Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH3:11][N:12]1[CH:16]=[CH:15][N:14]=[C:13]1/[CH:17]=[CH:18]/[C:19]1[C:27]2[C:22](=[CH:23][C:24]([CH:28]=O)=[CH:25][CH:26]=2)[N:21]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[N:20]=1>>[CH3:11][N:12]1[CH:16]=[CH:15][N:14]=[C:13]1/[CH:17]=[CH:18]/[C:19]1[C:27]2[C:22](=[CH:23][C:24](/[CH:28]=[C:3]3/[C:2](=[O:10])[NH:1][C:9]4[C:4]/3=[CH:5][CH:6]=[CH:7][CH:8]=4)=[CH:25][CH:26]=2)[N:21]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:35])[CH3:36])[N:20]=1
Reactant: O=C1Cc2ccccc2N1
Reactant: Cn1ccnc1/C=C/c1nn(COCC[Si](C)(C)C)c2cc(C=O)ccc12
Product: Cn1ccnc1/C=C/c1nn(COCC[Si](C)(C)C)c2cc(/C=C3/C(=O)Nc4ccccc43)ccc12

Procedure:
Synthesized according to the method of Example A19, utilizing indolin-2-one (14.5 mg, 0.11 mmol) and (E)-3-(2-(1-methyl-1H-imidazol-2-yl)vinyl)-1-((2-(trimethylsilyl)-ethoxy)methyl)-1H-indazole-6-carbaldehyde (41.6 mg, 0.11 mmol). The crude mixture was concentrated under reduced pressure and purified by prepTLC (SiO2 10% MeOH/DCM) to provide the title compound to as a yellow material (35.4 mg, 65%); MS ESI 498.4 [M+H]+, calcd for [C28H31N5O2Si+H]+ 498.7.
Reaction SMILES: [Cl:1][C:2]([F:10])([F:9])[C:3](=[O:8])[CH2:4][C:5](=[O:7])[CH3:6].[CH:11]([O-])([O-])[O:12][CH2:13][CH3:14].C(OC(=O)C)(=O)C>O>[Cl:1][C:2]([F:10])([F:9])[C:3](=[O:8])[C:4](=[CH:11][O:12][CH2:13][CH3:14])[C:5](=[O:7])[CH3:6]
Reactant: CC(=O)CC(=O)C(F)(F)Cl
Reactant: CCOC([O-])[O-]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CCOC=C(C(C)=O)C(=O)C(F)(F)Cl
Reaction time: 2 h
Yield: 48.5 %

Procedure:
A mixed solution containing 50 g of 1-chloro-1,1-difluoro-2,4-pentanedione, 60 g of ethyl orthoformate and 82 g of acetic anhydride was refluxed with stirring for 2 hours. After a Dean-Stark apparatus (water separator) was fixed, the solution was refluxed for additional 4 hours, while about 100 ml of water was removed. After it was allowed to cool, vacuum distillation was conducted to obtain 32.2 g of the desired product as a pale red liquid. Boiling point 95°-118° C./1.6 mmHg.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([CH2:9][CH2:10][CH3:11])[CH:6]=[CH:5][C:3]=1[NH2:4].[N+:12]([C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1)([O-:14])=[O:13]>>[N+:12]([C:15]1[CH:20]=[C:19]([C:2]2[CH:8]=[C:7]([CH2:9][CH2:10][CH3:11])[CH:6]=[CH:5][C:3]=2[NH2:4])[CH:18]=[CH:17][CH:16]=1)([O-:14])=[O:13]
Reactant: CCCc1ccc(N)c(Br)c1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Product: CCCc1ccc(N)c(-c2cccc([N+](=O)[O-])c2)c1

Procedure:
2-bromo-4-propylaniline and 3-nitrobenzene boronic acid can be combined to form 2-(3-nitrophenyl)-4-propylaniline,
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[C:31](=[O:32])[N:30]([CH3:33])[C:23]4[N:24]=[C:25](SC)[N:26]=[CH:27][C:22]=4[CH:21]=3)[CH:17]=[CH:16][C:15]=2[F:34])=[O:12])[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=O)C=1.[CH3:46][NH2:47].Cl>>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[C:31](=[O:32])[N:30]([CH3:33])[C:23]4[N:24]=[C:25]([NH:47][CH3:46])[N:26]=[CH:27][C:22]=4[CH:21]=3)[CH:17]=[CH:16][C:15]=2[F:34])=[O:12])[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CSc1ncc2cc(-c3ccc(F)c(NC(=O)Nc4cc(C(C)(C)C)no4)c3)c(=O)n(C)c2n1
Reactant: CN
Agent: Cl
Agent: O=C(OO)c1cccc(Cl)c1
Product: CNc1ncc2cc(-c3ccc(F)c(NC(=O)Nc4cc(C(C)(C)C)no4)c3)c(=O)n(C)c2n1
Yield: 26.5 %

Procedure:
Using a procedure analogous to Example A1, 1-(3-t-butylisoxazol-5-yl)-3-(2-fluoro-5-(8-methyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (0.180 g, 0.373 mmol, 1.00 eq) was oxidized with MCPBA (70.00 wt %, 0.276 g, 1.12 mmol, 3.00 eq) and then subjected to MeNH2.HCl (0.019 g, 0.28 mmol, 2.00 eq) to afford 1-(3-t-butylisoxazol-5-yl)-3-(2-fluoro-5-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (0.0346 g, 53% yield) as an off-white solid. The free base thus obtained converted to the hydrochloride (32.3 mg) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 10.45 (s, 1H), 8.840 (s, 1H), 8.69 (brs, 1H), 8.42 (dd, J=8.0, 2.0 Hz, 1H), 7.92 (s, 1H), 7.90 (brs, 1H), 7.39-7.29 (m, 2H), 6.09 (s, 1H), 3.64 (brs, 3H), 2.93 (brs, 3H), 1.26 (s, 9H); MS (ESI) m/z: 466.2 (M+H+).
Reaction SMILES: [CH:1]1[C:6]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=2)=[CH:5][CH:4]=[C:3]([Br:15])[CH:2]=1.[C:16]1(=O)[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH:16]1[CH:21]=[CH:20][C:19]([N:7]([C:8]2[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=2)[C:6]2[CH:1]=[CH:2][C:3]([Br:15])=[CH:4][CH:5]=2)=[CH:18][CH:17]=1
Reactant: Brc1ccc(Nc2ccc(Br)cc2)cc1
Reactant: O=C1CCC(=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Brc1ccc(N(c2ccccc2)c2ccc(Br)cc2)cc1
Yield: 67 %

Procedure:
A mixture of 4,4′-dibromodiphenylamine (7.3 g. 22 mmol), cyclohexane-1,4-dione (2.5 g., 23.3 mole), para-toluenesulfonic acid (0.1 g.) and toluene (100 ml) was kept at reflux with a Dean-Stark phase separator containing 4A molecular sieves. After 18 hours at reflux, the reaction was diluted with toluene, and the toluene solution was washed with water, dried and concentrated. The residue was dissolved in hexanes, and the hexanes solution was passed through a column of silica gel to afford 4,4′-dibromotriphenylamine as a colorless glass, 5.04 g., 67% yield. Mass Spec (m/z): 401, 403, 405 (M+).
Reaction SMILES: [F:1][C:2]1([CH3:47])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:11][CH2:12][CH2:13][N:14]2[CH2:45][CH2:44][C:17]3([N:21]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[CH2:20][N:19]([CH2:29][C:30]4[CH:31]=[C:32]([CH:40]=[CH:41][CH:42]=4)[C:33]([O:35]C(C)(C)C)=[O:34])[C:18]3=[O:43])[CH2:16][CH2:15]2)[C:3]1=[O:46].Cl>O1CCOCC1>[F:1][C:2]1([CH3:47])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:11][CH2:12][CH2:13][N:14]2[CH2:15][CH2:16][C:17]3([N:21]([C:22]4[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=4)[CH2:20][N:19]([CH2:29][C:30]4[CH:31]=[C:32]([CH:40]=[CH:41][CH:42]=4)[C:33]([OH:35])=[O:34])[C:18]3=[O:43])[CH2:44][CH2:45]2)[C:3]1=[O:46]
Reactant: CC(C)(C)OC(=O)c1cccc(CN2CN(c3ccc(F)cc3)C3(CCN(CCCN4C(=O)C(C)(F)c5ccccc54)CC3)C2=O)c1
Agent: Cl
Solvent: C1COCCO1
Product: CC1(F)C(=O)N(CCCN2CCC3(CC2)C(=O)N(Cc2cccc(C(=O)O)c2)CN3c2ccc(F)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To tert-butyl 3-((8-(3-(3-fluoro-3-methyl-2-oxoindolin-1-yl)propyl)-1-(4-fluorophenyl)-4-oxo-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (0.26 g, 0.4 mmol) was added concentrated 4M HCl in dioxane (4 mL) and triethylsilane (0.05 mL). After stirring at room temperature for 4 hours, the reaction mixture was concentrated, isolated by preparatory TLC (10% methanol/dichloromethane) and lyophilized with 4M HCl in dioxane (1 mL) to obtain the title compound as a hydrochloride salt (0.16 g, 64%); 1H NMR (DMSO-d6): δ 1.72 (d, 3H, J=22.4 Hz), 1.92 (d, 2H, J=13.6 Hz), 2.06 (br, 2H), 2.67 (t, 2H, J=10 Hz), 3.19 (br, 2H), 3.45-3.71 (m, 4H), 3.76 (t, 2H, J=7.2 Hz), 4.62 (s, 4H), 7.07 (d, 4H, J=6.4 Hz), 7.15 (t, 1H, J=8 Hz), 7.24 (d, 1H, J=8 Hz), 7.44-7.59 (m, 4H), 7.87 (dd, 2H, J=6.8 and 2 Hz), 10.27 (br, 1H), 13.03 (s, 1H); MS for C33H34F2N4O4 m/z 589.3 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:18]=[CH:17][N:16]=[C:15]3[C:10]=2[C:11]2[CH:23]=[CH:22][CH:21]=[CH:20][C:12]=2[C:13](=[O:19])[NH:14]3)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[C:33]1([S:39](Cl)(=[O:41])=[O:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>COCCOC>[O:19]=[C:13]1[C:12]2[CH:20]=[CH:21][CH:22]=[CH:23][C:11]=2[C:10]2[C:15](=[N:16][CH:17]=[CH:18][C:9]=2[NH:8][C:5]2[CH:4]=[CH:3][C:2]([NH:1][S:39]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)(=[O:41])=[O:40])=[CH:7][CH:6]=2)[NH:14]1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1ccc(Nc2ccnc3[nH]c(=O)c4ccccc4c23)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCOC
Product: O=c1[nH]c2nccc(Nc3ccc(NS(=O)(=O)c4ccccc4)cc3)c2c2ccccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 34.8 %

Procedure:
340 (40 mg, 0.13 mmol), DIEA (34 mg, 0.26 mmol), and benzenesulfonyl chloride (47 mg, 0.26 mmol) were suspended in DME (2 mL), and stirred for 4 h at room temperature. The precipitate formed during the reaction was filtered, washed with EtOAc, and dried under vacuum to provide 341 (20 mg, 34% yield) as a solid. LC-MS (M+H=443, obsd.=443).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[C:27]([CH3:37])=[N:28][N:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=2)[CH:30]=1)[CH2:6][O:7][C:8]1[C:12]([CH:13]=O)=[CH:11][N:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]=1.[CH2:38]([P:47](=[O:54])([O:51][CH2:52][CH3:53])[O:48][CH2:49][CH3:50])P(=O)(OCC)OCC.CN(C)C=O.[H-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[C:27]([CH3:37])=[N:28][N:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=2)[CH:30]=1)[CH2:6][O:7][C:8]1[C:12](/[CH:13]=[CH:38]/[P:47](=[O:54])([O:48][CH2:49][CH3:50])[O:51][CH2:52][CH3:53])=[CH:11][N:10]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:9]=1
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1cn(-c2ccccn2)nc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2cn(-c3ccccn3)nc2C)c(OC)c1)OCC
Reaction time: 15 h
Yield: 67.5 %

Procedure:
To a mixture of 3-({3-methoxy-4-[(3-methyl-1-pyridin-2-yl-1H-pyrazol-4-yl)methoxy]benzyl}oxy)-1-phenyl-1H-pyrazole-4-carbaldehyde (0.28 g), tetraethyl methylenediphosphonate (0.18 g) and N,N-dimethylformamide (10 mL) was added sodium hydride (60% in oil, 0.030 g) at room temperature, and the mixture was stirred at the same temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give diethyl (E)-2-[3-({3-methoxy-4-[(3-methyl-1-pyridin-2-yl-1H-pyrazol-4-yl)methoxy]benzyl}oxy)-1-phenyl-1H-pyrazol-4-yl]ethenylphosphonate as colorless crystals (0.24 g, yield 67%) from a fraction eluted with ethyl acetate-hexane (5:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 103-104° C.
Reaction SMILES: I[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][CH:3]=1.[CH:13]([C@H:16]1[CH2:20][O:19][C:18](=[O:21])[NH:17]1)([CH3:15])[CH3:14]>>[CH:13]([C@H:16]1[CH2:20][O:19][C:18](=[O:21])[N:17]1[C:2]1[CH:3]=[CH:4][C:5]([C:6]([OH:8])=[O:7])=[CH:11][CH:12]=1)([CH3:15])[CH3:14]
Reactant: CC(C)[C@H]1COC(=O)N1
Reactant: CCOC(=O)c1ccc(I)cc1
Product: CC(C)[C@H]1COC(=O)N1c1ccc(C(=O)O)cc1

Procedure:
By reaction and treatment in the same manner as in Preparation Example 18 and using ethyl 4-iodobenzoate (2.9 mL) and (S)-4-isopropyloxazolidin-2-one (2.5 g), the title compound (4.5 g) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14](C(O)=O)=[C:10]3[CH2:9][N:8]([CH3:18])[C:7](=[O:19])[C:6]=2[CH:20]=1.C(=O)=O.CCCCCC>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][CH:14]=[C:10]3[CH2:9][N:8]([CH3:18])[C:7](=[O:19])[C:6]=2[CH:20]=1
Reactant: CN1Cc2c(C(=O)O)ncn2-c2ccc(F)cc2C1=O
Agent: O=C=O
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Product: CN1Cc2cncn2-c2ccc(F)cc2C1=O

Procedure:
9.2 g of 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid are heated to 290°. After completion of the carbon dioxide evolution, the product is dissolved in chloroform and treated with hexane. The precipitated crystals are filtered off under suction and dried. There is obtained 8-fluoro-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]-benzodiazepin-6-one of melting point 236°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH:9]2[C:13](=[O:14])[C:12](=[CH:15][CH:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[CH2:11][C:10]2=[O:22])=[C:4]([CH3:23])[CH:3]=1.[H][H]>CO.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([CH3:23])[C:5]([CH:9]2[C:13](=[O:14])[CH:12]([CH2:15][CH:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[CH2:11][C:10]2=[O:22])=[C:6]([CH3:8])[CH:7]=1
Reactant: [H][H]
Reactant: Cc1cc(F)cc(C)c1C1C(=O)CC(=CC2CCOCC2)C1=O
Agent: [Pd]
Solvent: CO
Product: Cc1cc(F)cc(C)c1C1C(=O)CC(CC2CCOCC2)C1=O
Yield: 92.8 %

Procedure:
To a solution of 2-(4-fluoro-2,6-dimethylphenyl)-4-[1-(tetrahydropyran-4-yl)-methylidene]-cyclopentane-1,3-dione (0.14 g, 0.44 mmol) in methanol (3 ml) is added 10% palladium on carbon (1.5 mg), followed by stirring under a 1 bar hydrogen atmosphere for 8 hours. The reaction mixture is then filtered through diatomaceous earth and concentrated to give a crude product which is purified by flash chromatography (hexane/ethyl acetate) to afford 2-(4-fluoro-2,6-dimethylphenyl)-4-[tetrahydropyran-4-ylmethyl)-cyclopentane-1,3-dione (0.13 g).
Reaction SMILES: [CH3:1][Li].[C:3]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)(=[O:5])[CH3:4]>C(OCC)C.C1COCC1>[N:8]1[CH:9]=[CH:10][CH:11]=[C:6]([C:3]([OH:5])([CH3:1])[CH3:4])[CH:7]=1
Reactant: CC(=O)c1cccnc1
Reactant: [Li]C
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(O)c1cccnc1
Yield: 45.9 %

Procedure:
The method followed that of Example 4a, but using methyllithium (1.4 M; 14 ml, 20 mmol) in diethyl ether and 3-acetylpyridine (2.2 ml, 20 mmol) in dry THF (40 ml). Work-up and chromatography, on elution with ether-petrol-triethylamine 30:10:1, afforded the title compound (1.26 g, 46%) as an oil. 1H-NMR (CDCl3) δ1.58 (6H, s, CMe2), 7.22 (1H, m, Py 5-H), 7.85 (1H, m, Py 4-H), 8.32 (1H, m, Py 6-H), 8.65 (1H, m, Py 2-H); MS m/z 137 (M+).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[C:4]#[N:5].[CH3:11][C:12]([CH3:15])([O-:14])[CH3:13].[K+].O>COCCOC>[CH3:11][C:12]([O:14][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[C:4]#[N:5])([CH3:15])[CH3:13]
Reactant: N#Cc1c(F)cccc1Cl
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)Oc1cccc(Cl)c1C#N
Temperature: 25 °C
Yield: 97 %

Procedure:
To a solution of 2-fluoro-6-chlorobenzonitrile (10.35 g, 66.5 mmol) in 1,2-dimethoxyethane (50 mL) at 0° C. was added potassium t-butoxide (9.06 g, 80.7 mmol). The mixture was slowly allowed to warm to room temperature over 3 h. The reaction was poured into water and extracted with ether (3 times). The organic layers were washed with brine, dried (MgSO4) and concentrated to afford 13.52 g (97%) of 2-[(1,1-dimethylethyl)oxy]-6-chlorobenzonitrile as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13](OCC)=[O:14])=[CH:11][NH:10][N:9]=2)=[CH:4][CH:3]=1>O1CCCC1.C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][OH:14])=[CH:11][NH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c[nH]nc1-c1ccc(Cl)cc1
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: OCc1c[nH]nc1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 12 g of ethyl-(4-chloro-phenyl-4-ethoxycarbonyl-pyrazole in 150 ml of tetrahydrofuran is cooled in an ice bath. Then 25 ml of a 1 molar solution of aluminum hydride triethylamine complex in benzene is added dropwise. After the addition, the ice bath is removed and the gelatinous mixture stirred at room temperature for 21/2 hours. Excess reagent is then destroyed by the dropwise addition of water followed by 30 ml of an aqueous 2N solution of sodium hydroxide. The layers are separated, the aqueous phase reextracted with ethyl acetate and the combined organic layers dried over anhydrous sodium sulfate. The recrystallization of the solid residue from hot ethyl acetate gives the 3-(4-chloro-phenyl)-4-hydroxymethyl-pyrazole, m.p. 149°-150°.
Reaction SMILES: [OH:1][CH2:2][C@H:3]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[C:4]([O:6][CH3:7])=[O:5].[C:19]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C>[OH:1][CH2:2][C@H:3]([N:8]([CH3:19])[S:9]([C:12]1[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=1)(=[O:11])=[O:10])[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)[C@H](CO)NS(=O)(=O)c1ccc(C)cc1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CO)N(C)S(=O)(=O)c1ccc(C)cc1
Temperature: 50 °C

Procedure:
A solution of 2E (2 g, 7.35 mmol) in DMF (15 mL) was added with an .K2CO3 (1.5 mol eq, 1.52 g) and, after few minutes, iodomethane (1.2 mol eq, 0.81 ml) was added and the mixture was heated at 50° C. overnight. The solvent was removed under reduced pressure, water was added to the residue (120 mL) and the aqueous phase was extracted with EtOAc (3×50 mL). The combined organic phases were dried over Na2SO4 and evaporated under reduced pressure to afford 3E as a pale yellow oil (2.1 g, quantitative yield). 1HNMR (DMSO, 200 MHz) δ 2.38 (s, 3H), 2.87 (s, 3H), 3.64 (s, 3H), 3.70 (t, 2H), 4.58 (t, 1H), 5.11 (t, 1H), 7.40 (d, 2H, J=8), 7.61 (d, 2H, J=8).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][C:11]([CH3:16])([N+:13]([O-])=O)[CH3:12])=[CH:4][C:3]=2[O:2]1.C(O)(=O)C.COCCOC>[H][H].[Pt](=O)=O>[CH3:16][C:11]([NH2:13])([CH3:12])[CH2:10][C:5]1[CH:6]=[CH:7][C:8]2[O:9][CH2:1][O:2][C:3]=2[CH:4]=1
Reactant: [H][H]
Reactant: CC(C)(Cc1ccc2c(c1)OCO2)[N+](=O)[O-]
Agent: O=[Pt]=O
Solvent: CC(=O)O
Solvent: COCCOC
Product: CC(C)(N)Cc1ccc2c(c1)OCO2
Yield: 72.2 %

Procedure:
A mixture of 0.8 g of 1-(3,4-methylenedioxyphenyl)-2-methyl-2-nitropropane, 100 mg of platinum dioxide, one ml of acetic acid and 20 ml of 1,2-dimethoxyethane is shaken at 60°-70° C. for 18 hours in hydrogen gas atmosphere under elevated pressure (initial pressure: 80 atmospheric pressures). After the reaction, the insoluble materials are removed by filtration, and the filtrate is evaporated to remove solvent. The residue is dissolved in ethyl acetate, and the solution is extracted with 5% hydrochloric acid. The extract is alkalized with potassium carbonate, and then extracted with ethyl acetate. The extract is washed with a saturated sodium chloride solution, dried and then evaporated to remove solvent. The residue (oil) is distilled at 100°-120° C. (bath temperature) under reduced pressure (0.04 mm Hg). 0.5 g of α,α-dimethyl-3,4-methylenedioxyphenethylamine are thereby obtained as an oil.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:38][O:39][C:40](=[O:48])[CH2:41][CH:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1>>[CH3:38][O:39][C:40](=[O:48])[CH2:41][CH:42]1[CH2:43][CH2:44][N:45]([C:32]([N:12]2[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=[C:11]2[C:8]2[CH:9]=[N:10][C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])=[CH:6][C:7]=2[O:35][CH2:36][CH3:37])=[O:33])[CH2:46][CH2:47]1
Reactant: COC(=O)CC1CCNCC1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)OC)CC1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with piperidin-4-yl-acetic acid methyl ester (Astatech) to give the title compound. HR-MS (ES, m/z) calculated for C37H45Cl2N4O4 [(M+H)+] 679.2813, observed 679.2808.
Reaction SMILES: C([O:5][C:6](=[O:125])[CH2:7][N:8]([CH2:117][C:118](=[O:124])[O:119]C(C)(C)C)[C:9](=[O:116])[CH2:10][N:11]1[CH:15]=[CH:14][N:13]=[C:12]1[CH2:16][N:17]([CH2:59][C:60]1[CH:65]=[CH:64][C:63]([O:66][CH2:67][C:68]2[N:69]=[N:70][N:71]([CH2:73][CH2:74][CH2:75][NH:76][C:77](=[O:115])[CH2:78][N:79]3[CH2:90][CH2:89][N:88]([CH2:91][C:92](=[O:98])[O:93]C(C)(C)C)[CH2:87][CH2:86][N:85]([CH2:99][C:100](=[O:106])[O:101]C(C)(C)C)[CH2:84][CH2:83][N:82]([CH2:107][C:108]([O:110]C(C)(C)C)=[O:109])[CH2:81][CH2:80]3)[CH:72]=2)=[CH:62][CH:61]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](=[O:58])[NH:24][CH2:25][CH2:26][CH2:27][CH2:28][C@@H:29]([C:51]([O:53]C(C)(C)C)=[O:52])[NH:30][C:31](=[O:50])[NH:32][C@H:33]([C:43]([O:45]C(C)(C)C)=[O:44])[CH2:34][CH2:35][C:36]([O:38]C(C)(C)C)=[O:37])(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[C:118]([CH2:117][N:8]([CH2:7][C:6]([OH:125])=[O:5])[C:9](=[O:116])[CH2:10][N:11]1[CH:15]=[CH:14][N:13]=[C:12]1[CH2:16][N:17]([CH2:59][C:60]1[CH:61]=[CH:62][C:63]([O:66][CH2:67][C:68]2[N:69]=[N:70][N:71]([CH2:73][CH2:74][CH2:75][NH:76][C:77](=[O:115])[CH2:78][N:79]3[CH2:90][CH2:89][N:88]([CH2:91][C:92]([OH:98])=[O:93])[CH2:87][CH2:86][N:85]([CH2:99][C:100]([OH:106])=[O:101])[CH2:84][CH2:83][N:82]([CH2:107][C:108]([OH:110])=[O:109])[CH2:81][CH2:80]3)[CH:72]=2)=[CH:64][CH:65]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](=[O:58])[NH:24][CH2:25][CH2:26][CH2:27][CH2:28][C@@H:29]([C:51]([OH:53])=[O:52])[NH:30][C:31](=[O:50])[NH:32][C@H:33]([C:43]([OH:45])=[O:44])[CH2:34][CH2:35][C:36]([OH:38])=[O:37])([OH:124])=[O:119]
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)N[C@@H](CCCCNC(=O)CCCCCN(Cc1ccc(OCc2cn(CCCNC(=O)CN3CCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CC3)nn2)cc1)Cc1nccn1CC(=O)N(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CC[C@H](NC(=O)N[C@@H](CCCCNC(=O)CCCCCN(Cc1ccc(OCc2cn(CCCNC(=O)CN3CCN(CC(=O)O)CCN(CC(=O)O)CCN(CC(=O)O)CC3)nn2)cc1)Cc1nccn1CC(=O)N(CC(=O)O)CC(=O)O)C(=O)O)C(=O)O

Procedure:
A solution of ((14S,18S)-tri-tert-butyl 1-(1-(2-(bis(2-(tert-butoxy)-2-oxoethyl)amino)-2-oxoethyl)-1H-imidazol-2-yl)-8,16-dioxo-2-(4-((1-(3-(2-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecan-1-yl)acetamido)propyl)-1H-1,2,3-triazol-4-yl)methoxy)benzyl)-2,9,15,17-tetraazaicosane-14,18,20-tricarboxylate (21 mg, 0.012 mmol) in TFA (2.0 mL) and DCM (2.0 mL) was stirred at rt overnight. The solvent was removed under a stream of nitrogen to give a crude ((14S,18S)-1-(1-(2-(bis(carboxymethyl)amino)-2-oxoethyl)-1H-imidazol-2-yl)-8,16-dioxo-2-(4-((1-(3-(2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl)acetamido)propyl)-1H-1,2,3-triazol-4-yl)methoxy)benzyl)-2,9,15,17-tetraazaicosane-14,18,20-tricarboxylic acid, (MIP-1459), which was dissolved in ammonium acetate (0.30 mL, 0.50 N) solution in water (0.50 mL) with InCl3 (10 mg). The reaction mixture was heated at
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:4]=[C:5]([CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=1)[CH2:6][O:7][CH:8]1[O:13][CH2:12][CH2:11][NH:10][CH:9]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)C(C)C)(C)C.Br[CH2:39][C:40]([O:42][CH3:43])=[O:41]>C(#N)C>[F:28][C:2]([F:1])([F:27])[C:3]1[CH:4]=[C:5]([CH:20]=[C:21]([C:23]([F:24])([F:25])[F:26])[CH:22]=1)[CH2:6][O:7][CH:8]1[O:13][CH2:12][CH2:11][N:10]([CH2:39][C:40]([O:42][CH3:43])=[O:41])[CH:9]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: FC(F)(F)c1cc(COC2OCCNC2c2ccccc2)cc(C(F)(F)F)c1
Reactant: COC(=O)CBr
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CN1CCOC(OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1c1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 150 mg (0.37 mmol) of the trans-isomer of (+/−)-2-(3,5-bis(trifluoromethyl)benzyloxy)-3-phenyl morpholine (Example 4) and 0.18 mL (1.00 mmol) of N,N-diisopropyl-ethyl- amine in 2 mL of acetonitrile was treated with 0.095 mL (1.00 mmol) of methyl bromoacetate and the resulting solution was stirred at rt for 20 h. The solution was concentrated in vacuo and the residue was partitioned between 20 mL of ethyl acetate and 5 mL of 0.5 N aqueous potassium hydrogen sulfate solution. The layers were separated; the organic layer was washed with 10 mL of saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. Flash chromatography on 10 g of silica gel using 4:1 v/v hexanes/ether as the eluant afforded 164 mg (93%) of the trans-isomer of the title compound as an oil: 1H NMR 2.79 (dt, 1H, J=3.2, 11.2), 2.93 (dt, 1H, J=11.2, 1.6), 3.52 (d, 1H, J=7.2), 3.63 (s, 3H), 3.92 (dt, 1H, J=2.8, 11.6), 4.04 (ddd, 1H, J=11.6, 3.2, 1.6), 4.45 and 4.84 (AB q, 2H, J=13.2), 4.46 (d, 1H, J=7.2), 7.31-7.38 (m, 6H), 7.68 (s, 1H);