Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C([N:9]1[CH2:36][CH2:35][CH2:34][C@@:10]1([CH3:37])[C:11]([NH:13][C@H:14]([C:31]([OH:33])=[O:32])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]#[N:30])=[CH:18][CH:17]=1)=[O:12])(OC(C)(C)C)=O.[Cl:38][C:39]1[CH:40]=[C:41]([S:46](Cl)(=[O:48])=[O:47])[CH:42]=[C:43]([Cl:45])[CH:44]=1.O1CCC[CH2:51]1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Cl:38][C:39]1[CH:40]=[C:41]([S:46]([N:9]2[CH2:36][CH2:35][CH2:34][C@@:10]2([CH3:37])[C:11]([NH:13][C@H:14]([C:31]([O:33][CH3:51])=[O:32])[CH2:15][C:16]2[CH:17]=[CH:18][C:19]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]#[N:30])=[CH:20][CH:21]=2)=[O:12])(=[O:48])=[O:47])[CH:42]=[C:43]([Cl:45])[CH:44]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@]1(C)C(=O)N[C@@H](Cc1ccc(Oc2ccccc2C#N)cc1)C(=O)O
Reactant: C1CCOC1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(Oc2ccccc2C#N)cc1)NC(=O)[C@]1(C)CCCN1S(=O)(=O)c1cc(Cl)cc(Cl)c1
Temperature: 25 °C

Procedure:
To a solution of 95 mg of N-Boc-2-(S)-methyl-(L)-prolyl-4-(2-cyanophenoxy)-phenylalanine, hydrochloride, 61 mg 3,5-dichlorobenzenesulfonyl chloride, and 2.5 mL of tetrahydrofuran at 0° C. was added 110 uL of diisopropylethylamine via syringe. The reaction was allowed to warm to room temperature and run at said temperature overnight. The reaction was diluted with methylene chloride, washed with water, 1N hydrochloric acid, saturated sodium bicarbonate solution, and saturated salt solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. The product was purified via silica gel chromatography, eluted with 80% hexane:20% acetone to yield 62 mg of of N-(3,5-dichlorobenzenesulfonyl)-2-(S)-methyl-(L)-prolyl-4-(2-cyanophenoxy)-phenylalanine, methyl ester.
Reaction SMILES: CS(O)(=O)=O.[CH2:6]([O:8][C:9]([C:11]1[C:12](=[O:37])[C:13]2[C:28]([CH2:29][Br:30])=[C:27]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[S:26][C:14]=2[N:15]([CH2:17][C:18]2[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=2[F:25])[CH:16]=1)=[O:10])[CH3:7].[N+:38]([O-])([O-:40])=[O:39].[Na+]>>[CH2:6]([O:8][C:9]([C:11]1[C:12](=[O:37])[C:13]2[C:28]([CH2:29][Br:30])=[C:27]([C:31]3[CH:36]=[CH:35][C:34]([N+:38]([O-:40])=[O:39])=[CH:33][CH:32]=3)[S:26][C:14]=2[N:15]([CH2:17][C:18]2[C:19]([F:25])=[CH:20][CH:21]=[CH:22][C:23]=2[F:24])[CH:16]=1)=[O:10])[CH3:7]
Reactant: O=[N+]([O-])[O-]
Reactant: CCOC(=O)c1cn(Cc2c(F)cccc2F)c2sc(-c3ccccc3)c(CBr)c2c1=O
Agent: CS(=O)(=O)O
Agent: [Na+]
Product: CCOC(=O)c1cn(Cc2c(F)cccc2F)c2sc(-c3ccc([N+](=O)[O-])cc3)c(CBr)c2c1=O
Temperature: 0 °C
Yield: 75 %

Procedure:
To methanesulfonic acid (4.5 L), 900 g of the compound obtained in Example 1 described above was added over a period of 30 minutes (internal temperature 19 to 23° C.). After cooling on ice with stirring, sodium nitrate (147 g)/methanesulfonic acid (1.98 L) was added dropwise over a period of 2 hours (internal temperature 12 to 14° C.). Subsequently, the reaction mixture was stirred for 1.5 hours at 11 to 12° C., and was added to 155 L of an ice-water, and the precipitated crystal was recovered by a filtration, washed with water and then dried. 1The crystal was dried in vacuo for 26 hours at 50° C. to obtain 944 g of a crude product of the title compound (yield: 75%, HPLC). The crystal was suspended in ethyl acetate (2.9 L), and the mixture was stirred under reflux for 30 minutes, at room temperature for 30 minutes, and then stirred with cooling on ice for 1 hour and 20 minutes. The crystal was recovered by a filtration, washed with cool ethyl acetate (0.8 L), dried under reduced pressure for 8 hours at 50° C. to obtain 837 g of the title compound (yield: 86%).
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[N:10]=[CH:11][C:12](I)=[CH:13][C:8]=2[C:7](=[O:15])[N:6]([CH3:16])[C:5]2[CH:17]=[CH:18][CH:19]=[N:20][C:4]1=2)[CH3:2].[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)#[CH:22]>>[CH2:1]([N:3]1[C:9]2[N:10]=[CH:11][C:12]([C:22]#[C:21][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[CH:13][C:8]=2[C:7](=[O:15])[N:6]([CH3:16])[C:5]2[CH:17]=[CH:18][CH:19]=[N:20][C:4]1=2)[CH3:2].[CH2:1]([N:3]1[C:9]2[N:10]=[CH:11][C:12]([CH2:22][CH2:21][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[CH:13][C:8]=2[C:7](=[O:15])[N:6]([CH3:16])[C:5]2[CH:17]=[CH:18][CH:19]=[N:20][C:4]1=2)[CH3:2]
Reactant: C#Cc1ccccn1
Reactant: CCN1c2ncc(I)cc2C(=O)N(C)c2cccnc21
Product: CCN1c2ncc(C#Cc3ccccn3)cc2C(=O)N(C)c2cccnc21
Product: CCN1c2ncc(CCc3ccccn3)cc2C(=O)N(C)c2cccnc21

Procedure:
5,11-Dihydro-11-ethyl-5-methyl-8-(pyrid-2-yl)ethynyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (0.15 g) was prepared by coupling 5,11-dihydro-11-ethyl-8-iodo-5-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one with 2-ethynylpyridine by a procedure analogous to that described in Example 42a. Hydrogenation as described in Example 42b afforded 24 mg of the title compound, m.p. 70°-72° C. (ethyl acetate/hexanes).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([OH:15])[CH:12]=2)[NH:7]1)=[O:5])C.C(=O)(O)[O-].[Na+].C([S:24][CH2:25][CH:26]([CH3:30])[C:27](Cl)=[O:28])(=O)C>C(Cl)Cl>[SH:24][CH2:25][CH:26]([CH3:30])[C:27]([N:7]1[C:8]2[C:13](=[CH:12][C:11]([OH:15])=[CH:10][CH:9]=2)[CH2:14][CH:6]1[C:4]([O-:3])=[O:5])=[O:28].[CH:8]1([NH2+:7][CH:6]2[CH2:4][CH2:27][CH2:26][CH2:25][CH2:14]2)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: CC(=O)SCC(C)C(=O)Cl
Reactant: CCOC(=O)C1Cc2cc(O)ccc2N1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C1CCC([NH2+]C2CCCCC2)CC1
Product: CC(CS)C(=O)N1c2ccc(O)cc2CC1C(=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To the stirred solution of 1.8 g of 5-hydroxyindoline-2-carboxylic acid ethyl ester in 50 ml of methylene chloride, is added 1.5 g of solid sodium bicarbonate, followed by 1.6 g of 3-acetylthio-2-methylpropanoyl chloride during 1 minute. The mixture is stirred for 3 hours at room temperature, diluted with 100 ml of methylene chloride and washed with 50 ml of water, 50 ml of 1N hydrochloric acid and 50 ml of saturated aqueous sodium bicarbonate. The organic layer is dried, evaporated and the residue taken up in 20 ml of methanol. This solution, and 17 ml of 2.03N aqueous potassium hydroxide, are each deoxygenated by bubbling nitrogen through for 10 minutes. The latter solution is added to the former and the mixture stirred for 2 hours at room temperature. It is combined with 50 ml of 1N hydrochloric acid, extracted thrice with 50 ml of methylene chloride, the extract dried and evaporated at room temperature. The residue is converted to its dicyclohexylamine salt as described previously, to yield the dicyclohexylammonium 1-(3-mercapto-2-methylpropanoyl)-5-hydroxyindoline-2-carboxylate melting at 208°-211°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:24])[CH:15]([NH:19][C:20]([O:22][CH3:23])=[O:21])[CH:16]([CH3:18])[CH3:17])[CH:10]([C:25]2[NH:26][CH:27]=[C:28]([C:30]3[CH:35]=[CH:34][C:33](Br)=[CH:32][CH:31]=3)[N:29]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:37][O:38][C:39](=[O:65])[NH:40][CH:41]([C:45]([N:47]1[CH2:51][CH2:50][CH2:49][CH:48]1[C:52]1[NH:53][C:54]([C:57]2[CH:62]=[CH:61][C:60]([C:63]#[CH:64])=[CH:59][CH:58]=2)=[CH:55][N:56]=1)=[O:46])[CH:42]([CH3:44])[CH3:43].C(N(CC)CC)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I.CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:24])[CH:15]([NH:19][C:20]([O:22][CH3:23])=[O:21])[CH:16]([CH3:18])[CH3:17])[CH:10]([C:25]2[NH:26][CH:27]=[C:28]([C:30]3[CH:35]=[CH:34][C:33]([C:64]#[C:63][C:60]4[CH:61]=[CH:62][C:57]([C:54]5[NH:53][C:52]([CH:48]6[CH2:49][CH2:50][CH2:51][N:47]6[C:45](=[O:46])[CH:41]([NH:40][C:39]([O:38][CH3:37])=[O:65])[CH:42]([CH3:44])[CH3:43])=[N:56][CH:55]=5)=[CH:58][CH:59]=4)=[CH:32][CH:31]=3)[N:29]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)NC(C(=O)N1CCN(C(=O)OC(C)(C)C)CC1c1nc(-c2ccc(Br)cc2)c[nH]1)C(C)C
Reactant: C#Cc1ccc(-c2cnc(C3CCCN3C(=O)C(NC(=O)OC)C(C)C)[nH]2)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)NC(C(=O)N1CCN(C(=O)OC(C)(C)C)CC1c1nc(-c2ccc(C#Cc3ccc(-c4cnc(C5CCCN5C(=O)C(NC(=O)OC)C(C)C)[nH]4)cc3)cc2)c[nH]1)C(C)C
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 58.2 %

Procedure:
3-[4-(4-Bromo-phenyl)-1H-imidazol-2-yl]-4-(2-methoxycarbonylamino-3-methyl-butyryl)-piperazine-1-carboxylic acid tert-butyl ester (600 mg, 1.06 mmol) was combined with (1-{2-[5-(4-Ethynyl-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (503 mg, 1.27 mmol) and Pd(PPh3)4 (122 mg, 0.106 mmol) under an argon atmosphere. DMF (degassed with Argon) was added followed by triethylamine (1.47 mL, 10.6 mmol) and copper(I) iodide (20.0 mg, 0.106 mmol). The mixture was heated at 80° C. After 20 minutes, volatiles were removed in vacuo and the crude material was semi-purified via chromatography on silica gel (eluent: EtOAc w MeOH 10%/hexanes) to yield the product 4-(2-Methoxycarbonylamino-3-methyl-butyryl)-3-{4-[4-(4-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenylethynyl)-phenyl]-1H-imidazol-2-yl}-piperazine-1-carboxylic acid tert-butyl ester (542 mg). LCMS-ESI+: calc'd for C47H59N9O8: 878.0 (M+). Found: 878.5 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([NH:12]C(=O)CCl)([CH3:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.NC(N)=S.C(O)(=O)C>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([NH2:12])([CH3:10])[CH3:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(Cc1cccc(Br)c1)NC(=O)CCl
Agent: NC(N)=S
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(N)Cc1cccc(Br)c1
Temperature: 25 °C
Yield: 96 %

Procedure:
A solution of N-[2-(3-bromophenyl)-1,1-dimethylethyl]-2-chloroacetamide (Preparation 17) (32.0 g, 105 mmol), thiourea (9.60 g, 126 mmol) and acetic acid (50 mL) in ethanol (250 mL) was heated to reflux overnight. The reaction mixture was cooled to room temperature and filtered, the filtrate was concentrated in vacuo and basified using aqueous sodium hydroxide solution (1M, 450 mL). The product was extracted with dichloromethane (2×500 mL) and the combined organics washed with brine (50 mL), dried (sodium sulfate) and the solvent removed in vacuo to afford the title compound as a black oil (23 g).
Reaction SMILES: [CH3:1][O:2][CH:3]([C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=1)[C:4]([OH:6])=O.[NH2:18][CH2:19][C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1>>[C:19]([C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH:25][C:4](=[O:6])[CH:3]([O:2][CH3:1])[C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=2)=[CH:22][CH:21]=1)#[N:18]
Reactant: COC(C(=O)O)c1ccc(OC(F)(F)F)cc1
Reactant: N#Cc1ccc(CN)cc1
Product: COC(C(=O)NCc1ccc(C#N)cc1)c1ccc(OC(F)(F)F)cc1

Procedure:
(RS)-Methoxy-(4-trifluoromethoxy-phenyl)-acetic acid was coupled with 4-aminomethyl benzonitrile according to general procedure B to give (RS)-N-(4-cyano-benzyl)-2-methoxy-2-(4-trifluoromethoxy-phenyl)-acetamide. Light blue semisolid. MS 365.2 ([M+H]+)
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]([CH2:17][C:18]#N)[C:7](SC2C=CC=CC=2)=[CH:8][CH:9]=1)([O-])=O.[OH2:20].S(=O)(=O)(O)[OH:22]>C(O)(=O)C>[C:6]1([CH2:17][C:18]([OH:22])=[O:20])[CH:7]=[CH:8][CH:9]=[CH:4][CH:5]=1
Reactant: O=S(=O)(O)O
Reactant: O
Reactant: N#CCc1cc([N+](=O)[O-])ccc1Sc1ccccc1
Solvent: CC(=O)O
Product: O=C(O)Cc1ccccc1

Procedure:
210.3 g of 3-nitro-6-(phenylthio)-phenylacetonitrile, 210 ml of water, 210 ml of concentrated sulphuric acid and 210 ml of acetic acid are heated to reflux for 20 hours. The mixture is cooled and extracted with ether. The organic phase is washed successively with water and aqueous sodium carbonate solution. The aqueous phase is made acid with hydrochloric acid and extracted with ethyl acetate. The organic phase is washed with water, dried over magnesium sulphate, evaporated under reduced pressure and the residue recrystallised from benzene. There is obtained 3-nitro-6 -phenylthio)-phenylacetic acid of melting point 138° - 140° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[CH:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH3:21])=[O:20])=[CH:15][CH:14]=1)[C:7]([CH3:22])=[C:6]2[CH2:23][C:24]([OH:26])=[O:25])#[N:2].[C:27](=[O:30])([O-])[O-].[K+].[K+].[CH3:33]C(C)=O>C(OCC)C>[C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[CH:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH3:21])=[O:20])=[CH:15][CH:14]=1)[C:7]([CH3:22])=[C:6]2[CH2:23][C:24]([O:26][CH2:33][O:30][CH3:27])=[O:25])#[N:2]
Reactant: O=C([O-])[O-]
Reactant: CC(C)=O
Reactant: CC1=C(CC(=O)O)c2cc(C#N)ccc2C1=Cc1ccc(S(C)=O)cc1
Agent: [K+]
Solvent: CCOCC
Product: COCOC(=O)CC1=C(C)C(=Cc2ccc(S(C)=O)cc2)c2ccc(C#N)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Alkoxyalkyl Esters - Chloromethyl methyl ether (0.055 mole) is added to a suspension of 5-cyano-2-methyl-1-(p-methylsulfinylbenzylidene)-3-indenylacetic acid (0.05 mole) and anhydrous potassium carbonate (0.15 mole) in 250 ml. of anhydrous acetone. The mixture is allowed to stir overnight at room temperature. Diethyl ether is added (about 200 ml.) and the mixture is filtered. The filtrate is washed once with 100 ml. of water and dried over anhydrous sodium sulfate. It is then filtered and the solvent is removed in vacuo. The residue is chromatographed on 200 g. of acid-washed alumina, using ether-petroleum ether (varying from 10-60% ether by volume) as the eluent, to give methoxymethyl 5-cyano-2-methyl-1-(p-methylsulfinylbenzylidene)-3-indenylacetate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[C:11]3=[CH:20][C:21]([C:23]([N:25]([CH3:27])[CH3:26])=O)=[CH:22][N:10]3[N:9]=2)=[CH:4][CH:3]=1.O1CCCC1.CSC.B>O1CCOCC1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[C:11]3=[CH:20][C:21]([CH2:23][N:25]([CH3:27])[CH3:26])=[CH:22][N:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: CN(C)C(=O)c1cc2c(N3CCOCC3)nc(-c3ccc(N)cc3)nn2c1
Agent: B
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: CSC
Product: CN(C)Cc1cc2c(N3CCOCC3)nc(-c3ccc(N)cc3)nn2c1
Yield: 97.7 %

Procedure:
1 g of compound 12a (2.7 mmol) and 50 mL of tetrahydrofuran or dioxane were added into a 150 mL two-neck flask and refluxed under nitrogen atmosphere. 2 M of borane-dimethyl sulfide solution (10.8 mmol) was slowly added dropwise and refluxed for 2 hours. The reaction mixture was quenched with methanol and purified by column chromatography with dichloromethane to give white solid 13a (930 mg, 96.7%). m.p. 205° C. (decomposition). 1H NMR (300 MHz, DMSO-d6): δ 7.92 (d, J=8.5 Hz, 2H), 7.86 (s, 1H), 7.05 (s, 1H), 6.60 (d, J=8.5 Hz, 2H), 5.48 (br s, 2H), 4.02 (t, J=4.5 Hz, 4H), 3.92 (s, 2H), 3.77 (t, J=4.5 Hz, 4H), 2.42 (s, 6H). MS (EI) m/e (%): 352 (M+, 24).
Reaction SMILES: [CH3:1][C:2]1[C:8]([CH3:9])=[C:7]([OH:10])[C:6]([CH3:11])=[CH:5][C:3]=1O.CCCCCC.Cl.[CH3:19][CH:20]([CH2:22][CH2:23][CH2:24][CH:25]([CH2:27][CH2:28][CH2:29][CH:30]([CH2:32][CH2:33][CH2:34][C:35]([OH:39])([CH:37]=[CH2:38])[CH3:36])[CH3:31])[CH3:26])[CH3:21]>[Cl-].[Zn+2].[Cl-].C(O)CCC>[CH3:9][C:8]1[C:7]([OH:10])=[C:6]([CH3:11])[C:5]2[CH2:38][CH2:37][C@:35]([CH2:34][CH2:33][CH2:32][C@@H:30]([CH2:29][CH2:28][CH2:27][C@@H:25]([CH2:24][CH2:23][CH2:22][CH:20]([CH3:19])[CH3:21])[CH3:26])[CH3:31])([CH3:36])[O:39][C:3]=2[C:2]=1[CH3:1]
Reactant: Cc1cc(O)c(C)c(C)c1O
Reactant: C=CC(C)(O)CCCC(C)CCCC(C)CCCC(C)C
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCCCCC
Solvent: CCCCO
Product: Cc1c(C)c2c(c(C)c1O)CC[C@@](C)(CCC[C@H](C)CCC[C@H](C)CCCC(C)C)O2
Reaction time: 3 h
Yield: 98.6 %

Procedure:
To a mixture consisting of 23.3 g (0.153 mol) of 2,3,5-trimethylhydroquinone, 17.5 g (0.128 mol) of zinc chloride, 47.5 ml of hexane, 2.5 ml of n-butanol and 2.5 g of concentrated hydrochloric acid, 46.1 g (0.153 mol) of isophytol (purity: 98.3%) were added dropwise under stirring at 30°-40° C. over 3 hours. At the same temperature, the reaction mixture was stirred for additional 2 hours. After the reaction mixture was washed with 10 ml of water, the solvents were distilled off. Toluene (100 ml ) was added to the residue to dissolve the same. The resulting solution was washed successively with water, alkaline water and a saturated aqueous solution of NaCl, dried over magnesium sulfate and then concentrated under reduced pressure, whereby 65.0 g of the title compound were obtained as a brown oil (yeld: 95.9%, GLC purity: 97.2%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3]CC(Cl)=O.CC1[O:14][CH:13]([CH3:15])[O:12][CH:11]([CH3:16])O1.C(=O)(O)[O-].[Na+].[Cl:22]CCl>>[Cl:1][CH2:2][CH2:3][CH2:15][C:13]([O:12][CH:11]([CH3:16])[Cl:22])=[O:14]
Reactant: ClCCl
Reactant: O=C(Cl)CCCCl
Reactant: CC1OC(C)OC(C)O1
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(Cl)OC(=O)CCCCl
Temperature: 85 °C
Yield: 58.6 %

Procedure:
4-Chlorobutyryl chloride (12.69 g, 90 mmol) was mixed with paraldehyde (3.964 g, 30 mmol) and heated at 85° C. for 90 minutes. Additional paraldehyde (1.35 g) was added and the reaction mixture was stirred at 85° C. for an additional hour. The reaction mixture as cooled to room temperature, diluted with dichloromethane (100 ml) and stirred with saturated aqueous sodium bicarbonate (50 ml) at room temperature for 10 minutes. The dichloromethane layer was separated, dried over sodium sulfate and concentrated in vacuo to yield Cl(CH2)3CO2CHClCH3 which was vacuum distilled (55°-58° C. at 0.1 mm, 9.65 g, 58.6% yield) whose structure was confirmed by NMR.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([OH:23])[CH:10]([NH2:22])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[F:31][C:32]([F:43])([F:42])[C:33]1[CH:38]=[CH:37][C:36]([N:39]=[C:40]=[O:41])=[CH:35][CH:34]=1>C(#N)C.O>[F:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([OH:23])[CH:10]([NH:22][C:40]([NH:39][C:36]2[CH:35]=[CH:34][C:33]([C:32]([F:31])([F:42])[F:43])=[CH:38][CH:37]=2)=[O:41])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:7][CH:8]=1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: O=C(Nc1ccc(C(F)(F)F)cc1)NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.6 %

Procedure:
To a solution of (1RS,2SR)-1-(4-fluorophenyl)-1-hydroxy-3-(4-(trifluoromethyl)phenyl)-2-propylamine hydrochloride (150 mg, 0.43 mmol) in acetonitrile (10 ml) were added triethylamine (0.089 ml, 0.64 mmol) and 4-trifluoromethylphenyl isocyanate (0.061 ml, 0.43 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (50 ml) and extracted with ethyl acetate (50 ml×2). The extract was washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (139 mg, 65%).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][CH2:9][C:10](=[O:14])[CH:11]([CH3:13])[CH3:12])=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].C(O)(=O)C>CN(C)C=O.O>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][CH:9]([C:10](=[O:14])[CH:11]([CH3:13])[CH3:12])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:7])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CBr
Reactant: CC(C)C(=O)CNC(=O)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CC(NC(=O)c1ccc(Cl)cc1)C(=O)C(C)C
Yield: 92 %

Procedure:
6 g of N-(4-chlorobenzoyl)isobutyrylmethylamine are dissolved in 30 ml of dimethylformamide, and 1.4 g of 61% sodium hydride are added thereto at -50° C. to -40° C. under stirring. When, 6.0 g of ethyl bromoacetate are added to the mixture at the same temperature. After the temperature of the mixture is risen to about 0° C. gradually, said mixture is further stirred until it becomes a clear solution. After the reaction, the mixture is neutralized with acetic acid, and then water is added thereto. The aqueous solution is extracted with ethyl acetate. The extract is washed with water, dried and then condensed under reduced pressure to remove solvent. The residue is recrystallized from a mixture of isopropyl ether and n-hexane. 7.5 g of ethyl 3-(4-chlorobenzoylamino)-3-isobutyrylpropionate are obtained. Yield: 92.0%.
Reaction SMILES: [F:1][C:2]1[C:7](I)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:9][Si:10]([C:13]#[CH:14])([CH3:12])[CH3:11].C(N(CC)CC)C>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[F:1][C:2]1[C:7]([C:14]#[C:13][Si:10]([CH3:12])([CH3:11])[CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Fc1ncccc1I
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cccnc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.9 %

Procedure:
Into a 1-neck round-bottom flask was added 2-fluoro-3-iodopyridine (1.0 g, 0.0045 mol), trimethylsilylacetylene (0.95 mL, 6.7 mmol), bis(triphenylphosphine)palladium(II) chloride (0.2 g, 0.2 mmol), copper(I) iodide (0.07 g, 0.4 mmol), and triethylamine (0.94 mL, 6.7 mmol) in N,N-dimethylformamide (20 mL). The reaction was stirred at 25° C. for 16 hours. The reaction was extracted with EtOAc, washed with brine, dried over MgSO4, and concentrated under vacuum. The product was purified by column chromatography on silica gel (10% ethyl acetate 90% hexanes) to give 0.747 g of the desired product. 1H NMR (400 MHz, CDCl3): δ 7.86-7.89 (m, 1H), 7.55-7.61 (m, 1H), 6.86-6.90 (m, 1H). MS [M+H]=194.0
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:22])=[O:21])=[CH:15][CH:14]=1.Br.Br[CH2:25][C:26]([C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1)=O.C1CCN2C(=NCCC2)CC1>C(#N)C>[N:31]1[CH:32]=[CH:33][C:28]([C:26]2[CH2:25][O:21][C:20](=[O:22])[C:19]=2[C:16]2[CH:15]=[CH:14][C:13]([O:12][CH2:11][C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:1]=3)=[CH:18][CH:17]=2)=[CH:29][CH:30]=1
Reactant: O=C(O)Cc1ccc(OCc2ccc3ccccc3n2)cc1
Reactant: O=C(CBr)c1ccncc1
Agent: Br
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C1OCC(c2ccncc2)=C1c1ccc(OCc2ccc3ccccc3n2)cc1
Reaction time: 1 h
Yield: 15.2 %

Procedure:
To a solution of 2-(4-(quinolin-2-ylmethoxy)phenyl)acetic acid (3.0 g, 0.01 mol) in acetonitrile (40 mL) were added TEA (1.3 mL, 0.01 mol) and 2-bromo-1-(pyridin-4-yl) ethanone hydrobromide (2.86 g, 0.01 mol) at RT under an inert atmosphere. The reaction mixture was stirred for 1 h followed by addition of DBU (46.6 g, 0.03 mol) at 0° C. and stirring was continued for another 2 h at 0° C. The reaction mixture was quenched with HCl (1 N), aqueous layer was basified with NaHCO3 solution and extracted with DCM (2×50 mL). The combined organic layers were washed with water, dried over Na2SO4 and concentrated in vacuo to obtain the crude product. The crude product was purified via silica gel column chromatography eluting with 25% EtOAc hexanes to afford 4-(pyridin-4-yl)-3-(4-(quinolin-2-ylmethoxy)phenyl)furan-2(5H)-one (600 mg, 15%) as a solid.