Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]4[NH:19][C:20]([C:22]5[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][N:29]([CH3:31])[CH3:30])[CH:23]=5)=[CH:21][C:14]=34)=[CH:11][N:10]([CH2:32][CH3:33])[N:9]=2)=[CH:4][CH:3]=1.[C:34]1([N:40]=[C:41]=[O:42])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>O1CCCC1.CCN(CC)CC>[CH3:33][CH2:32][N:10]1[N:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:41]([NH:40][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:42])=[CH:7][CH:6]=2)[C:12]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]3[C:14]=2[CH:21]=[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][N:29]([CH3:30])[CH3:31])[CH:23]=2)[NH:19]3)=[CH:11]1
Reactant: O=C=Nc1ccccc1
Reactant: CCn1cc(-c2ccnc3[nH]c(-c4cccc(CN(C)C)c4)cc23)c(-c2ccc(N)cc2)n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCn1cc(-c2ccnc3[nH]c(-c4cccc(CN(C)C)c4)cc23)c(-c2ccc(NC(=O)Nc3ccccc3)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44 %

Procedure:
To a stirred solution of 4-[3-(4-aminophenyl)-1-ethyl-1H-pyrazol-4-yl]-2-[3-(dimethylaminomethyl)phenyl]-1H-pyrrolo[2,3-b]pyridine (0.34 mmol) in tetrahydrofuran (5 mL) was added phenyl isocyanate (0.41 mmol) and two drops of Et3N. The reaction was stirred at room temperature for 1 h and concentrated to dryness under vacuum. The remaining solid was triturated with (1:1) diethyl ether: petroleum ether, filtered, and dried under vacuum. Purification by Gilson reverse phase HPLC gave the title compound as an off-white solid (44%). ESMS (M+H)+: 556.4
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([CH3:22])=[C:18](Cl)[N:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:24][O:25][C:26]1[N:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)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>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[N:17]=[C:18]([C:29]5[CH:30]=[N:31][C:26]([O:25][CH3:24])=[CH:27][CH:28]=5)[C:19]([CH3:22])=[CH:20][CH:21]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1Cl
Reactant: COc1ccc(B(O)O)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COc1ccc(-c2nc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2C)cn1
Temperature: 80 °C
Yield: 42.1 %

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(6-chloro-5-methylpyridin-2-yl)cyclopropanecarboxamide (66 mg, 0.20 mmol) was dissolved in 2 mL of 1,2-dimethoxyethane in a reaction tube. 6-Methoxypyridin-3-ylboronic acid (37 mg, 0.24 mmol), 0.2 mL of an aqueous 2 M sodium carbonate solution, and tetrakis(triphenylphosphine)palladium(0) (12 mg, 0.010 mmol) were added and the reaction mixture was heated at 80° C. overnight. The reaction was diluted with ethyl acetate (5 mL) and washed with water (5 mL). The organics were dried over sodium sulfate and evaporated to dryness. The resulting residue was purified by silica gel chromatography eluting with a gradient of 0-100% ethyl acetate in hexane to yield 1-(benzo[d][1,3]dioxol-5-yl)-N-(6′-methoxy-3-methyl-2,3′-bipyridin-6-yl)cyclo-propanecarboxamide (34 mg, 51%). ESI-MS m/z calc. 403.2. found 404.7 (M+1)+. Retention time 1.84 minutes.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[OH:11])#[N:2].[CH3:12][C:13]([O:16][C:17](=[O:30])[N:18]([CH2:20][CH2:21][C@H:22](O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:19])([CH3:15])[CH3:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+](C(OCC)=O)(C(OCC)=O)=[N-]>O1CCCC1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[O:11][C@@H:22]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:21][CH2:20][N:18]([CH3:19])[C:17](=[O:30])[O:16][C:13]([CH3:15])([CH3:14])[CH3:12])#[N:2]
Reactant: COc1ccc(C#N)c(O)c1
Reactant: CN(CC[C@H](O)c1ccccc1)C(=O)OC(C)(C)C
Agent: CCOC(=O)[N+](=[N-])C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(C#N)c(O[C@H](CCN(C)C(=O)OC(C)(C)C)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 69.4 %

Procedure:
To a stirred mixture of 2-cyano-5-methoxyphenol (149 mg, 1.00 mmol) and [(3S)-3-hydroxy-3-phenylpropyl]methylcarbamic acid 1,1-dimethylethyl ester (265 mg, 1.00 mmol) in tetrahydrofuran (10 ml) under nitrogen was added triphenylphosphine (290 mg, 1.10 mmol) followed by diethyl diazodicarboxylate (192 mg, 1.10 mmol). The reaction mixture was stirred at room temperature for 24 h, then evaporated to dryness. The residue was eluted down a flash chromatography column using 30% ethyl acetate/isohexane as eluent to give 275 mg (69%) of the subtitle compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=O)=[CH:4][CH:3]=1.[NH2:16][CH2:17][CH2:18][CH2:19][N:20]1[CH:24]=[CH:23][N:22]=[CH:21]1.[BH4-].[Na+].ClCCl>C(O)C>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH:6]([NH:16][CH2:17][CH2:18][CH2:19][N:20]2[CH:24]=[CH:23][N:22]=[CH:21]2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)c1ccc(Cl)cc1
Reactant: NCCCn1ccnc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: Clc1ccc(C(NCCCn2ccnc2)c2ccccc2)cc1
Temperature: 130 °C

Procedure:
In a similar manner to Example 1, a mixture of 4-chlorobenzophenone (8.0 g) and 1-(3-aminopropyl)imidazole (4.6 g) was heated at 130° C. for 12 hours. The mixture was cooled, dissolved in absolute ethanol (100 ml), treated with sodium borohydride (2.8 g) and the mixture boiled under reflux for 8 hours. The oil obtained after work-up, using dichloromethane as the extracting solvent, was distilled to give N-[α-(4-chlorophenyl)benzyl]-3-(imidazol-1-yl)propylamine, b.p. 240° C. (0.3 mmHg).
Reaction SMILES: [CH3:1][CH:2]([CH3:20])[CH:3]([C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([F:19])([F:18])[CH:15]([F:17])[F:16])=[CH:9][CH:8]=1)[C:4](O)=[O:5].S(Cl)([Cl:23])=O>C1C=CC=CC=1>[CH3:1][CH:2]([CH3:20])[CH:3]([C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([F:19])([F:18])[CH:15]([F:17])[F:16])=[CH:9][CH:8]=1)[C:4]([Cl:23])=[O:5]
Reactant: CC(C)C(C(=O)O)c1ccc(OC(F)(F)C(F)F)cc1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CC(C)C(C(=O)Cl)c1ccc(OC(F)(F)C(F)F)cc1
Yield: 105.6 %

Procedure:
A stirred mixture of 20.00 g (0.0680 mol) of 3-methyl-2-[p-(1,1,2,2-tetrafluoroethoxy)phenyl]butyric acid, 20.00 ml (33.2 g, 0.280 mol) of thionyl chloride (Baker), and 75 ml of dried benzene is refluxed for 4 hours. The reaction mixture is then evaporated and the resulting residue is diluted with 50 ml of benzene and again evaporated to give 22.46 g (106%) of a clear dark brown liquid. This product is used as is in the subsequent reactions. The liquid is examined by infrared analysis and determined to be the above-named product.
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1.N[C:20]1C=CC(N2CCC(N(C)C)C2)=C[CH:21]=1>>[F:1][C:2]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([C:9]([O:11][CH2:20][CH3:21])=[O:10])=[CH:12][CH:13]=1
Reactant: O=C(O)c1ccc(Oc2ccc(F)cc2F)cc1
Reactant: CN(C)C1CCN(c2ccc(N)cc2)C1
Product: CCOC(=O)c1ccc(Oc2ccc(F)cc2F)cc1

Procedure:
4-(2,4-Difluorophenoxy)benzoic acid was reacted with [1-(4-aminophenyl)pyrrolidin-3-yl]-dimethylamine by method E-b. This resulted in the product with the molecular weight of 437.19 (C25H25F2N3O2); MS (ESI): 438 (M+H+) as hydrotrifluoroacetate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][C:12](=O)[CH2:11][C:10](=[O:15])[CH2:9]1.P(Cl)(Cl)[Cl:17]>C(Cl)(Cl)Cl>[Cl:17][C:12]1[CH2:13][CH:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[CH2:9][C:10](=[O:15])[CH:11]=1
Reactant: O=C1CC(=O)CC(c2ccccc2Cl)C1
Reactant: ClP(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=C1C=C(Cl)CC(c2ccccc2Cl)C1
Temperature: 100 °C
Reaction time: 2.5 h

Procedure:
To a solution of 5-(2-chlorophenyl)cyclohexane-1,3-dione (3.0 g) in chloroform(10 ml) was added phosphorus trichloride (0.62 g), and the mixture was stirred at 100° C. for 2.5 hours. To the mixture was added phosphorus trichloride (0.62 g), and the mixture was stirred at 100° C. for 2 hours. The reaction solution was concentrated under reduced pressure, and to the residue was added ice-water. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure to give 3-chloro-5-(2-chlorophenyl)-2-cyclohexen-1-one, which was dissolved in ethanol (3 ml). To the solution were added sodium sulfide 9 hydrate (2.0 g) and water (3 ml), and the mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure. The residue was dissolved in water, and the solution was washed with diethylether. To the aqueous layer was added 4N hydrochloric acid to make the solution acidic, and the solution was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure to give oil of 5-(2-chlorophenyl)-3-mercapto-2-cyclohexen-1-one (1.8 g).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]=[C:10]([NH2:12])[CH:9]=[CH:8][CH:7]=2)=[CH:2]1.[CH2:13]([O:15][C:16]([N:18]=[C:19]=[S:20])=[O:17])[CH3:14]>O1CCOCC1>[CH2:13]([O:15][C:16](=[O:17])[NH:18][C:19]([NH:12][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]([C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)[N:11]=1)=[S:20])[CH3:14]
Reactant: CCOC(=O)N=C=S
Reactant: Nc1cccc(-c2ccsc2)n1
Solvent: C1COCCO1
Product: CCOC(=O)NC(=S)Nc1cccc(-c2ccsc2)n1
Yield: 73.3 %

Procedure:
A solution of 6-(3-thienyl)pyridin-2-amine (3.70 g; 21.0 mmol; 1.0 eq.) and ethoxycarbonyl isothiocyanate (2.73 mL; 24.1 mmol; 1.15 eq.) in dioxane (100 mL) was stirred at rt overnight. The precipitate formed was filtered and washed with c-Hex to give the title compound as a white solid (4.73 g; 73%). HPLC, Rt: 4.26 min. (purity 99.9%). LC/MS, M+(ESI): 308.3.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)[CH:21]=[CH:20][C:3]=1[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:8][CH:7]=1.C(N(CC)CC)C.[Cl:38][C:39]1[CH:44]=[C:43]([Cl:45])[CH:42]=[CH:41][C:40]=1[S:46](Cl)(=[O:48])=[O:47].[N-]=C=O>C(Cl)Cl>[Cl:38][C:39]1[CH:44]=[C:43]([Cl:45])[CH:42]=[CH:41][C:40]=1[S:46]([N:5]([CH2:4][C:3]1[CH:20]=[CH:21][C:22]([O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)=[CH:23][C:2]=1[Cl:1])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][N:15]2[CH2:16][CH2:17][CH2:18][CH2:19]2)=[CH:8][CH:7]=1)(=[O:48])=[O:47]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Reactant: Clc1cc(OC2CCCCO2)ccc1CNc1ccc(OCCN2CCCC2)cc1
Agent: [N-]=C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccc(Cl)cc1Cl)N(Cc1ccc(OC2CCCCO2)cc1Cl)c1ccc(OCCN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 144 h
Yield: 100 %

Procedure:
To a solution of [2-chloro-4-(tetrahydro-pyran-2-yloxy)-benzyl]-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amine (0.060 g, 0.15 mmol) in 0.4 mL methylene chloride was added triethylamine (0.06 mL, 0.45 mmol) and 2,4-dichlorobenzenesulfonyl chloride (0.074 g, 0.3 mmol). The reaction mixture was stirred at room temperature for 6 days. PS-isocyanate resin (0.050 g) and PStrisamine resin (0.050 g) were added and the reaction mixture was stirred for 2 hr. at room temperature. The resin was filtered off with the aid of methylene chloride. The filtrate was concentrated to afford the title compound of Step A (0.096 g). MS 639.3 (M+1)+
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH:9]=[C:10]([C@:14]3([CH3:24])[CH2:19][CH2:18][S:17][C:16]([NH:20]C(=O)C)=[N:15]3)[CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+]>CO.CO.O>[F:1][C:2]1[C:7]([C:8]2[CH:9]=[C:10]([C@:14]3([CH3:24])[CH2:19][CH2:18][S:17][C:16]([NH2:20])=[N:15]3)[CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CC(=O)NC1=N[C@](C)(c2cccc(-c3cccnc3F)c2)CCS1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: C[C@@]1(c2cccc(-c3cccnc3F)c2)CCSC(N)=N1
Temperature: 25 °C
Reaction time: 6 h
Yield: 65 %

Procedure:
To a solution of (S)-N-(4-(3-(2-fluoropyridin-3-yl)phenyl)-4-methyl-5,6-dihydro-4H-1,3-thiazin-2-yl)acetamide (450 mg, 1.3 mmoles) in methanol (40 mL) is added a solution of K2CO3 (210 mg, 1.5 mmoles) in methanol:water (2:1, 15 mL). The reaction is stirred at room temperature for 6 h. The solvent is removed under reduced pressure and the residue is dissolved in ethyl acetate. The ethyl acetate layer is washed with water and saturated aqueous NaCl, dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue is purified by using SCX column chromatography to give the title compound (65% yield): MS (m/z): 302 (M+1).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C:13](O)([C:25]([F:28])([F:27])[F:26])[CH2:14][C:15]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([Cl:24])[CH:18]=2)=[O:16])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C1(C)C=CC=CC=1.S(Cl)(Cl)=O>N1C=CC=CC=1>[F:30][C:2]([F:1])([F:31])[C:3]1[CH:4]=[C:5]([C:13]([C:25]([F:28])([F:27])[F:26])=[CH:14][C:15]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([Cl:24])[CH:18]=2)=[O:16])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: Cc1ccc(C(=O)CC(O)(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(F)(F)F)cc1Cl
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: Cc1ccc(C(=O)C=C(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(F)(F)F)cc1Cl
Temperature: 70 °C
Reaction time: 6 h
Yield: 99.6 %

Procedure:
0.96 g of 3-(3,5-bis(trifluoromethyl)phenyl)-1-(3-chloro-4-methylphenyl)-4,4,4-trifluoro-3-hydroxybutan-1-one, 1.92 g of toluene, 0.48 g of thionyl chloride and 0.32 g of pyridine were fed, and stirred for 6 hours at 70° C. The mixture was cooled to room temperature, and separated by adding 10 ml of toluene and iced water. The organic phase was washed with water, and the solvent was distilled off under reduced pressure. The obtained residue was roughly purified by using a small amount of silica gel to obtain 0.92 g of 3-(3,5-bis(trifluoromethyl)phenyl)-1-(3-chloro-4-methylphenyl)-4,4,4-trifluoro-2-buten-1-one as yellow liquid.
Reaction SMILES: [CH3:1][C:2]1[C:11]([O:12][C:13]2[C:14]([C:19](=[O:21])[CH3:20])=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:10][C:9]2[C:4](=[C:5]([F:22])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:23][Mg]Cl.Cl.C(=O)(O)[O-].[Na+]>O1CCCC1>[F:22][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([CH3:1])[C:11]([O:12][C:13]1[C:14]([C:19]([OH:21])([CH3:23])[CH3:20])=[N:15][CH:16]=[CH:17][CH:18]=1)=[CH:10]2
Reactant: C[Mg]Cl
Reactant: CC(=O)c1ncccc1Oc1cc2cccc(F)c2nc1C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nc2c(F)cccc2cc1Oc1cccnc1C(C)(C)O
Reaction time: 3 h

Procedure:
1.58 g of 1-[3-(2-methyl-8-fluoroquinolin-3-yloxy)-pyridin-2-yl]-ethanone were dissolved in 20 ml of dehydrated tetrahydrofuran. 2.7 ml of a 3 M tetrahydrofuran solution of methylmagnesium chloride were dropped therein while cooling with ice followed by stirring the reaction solution for 3 hours while continuing to cool with ice. Subsequently, the reaction solution was added to 1 N hydrochloric acid solution followed by neutralizing with aqueous sodium bicarbonate and then extracting with ethyl acetate. The extract was washed with saturated saline and dried with magnesium sulfate followed by distilling off the solvent under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 1.69 g of 2-[(8-fluoro-2-methylquinolin-3-yloxy)pyridin-2-yl]propan-2-ol.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([OH:16])=O)[CH2:10][CH:11]([CH3:13])C)=[O:7])([CH3:4])([CH3:3])C.[F:17][C:18]([F:35])([F:34])[C:19]1[CH:20]=[CH:21][C:22]([N:25]2[CH2:29][C@@H:28]3[C@@H:30]([NH2:33])[CH2:31][CH2:32][C@@H:27]3[CH2:26]2)=[N:23][CH:24]=1.C(N1C[C@@H]2[C@@H](N)CC[C@@H]2C1)C1C=CC=CC=1>>[O:16]=[C:14]([NH:33][C@@H:30]1[C@@H:28]2[C@@H:27]([CH2:26][N:25]([C:22]3[CH:21]=[CH:20][C:19]([C:18]([F:35])([F:34])[F:17])=[CH:24][N:23]=3)[CH2:29]2)[CH2:32][CH2:31]1)[C@@H:9]([NH:8][C:6](=[O:7])[O:5][CH:1]([CH3:3])[CH3:4])[CH2:10][CH2:11][CH3:13]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: N[C@H]1CC[C@@H]2CN(c3ccc(C(F)(F)F)cn3)C[C@@H]21
Agent: N[C@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21
Product: CCC[C@H](NC(=O)OC(C)C)C(=O)N[C@H]1CC[C@@H]2CN(c3ccc(C(F)(F)F)cn3)C[C@@H]21

Procedure:
The title compound was prepared by substituting (S)-2-(isopropoxycarbonylamino)pentanoic acid from Step A for N-(tert-butoxycarbonyl)-L-leucine and (3aR,4S,6aS)-2-(5-(trifluoromethyl)pyridin-2-yl)octahydrocyclopenta[c]pyrrol-4-amine from Step B of Example 262 for (3aR,4S,6aS)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine in the procedure described in Example 221: 1H NMR (400 MHz, pyridine-d5) δ ppm 8.52 (d, J=1.0, 1H), 7.94 (dd, J=4.3, 2.4, 1H), 7.60 (dd, J=8.9, 2.5, 1H), 7.07 (d, J=7.0, 1H), 6.35 (d, J=8.9, 1H), 5.03 (dt, J=12.5, 6.2, 1H), 4.49 (dd, J=13.9, 8.0, 1H), 4.35-4.19 (m, 1H), 3.73 (dd, J=11.3, 3.6, 1H), 3.66 (dd, J=11.3, 7.6, 1H), 3.57 (dd, J=11.0, 8.0, 1H), 3.32 (dd, J=11.2, 3.9, 1H), 2.81-2.66 (m, 2H), 2.10 (dt, J=12.4, 7.0, 1H), 2.04-1.88 (m, 2H), 1.86-1.75 (m, 1H), 1.72-1.60 (m, 1H), 1.57-1.46 (m, 2H), 1.45-1.33 (m, 1H), 1.21 (d, J=6.2, 3H), 1.18 (d, J=6.2, 3H), 0.87 (t, J=7.4, 3H); MS (ESI+) m/z 457 (M+H)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.[H-].[Na+].Br[C:12]([CH3:26])([CH3:25])[C:13]([NH:15][C:16]1[O:20][N:19]=[C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:17]=1)=[O:14]>C1COCC1>[C:21]([C:18]1[CH:17]=[C:16]([NH:15][C:13](=[O:14])[C:12]([CH3:25])([O:8][CH2:7][CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)[CH3:26])[O:20][N:19]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: OCC1CCOCC1
Reactant: CC(C)(Br)C(=O)Nc1cc(C(C)(C)C)no1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(OCC1CCOCC1)C(=O)Nc1cc(C(C)(C)C)no1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 17 %

Procedure:
To a solution of (tetrahydro-pyran-4-yl)-methanol (4 mL) at room temperature is added NaH (55 mg of a 60% dispersion in oil, 1.4 mmol). The reaction is warmed to 50° C. and stirred for 30 min. After this time, 2-bromo-N-(3-tert-butyl-isoxazol-5-yl)-2-methyl-propionamide (0.20 g, 0.69 mmol) is added and THF (2 mL) is introduced. The reaction is stirred at 60° C. for 5 h before it is quenched by the addition of methanol. The solvent is removed under reduced pressure and the crude residue that remains is purified by preparative HPLC to give the title compound (38 mg, 17%). m/z 289 [M+H+].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH2:11].Cl.Cl[CH2:14][CH2:15][N:16]([CH2:18][CH2:19]Cl)[CH3:17]>ClC1C=CC=CC=1.CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N:11]1[CH2:19][CH2:18][N:16]([CH3:17])[CH2:15][CH2:14]1
Reactant: Nc1cc([N+](=O)[O-])ccc1F
Reactant: CN(CCCl)CCCl
Agent: Cl
Solvent: CO
Solvent: Clc1ccccc1
Product: CN1CCN(c2cc([N+](=O)[O-])ccc2F)CC1
Yield: 30.5 %

Procedure:
A mixture of 2-fluoro-5-nitrobenzenamine (4.06 g) and 2-chloro-N-(2-chloroethyl)-N-methylethanamine hydrochloride (5.006 g) in chlorobenzene (20 ml) was heated at reflux under nitrogen for 21/2 days. The dark solid was dissolved in methanol (150 ml) and the solution was then concentrated in vacuo onto silica and purified by FCC eluting with System A (400:8:1) to give impure material (1.9 g). This was purified again by FCC eluting with System A (300:8:1) to give the title compound as a crystalline brown solid (360 mg).
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:8]([O:15][CH:16]([CH2:19]O)[CH2:17][OH:18])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1C=CC=CC=1>[CH2:8]([O:15][CH:16]1[CH2:17][O:18][C:1]2([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[O:7][CH2:19]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C1CCCCC1
Reactant: OCC(CO)OCc1ccccc1
Solvent: c1ccccc1
Product: c1ccc(COC2COC3(CCCCC3)OC2)cc1

Procedure:
Using the procedure of Example 51, cyclohexanone and 2benzyloxy-1,3-propanediol were reacted, using benzene as solvent, to give after distillation, 3-benzyloxy-1,5-dioxaspiro[5.5]undecane, b.p. 120°-121°/0.05 mm. The ir spectrum was consistent with the assigned structure.
Reaction SMILES: [CH:1]([OH:4])([CH3:3])[CH3:2].N12CCCC1=NCCC2.[Cl:14][C:15]1[CH:23]=[C:22]([F:24])[C:21]([C:25]2[C:29]([Br:30])=[C:28]([C:31]([F:34])([F:33])[F:32])[N:27]([CH3:35])[C:26]=2[Br:36])=[CH:20][C:16]=1[C:17](O)=[O:18].O>CN(C=O)C>[Cl:14][C:15]1[CH:23]=[C:22]([F:24])[C:21]([C:25]2[C:29]([Br:30])=[C:28]([C:31]([F:33])([F:34])[F:32])[N:27]([CH3:35])[C:26]=2[Br:36])=[CH:20][C:16]=1[C:17]([O:4][CH:1]([CH3:3])[CH3:2])=[O:18]
Reactant: Cn1c(Br)c(-c2cc(C(=O)O)c(Cl)cc2F)c(Br)c1C(F)(F)F
Reactant: CC(C)O
Agent: C1CN=C2CCCN2C1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)OC(=O)c1cc(-c2c(Br)c(C(F)(F)F)n(C)c2Br)c(F)cc1Cl
Temperature: 40 °C
Yield: 47.9 %

Procedure:
Isopropanol (0.2 g; 3.2 mmoles), 1,5-diazabicyclo -[4.3.0]non-5-ene (0.21 g; 1.6 mmoles) are added to a mixture of 2-chloro-5-(2,4-dibromo-1-methyl-5-trifluorometh-ylpyrrol-3-yl)-4-fluorobenzoic acid (0.8 g; 1.6 mmoles) and N,N′-carbonyldiimidazole (0.77 g; 1.6 mmoles) in DMF (4 ml) heated to 40° C. for 1.5 hours, and the mixture is heated to 40° C. for 2 hours. The reaction mixture is poured into water (10 ml), extracted with ethyl ether (3×20 ml), the ether phase is washed with a saturated solution of sodium chloride, anhydrified on sodium sulfate and concentrated in a rotavapor. The raw product obtained (0.8 g) is chromatographed on silica gel, eluating with n-hexane/ethyl acetate 90:10. 0.4 g of product are obtained in the form of a colourless oil.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:13])[C@@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[CH:6]=1)[OH:4].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[C:29]3[C:24](=[CH:25][C:26](I)=[CH:27][CH:28]=3)[CH:23]=[N:22]2)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)CCC.[Cu]I>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]2[C:29]3[C:24](=[CH:25][C:26]([O:4][C@H:3]([C:5]4[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[CH:6]=4)[C@@H:2]([NH2:1])[CH3:13])=[CH:27][CH:28]=3)[CH:23]=[N:22]2)=[CH:19][CH:20]=1
Reactant: Clc1ccc(-n2ncc3cc(I)ccc32)cc1
Reactant: COc1cccc([C@@H](O)[C@H](C)N)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCC#N
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(Cl)cc3)c2)[C@H](C)N)c1
Reaction time: 16 h

Procedure:
The subtitle compound was prepared analogous to the method described in Example 6 (step 6a). Starting from the hydrochloride salt of (1R,2S)-2-amino-1-(3-methoxyphenyl)propan-1-ol (6b) (0.88 g, 4.04 mmol), 1-(4-chlorophenyl)-5-iodo-1H-indazole (1.720 g, 4.85 mmol), CuI (0.154 g, 0.81 mmol) and cesium carbonate (3.95 g, 12.13 mmol) in butyronitrile (14 mL) stirred at +110° C. for 16 h. Work up and final purification by HPLC was followed by extraction of product into EtOAc from basic water solution, evaporation of solvents gave the subtitle compound as a sticky oil. Yield 490 mg (29%)
Reaction SMILES: [CH3:1]/[C:2](/[C:6]#[C:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[CH:3]\[CH2:4][OH:5].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[CH2:45]([O:47][C@@H:48]([CH2:54][C:55]1[CH:60]=[CH:59][C:58](O)=[CH:57][CH:56]=1)[C:49]([O:51][CH2:52][CH3:53])=[O:50])[CH3:46]>C1C=CC=CC=1>[CH2:52]([O:51][C:49](=[O:50])[C@@H:48]([O:47][CH2:45][CH3:46])[CH2:54][C:55]1[CH:60]=[CH:59][C:58]([O:5][CH2:4]/[CH:3]=[C:2](\[CH3:1])/[C:6]#[C:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:57][CH:56]=1)[CH3:53]
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Reactant: C/C(C#Cc1ccccc1)=C\CO
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: c1ccccc1
Product: CCOC(=O)[C@H](Cc1ccc(OC/C=C(\C)C#Cc2ccccc2)cc1)OCC
Yield: 70.3 %

Procedure:
The title compound was prepared from of (E)-3-methyl-5-phenyl-pent-2-en-4-yn-1-ol (0.172 g, 1.0 mmol), (J. Med. Chem. 1998, 41(14), 2524–2536), tributylphosphine (0.370 mL, 1.5 mmol), 1,1′-(azodicarbonyl) dipiperidine (0.378 g, 1.5 mmol) and (S)-ethyl 2-ethoxy-3-(4-hydroxy-phenyl)-propionate (0.262 g, 1.1 mmol) in dry benzene (20 mL) by a procedure analogous to that described in example 3, yielding 0.276 g (68%) of (E)-(S)-2-ethoxy-3-[4-(3-methyl-5-phenyl-pent-2-en-4-ynyloxy)-phenyl]-propionic acid ethyl ester.