnesium sulphate and concentrated in vacuo. The resulting residue was purified by crystallization from pentane to yield 9.60 g of 1-(2-phenoxy-ethoxy)-naphthalene-2-carboxylic acid methyl ester.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C:22]#[N:23])[CH2:13][CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+].[N-:26]=[N+:27]=[N-:28].[Na+]>CN(C=O)C>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C:22]1[NH:28][N:27]=[N:26][N:23]=1)[CH2:13][CH2:14][C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)CC[C@H](C#N)NC(=O)OCc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CC[C@@H](NC(=O)OCc1ccccc1)c1nnn[nH]1
Yield: 84.3 %

Procedure:
A mixture of tert-butyl (4R)-4-(benzyloxycarbonylamino)-4-cyanobutyrate (1.53 g, 4.8 mmol), ammonium chloride (0.28 g, 5.2 mmol), sodium azide (0.345 g, 5.3 mmol) and dry DMF (6 ml) was stirred and heated at 90°-95° C. under argon for 20 hours. The mixture was cooled and concentrated and the residue partitioned between ice-cooled water (40 ml) and ethyl acetate (30 ml) with the pH of the aqueous phase being adjusted to 3 by the addition of 10% aqueous citric acid solution (ca. 10 ml). The aqueous layer was extracted with further ethyl acetate (3×30 ml) and the combined organic solution washed with water (4×25 ml), dried (MgSO4) and evaporated. A solution of the residue in dichloromethane (3 ml) was added dropwise to stirred hexane (20 ml) and the precipitate was collected, washed with hexane and dried to give tert-butyl (4R)-4-(benzyloxycarbonylamino)-4-(tetrazol-5-yl)butyrate (1.462 g, 84%), m.p. 99°-101° C.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][C:5]=1[OH:18])=[O:3].Cl[CH:20]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O>[C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][C:5]=1[O:18][CH:20]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])(=[O:3])[CH3:1]
Reactant: CC(=O)c1ccc(OCc2ccccc2)cc1O
Reactant: CCOC(=O)CCC(Cl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCC(Oc1cc(OCc2ccccc2)ccc1C(C)=O)c1ccccc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 34.1 %

Procedure:
A mixture of 4-benzyloxy-2-hydroxyaceto-phenone (1.2 g), ethyl (RS)-4-chloro-4-phenyl-butanoate (1.21 g), potassium carbonate (760 mg), potassium iodide (35 mg) and dimethylformamide (30 mL) is stirred at 100° C. for 8 hours. It is evaporated to dryness and the resulting residue is partitioned between ethyl acetate (200 mL) and water (200 mL). The organic layer is dried over magnesium sulphate, filtered and concentrated in vacuo. Flash chromatography of the resulting oil, eluting with 15-30% ethyl acetate/hexane, affords ethyl (RS)-4-(2-acetyl-5-benzyloxy-phenoxy)-4-phenylbutanoate (0.73 g), in the form of a yellow oil.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:13][N:14]([C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH:39]([CH3:41])[CH3:40])=[CH:34][CH:33]=2)=[CH:28][CH:27]=1)[C:15]([CH:17]1[CH2:19][CH:18]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)=[O:16])[C@@H:9]([CH3:12])[CH2:10][CH3:11])(C)(C)C.ClCCl.Cl>O1CCOCC1>[NH2:7][C@@H:8]([C@@H:9]([CH3:12])[CH2:10][CH3:11])[CH2:13][N:14]([C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:33]=[CH:34][C:35]([O:38][CH:39]([CH3:40])[CH3:41])=[CH:36][CH:37]=2)=[CH:28][CH:27]=1)[C:15]([C@@H:17]1[CH2:19][C@H:18]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)=[O:16]
Reactant: CC[C@H](C)[C@@H](CN(C(=O)C1CC1c1ccccn1)c1ccc(-c2ccc(OC(C)C)cc2)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC[C@H](C)[C@H](N)CN(C(=O)[C@@H]1C[C@H]1c1ccccn1)c1ccc(-c2ccc(OC(C)C)cc2)cc1
Temperature: 25 °C
Yield: 95.9 %

Procedure:
A solution of ((1S,2S)-1-{[(4′-isopropoxy-biphenyl-4-yl)-(2-pyridin-2-yl-cyclopropanecarbonyl)-amino]-methyl}-2-methyl-butyl)-carbamic acid tert-butyl ester (48 mg, 0.084 mmol) and dichloromethane (4 mL) was treated with a solution of HCl in dioxane (4 N, 0.5 mL) and the resulting reaction mixture was maintained at room temperature for 12 h. The reaction was then concentrated to dryness to afford (1R,2R)-2-pyridin-2-yl-cyclopropanecarboxylic acid ((2S,3S)-2-amino-3-methyl-pentyl)-(4′-isopropoxy-biphenyl-4-yl)-amide (38 mg, 95% yield) as a white solid: 1H NMR (400 MHz, MeOD) δ 8.34 (d, J=5.3 Hz, 1H), 7.95 (t, J=7.6 Hz, 1H), 7.55 (d, J=8.1 Hz, 2H), 7.38-7.45 (m, 3H), 7.29-7.37 (m, 3H), 6.88 (d, J=8.6 Hz, 2H), 4.54 (dt, J=12.1, 6.1 Hz, 1H), 4.22 (dd, J=15.0, 9.0 Hz, 1H), 3.65 (dd, J=15.0, 2.7 Hz, 1H), 3.23-3.30 (m, 1H), 2.66-2.76 (m, 1H), 1.99-2.06 (m, 1H), 1.72-1.80 (m, 1H), 1.63-1.71 (m, 1H), 1.45-1.54 (m, 1H), 1.26-1.36 (m, 1H), 1.24 (d, J=6.1 Hz, 6H), 1.05-1.17 (m, 1H), 0.88 (d, J=6.8 Hz, 3H), 0.75 (t, 3H); LRMS (ESI) m/e 472.3 [(M+H)+, calcd for C30H38N3O2 472.3].
Reaction SMILES: C[O:2][C:3](=[O:30])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[CH:8][C:9]2[O:27][C:13]3([CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:15][CH2:14]3)[NH:12][C:11](=[O:28])[C:10]=2[CH:29]=1.[OH-].[Na+].Cl>O1CCOCC1.O>[C:21]1([CH2:20][CH2:19][N:16]2[CH2:15][CH2:14][C:13]3([NH:12][C:11](=[O:28])[C:10]4[CH:29]=[C:6](/[CH:5]=[CH:4]/[C:3]([OH:30])=[O:2])[CH:7]=[CH:8][C:9]=4[O:27]3)[CH2:18][CH2:17]2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)NC1(CCN(CCc3ccccc3)CC1)O2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)/C=C/c1ccc2c(c1)C(=O)NC1(CCN(CCc3ccccc3)CC1)O2
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.9 %

Procedure:
(E)-3-{1′-(2-Phenyl-ethyl)-3,4-dihydro-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4′-piperidin]-6-yl}-acrylic acid methyl ester (292 mg, 0.719 mmol) was suspended in dioxane (5 ml) and water (5 ml). 1 M NaOH (0.93 ml) was added and the resulting mixture was stirred overnight at RT. The mixture was neutralized with 1 M HCl and concentrated under vacuum. The pH was brought to 4 with 1 M HCl and the resulting solid was decanted and dried to give (E)-3-{1′-(2-phenyl-ethyl)-3,4-dihydro-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4′-piperidin]-6-yl}-acrylic acid (265 mg).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[C:9]([CH3:18])[CH:8]=1.C[O:20][B:21](C)[O:22]C.Cl>CCCCCC.C1COCC1>[CH3:18][C:9]1[CH:8]=[C:7]([B:21]([OH:22])[OH:20])[CH:12]=[CH:11][C:10]=1[O:13][C:14]([F:17])([F:16])[F:15]
Reactant: COB(C)OC
Reactant: Cc1cc(Br)ccc1OC(F)(F)F
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1cc(B(O)O)ccc1OC(F)(F)F
Temperature: -78 °C
Reaction time: 2 h

Procedure:
At −78° C., 8.5 ml (1.4 g, 21.1 mmol) of a 2.5M solution of n-butyllithium in hexane were initially charged in 30 ml of THF. 4.9 g (19.2 mmol) of 4-bromo-2-methyl(trifluoromethoxy)benzene were dissolved in 15 ml of THF and slowly added dropwise. 3.0 g (28.8 mmol) of trimethylboronic acid were then added dropwise. The mixture was stirred at −78° C. for 2 h, and 11 ml of 2 N hydrochloric acid were then added. The mixture was allowed to warm to RT, and the organic phase was separated off. The solvent was removed under reduced pressure and the residue was recrystallized from n-heptane. Yield: 3.3 g (78% of theory)
Reaction SMILES: [B-](F)(F)(F)F.[K+].[O:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1>S(=O)(=O)(O)O>[CH3:8][CH2:9][CH2:10][CH2:11][O:7][C@H:10]([CH2:11][OH:7])[CH2:9][CH3:8]
Reactant: C1CCOC1
Agent: F[B-](F)(F)F
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCCCO[C@@H](CC)CO
Temperature: 10 °C

Procedure:
In the same reaction apparatus as in Example 1, a solution prepared by dissolving 0.82 g of potassium borofluoride in 105 g of 25% fuming sulfuric acid was drowpise added to 500 g of tetrahydrofuran at -10° C. over a period of 40 minutes, and thereafter the mixture was subjected to reaction at -10° C. for one hour. The tetrahydrofuran conversion at the end of this reaction was 38%. Then, the reaction mixture was heated to 10° C. and further subjected to reaction for 2 hours. The conversion at the end of this reaction was 60%. Neither solidification nor coloration of the reaction system was observed in the entire course of the reaction. The polymerization product was then treated in the same manner as in Example 1 to obtain colorless PTMG. Its analytical results and the catalytic efficiency α were as shown in Table 1.
Reaction SMILES: C[O:2][C:3](=[O:23])[C@H:4]([CH2:15][C:16]1(C)[CH:21]=[CH:20][CH:19]=[CH:18][CH2:17]1)[NH:5][C:6]([O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7].[CH3:24]O.[OH-].[Na+].S(=O)(=O)(O)O>O>[CH3:24][C:9]1([O:8][C:6]([NH:5][C@H:4]([C:3]([OH:2])=[O:23])[CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:7])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: CO
Reactant: COC(=O)[C@H](CC1(C)C=CC=CC1)NC(=O)OC1CCCCC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1(OC(=O)N[C@@H](Cc2ccccc2)C(=O)O)CCCCC1
Temperature: 25 °C
Reaction time: 46 h

Procedure:
Saponification of the above ester is accomplished by dissolving the oil in 10 ml. of methanol; 10 ml. of water is added and the pH of the mixture adjusted to 12 by addition of 1 N sodium hydroxide. The reaction is allowed to stir for 46 hours at 25°C. The pH of the reaction is adjusted to 7 by addition of 2 N sulfuric acid. The methanol solvent is removed in vacuo, saturated sodium bicarbonate is added to the residual aqueous solution, and then washed twice with ether. The reaction mixture is acidified by dropwise addition of concentrated sulfuric acid to pH 3.0, extracted three times with ethyl acetate, wash the combined organic layers twice with sodium chloride solution and dry over sodium sulfate. After removing the solvent in vacuo, 758 mg. of substantially pure N-(1-methylcyclohexyloxycarbonyl)-phenylalanine is obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:20])[N:4]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:5](=[O:10])[N:6]([CH3:9])[C:7]=1[NH2:8].[F:21][C:22]([F:35])([F:34])[O:23][C:24]1[CH:25]=[C:26]([CH2:30][C:31](O)=[O:32])[CH:27]=[CH:28][CH:29]=1.CCN=C=NCCCN(C)C>C(O)C.O>[NH2:8][C:7]1[N:6]([CH3:9])[C:5](=[O:10])[N:4]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:3](=[O:20])[C:2]=1[NH:1][C:31](=[O:32])[CH2:30][C:26]1[CH:27]=[CH:28][CH:29]=[C:24]([O:23][C:22]([F:34])([F:21])[F:35])[CH:25]=1
Reactant: O=C(O)Cc1cccc(OC(F)(F)F)c1
Reactant: COc1ccc(Cn2c(=O)c(N)c(N)n(C)c2=O)cc1
Agent: CCN=C=NCCCN(C)C
Solvent: CCO
Solvent: O
Product: COc1ccc(Cn2c(=O)c(NC(=O)Cc3cccc(OC(F)(F)F)c3)c(N)n(C)c2=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.8 %

Procedure:
To a solution of 5,6-diamino-3-(4-methoxybenzyl)-1-methylpyrimidine-2,4(1H,3H)-dione (50 mg, 0.181 mmol, intermediate 59) in ethanol (3 ml) was added 2-(3-(trifluoromethoxy)phenyl)acetic acid (40 mg, 0.181 mmol) and EDCI (52 mg, 0.271 mmol) The mixture was stirred at room temperature for 2 h. The reaction was diluted with water, filtered and the solids were rinsed with water. The solid residue was dissolved in ethyl acetate, dried over sodium sulfate, filtered and concentrated to give N-(6-amino-3-(4-methoxybenzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-2-(3-(trifluoromethoxy)phenyl)acetamide (70 mg, 80.1%) as light gray solid. LCMS retention time 1.239 min; LCMS MH+ 479.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=O)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:14][C:15]1[CH:16]=[C:17]([NH:22][C:23](=[O:32])[CH2:24][CH2:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[CH:18]=[CH:19][C:20]=1[CH3:21]>>[CH:26]1([CH2:25][CH2:24][C:23]([NH:22][C:17]2[CH:18]=[CH:19][C:20]([CH3:21])=[C:15]([NH:14][C:11]([C:7]3[CH:6]=[C:5]4[C:10](=[CH:9][CH:8]=3)[N:1]=[CH:2][CH:3]=[CH:4]4)=[O:13])[CH:16]=2)=[O:32])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: O=C(O)c1ccc2ncccc2c1
Reactant: Cc1ccc(NC(=O)CCC2CCCCC2)cc1N
Product: Cc1ccc(NC(=O)CCC2CCCCC2)cc1NC(=O)c1ccc2ncccc2c1

Procedure:
Using an analogous procedure to that described in Example 5, quinoline-6-carboxylic acid was reacted with N-(3-amino-4-methylphenyl)-3-cyclohexylpropionamide to give the title compound; NMR Spectrum: (DMSOd6) 0.76-1.28 (m, 6H), 1.42-1.78 (m, 7H), 2.2 (s, 3H), 2.28 (t, 2H), 7.17 (d, 1H), 7.39 (d, 1H), 7.6 (m, 1H)), 7.69 (s, 1H), 8.12 (d, 1H), 8.24 (d, 1H), 8.49 (d, 1H), 8.63 (s, 1H), 9.0 (m, 1H), 9.82 (s, 1H), 10.09 (s, 1H); Mass Spectrum: M+H+ 437.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].ClS([N:17]=[C:18]=O)(=O)=O.C(N(CC)CC)C>C(#N)C>[N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:18]#[N:17])=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2cc[nH]c2c1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: N#Cc1c[nH]c2cc([N+](=O)[O-])ccc12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
6.1 g 6-nitro-1H-indole are dissolved in 100 ml acetonitrile and cooled to 0° C. A solution of 3.2 ml chlorosulphonyl isocyanate in 25 ml acetonitrile is added dropwise and the mixture is stirred for 2 hours. Then a solution of 5 ml triethylamine in 25 ml acetonitrile is added dropwise. The mixture is stirred for 1 hour at ambient temperature and for 50 minutes at 80° C. Then the solvents are eliminated in vacuo, the residue is extracted from cold water, the solid is suction filtered and washed successively with water, saturated sodium hydrogen carbonate solution and water. The solid thus obtained is dried in the desiccator. Then the solid is taken up in 500 ml dichloromethane/methanol 95:5 and stirred with some aluminium oxide. It is suction filtered through a thin layer of aluminium oxide and washed with 400 ml dichloromethane/methanol 95:5. The filtrate is evaporated down in vacuo and the residue is dried in vacuo.