Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:10]([C:11]2[S:15][C:14]([C:16]([O:18]CC)=[O:17])=[C:13]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:12]=2)=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[OH-].[Na+].C1COCC1.Cl>O.C(O)C>[CH3:1][C:2]1[C:10]([C:11]2[S:15][C:14]([C:16]([OH:18])=[O:17])=[C:13]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:12]=2)=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1
Reactant: CCOC(=O)c1sc(-c2c(C)nn3ccccc23)cc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1nn2ccccc2c1-c1cc(-c2ccccc2)c(C(=O)O)s1
Temperature: 0 °C
Yield: 102.4 %

Procedure:
A mixture of ethyl 5-(2-methylpyrazolo[1,5-a]pyridin-3-yl)-3-phenylthiophene-2-carboxylate (119 mg, 0.327 mmol), a 8N aqueous solution of sodium hydroxide (5 mL), THF (5 mL) and ethanol (10 mL) and water (1 mL) was stirred for 1 h at 70° C. The mixture was allowed to cool to 0° C. To the mixture, was added a 6N aqueous solution of hydrogen chloride to adjust ca pH 3-4. The mixture was extracted with EtOAc-THF mixed solvent and the organic phase was washed with brine and dried over anhydrous magnesium sulfate. Insoluble materials were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was washed with diisopropyl ether and dried under vacuum to yield the title compound (112 mg, over yield) as a pale yellow solid. 1H NMR (300 MHz, d6-DMSO) δ: 12.83 (br s, 1H), 8.80-8.65 (m, 1H), 8.00-7.93 (m, 1H), 7.61-7.53 (m, 2H), 7.44-7.36 (m, 4H), 7.28 (s, 1H), 7.02-6.95 (m, 1H), 2.60 (s, 3H).
Reaction SMILES: I.CS[C:4]1[NH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]=1.[C:12]1([CH:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:19][NH2:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[ClH:27].C>CO.[OH-].[Na+].C(Cl)Cl>[ClH:27].[C:21]1([CH:18]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:19][NH:20][C:4]2[NH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]=2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CSC1=NCCCCCN1
Reactant: NCC(c1ccccc1)c1ccccc1
Agent: Cl
Agent: I
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: c1ccc(C(CNC2=NCCCCCN2)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A flask containing 2-methylthio-1,4,5,6,7,8-hexahydro-1,3-diazocine hydroiodide (3.00 g, 1.05×10-2 mole) and 2,2-diphenylethylamine (2.08 g, 1.05×10-2 mole) was immersed in an oil bath which had been preheated to ca. 155° C. The reaction was stirred at between 150°-160° C. for ca. 1 hour. The resulting yellow glass was dissolved in methanol. The methanol was evaporated leaving a foam which was dissolved in a two phase mixture of 5 molar aqueous NaOH (65 ml) and CH2Cl2 (60 ml). After stirring overnight the CH2Cl2 layer was separated. The aqueous alkaline layer was extracted with CH2Cl2 (2×). The CH2Cl2 layers were combined, washed with H2O (2×), washed with saturated aqueous NaCl, and dried over anhydrous Na2SO4. The drying agent was removed by filtration and the filtrate was evaporated at reduced pressure leaving a foam. The foam was dissolved in methanol (15 ml) and the solution was cooled to 0° C. This solution was then treated with a methanolic solution of HCl. The solution was treated with charcoal which was subsequently removed by filtration through a pad of celite. The filtrate was concentrated on the steam bath and 2-butanone was added periodically until the temperature of the solution reached ca. 80° C. Upon cooling the solution deposited a solid which was collected by filtration. This material was recrystallized two times from methanol/2-butanone affording 2-(2,2-diphenylethylamino)-1,4,5,6,7,8-hexahydro-1,3-diazocine hydrochloride as an off-white solid: 0.80 g (22%), m.p. 195°-197° C.
Reaction SMILES: [C:1]1([CH2:7][C:8]#N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:10][C:11]1([C:16]2[CH:21]=C[C:19]([N+:22]([O-])=[O:23])=[CH:18][CH:17]=2)[O:15][CH2:14][CH2:13][O:12]1.[OH-].[Na+]>CO>[CH3:10][C:11]1([C:16]2[CH:17]=[CH:18][C:19]3[C:8]([CH:21]=2)=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:23][N:22]=3)[O:12][CH2:13][CH2:14][O:15]1
Reactant: N#CCc1ccccc1
Reactant: CC1(c2ccc([N+](=O)[O-])cc2)OCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(c2ccc3noc(-c4ccccc4)c3c2)OCCO1
Reaction time: 16 h

Procedure:
Phenylacetonitrile (0.84 g, 7.2 mmol) and 2-methyl-2-(4-nitrophenyl)-1,3-dioxolane (mp. 69°-71° C. (1.50 g 7.2 mmol) were added to a room temperature solution of sodium hydroxide (1.44 g, 36 mmol) in methanol (8 ml). A slight exotherm was noted and stirring was continued for 16 hrs. The mixture was filtered and the collected solid washed several times with water and once with cold methanol to yield a yellow powder (1.60 g) with mp. 137° C. (lit. mp. 137°-138° C., see J. Heterocyclic Chem. 11, 107 (1974)).
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([C:11]1[CH:29]=[CH:28][C:14]([O:15][CH:16]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:17](=O)[OH:18])=[C:13]([Cl:30])[CH:12]=1)([CH2:8][CH2:9][CH3:10])([CH3:7])[CH3:6]>C1(C)C=CC=CC=1>[C:5]([C:11]1[CH:29]=[CH:28][C:14]([O:15][CH:16]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:17]([Cl:3])=[O:18])=[C:13]([Cl:30])[CH:12]=1)([CH2:8][CH2:9][CH3:10])([CH3:7])[CH3:6]
Reactant: CCCCCCCCC(Oc1ccc(C(C)(C)CCC)cc1Cl)C(=O)O
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CCCCCCCCC(Oc1ccc(C(C)(C)CCC)cc1Cl)C(=O)Cl
Temperature: 60 °C
Reaction time: 2 h

Procedure:
9.7 ml of thionyl chloride was added dropwise with stirring to 34.4 g of 2-(4-t-hexyl-2-chlorophenoxy)capric acid dissolved in 34 ml of toluene heated to 60° C. The reaction was carried out at 60° C. for 2 hours. Excess thionyl chloride and toluene were distilled off under reduced pressure. 40.1 g of 2-(4-t-hexyl-2-chlorophenoxy)capric acid chloride was obtained.
Reaction SMILES: [F:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[CH:12]=[N:11][CH:10]=[CH:9][C:8]=3[C:7](=[O:17])[C:6]=2[C:5]([OH:18])=[CH:4][CH:3]=1.ClC1C2C(=O)C3C=NC=CC=3C(=O)C=2C(O)=CC=1.[C:37]1([CH3:47])[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[CH:39][CH:38]=1.C(N(CC)CC)C>N1C=CC=CC=1>[F:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[CH:12]=[N:11][CH:10]=[CH:9][C:8]=3[C:7](=[O:17])[C:6]=2[C:5]([O:18][S:43]([C:40]2[CH:41]=[CH:42][C:37]([CH3:47])=[CH:38][CH:39]=2)(=[O:45])=[O:44])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C1c2ccncc2C(=O)c2c(F)ccc(O)c21
Agent: O=C1c2ccncc2C(=O)c2c(Cl)ccc(O)c21
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)Oc2ccc(F)c3c2C(=O)c2ccncc2C3=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The 1:1 mixture of 9-fluoro-6-hydroxybenzo[g]isoquinoline-5,10-dione and 9-chloro-6-hydroxybenzo[g]isoquinoline-5,10-dione, of Preparative Example 14a, (0.060 g) is dissolved in dry pyridine (2 mL) and p-toluenesulfonyl chloride (0.095 g) is added. After stirring at room temperature for one hour, triethylamine (0.25 mL) is added and stirring is continued for one additional hour. The reaction mixture is concentrated almost to dryness and partitioned between 1 N HCl (4 mL)-20% ammonium sulfate (6 mL) and ethyl acetate (10 mL). The aqueous phase is separated, extracted with ethyl acetate (3×5 mL) and discarded. The combined organic solutions are dried over anhydrous sodium sulphate and concentrated to dryness to give an approximately 1:1 mixture (0.095 g) of 9-fluoro-6-(p-toluenesulfonyloxy)benzo[g]isoquinoline-5,10-dione and 9-chloro-6-(p-toluenesulfonyloxy)benzo[g]isoquinoline-5,10-dione which is sued without further purification for the next step.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[N:11]([CH3:12])[N:10]=[C:9]([CH3:13])[C:8]=2[CH:14]=O)=[CH:4][CH:3]=1.[NH2:18][O:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2([CH3:32])[O:31][CH2:30][CH2:29][O:28]2)=[CH:23][CH:22]=1>C(O)C>[F:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[N:11]([CH3:12])[N:10]=[C:9]([CH3:13])[C:8]=2[CH:14]=[N:18][O:19][CH2:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]3([CH3:32])[O:28][CH2:29][CH2:30][O:31]3)=[CH:25][CH:26]=2)=[CH:4][CH:3]=1
Reactant: Cc1nn(C)c(Oc2ccc(F)cc2)c1C=O
Reactant: CC1(c2ccc(CON)cc2)OCCO1
Solvent: CCO
Product: Cc1nn(C)c(Oc2ccc(F)cc2)c1C=NOCc1ccc(C2(C)OCCO2)cc1
Yield: 71.1 %

Procedure:
1.1 Gram (0.0043 mole) of 5-(4-fluorophenoxy)-1,3-dimethylpyrazol-4-carbaldehyde and 0.9 g (0.0043 mole) of 2-[4-(aminooxymethyl)phenyl]-2-methyl-1,3-dioxolane were added to 20 ml of ethanol, and the resulting mixture was heated for 3 hours to carry out reaction. After completion of the reaction, ethanol was removed by evaporation under reduced pressure, after which water was added to the residue and extraction was carried out with ethyl acetate. The ethyl acetate extract was washed with water and dried, and ethyl acetate was removed by evaporation to obtain an oily product. This oily product was column-chromatographed on silca gel to obtain 1.3 g of the desired compound.
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:7]([O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O>N1C=CC=CC=1>[CH:1]1([O:6][C:19]([C:18]2[CH:22]=[CH:23][C:15]([O:14][CH2:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[CH:16][CH:17]=2)=[O:20])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OC1CCCC1
Reactant: O=C(Cl)c1ccc(OCc2ccccc2)cc1
Solvent: O
Solvent: c1ccncc1
Product: O=C(OC1CCCC1)c1ccc(OCc2ccccc2)cc1

Procedure:
Cyclopentanol (2.58g.; 0.03 m) was dissolved in pyridine (50 ml), 4-benzyloxybenzoyl chloride (6.76g; 0.03 m) was added and the mixture was boiled under reflux 6 hours. The resulting mixture was added to iced-water, extracted with ether, the organic extract washed with 2×100 ml. of 2N hydrochloric acid, 2×100 ml. saturated sodium bicarbonate solution and 1×100 ml. of water, dried (MgSO4) and evaporated. The ester was purified by elution from a column of silica in toluene.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]2[C:4]=1[C:5](=[O:15])C(=O)[NH:7]2.[OH-].[Na+].OO.CC[N:22]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>>[NH2:7][C:8]1[CH:9]=[C:10]([O:12][CH3:13])[CH:11]=[C:3]([O:2][CH3:1])[C:4]=1[C:5]([NH2:22])=[O:15]
Reactant: CCN=C=NCCCN(C)C
Reactant: COc1cc2c(c(OC)c1)C(=O)C(=O)N2
Agent: OO
Agent: On1nnc2ccccc21
Agent: [Na+]
Product: COc1cc(N)c(C(N)=O)c(OC)c1

Procedure:
2-Amino-4,6-dimethoxybenzamide has been prepared from 4,6-dimethoxyisatoic anhydride. The 4,6-dimethoxyisatoic anhydride was, in turn, prepared by a reaction of 4,6-dimethoxyanthranilic acid with phosgene (U.S. Pat. No. 4,191,840 and Org. Synth. 1947, 27, 45). A different route converts 3,5-dimethoxyaniline to its hydrochloride salt, after which the salt is reacted with oxalyl chloride to give 4,6-dimethoxyisatin. The isatin is converted to the target compound via an unstable carboxyl intermediate by reaction with sodium hydroxide and hydrogen peroxide followed by an EDCI/HOBt-mediated coupling to produce 2-amino-4,6-dimethoxybenzamide (WO 2008/92231).
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[CH:13]=[CH:14][S:15][C:8]=12.S([C:26]#[N:27])(C1C=CC(C)=CC=1)(=O)=O>C1COCC1>[Cl:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[CH:13]=[C:14]([C:26]#[N:27])[S:15][C:8]=12
Reactant: Clc1ccnc2ccsc12
Reactant: Cc1ccc(S(=O)(=O)C#N)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N#Cc1cc2nccc(Cl)c2s1
Temperature: 25 °C
Yield: 31.9 %

Procedure:
n-Butyllithium (2.2 mmol, 0.88 mL) was added dropwise to a solution of 7-chloro-thieno[3,2-b]pyridine (0.250 g, 1.48 mmol) in THF (10 mL) at −78° C. while the internal temperature was kept below −70° C. After 1 h TsCN (0.804 mg, 4.44 mmol) was added. After 3 h the reaction was quenched with distilled water (10 mL), warmed to rt, and the layers were separated. The aqueous layer was further extracted with ethyl acetate (3×10 mL). The combined organic extracts were dried (Na2SO4), then concentrated under reduced pressure. Purification by flash chromatography using a Biotage 40 S column eluting with hexane/ethyl acetate (7/3) afforded the title compound as a white solid (92 mg, 32%). MS: 195/197 (MH+); HPLC Rf: 4.89 min; HPLC purity: 85%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]([CH2:33][CH2:34][CH:35]([CH3:37])[CH3:36])[C:18]3[S:19][CH:20]=[C:21]([C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=4)[N:22]=3)=[CH:12][CH:11]=2)[CH:5]=[CH:4][C:3]=1[CH2:38][CH2:39][C:40]([O:42]CC)=[O:41].[OH-].[Na+].Cl>C(O)C.O1CCCC1>[F:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]([CH2:33][CH2:34][CH:35]([CH3:37])[CH3:36])[C:18]3[S:19][CH:20]=[C:21]([C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:31])([F:30])[F:32])=[CH:25][CH:24]=4)[N:22]=3)=[CH:12][CH:11]=2)[CH:5]=[CH:4][C:3]=1[CH2:38][CH2:39][C:40]([OH:42])=[O:41]
Reactant: CCOC(=O)CCc1ccc(NCc2ccc(CN(CCC(C)C)c3nc(-c4ccc(C(F)(F)F)cc4)cs3)cc2)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)CCN(Cc1ccc(CNc2ccc(CCC(=O)O)c(F)c2)cc1)c1nc(-c2ccc(C(F)(F)F)cc2)cs1
Temperature: 60 °C
Reaction time: 1 h
Yield: 63.5 %

Procedure:
To a solution of ethyl 3-[2-fluoro-4-({4-[((3-methylbutyl){4-[4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}amino)methyl]benzyl}amino)phenyl]propanoate (0.450 g, 0.720 mmol) in a mixture of ethanol (6 mL) and tetrahydrofuran (15 mL) was added 1 N sodium hydroxide (4.32 mL, 4.32 mmol), and the mixture was stirred at 60° C. for 1 hr. The reaction mixture was neutralized with 1 N hydrochloric acid, 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 recrystallized from diethyl ether-hexane to give the title compound (0.274 g, yield 64%) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][C:8]([CH3:27])([C:23]([O:25]C)=[O:24])[NH:9][C:10]([O:12][CH:13]2[CH:20]3[CH2:21][CH:16]4[CH2:17][CH:18]([CH2:22][CH:14]2[CH2:15]4)[CH2:19]3)=[O:11])=[CH:5][CH:4]=1.O.[OH-].[Li+]>>[CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][C:8]([CH3:27])([C:23]([OH:25])=[O:24])[NH:9][C:10]([O:12][CH:13]2[CH:20]3[CH2:21][CH:16]4[CH2:17][CH:18]([CH2:22][CH:14]2[CH2:15]4)[CH2:19]3)=[O:11])=[CH:5][CH:4]=1
Reactant: COC(=O)C(C)(Cc1ccc(OC)cc1)NC(=O)OC1C2CC3CC(C2)CC1C3
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(CC(C)(NC(=O)OC2C3CC4CC(C3)CC2C4)C(=O)O)cc1

Procedure:
The title compound was prepared from methyl O,α-dimethyl-N-[(tricyclo[3.3.1.13,7 ]dec-2-yloxy)carbonyl]-DL-tyrosinate (0.40 g, 0.001 mmol) and lithium hydroxide monohydrate (0.066 g, 0.001 mol, 1.5 eq) using the procedure described in Example 47, Step C. MS: 388.0 (MH+); 387.0 (M+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4](F)[C:3]=1[C:11]1[S:12][CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=1.FC1C=C(OC)C=CC=1B(O)O>>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:11]1[S:12][CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=1
Reactant: COc1cc(F)c(-c2nc(C(=O)O)cs2)c(F)c1
Agent: COc1ccc(B(O)O)c(F)c1
Product: COc1ccc(-c2nc(C(=O)O)cs2)c(F)c1

Procedure:
Following the procedure of Intermediate 104, replacing 2,6-difluoro-4-methoxyphenylboronic acid with 2-fluoro-4-methoxyphenylboronic acid gave the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:9]=[C:10]([C:14](=[O:16])[CH3:15])[CH:11]=[CH:12][CH:13]=2)=[N:6][CH:7]=1.N#N.[Cl-].[Cl-].[Ca+2].[CH3:22][N:23]([CH3:28])[CH2:24][CH2:25][CH2:26]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[CH3:22][N:23]([CH3:28])[CH2:24][CH2:25][CH2:26][O:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:9]=[C:10]([C:14](=[O:16])[CH3:15])[CH:11]=[CH:12][CH:13]=2)=[N:4][CH:3]=1
Reactant: CN(C)CCCO
Reactant: CC(=O)c1cccc(-c2ncc(O)cn2)c1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: N#N
Agent: [Ca+2]
Solvent: C1CCOC1
Product: CC(=O)c1cccc(-c2ncc(OCCCN(C)C)cn2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2.4 g of 1-[3-(5-hydroxypyrimidin-2-yl)phenyl]ethanone (11.2 mmol) are suspended in 40 ml of abs. THF in an N2-flushed apparatus with CaCl2 protection, 1.576 ml of 3-(dimethylamino)-1-propanol (13.44 mmol) and 5.602 g of polymer-bound triphenylphosphine (16.81 mmol) are added, and the mixture is stirred at RT for 30 min. 3.87 g of di-tert-butyl azodicarboxylate (16.81 mmol) are added with ice/H2O cooling and stirring, and the mixture is stirred at RT for a further 2 h. For work-up, the polymer is removed by filtration and rinsed with copious dichloromethane, and the filtrate is extracted 1× with water and 2× with aqueous 1 N HCl. The combined HCl extracts are rendered alkaline using NaOH and extracted 3× with 50 ml of dichloromethane. The dichloromethane extracts are combined, dried over sodium sulfate, evaporated to dryness and crystallised from petroleum ether 40-60; m.p. 61-2° C.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH:17][C:18](=[O:20])[CH3:19])#[CH:10]>>[C:5]1([CH3:8])[CH:6]=[CH:7][C:2]([C:10]2[N:17]([C:18](=[O:20])[CH3:19])[C:12]3[C:11]([CH:9]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:3][CH:4]=1
Reactant: Cc1ccc(I)cc1
Reactant: C#Cc1ccccc1NC(C)=O
Product: CC(=O)n1c(-c2ccc(C)cc2)cc2ccccc21
Yield: 57 %

Procedure:
The general procedure was used to convert 1-iodo-4-methylbenzene and N-(2-ethynylphenyl)acetamide to the title product. Purification by flash chromatography gave the analytically pure product as a white solid, 57% yield. 1H NMR (300 MHz, DMSO) δ 8.24-8.22 (d, J=8.2, 1H), 7.61-7.59 (d, J=6.3, 1H), 7.43-7.40 (d, J=8.0, 2H), 7.36-7.24 (m, 4H), 6.71 (s, 1H), 2.37 (s, 3H), 2.07 (s, 3H). 13C NMR (75 MHz, DMSO) δ 171.94, 140.70, 138.95, 137.81, 131.53, 130.12, 129.67, 129.64, 125.44, 124.26, 121.31, 116.24, 111.41, 28.41, 21.70. Anal. Calcd. for C17H15NO: C, 81.90; H, 6.06; N, 5.62. Found C, 81.66; H, 6.02; N, 5.62. m.p.: 67-69° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10](=O)[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].OC1C(OS(C2C=CC(C)=CC=2)(=O)=O)=C(I)C=CC=1.[NH2:37][C:38]([NH2:40])=[S:39]>C(#N)C>[NH2:40][C:38]1[S:39][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[N:37]=1
Reactant: NC(N)=S
Reactant: CCOC(=O)CC(=O)c1cccc([N+](=O)[O-])c1
Agent: Cc1ccc(S(=O)(=O)Oc2c(O)cccc2I)cc1
Solvent: CC#N
Product: CCOC(=O)c1sc(N)nc1-c1cccc([N+](=O)[O-])c1
Temperature: 65 °C
Reaction time: 1 h
Yield: 70.5 %

Procedure:
To a solution of ethyl 3-(3-nitrophenyl)-3-oxopropionate (3.45 g, 14.5 mmol) in 100 mL of acetonitrile was added hydroxy(tosyloxy)iodobenzene (6.3 g, 16.0 mmol). The resulting suspension was stirred at 65° C. for 1 h at which time the reaction was a homogeneous solution. Thiourea (1.22 g, 16.0 mmol) was added and stirring was continued at 65° C. for 2 h. The mixture was cooled and concentrated, and the residue was taken up in ethyl acetate, washed with saturated aq Na2CO3 and brine, dried (MgSO4) and concentrated. The residue was triturated with ethyl ether to afford 3.0 g (71%) of the title compound as a yellow solid. 1H NMR (DMSO-d6) δ: 8.47 (t, 1H, J=1.9 Hz); 8.24 (m, 1H) ; 8.21 (m, 1H); 7.97 (broad s, 2H); 7.65 (t, 1H, J=8.1 Hz); 4.08 (q, 2H, J=7.1 Hz); 1.11 (t, 3H, J=7.1 Hz).
Reaction SMILES: [C:1]([C:3](=[C:7](SC)[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)[C:4]([NH2:6])=[O:5])#[N:2].[NH:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)[NH2:18]>>[NH2:2][C:1]1[N:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[N:18]=[C:7]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: NNc1ccccn1
Reactant: CSC(=C(C#N)C(N)=O)c1ccc(C)cc1
Product: Cc1ccc(-c2nn(-c3ccccn3)c(N)c2C(N)=O)cc1

Procedure:
The title compound was prepared from 2-cyano-3-methylthio-3-(4-tolyl)acrylamide (4.64 mg, 2.0 mmol) and 2-hydrazinopyridine (218 mg, 2.0 mmol) following the procedure used for the compound of Example 12. The title compound was obtained as a white crystalline solid (350 mg) m.p. 244-247°. δH (d6DMSO) 8.46 (1H, dm, J 5.0 Hz), 7.97 (1H, ddd, J 8.4, 7.4, 1.9 Hz), 7.85 (1H, d, J 8.4 Hz), 7.68 (2H, br s), 7.47 (2H, d, J 8.1 Hz), 7.31 (2H, d, J 7.6 Hz), 7.29 (1H, signal obscured by overlapping d), 3.30 (2H, s) and 2.37 (3H, s). MS (ES+) 294 (MH+, 100%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][NH:25][CH2:26][CH3:27])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[OH:29][C:30]1([C:33]([OH:35])=O)[CH2:32][CH2:31]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][C:15]=2[CH2:24][N:25]([CH2:26][CH3:27])[C:33]([C:30]2([OH:29])[CH2:32][CH2:31]2)=[O:35])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: O=C(O)C1(O)CC1
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OCC)ccc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)C2(O)CC2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(2′-Ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester (0.240 g, 0.61 mmol), 1-hydroxy-1-cyclopropanecarboxylic acid (0.074 g, 0.73 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.175 g, 0.92 mmol), 1-hydroxybenzotriazole (0.124 g, 0.92 mmol), and triethylamine (0.21 mL, 1.53 mmol) were combined in CH2Cl2 (2 mL) and stirred at room temperature for 2 hours. The mixture was concentrated, and the residue was purified by silica gel chromatography (20-90% EtOAc in hexanes) to give the title compound.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[N:10]1([CH2:15][CH2:16][NH:17][C:18]2[N:23]=[C:22]([C:24]3[S:28][C:27]4[C:29]([C:33]5[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=5[C@H:40]([NH2:42])[CH3:41])=[CH:30][CH:31]=[CH:32][C:26]=4[CH:25]=3)[C:21]([F:43])=[CH:20][N:19]=2)[CH:14]=[CH:13][N:12]=[N:11]1.[CH:44]1[C:56]2[CH:55]([CH2:57][O:58][C:59]([NH:61][C@@H:62]([C:64](Cl)=[O:65])[CH3:63])=[O:60])[C:54]3[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=3)[C:48]=2[CH:47]=[CH:46][CH:45]=1>O1CCOCC1.C(Cl)(Cl)Cl.C(O)(C)C>[N:10]1([CH2:15][CH2:16][NH:17][C:18]2[N:23]=[C:22]([C:24]3[S:28][C:27]4[C:29]([C:33]5[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=5[C@H:40]([NH:42][C:64](=[O:65])[C@H:62]([NH:61][C:59](=[O:60])[O:58][CH2:57][CH:55]5[C:54]6[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=6[C:48]6[C:56]5=[CH:44][CH:45]=[CH:46][CH:47]=6)[CH3:63])[CH3:41])=[CH:30][CH:31]=[CH:32][C:26]=4[CH:25]=3)[C:21]([F:43])=[CH:20][N:19]=2)[CH:14]=[CH:13][N:12]=[N:11]1
Reactant: C[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)Cl
Reactant: C[C@@H](N)c1ccc(F)cc1-c1cccc2cc(-c3nc(NCCn4ccnn4)ncc3F)sc12
Solvent: CC(C)O
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: C[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N[C@H](C)c1ccc(F)cc1-c1cccc2cc(-c3nc(NCCn4ccnn4)ncc3F)sc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.2 %

Procedure:
Add diisopropylethylamine (43 mg, 335 μmol) to a solution of (R)—N-(2-(1H-1,2,3-triazol-1-yl)ethyl)-4-(7-(2-(1-aminoethyl)-5-fluorophenyl)benzo[b]thiophen-2-yl)-5-fluoropyrimidin-2-amine (80 mg, 167 μmol), (9-fluorenyl methoxycarbonyl)-D-alanine-chloride (83 mg, 251 μmol) in 1,4-dioxane (5 mL). Stir the mixture at RT for 3 h. Dilute the mixture with chloroform/IPA (3/1, 100 mL), wash with water/aqueous saturated sodium chloride, dry over sodium sulfate, and concentrate in vacuo. Purify the crude product by FCC (10% methanol in DCM as elute) to give the title compound as a yellow solid (129 mg, 100%). MS (ES) m/z 770 [M+1]+.