Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:20](=[O:36])[C:21]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)([CH3:23])[CH3:22])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:54])[C@@H:15]2[CH2:37][CH2:38][C@H:39]2[O:44][C:43](=[O:45])[CH2:42][C@H:41]([O:46][Si](C(C)(C)C)(C)C)[CH2:40]2)=[CH:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:20](=[O:36])[C:21]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)([CH3:22])[CH3:23])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:54])[C@@H:15]2[CH2:37][CH2:38][C@H:39]2[O:44][C:43](=[O:45])[CH2:42][C@H:41]([OH:46])[CH2:40]2)=[CH:10]1
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](OC(=O)C(C)(C)OCc3ccc(C(F)(F)F)cc3)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C[C@H]1C=CC2=C[C@@H](O)C[C@H](OC(=O)C(C)(C)OCc3ccc(C(F)(F)F)cc3)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O)CC(=O)O1
Yield: 90.7 %

Procedure:
A procedure similar to that described in Example 2, above, was followed, but using 1.16 g of (4R,6R)-6-([1S,2S,6S,8S,8aR]-2-{1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-[2-(4-trifluoromethylbenzyloxy)-2-methylpropionyloxy]-2-methyl-1-naphthyl}ethyl)tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [preparedas described in Example 145, above] and 20.4 ml of a 1.0 molar solution of tetrabutylammonium fluoride in tetrahydrofuran, to give 0.75 g of the title compound as a colorless foam.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([O:11][CH:12]([O:15][CH2:16][CH3:17])[CH2:13][NH2:14])[CH3:10].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C>O1CCCC1.C(OCC)(=O)C>[CH2:1]([NH:14][CH2:13][CH:12]([O:15][CH2:16][CH3:17])[O:11][CH2:9][CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: CCOC(CN)OCC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(CNCc1ccccc1)OCC
Reaction time: 8 h
Yield: 69.9 %

Procedure:
A solution of benzaldehyde 5.1 ml (50.0 mmol) in 2,2-diethoxyethanamine 10.9 ml (75.0 mmol) was stirred at room temperature for 0.5 hour. The reaction mixture was diluted with tetrahydrofuran 450 ml and triacetoxyborohydride 32.0 g (150 mmol) was added and the mixture was stirred overnight. The reaction mixture was diluted with ethyl acetate 500 ml and washed with saturated sodium bicarbonate 500 ml, water 500 ml and brine 500 ml. The organic phase was dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified on silica gel column chromatography (n-hexane:ethyl acetate=70:30 to 50:50) to obtain the title compound 7.8 g (yield 70%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([F:10])[C:8]=1[F:9])[NH2:5].[N:11]([O-])=O.[Na+].[F:15][B-:16]([F:19])([F:18])[F:17].[H+]>O>[F:15][B-:16]([F:19])([F:18])[F:17].[F:1][C:2]1[CH:3]=[C:4]([N+:5]#[N:11])[CH:6]=[C:7]([F:10])[C:8]=1[F:9]
Reactant: Nc1cc(F)c(F)c(F)c1
Reactant: O=N[O-]
Agent: F[B-](F)(F)F
Agent: [H+]
Agent: [Na+]
Solvent: O
Product: N#[N+]c1cc(F)c(F)c(F)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To an ice-cooled solution of 3,4,5-trifluoroaniline (2.00 g; 13.6 mmol) in 50% tetrafluoroboric acid (5.0 ml) was added dropwise, with stirring, a solution of sodium nitrite (1.04 g; 15.1 mmol) in water (1.5 ml). After a further 15 minutes at 0° C., the precipitated solid was filtered off and washed with cold diethyl ether. After drying under reduced pressure, 2.91 g (11.8 mmol; 87% of theory) of the title compound were obtained in the form of a colorless powder.
Reaction SMILES: [C:1]([O:9][CH2:10][C@H:11]1[S:15][CH2:14][C@H:13]([OH:16])[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:17][C:18]([Cl:25])([Cl:24])[CH2:19][O:20][C:21](Cl)=[O:22]>N1C=CC=CC=1.ClCCl>[C:1]([O:9][CH2:10][C@H:11]1[S:15][CH2:14][C@H:13]([O:16][C:21]([O:20][CH2:19][C:18]([Cl:25])([Cl:24])[Cl:17])=[O:22])[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: O=C(OC[C@@H]1O[C@@H](O)CS1)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(OCC(Cl)(Cl)Cl)O[C@H]1CS[C@H](COC(=O)c2ccccc2)O1
Yield: 72.9 %

Procedure:
A mixture of cis and trans 2-benzoyloxymethyl-5-hydroxy-1,3-oxathiolane 4.47 g (19.8 mmol) (as prepared in example 1) was reacted with 8.2 mL (59.4 mmol) of 2,2,2-trichloroethylchloroformate in pyridine (4.8 mL) and dichloromethane (150 mL) as described in example 2 to give 6.0 g of the title compound in 2:1 ratio.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][C:9](N(OC)C)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:15]1([Mg]Br)[CH2:17][CH2:16]1>C1COCC1>[CH:1]1([CH2:7][CH2:8][C:9]([CH:15]2[CH2:17][CH2:16]2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Br[Mg]C1CC1
Reactant: CON(C)C(=O)CCC1CCCCC1
Solvent: C1CCOC1
Product: O=C(CCC1CCCCC1)C1CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.2 %

Procedure:
3-Cyclohexyl-N-methoxy-N-methylpropaneamide (100 mg, 0.502 mmol) obtained in step 1 was dissolved in THF (1.0 mL). Under ice-cooled condition, cyclopropylmagnesium bromide (0.5 mol/L THF solution) (1.20 mL, 0.600 mmol) was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was extracted with ethyl acetate after adding a saturated ammonium chloride aqueous solution. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10→80/20) to give 3-cyclohexyl-1-cyclopropylpropan-1-one (61.7 mg, yield 68%).
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[F:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[C:28]([C:35]([F:38])([F:37])[F:36])[CH:27]=1>>[Cl:22][C:17]1[CH:16]=[C:15]([C:13]2[N:14]=[C:10]([C:8]3[CH:9]=[C:4]([C:3]([OH:2])=[O:24])[C:5]([C:29]4[CH:30]=[CH:31][C:26]([F:25])=[CH:27][C:28]=4[C:35]([F:36])([F:38])[F:37])=[CH:6][CH:7]=3)[S:11][CH:12]=2)[CH:20]=[CH:19][C:18]=1[Cl:21]
Reactant: OB(O)c1ccc(F)cc1C(F)(F)F
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Product: O=C(O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1ccc(F)cc1C(F)(F)F
Yield: 3.1 %

Procedure:
Using the conditions of General Procedure A for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 111 mg, 0.25 mmol) was reacted with 4-fluoro-2-(trifluoromethyl)benzeneboronic acid (available from Frontier Scientific, Inc.; 87 mg, 0.5 mmol). The resulting ester was hydrolyzed and the acid was purified to give 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-4′-fluoro-2′-trifluoromethyl-biphenyl-2-carboxylic acid (4 mg, 3%). 1H NMR (300 MHz, DMSO-d6) δ 13.14 (br s, 1H), 8.58 (s, 1H), 8.49 (s, 1H), 8.34 (d, J=1.9 Hz, 1H), 8.26 (d, J=6.6 Hz, 1H), 8.10 (d, J=8.3 Hz, 1H), 7.77 (d, J=8.5 Hz, 1H), 7.71 (d, J=9.4 Hz, 1H), 7.57 (d, J=8.1 Hz, 2H), 7.44 (d, J=8.3 Hz, 1H).
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:38]=[N:39][C:40]([N:43]2[CH:47]=[C:46]([CH3:48])[N:45]=[C:44]2[CH3:49])=[N:41][CH:42]=1>>[CH3:49][C:44]1[N:43]([C:40]2[N:39]=[CH:38][C:37]([C:16]3[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]4[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:34])[CH3:35])([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[O:9][C:8]4=[O:10])[CH3:12])=[CH:18][CH:17]=3)=[CH:42][N:41]=2)[CH:47]=[C:46]([CH3:48])[N:45]=1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: Cc1cn(-c2ncc(Br)cn2)c(C)n1
Product: Cc1cn(-c2ncc(-c3ccc([C@H](C)N4CC[C@](CC(C)(C)O)(c5ccccc5)OC4=O)cc3)cn2)c(C)n1

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 5-bromo-2-(2,4-dimethyl-1H-imidazol-1-yl)-pyrimidine following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 2 tR=0.962 min, m/z=526.3; 1H NMR (CD3OD) 0.86 (s, 3H), 1.16 (s, 3H), 1.49 (m, 3H), 2.06 (m, 2H), 2.12 (m, 1H), 2.20 (s, 3H), 2.35-2.48 (m, 2H), 2.82 (s, 3H), 3.03 (m, 1H), 5.53 (m, 1H), 7.07 (m, 2H), 7.19-7.32 (m, 6H), 7.45 (m, 2H), 7.80 (m, 1H), 8.96 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[CH2:17]([N:24]=[C:25]=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)Cl>[CH2:17]([NH:24][C:25]([NH:16][C:10]1[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:8]([C:3]2[N:4]([CH3:7])[N:5]=[CH:6][C:2]=2[Br:1])[CH:9]=1)=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C=NCc1ccccc1
Reactant: COc1ccc(N)cc1-c1c(Br)cnn1C
Solvent: ClCCl
Product: COc1ccc(NC(=O)NCc2ccccc2)cc1-c1c(Br)cnn1C
Yield: 66.7 %

Procedure:
3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.034 g, 0.12 mmol) was treated with benzyl isocyanate (0.017 g, 16.0 μL, 0.13 mmol, 1.05 equiv.) in CH2Cl2 (1 mL), in a similar manner as described in Example 1.10 to afford Compound 74 (0.031 g, 0.08 mmol, 62%) as a solid film. LCMS m/z (%)=415 (M+H79Br, 86), 417 (M+H81Br, 100). 1H NMR (400 MHz, acetone-d6) δ: 8.05 (s, 1H), 7.64 (dd, J=2.7, 9.0 Hz, 1H), 7.47 (s, 1H), 7.40 (d, J=2.7 Hz, 1H), 7.27-7.37 (m, 4H), 7.22 (t, J=7.0 Hz, 1H), 7.07 (d, J=9.0 Hz, 1H), 6.21 (s, 1H), 4.41 (d, J=4.0 Hz, 2H), 3.79 (s, 3H), 3.66 (s, 3H).
Reaction SMILES: [C:1]([C:5]1[O:6][CH:7]=[C:8]([C:10](=[C:13]([C:15]2[C:16]([C:22]([F:25])([F:24])[F:23])=[N:17][N:18]([CH3:21])[C:19]=2[Cl:20])[OH:14])[C:11]#[N:12])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:28]([O:30][CH2:31]Cl)[CH3:29]>C1COCC1>[C:1]([C:5]1[O:6][CH:7]=[C:8]([C:10](=[C:13]([C:15]2[C:16]([C:22]([F:23])([F:24])[F:25])=[N:17][N:18]([CH3:21])[C:19]=2[Cl:20])[O:14][CH2:31][O:30][CH2:28][CH3:29])[C:11]#[N:12])[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1nc(C(F)(F)F)c(C(O)=C(C#N)c2coc(C(C)(C)C)n2)c1Cl
Reactant: CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOCOC(=C(C#N)c1coc(C(C)(C)C)n1)c1c(C(F)(F)F)nn(C)c1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 14.4 %

Procedure:
0.6 g of 2-{2-tert-butyloxazol-4-yl}-3-(5-chloro-3-trifluoromethyl-1-methyl-pyrazol-4-yl)-3-hydroxyacrylonitrile was dissolved in 5 ml of THF, and 0.07 g of 60% sodium hydride was added thereto with cooling with ice, and then stirred for 15 minutes at room temperature. 0.17 g of ethoxymethyl chloride was added thereto and stirred for 6 days at room temperature. The reaction mixture was poured into ice water, extracted with ethyl acetate, and washed with saturated saline. The resulting product was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residual product was purified through silica gel thin-layer chromatography (ethyl acetate:n-hexane=1:4) to obtain 0.1 g of the intended compound in vitreous state.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[CH2:18]=[CH:19][CH2:20][N:21]=[C:22]=[O:23]>>[CH2:18]=[CH:19][CH2:20][NH:21][C:22]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:23]
Reactant: C=CCN=C=O
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Product: C=CCNC(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2n1
Yield: 73.1 %

Procedure:
Beginning with 0.15 gm (0.65 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.070 mL (0.78 mMol) prop-1-en-3-yl isocyanate, 0.149 gm (73%) of the title compound were recovered essentially by the procedure of Example 122. An analytical sample was crystallized from aqueous ethanol.
Reaction SMILES: [CH:1]([C:3]1[N:4]=[C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[S:6][CH:7]=1)=O.[I-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:29][CH2:30][CH:31]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH3:32])C=CC=CC=1>>[C:33]1([CH:31]([CH3:32])[CH2:30]/[CH:29]=[CH:1]\[C:3]2[N:4]=[C:5]([CH:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]3)[S:6][CH:7]=2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(C=O)cs2)CC1
Reactant: CC(CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1)c1ccccc1
Agent: [I-]
Product: CC(C/C=C\c1csc(C2CCN(C(=O)OC(C)(C)C)CC2)n1)c1ccccc1

Procedure:
tert-Butyl 4-(4-formyl-1,3-thiazol-2-yl)piperidine-1-carboxylate (1.00 g) is reacted with triphenyl(3-phenylbutyl)phosphonium iodide (3.53 g) and purified as described in IV-3. This gives tert-butyl 4-{4-[(1Z)-4-phenylpent-1-en-1-yl]-1,3-thiazol-2-yl}piperidine-1-carboxylate (1.23 g) in form of the Z isomer.
Reaction SMILES: C([Li:5])CCC.[CH3:6][Si:7]([CH3:20])([CH3:19])[CH:8]1[C:17]2[N:16]=[CH:15][CH:14]=[C:13]([CH3:18])[C:12]=2[CH2:11][CH2:10][CH2:9]1>CCCCCC.C1COCC1>[Li:5][C:8]1([Si:7]([CH3:19])([CH3:20])[CH3:6])[C:17]2[N:16]=[CH:15][CH:14]=[C:13]([CH3:18])[C:12]=2[CH2:11][CH2:10][CH2:9]1
Reactant: Cc1ccnc2c1CCCC2[Si](C)(C)C
Reactant: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: [Li]C1([Si](C)(C)C)CCCc2c(C)ccnc21

Procedure:
A mixture of a 1.55 molar solution of n-butyl lithium in hexane (14.2 ml, 22mM) and THF (25 ml), maintained below 5° was treated with a solution of 5,6,7,8-tetrahydro-8-trimethylsilyl- 4-methylquinoline (4.4 g, 20 mM) in THF (10 ml) to give 5,6,7,8-tetrahydro-8-lithio-8-trimethylsilyl -4-methylquinoline. After 0.5 hour a solution of t-butyldimethylsilyl isothiocyanate (22 mM) in benzene (15 ml) was added; after a further 0.5 hour the mixture was quenched with 0.5 N hydrochloric acid (60 ml). After 1 hour toluene (50 ml) was added, the aqueous layer was separated, adjusted to pH10 and extracted with dichloromethane. The organic extract was evaporated and chromatographed on silica using ether as eluant. The title thioamide was obtained in 60% yield (identical to authentic material) together with the corresponding nitrile (20%) and 5,6,7,8-tetrahydro-4-methylquinoline (20%).
Reaction SMILES: C([N:4]1[C:18]2[C:19]3[C@H:6]([CH2:7][C@@H:8]4[C@@H:13]([C:14]=3[C:15]([N+:20]([O-:22])=[O:21])=[CH:16][CH:17]=2)[CH2:12][C@H:11]([NH:23][C:24](=[O:30])[N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])[CH2:10][N:9]4[CH3:31])[CH2:5]1)(=O)C.O>NN.C(Cl)(Cl)Cl>[CH3:31][N:9]1[C@H:8]2[C@@H:13]([C:14]3[C:15]([N+:20]([O-:22])=[O:21])=[CH:16][CH:17]=[C:18]4[C:19]=3[CH:6]([CH2:7]2)[CH2:5][NH:4]4)[CH2:12][C@H:11]([NH:23][C:24](=[O:30])[N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])[CH2:10]1
Reactant: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3c([N+](=O)[O-])ccc4c3[C@H](C[C@H]2N(C)C1)CN4C(C)=O
Agent: NN
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3c([N+](=O)[O-])ccc4c3C(CN4)C[C@H]2N(C)C1
Yield: 59.4 %

Procedure:
One millimole of 3-(1-acetyl-2,3β-dihydro-6-methyl-12-nitro-8α-ergolinyl)-1,1-diethylurea is heated in a mixture of 2 ml of anhydrous hydrazine and 2 ml of chloroform for 3 hours to 50° C., poured into water, extracted with methylene chloride, the organic phase is dried, and evaporated under vacuum, yielding 230 mg of 3-(2,3-dihydro-6-methyl-12-nitro-8α-ergolinyl)-1,1-diethylurea. Yield: 25%. [α]D =+538° (0.5% in methanol) as the tartaric acid salt.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)=[CH:7][CH:6]=[CH:5][C:4]=1CC#N.Cl.[C:21]([OH:24])(=[O:23])[CH3:22]>>[CH3:1][O:2][C:3]1[C:8]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:22][C:21]([OH:24])=[O:23]
Reactant: CC(=O)O
Reactant: COc1c(CC#N)cccc1Oc1cccc(Cl)c1
Agent: Cl
Product: COc1c(CC(=O)O)cccc1Oc1cccc(Cl)c1

Procedure:
2-[2-Methoxy-3-(3-chlorophenoxy)phenyl]acetonitrile (16.4 g), glacial acetic acid (80 ml) and conc. hydrochloric acid (30 ml) were treated in a similar manner to that of Example 5-(4) to give oily 2-[2-methoxy-3-(3-chlorophenoxy)phenyl]acetic acid (10.1 g).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][CH3:10])[NH2:5].[Cl:11][C:12]1[N:17]=[C:16](Cl)[C:15]([Cl:19])=[CH:14][N:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:11][C:12]1[N:17]=[C:16]([NH:5][C:4]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:2]([I:1])[CH:3]=2)[C:15]([Cl:19])=[CH:14][N:13]=1
Reactant: COc1ccc(N)cc1I
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(Nc2nc(Cl)ncc2Cl)cc1I
Yield: 120.2 %

Procedure:
To a suspension of 3-iodo-4-methoxyaniline (8.0 g, 0.021 mol) and 2,4,5-trichloropyrimidine (4.13 g, 0.0225 mol) in N,N-dimethylformamide (57 mL) was added potassium carbonate (7.40 g, 0.0536 mol). The resultant mixture was stirred overnight at room temperature. The reaction mixture was filtered to remove K2CO3 and concentrated to give the residue (10 grams). The residue was triturated with EtOAc, and filtered under vacuum. The residue was purified by silica gel column chromatography to give the desired product (2.54 g, 30%). LCMS for C11H9Cl21N3O (M+H)+: m/z=396.0, 398.0.
Reaction SMILES: [C:1]([CH:4]1[CH:17]2[CH2:18][CH:6]([CH:7]3[CH:16]2[C:15]2[CH2:19][CH:8]3[CH:9]3[C:14]=2[CH:13]2[CH2:20][CH:10]3[CH2:11][CH2:12]2)[CH2:5]1)([OH:3])=[O:2].[O:21]1[CH:26]=[CH:25][CH2:24][CH2:23][CH2:22]1>O1CCCC1.C(OCC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]1[O:2][C:1]([CH:4]1[CH:17]2[CH2:18][CH:6]([CH:7]3[CH:16]2[C:15]2[CH2:19][CH:8]3[CH:9]3[C:14]=2[CH:13]2[CH2:20][CH:10]3[CH2:11][CH2:12]2)[CH2:5]1)=[O:3]
Reactant: C1=COCCC1
Reactant: O=C(O)C1CC2CC1C1C3=C4C5CCC(C5)C4C(C3)C21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(OC1CCCCO1)C1CC2CC1C1C3=C4C5CCC(C5)C4C(C3)C21
Yield: 72.6 %

Procedure:
Next, 2.1 g of the 12-carboxyhexacyclo[6.6.1.13,6.110,13.02,7.09,14]heptadecene and 1.71 g of 3,4-dihydro-2H-pyran were dissolved in 50 ml of tetrahydrofuran, into which 0.03 g of p-toluenesulfonic acid were added. The resultant mixture was reacted at room temperature for 2 hours. The reaction mixture was diluted with 100 ml of ethyl ether, followed by the successive washing with a 3% aqueous solution of Na2CO3, 3% aqueous solution of sodium chloride, and water. An organic layer was dried over MgSO4. The ethyl ether and unreacted 3,4-dihydro-2H-pyran were distilled off under reduced pressure by an evaporator, whereby 2 g of 12-tetrahydropyranyloxycarbonylhexacyclo[6.6.1.13,6.110,13.02,7.09,14]heptadecene were obtained as a viscous liquid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[I:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>>[I:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Product: CN1CCC(c2c[nH]c3ccc(NS(=O)(=O)c4ccc(I)cc4)cc23)CC1

Procedure:
Following the procedure described in detail in Example 39, 0.791 gm (3.45 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 1.1 gm (3.62 mMol) 4-iodobenzenesulfonyl chloride were used to prepare 0.809 (47.3%) of the title compound as a white powder. m.p.>250° C.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[Br:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Br:12][CH2:13][CH2:14][C:15](Cl)=[O:16]>>[Br:12][CH2:13][CH2:14][C:15]([C:9]1[CH:10]=[CH:11][C:6]([Br:5])=[CH:7][CH:8]=1)=[O:16]
Reactant: Brc1ccccc1
Reactant: O=C(Cl)CCBr
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(CCBr)c1ccc(Br)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 84.5 %

Procedure:
AlCl3 (23.8 g, 178 mmol) was added by portions to bromobenzene (155 ml, 1.47 mol) at 0° C. 3-Bromopropionyl chloride (25 g, 146 mmol) was added dropwise to the red solution kept at 0° C. over 30 min. After 1 h at RT, the reaction mixture was heated to 50° C. for 1 h. After cooling, the mixture was poured over ice/water and extracted with DCM. The organic layer was dried over Na2SO4 and concentrated to yield 3-bromo-1-(4-bromophenyl)propan-1-one (36 g) which was crystallized from petroleum ether (mp=66° C.). 1H NMR (CDCl3): 7.82 (2H, d, J=8.5 Hz), 7.62 (2H, d, J=8.5 Hz), 3.73 (2H, t, J=6.5 Hz), 3.55 (2H, t, J=6.5 Hz).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([CH2:27][CH:28]3[CH2:33][CH2:32][N:31]([C:34](=[O:37])[CH2:35]Cl)[CH2:30][CH2:29]3)=[N:9][C:10]=2[C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[CH:16][C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:18]3)=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.[CH3:38][NH:39][CH3:40]>C1COCC1>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([CH2:27][CH:28]3[CH2:33][CH2:32][N:31]([C:34](=[O:37])[CH2:35][N:39]([CH3:40])[CH3:38])[CH2:30][CH2:29]3)=[N:9][C:10]=2[C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[CH:16][C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:18]3)=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1
Reactant: Nc1nccn2c(CC3CCN(C(=O)CCl)CC3)nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c12
Reactant: CNC
Solvent: C1CCOC1
Product: CN(C)CC(=O)N1CCC(Cc2nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c3c(N)nccn23)CC1
Temperature: 80 °C

Procedure:
1-{4-[8-Amino-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-3-ylmethyl]-piperidin-1-yl}-2-chloro-ethanone (77.00 mg, 0.15 mmol) was transferred to a pressure reaction vessel and dissolved in 3.15 mL of 2M dimethylamine solution in THF. The reaction was heated at 80° C. overnight. The crude product was then condensed and purified by a 5 g Jones silica gel (dry loaded with silica gel; eluted with 100% CH2Cl2→2% (7N NH3) in MeOH/CH2Cl2→5% (7N NH3) in MeOH/CH2Cl2) and afforded the desired product; 1H NMR (400 MHz, CHLOROFORM-d) δ 8.41 (1H, d, J=0.80), 8.28 (1H, d, J=8.23), 8.19 (2H, dd, J=2.04, J=1.55), 7.93 (3H, m), 7.53 (3H, dd, J=1.70, J=1.70), 7.53 (3H, m), 7.23 (1H, d, J=5.08), 7.15 (1H, d, 5.06), 5.52 (2H, m), 4.63 (1H, d, J=14.08), 4.04 (1H, d, J=11.88), 2.43 (2H, q), 2.97 (4H, d, J=6.08), 2.60 (1H, t), 2.43 (6H, s), 2.29 (1H, m), 1.86 (2H, d, J=12.96), 1.30 (2H, m); MS (ES+): m/z 520.11 (5) [MH+]; HPLC: tR=1.73 min (OpenLynx, polar—5 min).
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:32]=[CH:31][C:8]([NH:9]/[C:10](=[C:17]2\[C:18](=[O:30])[NH:19][C:20]3[C:25]\2=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=3)/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(O)=[O:2].[NH4+].O[N:35]1C(=O)CCC1=O>>[NH2:35][C:1]([CH2:4][C:5]1[CH:6]=[CH:7][C:8]([NH:9]/[C:10](=[C:17]2\[C:18](=[O:30])[NH:19][C:20]3[C:25]\2=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=3)/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:31][CH:32]=1)=[O:2]
Reactant: COc1cc2c(cc1OC)/C(=C(/Nc1ccc(CC(=O)O)cc1)c1ccccc1)C(=O)N2
Reactant: O=C1CCC(=O)N1O
Agent: [NH4+]
Product: COc1cc2c(cc1OC)/C(=C(/Nc1ccc(CC(N)=O)cc1)c1ccccc1)C(=O)N2

Procedure:
Prepared from 3-(Z)-(1-[4-(carboxymethyl)-anilino]-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone and N-hydroxy-succinimide-ammonium salt
Reaction SMILES: [CH3:1][N:2]([CH3:9])[CH2:3][CH2:4][O:5][CH2:6][CH2:7][OH:8].[H-].[Na+].Cl[C:13]1[CH:18]=[C:17]([C:19]#[N:20])[CH:16]=[CH:15][N:14]=1>CN(C=O)C>[CH3:1][N:2]([CH3:9])[CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][C:13]1[CH:18]=[C:17]([C:19]#[N:20])[CH:16]=[CH:15][N:14]=1
Reactant: N#Cc1ccnc(Cl)c1
Reactant: CN(C)CCOCCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCOCCOc1cc(C#N)ccn1
Temperature: 50 °C
Yield: 105.8 %

Procedure:
To a DMF (30 mL) solution of 2-[2-(dimethylamino)ethoxy]ethan-1-ol (3.33 g, 25 mmol) was added NaH (60% in mineral oil, 900 mg, 22.5 mmol, hexane washed) and heated at 50° C. for 2 h. The warm sodium alkoxide solution was added to 2-chloro-4-cyanopyridine (3.12 g, 22.5 mmol) in DMF (10 mL). After the addition, the reaction mixture was heated to 70° C. for 2 h, then DMF was removed in vacuo. The residue was partitioned between CH2Cl2/H2O. The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo to give a light yellow oil (5.6 g).