Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([O:14][CH2:15][C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=1)=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(Cl)Cl.[OH-].[Na+]>C(OCC)C>[CH2:7]([O:14][CH2:15][CH2:16][NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(COCc1ccccc1)Nc1cccc(F)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: ClCCl
Product: Fc1cccc(NCCOCc2ccccc2)c1
Temperature: 0 °C
Yield: 61.9 %

Procedure:
To a suspension of LAH (1.25 g, 27 mmol) in dry diethyl ether (100 mL) was added dropwise a solution of 2-benzyloxy-N-(3-fluoro-phenyl)-acetamide (39) (7.0 g, 27 mmol) in dry diethyl ether (100 mL). The addition was such as a reflux was maintained. Once the addition was completed, the reaction mixture was heated to reflux for 4 h, then poured into ice-water and DCM was added. In order to break down the aluminium salt, 2M aqueous sodium hydroxide solution was added until strong basic pH was obtained. The layers were separated and the aqueous layer was washed with DCM, dried and concentrated in vacuo. The crude material was purified by silica gel chromatography eluting with petrol (A) and ethyl acetate (B) (5-50% B, 100 g, 12 CV, 60 mL/min) to afford 4.1 g (84%) of (2-benzyloxy-ethyl)-(3-fluoro-phenyl)-amine (40) as a yellow oil. The structure was confirmed by 13C NMR (75 MHz, CDCl3): δC 43.3, 68.2, 73.0, 99.4 (d, TCF=24 Hz), 103.5, 103.8, 108.8, 127.4 (d, JCF=3 Hz), 127.6, 128.4, 130.0 (d, JCF=9 Hz), and 138.8.
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-])[CH3:3].[K+].Br[C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[C:11]([NH:18][C:19](=[O:25])[CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[C:10]([Cl:26])[CH:9]=1>C1(C)C=CC=CC=1>[Cl:26][C:10]1[CH:9]=[C:8]([N:18]2[CH2:19][CH2:20][C:5]3[C:2](=[CH:3][CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=3)[CH2:1]2)[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[C:11]=1[NH:18][C:19](=[O:25])[CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)CC(=O)Nc1c(Cl)cc(Br)cc1C(F)(F)F
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(C)(C)CC(=O)Nc1c(Cl)cc(N2CCc3cc(C(F)(F)F)ccc3C2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Bis(dibenzylidineacetone)palladium (2 mg, 0.0035 mmol) and (2′-dicyclohexyl phosphanyl-biphenyl-2-yl)-dimethylamine (3.3 mg, 0.0084 mmol) were added to dry toluene (10 mL purged with argon) and stirred for 15 minutes under argon. Potassium tert-butoxide (197 mg, 1.75 mmol), 6-trifluoro-1,2,3,4-tetrahydroisoquinoline (154 mg, 0.65 mmol) and N-(4-bromo-2-chloro-6-(trifluoromethyl)phenyl)-3,3-dimethylbutanamide (200 mg, 0.54 mmol) were then added, and the reaction mixture was stirred at 90° C. overnight. The reaction mixture was then cooled to room temperature, concentrated, and purified by thin layer chromatography (dichloromethane:methanol 5%) to afford the title compound as a solid
Reaction SMILES: [CH2:1]([OH:13])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][OH:12].C(N(CC)CC)C.[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>C(Cl)Cl.Cl>[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][O:3][CH2:2][CH2:1][OH:13])(=[O:30])=[O:29])=[CH:24][CH:23]=1
Reactant: OCCOCCOCCOCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCOCCOCCOCCO)cc1
Temperature: 0 °C

Procedure:
Into a 250-mL round-bottom flask was placed a solution of tetraethylene glycol (50 g, 257.47 mmol, 9.81 equiv) in DCM (150 mL) and triethylamine (8 g, 79.05 mmol, 3.01 equiv). This was followed by the addition of a solution of 4-methylbenzene-1-sulfonyl chloride (5.0 g, 26.23 mmol, 1.00 equiv) in DCM (10 mL) dropwise with stirring at 0° C. The resulting solution was stirred for 2 h at room temperature, at which time it was diluted with 200 ml of hydrogen chloride (3N aq.). The resulting solution was extracted with 2×150 mL of DCM and the combined organic layers were washed with 3×150 mL of saturated sodium bicarbonate. The mixture was dried over sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5˜ethyl acetate). This resulted in 7.0 g (77%) of 2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)ethyl 4-methylbenzenesulfonate as colorless oil.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:35][C@@H:36]([NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[CH:37]=[CH2:38].[Cl:47][C:48]1[C:49]2[C:56]([I:57])=[CH:55][NH:54][C:50]=2[N:51]=[CH:52][N:53]=1>O1CCCC1>[Cl:47][C:48]1[C:49]2[C:56]([I:57])=[CH:55][N:54]([CH2:35][C@@H:36]([NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[CH:37]=[CH2:38])[C:50]=2[N:51]=[CH:52][N:53]=1
Reactant: C=C[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: Clc1ncnc2[nH]cc(I)c12
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=C[C@@H](Cn1cc(I)c2c(Cl)ncnc21)NC(=O)OC(C)(C)C
Yield: 186.2 %

Procedure:
Diisopropyl azodicarboxylate (2.44 ml) was slowly added to a solution of triphenylphosphine (13.1 g) in tetrahydrofuran (70 ml) under ice-cooling. The reaction mixture was stirred under ice-cooling for 1 hour, and then a solution of (S)-tert-butyl (1-hydroxybut-3-en-2-yl)carbamate (7.0 g) synthesized according to the method disclosed in Non-patent Literature Org. Lett., 2005, vol. 7, No. 5, pp. 847-849 and 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (6.97 g) in tetrahydrofuran (35 ml) was slowly added thereto. After the reaction mixture was stirred at room temperature for 2 hours, the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate) to obtain the title compound (20.84 g) as a light-yellow, oily substance.
Reaction SMILES: [C@H:1]([NH:5][C:6]1[C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:8][C:9]2[C:14]([N:15]=1)=[CH:13][C:12]([C:16]([O:18]C)=[O:17])=[CH:11][CH:10]=2)([CH2:3][CH3:4])[CH3:2].[H-].[Na+].[CH3:28]I>O1CCCC1>[C@H:1]([N:5]([CH3:28])[C:6]1[C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:8][C:9]2[C:14]([N:15]=1)=[CH:13][C:12]([C:16]([OH:18])=[O:17])=[CH:11][CH:10]=2)([CH2:3][CH3:4])[CH3:2]
Reactant: CC[C@@H](C)Nc1nc2cc(C(=O)OC)ccc2nc1-c1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC[C@@H](C)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of (R)-methyl 3-(sec-butylamino)-2-phenylquinoxaline-6-carboxylate (110 mg, 0.33 mmol, 1.00 equiv) in tetrahydrofuran (9 mL). sodium hydride (132 mg, 3.3 mmol, 10.00 equiv, 60%) was added. The resulting solution was stirred for 1 h at room temperature. This was followed by the dropwise addition of a solution of CH3I (922.5 mg, 6.50 mmol, 20.00 equiv) in tetrahydrofuran (2 mL) with stiffing at 0° C. The resulting solution was stirred for overnight at 20° C. The resulting mixture was concentrated under vacuum and diluted by 10 ml of H2O. The pH value of the aqueous solution was adjusted to 3-4 with 1N hydrogen chloride. The resulting solid was collected by filtration. This resulted solid in 67 mg (59%) of (R)-3-(sec-butyl(methyl)amino)-2-phenylquinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: S(O[CH2:12][CH2:13][N:14]1[C:18]2=[CH:19][C:20]3[N:21]=[C:22]([C:27]4[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([F:35])[CH:28]=4)[CH:23]=[N:24][C:25]=3[CH:26]=[C:17]2[CH:16]=[N:15]1)(C1C=CC(C)=CC=1)(=O)=O.[NH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1.CN(C=O)C>O>[N:36]1([CH2:12][CH2:13][N:14]2[C:18]3=[CH:19][C:20]4[N:21]=[C:22]([C:27]5[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([F:35])[CH:28]=5)[CH:23]=[N:24][C:25]=4[CH:26]=[C:17]3[CH:16]=[N:15]2)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: C1CCNCC1
Reactant: COc1ccc(-c2cnc3cc4cnn(CCOS(=O)(=O)c5ccc(C)cc5)c4cc3n2)cc1F
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2cnc3cc4cnn(CCN5CCCCC5)c4cc3n2)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.1 %

Procedure:
A mixture of 1-(2-tosyloxyethyl)-7-(3-fluoro-4-methoxyphenyl)-1H-pyrazolo[3,4-g]quinoxaline (0.3 g), piperdine (0.11 g) and 20 ml of anhydrous DMF is stirred at room temperature overnight. The mixture is heated to gentle reflux for 21/2 hours. After cooling, it is poured into water and the precipitate is filtered, washed with water and air dried. This is then purified by chromatography using (3:7-1:9) methylene chloride in ethylacetate as eluent. 0.220 g of desired product to obtain 1-(2-piperdin-1-ylethyl)-7-(3-fluoro-4-methoxyphenyl)-1H-pyrazolo[3,4-g]quinoxaline (m.p. 117°-120° C. (dec)).
Reaction SMILES: [CH2:1]([O:4][CH:5]([C:10]1[N:14]([CH3:15])[N:13]=[CH:12][C:11]=1[N+:16]([O-:18])=[O:17])[CH2:6][CH2:7][CH:8]=[CH2:9])C=C>C1(C)C=CC=CC=1>[CH3:15][N:14]1[C:10]([CH:5]2[CH2:6][CH2:7][CH:8]=[CH:9][CH2:1][O:4]2)=[C:11]([N+:16]([O-:18])=[O:17])[CH:12]=[N:13]1
Reactant: C=CCCC(OCC=C)c1c([N+](=O)[O-])cnn1C
Solvent: Cc1ccccc1
Product: Cn1ncc([N+](=O)[O-])c1C1CCC=CCO1
Temperature: 25 °C
Yield: 74.2 %

Procedure:
5-(1-Allyloxypent-4-enyl)-1-methyl-4-nitro-pyrazole (5 g, 19.92 mmol) was dissolved in toluene (1 L) and the mixture was degassed for 30 min before Benzylidene-bis(tricyclohexylphosphine)dichlororuthenium, Bis(tricyclohexylphosphine)benzylidine ruthenium(IV) dichloride, “Grubbs 1st generation catalyst” CAS No. 172222-30-9, Sigma-Aldrich Product No. 579726, U.S. Pat. No. 6,111,121, (878 mg, 0.99 mmol) was added. The reaction mixture was further degassed for 20 min, then heated at reflux for 2 hr, cooled to room temperature and filtered through Celite®. The filtrate was concentrated under reduced pressure. The residue was dissolved in EtOAc (200 mL), washed with aqueous 1 M HCl (150 mL), water (150 mL), saturated aqueous NaHCO3 (2×150 mL) and brine (150 mL). The organic layer was separated, dried over MgSO4 and concentrated under reduced pressure. Purification via silica gel column chromatography (0-20% EtOAc/isohexane) gave 1-methyl-4-nitro-5-(2,3,4,7-tetrahydrooxepin-2-yl)pyrazole as a clear oil (3.3 g, 75%). 1H NMR (400 MHz, CDCl3) δ 8.02 (s, 1H), 5.99-5.91 (m, 1H), 5.83-5.76 (m, 1H), 5.59 (dd, J=9.4, 3.0 Hz, 1H), 4.42 (dd, J=15.8, 5.5 Hz, 1H), 4.24-4.17 (m, 1H), 4.06 (s, 3H), 2.58-2.48 (m, 1H), 2.46-2.36 (m, 1H), 2.14 (ddt, J=14.1, 6.8, 3.5 Hz, 1H), 1.99-1.88 (m, 1H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[C:18]([C:29]([NH2:31])=[O:30])[CH:19]=[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:21]=3)[NH:16][CH:15]=2)[CH2:10][CH2:9]1)(=[O:7])=[O:6].[OH:32][C:33]1[CH:38]=[CH:37][C:36]([NH:39][C:40](=[O:42])[CH3:41])=[CH:35][CH:34]=1.C([O-])([O-])=O.[K+].[K+]>[I-].[Na+]>[C:40]([NH:39][C:36]1[CH:37]=[CH:38][C:33]([O:32][CH2:2][CH2:3][CH2:4][S:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[C:22]4[C:17](=[C:18]([C:29]([NH2:31])=[O:30])[CH:19]=[C:20]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[CH:21]=4)[NH:16][CH:15]=3)[CH2:10][CH2:9]2)(=[O:7])=[O:6])=[CH:34][CH:35]=1)(=[O:42])[CH3:41]
Reactant: CC(=O)Nc1ccc(O)cc1
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)c[nH]c12
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: CC(=O)Nc1ccc(OCCCS(=O)(=O)N2CCC(c3c[nH]c4c(C(N)=O)cc(-c5ccccc5)cc34)CC2)cc1
Yield: 42 %

Procedure:
Following the general procedure of example 159, 3-{1-[(3-chloropropyl)sulfonyl]-4-piperidinyl}-5-phenyl-1H-indole-7-carboxamide (40.0 mg, 0.087 mmol), N-(4-hydroxyphenyl)acetamide (151 mg, 0.87 mmol), K2CO3 (35.0 mg, 0.35 mmol) and sodium iodide (0.5 mg) were reacted to give the title compound (21.0 mg, 42%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15](Cl)=[N:16][OH:17])=[CH:10][CH:9]=2)=[CH:2]1.[C:19]([C:21]1[C:22]([NH2:28])=[N:23][C:24]([NH2:27])=[CH:25][CH:26]=1)#[CH:20].C(N(CC)CC)C>O1CCCC1>[S:1]1[CH:5]=[CH:4][C:3]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]3[CH:20]=[C:19]([C:21]4[C:22]([NH2:28])=[N:23][C:24]([NH2:27])=[CH:25][CH:26]=4)[O:17][N:16]=3)=[CH:10][CH:9]=2)=[CH:2]1
Reactant: ON=C(Cl)Cc1ccc(OCc2ccsc2)cc1
Reactant: C#Cc1ccc(N)nc1N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Nc1ccc(-c2cc(Cc3ccc(OCc4ccsc4)cc3)no2)c(N)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 56.9 %

Procedure:
To a tetrahydrofuran (3 mL) solution of (4-(thiophen-3-ylmethoxy)-phenyl)-acetohydroximoyl chloride (150 mg, 0.532 mmol) described in Manufacturing Example 77-1-4 and 3-ethynyl-pyridin-2,6-diamine (45.2 mg, 0.339 mmol) described in Manufacturing Example 13-1-3 was added triethylamine (185 μL, 1.33 mmol). This reaction mixture was stirred for 1.5 hours at room temperature. This mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:1˜ethyl acetate) to obtain the title compound (73 mg, 36%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:3]=1.Cl[CH2:14][C:15]1[S:16][CH:17]=[C:18]([CH:20]([CH3:22])[CH3:21])[N:19]=1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:20]([C:18]1[N:19]=[C:15]([CH2:14][O:1][C:2]2[CH:7]=[CH:6][N:5]=[C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:3]=2)[S:16][CH:17]=1)([CH3:22])[CH3:21]
Reactant: CC(C)c1csc(CCl)n1
Reactant: CCOC(=O)c1cc(O)ccn1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(OCc2nc(C(C)C)cs2)ccn1
Temperature: 110 °C
Reaction time: 1 h
Yield: 46.1 %

Procedure:
Ethyl 4-hydroxy-2-pyridinecarboxylate (19.5 g, 0.057 mol) dissolved in dimethylformamide (200 ml) was added with a solution of 2-(chloromethyl)-4-isopropyl-1,3-thiazole (11 g, 0.063 mol) in dimethylformamide (150 ml). The mixture was added with potassium iodide (9.5 g) and potassium carbonate (12 g) at room temperature, then heated to 110° C. and stirred for 1 hour. The reaction solution was returned to room temperature, and the solvent was evaporated under reduced pressure. The residue was diluted with chloroform and washed with water. The resulting organic layer was washed with saturated brine, and the organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (chloroform) to obtain 8.049 g (46%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].[CH3:11][O:12][C:13](=[O:31])[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[C:22](Cl)[C:23]3[CH:28]=[C:27]([Cl:29])[S:26][C:24]=3[N:25]=2)=[CH:16][CH:15]=1>>[CH3:11][O:12][C:13](=[O:31])[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[C:22]([NH:6][CH2:5][C:4]3[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=3)[C:23]3[CH:28]=[C:27]([Cl:29])[S:26][C:24]=3[N:25]=2)=[CH:16][CH:15]=1
Reactant: COC(=O)c1ccc(-c2nc(Cl)c3cc(Cl)sc3n2)cc1
Reactant: NCc1ccc(Cl)c(Cl)c1
Product: COC(=O)c1ccc(-c2nc(NCc3ccc(Cl)c(Cl)c3)c3cc(Cl)sc3n2)cc1

Procedure:
The reaction procedure as above in wherein 3,4-dichlorobenzylamine is reacted with 4-(4-chloro-6-chloro-thieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester yields 4-[4-(3,4-dichlorobenzylamino)-6-chloro-thieno-[2,3-d]-pyrimidin-2-yl]-benzoic acid methylester
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.O>CS(C)=O>[N:12]1([C:2]2[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=2)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: C1COCCN1
Solvent: O
Solvent: CS(C)=O
Product: Nc1cc(N2CCOCC2)ccc1[N+](=O)[O-]
Yield: 43 %

Procedure:
A solution of 5-chloro-2-nitrophenylamine (4.3 g, 25 mmol) and morpholine (4.4 mL, 500 mmol) in dimethylsulfoxide (DMSO) (25 mL) was stirred at 90° C. for 16 h. The reaction mixture was poured into water (500 mL) and the resulting precipitate was collected by vacuum filtration and recrystallized from methanol (300 mL) to yield the product as orange crystals (2.4 g, 43%). M.P. 177–178° C. (lit. 184–186° C.). See, Polymers 36:3401–3408 (1995).
Reaction SMILES: [CH:1](=O)[CH2:2][CH3:3].[F:5][C:6]1([Li])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]1[F:12].CC1C=CC(S(O)(=O)=O)=CC=1.S(=O)(=O)(O)O>C1COCC1.C1(C)C=CC=CC=1.O.CO>[CH:1]([C:8]1[C:7]([F:12])=[C:6]([F:5])[CH:11]=[CH:10][CH:9]=1)=[CH:2][CH3:3]
Reactant: [Li]C1(F)C=CC=CC1F
Reactant: CCC=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC=Cc1cccc(F)c1F
Temperature: 0 °C

Procedure:
A solution of 0.13 mol of propionaldehyde in 30 ml of THF is added dropwise to the solution of 1,2-difluorophenyllithium in THF prepared according to 1b). The mixture is subsequently warmed to 0° C. and worked up as customary. The resulting crude product of the carbinol is dissolved in 80 ml of toluene and heated to boiling for 1 hour in a water separator with 1 g of p-TsOH. 0.2 ml of concentrated sulfuric acid are then added and the mixture is again heated for 1 hour, as above. It is then worked up as customary, b.p.30 : 105° C.
Reaction SMILES: [OH:1][C:2]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([O:16]C)=[O:15])=[CH:11][CH:12]=2)[N:7]([C:18]2[CH:22]=[CH:21][S:20][CH:19]=2)[N:6]=1)([CH3:4])[CH3:3].CO.[OH-].[Na+]>O1CCCC1>[OH:1][C:2]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([OH:16])=[O:15])=[CH:11][CH:12]=2)[N:7]([C:18]2[CH:22]=[CH:21][S:20][CH:19]=2)[N:6]=1)([CH3:3])[CH3:4]
Reactant: COC(=O)c1ccc2c(C(C)(C)O)nn(-c3ccsc3)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(O)c1nn(-c2ccsc2)c2cc(C(=O)O)ccc12
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 92.4 %

Procedure:
Methyl 3-(2-hydroxypropan-2-yl)-1-(thiophen-3-yl)-1H-indazole-6-carboxylate (909.8 mg, 2.88 mmol) was dissolved in tetrahydrofuran (17.25 mL) and methanol (11.50 mL) at 25° C. 1M sodium hydroxide (11.50 mL, 11.50 mmol) was added and the reaction mixture heated to 50° C. The reaction mixture was allowed to stir for 15 min. The reaction was stopped, cooled to room temperature, quenched by addition of concentrated hydrochloric acid (0.950 mL), and concentrated under reduced pressure. The title compound (804.8 mg, 2.66 mmol, 93% yield) was recovered as a light orange/white solid. LC-MS: [M+1]=303.2.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([NH:10][C:11]([C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]=2[OH:23])=[O:12])[CH2:7][N:6]1[CH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)=O.[CH2:31]([NH2:34])[CH2:32][CH3:33].C[Al](C)C>>[CH2:31]([NH:34][C:3]([C@@H:5]1[CH2:9][C@H:8]([NH:10][C:11]([C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]=2[OH:23])=[O:12])[CH2:7][N:6]1[CH2:24][CH:25]1[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1)=[O:2])[CH2:32][CH3:33]
Reactant: CCCN
Reactant: COC(=O)[C@@H]1C[C@H](NC(=O)c2ccc3ccccc3c2O)CN1CC1CCCCC1
Agent: C[Al](C)C
Product: CCCNC(=O)[C@@H]1C[C@H](NC(=O)c2ccc3ccccc3c2O)CN1CC1CCCCC1
Temperature: 100 °C
Yield: 18.5 %

Procedure:
To a mixture of (2S,4S)-1-cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylic acid methyl ester (150 mg, 0.37 mmol) and 44 mg of n-propyl amine was added Me3Al (catalytic amount, 2M in toluene) under an argon atmosphere in a seal tube and the mixture was heated at 100° C. for 16 hr. The reaction mixture was then quenched with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The crude was then purified by silica gel column chromatography to give (2S,4S)-1-cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylic acid propylamide (30 mg, 18.7% yield) as a white solid. MS calcd. for C26H36N3O3 [(M+H)+] 438.0, obsd. 438.2.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=[O:16])[CH:10]=2)=[C:4]([CH3:17])[CH:3]=1.[CH2:18]([O:20][CH2:21][CH2:22]Cl)[CH3:19].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O.O>[CH2:18]([O:20][CH2:21][CH2:22][O:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=[O:16])[CH:10]=2)=[C:4]([CH3:17])[CH:3]=1)[CH3:19]
Reactant: CCOCCCl
Reactant: Cc1cc(O)cc(C)c1-c1cccc(C=O)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOCCOc1cc(C)c(-c2cccc(C=O)c2)c(C)c1
Temperature: 80 °C
Reaction time: 18 h
Yield: 88.9 %

Procedure:
To a solution of 4′-hydroxy-2′,6′-dimethylbiphenyl-3-carbaldehyde (8.52 g, 37.7 mmol) and 2-chloroethyl ethyl ether (6.15 g, 56.6 mmol) in N,N-dimethylformamide (40 mL) were added potassium carbonate (6.25 g, 45.2 mmol) and potassium iodide (1.25 g, 7.54 mmol), and the mixture was stirred at 80° C. for 18 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5%-25% ethyl acetate/hexane) to give the title compound (10.0 g, yield 89%) as a colorless oil.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([OH:16])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[C:17](OC=C)(=[O:19])[CH3:18].C(OCCCCCCCC)=C>C1(C)C=CC=CC=1>[C:17]([O:16][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])(=[O:19])[CH3:18]
Reactant: C=COC(C)=O
Reactant: CCCCCCCCO
Agent: C=COCCCCCCCC
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCCCCCOC(C)=O
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a mixture of di-μ-chlorobis(1,5-cyclooctadiene)diiridium(I) [Ir(cod)Cl]2 (0.01 mmol) and triethylamine (0.6 mmol) in toluene (1.0 ml), 1-octanol (130 mg, 1 mmol) and vinyl acetate (2 mmol) were added, followed by stirring at 100° C. in an atmosphere of argon gas for 2 hours. The reaction mixture was analyzed by gas chromatography to find that 1-octyl vinyl ether and octyl acetate were produced in yields of 19% and 2%, respectively, with a conversion from 1-octanol of 30%.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2([CH2:16][CH2:15][NH:14][CH2:13]2)[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:18]1[CH:19]=[N:20][CH:21]=[C:22]([O:24][CH2:25][CH3:26])[CH:23]=1.CC(C)([O-])C.[K+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:1]([N:8]1[C:12]2([CH2:16][CH2:15][N:14]([C:18]3[CH:19]=[N:20][CH:21]=[C:22]([O:24][CH2:25][CH3:26])[CH:23]=3)[CH2:13]2)[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOc1cncc(Br)c1
Reactant: c1ccc(CN2CCCC23CCNC3)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CCOc1cncc(N2CCC3(CCCN3Cc3ccccc3)C2)c1
Temperature: 90 °C
Yield: 66.7 %

Procedure:
1-Benzyl-1,7-diazaspiro[4.4]nonane (500.0 mg, 2.4 mmol) was dissolved in dry toluene (15 mL) in a 50 mL round bottom flask equipped with a magnetic stirring bar. Nitrogen was bubbled through the solution in a slow stream. To the stirring solution was added 3-bromo-5-ethoxypyridine (513.8 mg, 2.55 mmol), potassium tert-butoxide (1039.0 mg, 9.26 mmol), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (86.4 mg, 0.14 mmol) and tris(dibenzylideneacetone)dipalladium(0) (63.6 mg, 0.06 mmol), while continuing to purge with nitrogen. Nitrogen flow was discontinued and the flask was sealed and heated at 90° C. for 8 h. The reaction was cooled and the solvent was removed by rotary evaporation. The resulting residue was suspended in saturated aqueous sodium bicarbonate (10 mL) and extracted with chloroform (4×25 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated by rotary evaporation to a thick dark mass. Purification by column chromatography, using methanol/chloroform (2:98, v/v) as the eluent, gave 0.54 g of the desired compound as a light brown viscous liquid (69%).