Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:3]=1.Cl[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=1[Cl:27])=[O:19].[OH-].[Na+].C(OCC)(=O)C>CN(C)C=O.O>[NH2:9][C:8]1[C:7]2[CH:6]=[N:5][C:4]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[N:3][C:2]=2[O:1][C:17]=1[C:18]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=1[Cl:27])=[O:19]
Reactant: O=C(CCl)c1ccc(Cl)cc1Cl
Reactant: N#Cc1cnc(-c2ccccc2)nc1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1c(C(=O)c2ccc(Cl)cc2Cl)oc2nc(-c3ccccc3)ncc12
Temperature: 110 °C
Reaction time: 12 h
Yield: 9.5 %

Procedure:
To a stirred solution of 4-hydroxy-2-phenyl-pyrimidine-5-carbonitrile (12) (50 mg, 0.25 mmol, from step 1) and 2-chloro-1-(2,4-dichlorophenyl)ethanone (85 mg, 0.38mmol, 1.5 equiv) in anhydrous N,N-dimethylformamide (1.0 mL) was added NaOH (30.4 mg, 0.76 mmol, 3.0 equiv). The dark brown reaction mixture was stirred at 110° C. for 12 h. The reaction was then poured into ethyl acetate (10 mL) and water (10 mL). Extracted with ethyl acetate (3×10 mL). The organic layer was dried (Na2SO4), filtered, and evaporated in vacuo. The crude product was purified by pre-HPLC to provide 9.1 mg (9.3%) of the desired compound as yellow solid. 1H-NMR (CD3CN) δ 9.36 (s, 1H), 8.50 (d, 2H), 7.66 (d, 1H), 7.55 (m, 5H); MS LC-MS (MH+=384/386).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]=1[Cl:11])=[O:5])C.[OH-].[Li+].CO.Cl>O1CCCC1.O>[Cl:11][C:10]1[N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:8]=[CH:7][C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1cnn(-c2ccccc2)c1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cnn(-c2ccccc2)c1Cl
Temperature: 70 °C
Reaction time: 1 h
Yield: 89.5 %

Procedure:
To a solution of 5-chloro-1-phenyl-1H-pyrazole-4-carboxylic acid ethyl ester (Intermediate 1; 7.3 g, 29.1 mmol) in tetrahydrofuran (70 mL) was added a solution of lithium hydroxide in water (7.3 g, 305 mmol) in water (70 mL). Methanol (˜10 mL) was added dropwise to the reaction mixture until only one layer was visible. The reaction mixture was stirred at 70° C. for 1 hour (reaction progress monitored by TLC). The reaction mixture was acidified to pH 3 with 1N hydrochloric acid and washed with dichloromethane (3×200 mL). The organic layer was dried over magnesium sulfate and evaporated to give 5-chloro-1-phenyl-1H-pyrazole-4-carboxylic acid (5.8 g, 91%), which HPLC analysis indicated was 85% pure. This material was used directly in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].C([O-])([O-])=O.[K+].[K+].Cl.Cl[CH2:18][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1>CN(C=O)C>[N:22]1[CH:23]=[CH:24][C:19]([CH2:18][O:1][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=2)[C:5]#[N:6])=[CH:20][CH:21]=1
Reactant: N#Cc1cccc(O)c1
Reactant: ClCc1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1cccc(OCc2ccncc2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 107 %

Procedure:
To a mixture of 3-hydroxybenzonitrile (4.76 g, 0.04 mol), K2CO3 (16.6 g, 0.12 mol) and DMF (100 ml) under argon was added 4-chloromethylpyridine hydrochloride (6.56 g, 0.04 mol). The reaction mixture was stirred at room temperature for about two days, the solvent was evaporated and the residue was partitioned between water and CH2 Cl2. The organic layer was washed with 2N aqueous NaOH (1×100 ml), brine, then was dried over MgSO4. The solvent was removed in vacuo to afford, as an amber solid, 9.0 g of 3-(4-pyridinylmethoxy)benzonitrile.
Reaction SMILES: [F:1][C:2]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[C:12](OC(=O)C)(=[O:14])[CH3:13]>N1C=CC=CC=1>[F:1][C:2]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:12](=[O:14])[CH3:13]
Reactant: Nc1cccc([N+](=O)[O-])c1F
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Nc1cccc([N+](=O)[O-])c1F
Reaction time: 16 h
Yield: 33.3 %

Procedure:
To a solution (233 mL) of 2-fluoro-3-nitroaniline (18.2 g, 116 mol) in pyridine was added acetic anhydride (27.4 mL, 291 mmol) and the mixture was stirrred at room temperature for 16 hrs. The reaction solution was concentrated under reduced pressure and the obtained residue was treated with isopropyl ether to give the title compound (19.2 g) as a powder.
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[CH:9]=[C:10]([NH:14][C:15]2[N:20]=[C:19]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([NH:27][CH2:28][CH3:29])[CH:22]=3)[CH:18]=[CH:17][N:16]=2)[CH:11]=[CH:12][CH:13]=1.Cl[CH2:31][O:32][CH3:33]>O1CCCC1>[Cl:7][C:8]1[CH:9]=[C:10]([NH:14][C:15]2[N:20]=[C:19]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([N:27]([CH2:28][CH3:29])[CH2:31][O:32][CH3:33])[CH:22]=3)[CH:18]=[CH:17][N:16]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: COCCl
Reactant: CCNc1cc(-c2ccnc(Nc3cccc(Cl)c3)n2)ccn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCN(COC)c1cc(-c2ccnc(Nc3cccc(Cl)c3)n2)ccn1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Solid potassium-t-butoxide (0.27 g, 2.5 mmol) is added at room temperature to a solution of (3-chloro-phenyl)-[4-(2-ethylamino-pyridin-4-yl)-pyrimidin-2-yl]-amine (0.5 g,1.5 mmol) in dry tetrahydrofurane (15 ml). The resulting solution is cooled to 0° C. and chloromethylmethylether (0.16 g, 2.0 mmol) is added at such a rate that the temperature does not exceed 5° C. After stirring the mixture for 2 hours at room temperature, the solvent is evaporated under reduced pressure and the product is purified by chromatography. The product is obtained in form of slightly yellow crystals, m.p. 114–115° C.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1([N:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:19](=[O:22])[CH2:20][CH3:21])[CH2:10][CH2:9][N:8](CC2C=CC=CC=2)[CH2:7][CH2:6]1)[CH3:2].[H][H]>[Pd].C(O)(=O)C>[CH2:1]([O:3][CH2:4][C:5]1([N:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:19](=[O:22])[CH2:20][CH3:21])[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)[CH3:2]
Reactant: CCOCC1(N(C(=O)CC)c2ccccc2)CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: CCOCC1(N(C(=O)CC)c2ccccc2)CCNCC1

Procedure:
A mixture of 14.4 parts of N-[4-(ethoxymethyl)-1-(phenylmethyl)-4-piperidinyl]-N-phenylpropanamide and 200 parts of acetic acid is hydrogenated at normal pressure and at room temperature with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. The residue is taken up in water, cooled and basified with ammonium hydroxide. The product is extracted with trichloromethane. The extract is washed with water, dried, filtered and evaporated, yielding N-[4-(ethoxymethyl)-4-piperidinyl]-N-phenylpropanamide as an oily residue.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([CH2:14][NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:9]1)=O)(C)(C)C.[ClH:26].O1CCOCC1>>[ClH:26].[NH:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([CH2:14][NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](CNC(=O)OCc2ccccc2)C1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(NC[C@@H]1CCCNC1)OCc1ccccc1
Reaction time: 3 h

Procedure:
Benzyl ((S)-1-(tert-butoxycarbonyl)piperidin-3-yl)methylcarbamate(895 mg, 2.57 mmol) was treated with a 4.0 M HCl solution in dioxane (3.2 mL, 12.85 mmol) Formation of a white precipitate was observed. After 3 h, complete conversion of starting material was seen by TLC. The solvent and excess HCl were removed under reduced pressure to obtain benzyl ((R)-piperidin-3-yl)methylcarbamate hydrochloride as a white solid. This solid was suspended in DMF/CH2Cl2 (3 mL/3 mL), followed by the addition of 2-(4-chloro-7-methylquinazolin-2-yl)phenol (696 mg, 2.57 mmol), and triethylamine (1.8 mL, 1.3 g, 12.85 mmol). The mixture was stirred at room temperature under an N2 atmosphere for 16 h. The reaction was then partitioned between H2O/CH2Cl2, and separated and the aqueous layer was extracted twice with CH2Cl2. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification via silica gel chromatography using 0-5% MeOH in CH2Cl2 gave benzyl ((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate as a thick yellow oil (610 mg, 49%). LC/MS: m/z 483.3 (M+H)+ at 2.83 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [C:1]([N:4]1[CH2:10][CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]2[CH:17]=[C:18]([O:25][CH3:26])[C:19]([S:21](Cl)(=[O:23])=[O:22])=[CH:20][C:7]=2[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[OH-].[NH4+:28]>C(Cl)Cl>[C:1]([N:4]1[CH2:10][CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]2[CH:17]=[C:18]([O:25][CH3:26])[C:19]([S:21](=[O:23])(=[O:22])[NH2:28])=[CH:20][C:7]=2[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: COc1cc2c(cc1S(=O)(=O)Cl)CCN(C(C)=O)CC2c1ccccc1
Reactant: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1cc2c(cc1S(N)(=O)=O)CCN(C(C)=O)CC2c1ccccc1

Procedure:
3-Acetyl-7-chlorosulfonyl-8-methoxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (3.9 g, 0.01 m) is dissolved in methylene chloride (50 ml) and added to concentrated ammonium hydroxide (15 ml), then stirred and filtered to give 3-acetyl-8-methoxy-1-phenyl-7-sulfamoyl-2,3,4,5-tetrahydro-1H-3-benzazepine.
Reaction SMILES: [I:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH:19](OC)(OC)OC>CO>[CH3:19][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:2]=1[I:1]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1I
Reactant: COC(OC)OC
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)c1cccc([N+](=O)[O-])c1I

Procedure:
2-iodo-3-nitro-benzoic acid (61 g, 208 mmol, prepared as described in Org. Syn. Coll. Vol. 1, 56-58, and 125-127), sulfuric acid (40.8 g, 416 mmol), and trimethyl orthoformate (88.4 g, 833 mmol) were dissolved in 500 mL dry MeOH. The reaction was refluxed under argon for 20 h. The reaction mixture was concentrated to 100 mL then partitioned between saturated NaHCO3(aq) and CH2Cl2. The layers were separated and the aqueous layer extrated three times with CH2Cl2. The combined organic layers were dried (MgSO4) and concentrated in vacuo. The yellow solid was crystallized from CH2Cl2/hexanes yielding 2-iodo-3-nitro-benzoic acid methyl ester, 57.8 g (90%) as a yellow solid: m.p.64.0-64.5° C.; 1H NMR (300 MHz, CDCl3) 3.99 (s, 3H), 7.54 (app t, J=7.8 Hz, 1H), 7.70 (dd, J=8.1, 1.8 Hz, 1H), 7.77 (dd, J=7.8, 1.8 Hz, 1H).
Reaction SMILES: [CH:1]1([C:4]2[NH:5][C:6]3[C:11]([CH:12]=2)=[C:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=3)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28]>C(#N)C>[C:17]([C:9]1[C:10]([C:13]([F:14])([F:15])[F:16])=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]([CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:4]([CH:1]1[CH2:2][CH2:3]1)=[CH:12]2)#[N:18]
Reactant: N#Cc1ccc2[nH]c(C3CC3)cc2c1C(F)(F)F
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)Cn1c(C2CC2)cc2c(C(F)(F)F)c(C#N)ccc21
Temperature: 85 °C
Reaction time: 8 h
Yield: 84.4 %

Procedure:
To a solution of 2-cyclopropyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 165A) (1.0 g, 4.0 mmol) in dry acetonitrile (25 mL) was added cesium carbonate (2.6 g, 8.0 mmol) and t-butyl bromoacetate (768 uL, 5.2 mmol) at rt. The mixture was stirred at 85° C. overnight. The solid was filtered and the filtrate was then concentrated in vacuo. The residue was triturated with EtOAc-hexane to afford the title compound (1.23 g) in quantitative yield: MS (ES) m/z 365 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6](/[CH:7]=[CH:8]/[S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[F:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1>>[CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6](/[CH:7]=[CH:8]/[S:9]([NH:20][C:19]2[CH:21]=[CH:22][C:16]([F:15])=[CH:17][CH:18]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(/C=C/S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(F)cc1
Product: COc1ccc(/C=C/S(=O)(=O)Nc2ccc(F)cc2)cc1
Yield: 60.3 %

Procedure:
A solution of (E)-4-methoxystyrylsulfonyl chloride (10 mmol) and 4-fluoroaniline (10 mmol) was subjected to General Procedure 1, part B. The title compound was obtained in 60.3% yield.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:18]=[N:17][C:12]3[O:13][CH2:14][CH2:15][NH:16][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1.[Br:21][C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([Br:33])[C:30]=1[O:31][CH3:32])[C:25](Cl)=[O:26].C(N(CC)CC)C.O>ClCCl>[Br:21][C:22]1[CH:23]=[C:24]([C:25]([N:16]2[CH2:15][CH2:14][O:13][C:12]3[N:17]=[CH:18][C:9]([C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:19])[F:20])=[CH:8][CH:7]=4)=[CH:10][C:11]2=3)=[O:26])[CH:28]=[C:29]([Br:33])[C:30]=1[O:31][CH3:32]
Reactant: FC(F)(F)c1ccc(-c2cnc3c(c2)NCCO3)cc1
Reactant: COc1c(Br)cc(C(=O)Cl)cc1Br
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COc1c(Br)cc(C(=O)N2CCOc3ncc(-c4ccc(C(F)(F)F)cc4)cc32)cc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.8 %

Procedure:
In a 10 ml flask, 7-(4-trifluoromethyl-phenyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine (67 mg, 0.24 mmol) and 3,5-dibromo-4-methoxy-benzoyl chloride (118 mg, 0.36 mmol) were dissolved in dichloromethane. Triethylamine (0.17 ml, 1.20 mmol) was added thereto and then stirred at room temperature for 2 hours. After completion of the reaction by adding water dropwise, the mixture was extracted with dichloromethane, and the combined organic layer was dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica eluting with a solvent of dichloromethane:methanol=19:1. The fractions containing the product were collected and evaporated to obtain (3,5-dibromo-4-methoxy-phenyl)-[7-(4-trifluoromethyl-phenyl)-2,3-dihydro-pyrido[2,3-b][1,4]oxazin-1-yl]-methanone as white solid (122 mg, 89%).
Reaction SMILES: [NH2:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][S:5][C:4]2[CH:13]=[CH:14][CH:15]=[CH:16][C:3]1=2.[Cl:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22](Cl)=[O:23]>O1CCOCC1>[Cl:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([NH:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][S:5][C:4]2[CH:13]=[CH:14][CH:15]=[CH:16][C:3]1=2)=[O:23]
Reactant: O=C(Cl)CCCCCl
Reactant: NC1c2ccccc2CSc2ccccc21
Solvent: C1COCCO1
Product: O=C(CCCCCl)NC1c2ccccc2CSc2ccccc21
Yield: 93.4 %

Procedure:
A mixture of 8.8 g of 11-amino-6,11-dihydrodibenzo[b,e]thiepin, 6.0 g of 5-chlorovaleryl chloride and 100 ml of dioxane is heated with stirring under reflux for 15 hours. The solvent is distilled off under reduced pressure. The residue is recrystallized from ethanol to give 12.5 g of the title compound, m.p. 155°-156° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1/[CH:11]=[CH:12]/[CH2:13][OH:14].C(P(CCCC)CCCC)CCC.[CH2:28]([O:30][C:31](=[O:44])[C@@H:32]([O:41][CH2:42][CH3:43])[CH2:33][C:34]1[CH:39]=[CH:38][C:37](O)=[CH:36][CH:35]=1)[CH3:29].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1C=CC=CC=1>[CH2:28]([O:30][C:31](=[O:44])[C@@H:32]([O:41][CH2:42][CH3:43])[CH2:33][C:34]1[CH:39]=[CH:38][C:37]([O:14][CH2:13]/[CH:12]=[CH:11]/[C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)=[CH:36][CH:35]=1)[CH3:29]
Reactant: OC/C=C/c1ccc2ccccc2c1
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: c1ccccc1
Product: CCOC(=O)[C@H](Cc1ccc(OC/C=C/c2ccc3ccccc3c2)cc1)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.6 %

Procedure:
Under an atmosphere of nitrogen, (E)-3-naphthalen-2-yl-prop-2-en-1-ol (190 mg, 0.8 mmol), tributylphosphine (323 mg, 1.6 mmol) and (S)-2-ethoxy-3-(4-hydroxy-phenyl)-propionic acid ethyl ester (184 mg, 1.0 mmol) were successively dissolved in dry benzene (20 mL). Solid 1,1′-(azodicarbonyl) dipiperidine (403 mg, 1.6 mmol) was added at 0° C. with stirring. After 10 min. the reaction was warmed to room temperature and the stirring continued for 1 h. The reaction mixture was concentrated in vacuo and the product purified by flash column chromatography, eluting with heptane/ethyl acetate (3:2), to give 180 mg (55%) of the title compound.
Reaction SMILES: O=[C:2]1[CH2:5][CH:4]([C:6]([O:8][CH3:9])=[O:7])[CH2:3]1.[NH2:10][CH2:11][C@@H:12]1[C@H:16]2[O:17][C:18]([CH3:21])([CH3:20])[O:19][C@H:15]2[C@H:14]([N:22]2[CH:30]=[N:29][C:28]3[C:23]2=[N:24][CH:25]=[N:26][C:27]=3[NH2:31])[O:13]1.[BH3-]C#N.[Na+]>CO>[NH2:31][C:27]1[N:26]=[CH:25][N:24]=[C:23]2[C:28]=1[N:29]=[CH:30][N:22]2[C@H:14]1[C@@H:15]2[O:19][C:18]([CH3:20])([CH3:21])[O:17][C@@H:16]2[C@@H:12]([CH2:11][NH:10][C@H:2]2[CH2:5][C@H:4]([C:6]([O:8][CH3:9])=[O:7])[CH2:3]2)[O:13]1
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](CN)O[C@H]2n1cnc2c(N)ncnc21
Reactant: COC(=O)C1CC(=O)C1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COC(=O)[C@H]1C[C@H](NC[C@H]2O[C@@H](n3cnc4c(N)ncnc43)[C@@H]3OC(C)(C)O[C@@H]32)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of methyl 3-oxocyclobutanecarboxylate (4.60 g, 35.94 mmol), 9-((3aR,4R,6R,6aR)-6-(aminomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-9H-purin-6-amine (11.0 g, 35.94 mmol) and Ti(iPrO)4 (4.0 g, 14.08 mmol) in MeOH (80 mL) was stirred at 45° C. for 2 h, then NaCNBH3 (4.5 g, 71.87 mmol) was added. The reaction was stirred at RT overnight. The reaction was quenched with aq. sat. NaHCO3 (40 mL) and filtered, extracted with DCM (80 mL×3), dried over Na2SO4 and concentrated. The residue was purified by preparative-HPLC to obtain the title compound (6.2 g, Yield 41%). 1H NMR (500 MHz, CDCl3): δH 8.38-8.34 (m, 1H), 7.90 (s, 1H), 5.98 (d, J=3.0 Hz, 1H), 5.75 (br s, 2H), 5.48-5.46 (m, 1H), 5.03-5.01 (m, 1H), 4.35-4.33 (m, 1H), 3.69-3.66 (m, 3H), 3.50-3.17 (m, 1H), 3.05-2.73 (m, 3H), 2.48-2.44 (m, 2H), 1.95-1.91 (m, 2H), 1.62 (s, 3H), 1.39 (s, 3H) ppm; ESI-MS (m/z): 419.2[M+1]+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10](=O)[CH2:11][CH3:12])=[CH:9][C:4]=2[CH2:3][CH2:2]1.[Cl:14][C:15]1[N:20]=[CH:19][C:18]([C:21]([C:23]2[CH:28]=[CH:27][C:26]([O:29]C3CCCCO3)=[CH:25][CH:24]=2)=O)=[CH:17][CH:16]=1>>[Cl:14][C:15]1[N:20]=[CH:19][C:18]([C:21]([C:23]2[CH:24]=[CH:25][C:26]([OH:29])=[CH:27][CH:28]=2)=[C:10]([C:8]2[CH:7]=[CH:6][C:5]3[O:1][CH2:2][CH2:3][C:4]=3[CH:9]=2)[CH2:11][CH3:12])=[CH:17][CH:16]=1
Reactant: CCC(=O)c1ccc2c(c1)CCO2
Reactant: O=C(c1ccc(OC2CCCCO2)cc1)c1ccc(Cl)nc1
Product: CCC(=C(c1ccc(O)cc1)c1ccc(Cl)nc1)c1ccc2c(c1)CCO2
Yield: 37 %

Procedure:
According to general procedure of McMurry reaction as example 1, step D described, 1-(2,3-dihydrobenzofuran-5-yl)propan-1-one (610 mg, 1.1 eq) was reacted with (6-chloropyridin-3-yl)(4-(tetrahydro-2H-pyran-2-yloxy)phenyl)methanone (1.0 g, 1.0 eq) to give 440 mg desired product (37%, Z/E=1/1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5]([OH:7])=O.[NH2:27][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([NH:27][C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)=[O:7])[CH:8]=[CH:9][C:10]=1[C:11]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)=[O:26]
Reactant: Nc1cccnc1
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Product: O=C(Nc1cccnc1)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to 3-aminopyridine via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4-(pyridin-3-yl)terephthalamide. MS (Q1) 463 (M)+.
Reaction SMILES: [O:1]1[CH2:5][CH:4]([OH:6])[CH:3]2[O:7][CH2:8][CH:9]([OH:10])[CH:2]12.N1C=CC=CC=1.[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>ClCCl>[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([O:6][CH:4]2[CH2:5][O:1][CH:2]3[CH:9]([OH:10])[CH2:8][O:7][CH:3]23)(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC1COC2C(O)COC12
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC2COC3C(O)COC23)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 49.8 %

Procedure:
To a solution of hexahydrofuro[3,2-b]furan-3,6-diol (10.00 g, 68.4 mmol) in dichloromethane (60 mL) was added pyridine (1.08 g, 13.7 mmol) and then the mixture was cooled to 0° C., and 4-methylbenzenesulfonyl chloride (15.66 g, 82.1 mmol) was added. The mixture was stirred at 0° C. for 30 min, and then warmed to room temperature overnight. The resulting mixture was diluted with dichloromethane (250 mL), washed with 1M HCl (300 mL) followed by water (300 mL) and brine (300 mL). The separated organic phase was dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified with a silica gel column chromatography (EtOAc/PE (v/v)=2/1) to afford the desired product as colorless oil (10.24 g, 49.8%).
Reaction SMILES: NC1C=CC=CC=1NC(=O)/C=C/C1C=CN(S(C2C=CC(C)=CC=2)(=O)=O)C=1.C(OC(=O)[NH:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[NH:41][C:42](=[O:65])/[CH:43]=[CH:44]/[C:45]1[CH:49]=[CH:48][N:47]([S:50]([C:53]2[CH:58]=[CH:57][C:56]([C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=3)=[CH:55][CH:54]=2)(=[O:52])=[O:51])[CH:46]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[NH:41][C:42](=[O:65])/[CH:43]=[CH:44]/[C:45]1[CH:49]=[CH:48][N:47]([S:50]([C:53]2[CH:54]=[CH:55][C:56]([C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=3)=[CH:57][CH:58]=2)(=[O:52])=[O:51])[CH:46]=1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)/C=C/c1ccn(S(=O)(=O)c2ccc(-c3ccccc3)cc2)c1
Agent: Cc1ccc(S(=O)(=O)n2ccc(/C=C/C(=O)Nc3ccccc3N)c2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccccc1NC(=O)/C=C/c1ccn(S(=O)(=O)c2ccc(-c3ccccc3)cc2)c1

Procedure:
The method used for preparation of this compound is analogous to the method described for compound 5. Starting materials: (2-{(E)-3-[1-(biphenyl-4-sulfonyl)-1H-pyrrol-3-yl]-allanoylamino}-phenyl)-carbamic acid tert-butyl ester (compound A7) (0.460 mmol), CH2Cl2 (50 ml), TFA (5 ml). Reaction conditions: room temperature, 18 hours.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[C:9]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:10][C:11]([NH2:15])=[C:12]([NH2:14])[CH:13]=1.[CH3:22][O:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1.ClCCl>N1C=CC=CC=1>[NH2:15][C:11]1[N:10]=[C:9]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[C:8]([C:7]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=2[F:1])=[CH:13][C:12]=1[NH:14][C:28](=[O:29])[C:27]1[CH:31]=[CH:32][C:24]([O:23][CH3:22])=[CH:25][CH:26]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: Nc1cc(-c2ccncc2F)c(-c2cccnc2)nc1N
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(C(=O)Nc2cc(-c3ccncc3F)c(-c3cccnc3)nc2N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 115 %

Procedure:
To a solution of 3″-fluoro-3,2′:3′,4″-terpyridine-5′,6′-diamine (Intermediate 1, 0.1 g, 0.36 mmol) in pyridine (2 mL), 4-methoxybenzoyl chloride (0.066 g, 0.39 mmol) was added. The mixture was stirred at room temperature overnight and the solvent was evaporated. Dichloromethane (1.6 mL) and tris-(2-aminoethyl)amine polystyrene (0.180 g, 0.72 mmol) were added and the mixture was stirred at room temperature for 1 h. The resin was filtrated and washed twice with dichloromethane. The filtrates were combined and the solvent was evaporated to give the title compound (0.172 g) which was used in the next step without further purification.