Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[N:5]=[C:4]([NH:15][CH2:16][CH2:17][OH:18])[N:3]=1.[C:19]1([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[CH:12]1([CH2:11][NH:10][C:6]2[C:7]([C:8]#[N:9])=[C:2]([N:28]3[CH2:29][CH2:30][CH:25]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:26][CH2:27]3)[N:3]=[C:4]([NH:15][CH2:16][CH2:17][OH:18])[N:5]=2)[CH2:14][CH2:13]1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: N#Cc1c(Cl)nc(NCCO)nc1NCC1CC1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1c(NCC2CC2)nc(NCCO)nc1N1CCC(c2ccccc2)CC1

Procedure:
In analogy to the procedure described in example 20b, 4-chloro-6-(cyclopropylmethyl-amino)-2-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile (example 41b) was treated with 4-phenyl-piperidine in dioxane in the presence of N-ethyl-diisopropylamine at 90° C. to yield the 4-(cyclopropylmethyl-amino)-2-(2-hydroxy-ethylamino)-6-(4-phenyl-piperidin-1-yl)-pyrimidine-5-carbonitrile as an amorphous, white solid;
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[NH2:17][CH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:17][CH2:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:3]=1
Reactant: NCCCc1ccccc1
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Solvent: CCN(CC)CC
Product: Clc1nc(NCCCc2ccccc2)c2ncn(C3CCCC3)c2n1

Procedure:
2-Chloro-6-[3-(phenyl)propylamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 3-aminopropylbenzene, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [CH:1]1[C:13]2CC3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:14][C:15]([CH3:18])([O-])[CH3:16].[K+].IC>CS(C)=O>[CH3:14][C:15]1([CH3:18])[C:13]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[C:6]2[C:16]1=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: CS(C)=O
Product: CC1(C)c2ccccc2-c2ccccc21
Temperature: 10 °C
Reaction time: 24 h
Yield: 81.5 %

Procedure:
A 2000 mL round flask was charged with 9H-fluorene (50 g, 300.1 mmol) and potassium t-butoxide (77.0 g, 721.9 mmol), and then 700 mL of DMSO was slowly injected thereto. Under nitrogen atmosphere, iodomethane (113.5 g, 800 mmol) was slowly dropped through a dropping funnel while the reactor temperature was maintained at 10° C. or lower. The mixture was stirred at room temperature for 24 hours, and the reaction was terminated by addition of 500 mL of distilled water. The organic layer collected by extraction with n-hexane was dried over magnesium sulfate, followed by removal of volatile materials, and then purified with n-hexane by using silica gel column chromatography tube, followed by drying, to thereby obtain 47.5 g of 9,9-dimethyl-9H-fluorene (yield: 81.50%) as white solid.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]2[CH2:6][CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[NH:12]C(=O)OC(C)(C)C.FC(F)(F)C(O)=O>>[NH2:12][C:3]1[C:4]2[O:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:10]=[CH:11][C:2]=1[F:1]
Reactant: CC(C)(C)OC(=O)Nc1c(F)ccc2c1OCCC2
Solvent: O=C(O)C(F)(F)F
Product: Nc1c(F)ccc2c1OCCC2

Procedure:
Schema 5 illustrates the synthesis of an amino substituted 3,4-dihydro-2H-1-benzopyran, for example, 8-amino-5-chloro-3,4-dihydro-7-fluoro-2H-1-benzopyran, starting with the reaction of an appropriately halo-substituted phenol with 3-bromopropanol under basic conditions in acetone, yielding the corresponding substituted phenoxypropanol (XI). The propanol is oxidized with Jones reagent in water and acetone, giving an acid, for example, 3-(3-fluorophenoxy)propanecarboxylic acid (XII). The acid is in turn cyclized with phosphorous pentachloride and aluminium chloride in methylene chloride, affording the corresponding 3,4-dihydro-7-substituted-2H-1-benzopyran-4-one (XIII), which is then treated with sodium borohydride in methanol, yielding the appropriate 3,4-dihydro-7-substituted-4-hydroxy-2H-1-benzopyran, for example, 3,4-dihydro-7-fluoro-4-hydroxy-2H-1-benzopyran (XIV). The 4-hydroxybenzopyran is dehydrated with molecular sieves in the present of p-toluenesulfonic acid, yielding the corresponding 7-fluoro-2H-1-benzopyran (XV). This compound is then hydrogenated in the presence of 5% palladium on carbon in ethanol, yielding 3,4-dihydro-7-fluoro-2H-1 -benzopyran (XVI), which is in turn treated with n-butyllithium and carbon dioxide at -78° C. in tetrahydrofuran, affording the corresponding 3,4-dihydro-7-fluoro-2H-1-benzopyran-8-ylcarboxylic acid (XVII). The so-prepared acid is then refluxed with diphenylphosphoryl azide under mild basic conditions in t-butanol, giving the corresponding 1,1-dimethylethyl N-(3,4-dihydro-7-fluoro-2H-1-benzopyran-8-yl)carbamate (XVIII). The carbamate is then converted to the free amine by treating it with trifluoroacetic acid, yielding the 8-amino-3,4-dihydro-7-fluoro-2H-1-benzopyran intermediate (XIX). The intermediate benzopyran is optionally halogenated in the 5-position by treatment with, for example, N-chlorosuccinimide in N,N-dimethylformamide, yielding the desired 8-amino-5-chloro-3,4-dihydro-7-fluoro-2H-1-benzopyran (XX) intermediate. Examples 11 and 12 provide detailed descriptions of how these compounds are prepared.
Reaction SMILES: [CH2:1]([CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][NH:21][C:22]([C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[CH:31]=3)=[CH:26][CH:25]=2)=[O:23])=[CH:14][CH:13]=1)[C:6]([O:8]CC)=[O:7])[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>>[CH2:1]([CH:5]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:19][CH2:20][NH:21][C:22]([C:24]2[CH:25]=[CH:26][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[CH:31]=3)=[CH:28][CH:29]=2)=[O:23])=[CH:16][CH:17]=1)[C:6]([OH:8])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC(Cc1ccc(OCCNC(=O)c2ccc(-c3cccc(OC)c3)cc2)cc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: CCCCC(Cc1ccc(OCCNC(=O)c2ccc(-c3cccc(OC)c3)cc2)cc1)C(=O)O
Yield: 75.4 %

Procedure:
In a similar manner to that described in Example 2, ethyl 2-butyl-3-[4-[2-(3′-methoxybiphenyl-4-carbonylamino)ethoxy]phenyl]propionate (730 mg), which is the product of Example 31, was reacted with aqueous sodium hydroxide solution (1N, 4.50 ml) and the reaction mixture was treated to give the title compound (520 mg) as a white powder.
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.[C:16]([NH:26][C@H:27]([C:31]([OH:33])=[O:32])[CH:28]([CH3:30])[CH3:29])([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].[CH3:34][O:35][C:36]1[CH:55]=[CH:54][C:39]([CH2:40][O:41][C:42]([C:44]2[CH:49]=[CH:48][C:47](=[O:50])[N:46]([CH2:51][CH2:52]O)[CH:45]=2)=[O:43])=[CH:38][CH:37]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:34][O:35][C:36]1[CH:37]=[CH:38][C:39]([CH2:40][O:41][C:42]([C:44]2[CH:49]=[CH:48][C:47](=[O:50])[N:46]([CH2:51][CH2:52][O:32][C:31](=[O:33])[C@H:27]([CH:28]([CH3:29])[CH3:30])[NH:26][C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[CH:45]=2)=[O:43])=[CH:54][CH:55]=1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: COc1ccc(COC(=O)c2ccc(=O)n(CCO)c2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1ccc(COC(=O)c2ccc(=O)n(CCOC(=O)[C@@H](NC(=O)OCc3ccccc3)C(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.9 %

Procedure:
To a mixture of DCC (5.06 g, 24.5 mmol), DMAP (318 mg, 2.6 mmol) and N-CBz-L-valine (6.48 g, 25.8 mmol) in CH2Cl2 (200 mL) at 0° C., was added dropwise a solution of 1-(2-hydroxyethyl)-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid 4-methoxybenzyl ester (6.40 g, 24 mmol) in CH2Cl2 (200 mL). After 1 h at 0° C., the temperature of the reaction mixture was allowed to assume room temperature and then the mixture was stirred for 5 h at room temperature. The mixture was filtered through a glass filter and the solvent was removed under reduced pressure. The crude product was column chromatographed (silica gel, 2→5% MeOH in CH2Cl2), to give 6.81 g 1-(2-N-CBz-L-valyloxyethyl)-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid 4-methoxybenzyl ester.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9]Br)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC=CC=1.[H-].[Na+].[C:22]([NH:25][CH:26]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:27]([O:29][CH2:30][CH3:31])=[O:28])(=[O:24])[CH3:23]>O.C(O)C>[C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][CH2:23][C:22]([NH:25][CH:26]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:24])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: CC(C)(C)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)C(NC(=O)CCc1ccc(C(C)(C)C)cc1)C(=O)OCC
Temperature: 110 °C
Yield: 68.5 %

Procedure:
25 g of 4-tert-butylbenzyl bromide, 50 ml of anhydrous toluene and 3.1 g of sodium hydride as an 80% suspension in oil are added under a nitrogen atmosphere to a three-necked flask on which is mounted a condenser, followed by addition of 21.8 g of diethyl acetamidomalonate. The mixture is heated at 110° C. for 17 hours. After cooling, 15 ml of absolute ethanol, then 15 ml of 50% ethanol and then 50 ml of water are added slowly using a dropping funnel. The organic phase is separated out after settling has taken place and the aqueous phase is washed with 3 times 50 ml of diethyl ether. The organic phases are combined, washed with water and then dried over sodium sulphate. After filtering and concentrating under reduced pressure, the product is crystallized from petroleum ether to give 25 g of diethyl 4-(tert-butyl)benzylacetamidomalonate in the form of a white solid melting at 80° C.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH:12]1[CH:16]=[N:15][CH:14]=[N:13]1.C1CCN2C(=NCCC2)CC1>C(Cl)Cl>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][N:12]2[CH:16]=[N:15][CH:14]=[N:13]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: c1nc[nH]n1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: O=[N+]([O-])c1ccc(Cn2cncn2)cc1

Procedure:
1.0 g (4.63 mmol) of 4-nitrobenzyl bromide (Fluka, Buchs, Switzerland), 799 mg (11.6 mmol) of 1,2,4-triazole and 0.692 mL (4.63 mmol) of 1,5-diazabicyclo[5.4.0]-5-undecene (Fluka, Buchs, Switzerland) in 10 ml of CH2Cl2 are stirred at rt for 1.5 h. The reaction mixture is quenched with sat. aqueous NaHCO3 and extracted with CH2Cl2 (2×). The organic layers are washed with brine, dried over MgSO4, filtered and evaporated. The residue is purified by flash chromatography (CH2Cl2-MeOH 49:1 to 19:1) to provide the title compound as a pale yellow solid. ES-MS: 205 (M+H)+; analytical HPLC: tret=2.54 minutes (Grad 1).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([O:7][C:8]2[CH:13]=[CH:12][C:11](Br)=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.C([Li])CCC.[CH:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1>[O:7]([C:8]1[CH:13]=[CH:12][C:11]([CH:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[OH:27])=[CH:10][CH:9]=1)[C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: Brc1ccc(Oc2ccccc2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC(c1ccccc1)c1ccc(Oc2ccccc2)cc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a stirred solution of 4-bromodiphenyl ether (2.0 g, 8.03 mmol) in THF (15 mL) at −78° C. was added n-butyllithium (3.85 mL, 2.6 M solution in hexanes). The reaction was stirred under argon for 2 hrs before a solution of benzaldehyde (0.85 g, 8.03 mmol) in THF at −78° C. was added. After stirring at −78° C. for 2 hrs, the reaction was quenched with water and extracted with ether. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude mixture was purified via flash SiO2 chromatography (ethyl acetate/hexanes (10%/90%) to (15%/85%)) to give 127 (2.22 g, 97% yield): 1H-NMR (400 MHz, chloroform-d) δ 7.28-7.40 (m, 9 H), 7.10 (t, J=7.6, 1 H), 6.94-7.01 (m, 4 H), 5.84 (d, J=3.6 Hz, 1 H), 2.17 (d, J=3.6 Hz, 1 H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[C:20]3[CH:21]=[C:22]([C:25](=[N:27][OH:28])[NH2:26])[CH:23]=[CH:24][C:19]=3[NH:18][C:17]3[N:29]=[C:30]([C:33]([F:36])([F:35])[F:34])[CH:31]=[CH:32][C:16]=3[CH2:15]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.Cl[C:44](OCC)=[O:45]>C(Cl)Cl.CN(C=O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]2[C:20]3[CH:21]=[C:22]([C:25]4[NH:26][C:44](=[O:45])[O:28][N:27]=4)[CH:23]=[CH:24][C:19]=3[NH:18][C:17]3[N:29]=[C:30]([C:33]([F:35])([F:36])[F:34])[CH:31]=[CH:32][C:16]=3[CH2:15]2)(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N2Cc3ccc(C(F)(F)F)nc3Nc3ccc(C(N)=NO)cc32)cc1
Reactant: CCOC(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)c1ccc(S(=O)(=O)N2Cc3ccc(C(F)(F)F)nc3Nc3ccc(-c4noc(=O)[nH]4)cc32)cc1
Temperature: 25 °C

Procedure:
To 6-[(4-tert-butylphenyl)sulfonyl]-N′-hydroxy-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine-8-carboximidamide (intermediate 55, 0.040 g, 0.0771 mmol) in DCM (0.7 mL) and DMF (1 mL) at 0° C. was added pyridine (7.9 mg, 0.100 mmol) and ethyl chloroformate (8.8 mg, 0.081 mmol), and the reaction was allowed to warm room temperature over 2 h. The volatiles were removed, and the residue was purified by SiO2 column chromatography, eluting with 0-100% EtOAc in hexanes, to yield the desired product. LC/MS: m/e 592.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:31][CH3:32])=[C:6]([S:8]([NH:11][C:12]2[CH:13]=[C:14]([CH:28]=[CH:29][CH:30]=2)[C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24](=[NH:27])[NH:25][OH:26])=[CH:20][CH:19]=2)=[O:16])(=[O:10])=[O:9])[CH:7]=1.[C:33](N1C=CN=C1)(N1C=CN=C1)=[S:34].N12CCCC1=NCCC2>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:31][CH3:32])=[C:6]([S:8]([NH:11][C:12]2[CH:13]=[C:14]([CH:28]=[CH:29][CH:30]=2)[C:15]([NH:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[NH:27][C:33](=[S:34])[O:26][N:25]=3)=[CH:22][CH:23]=2)=[O:16])(=[O:10])=[O:9])[CH:7]=1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: COc1ccc(Cl)cc1S(=O)(=O)Nc1cccc(C(=O)Nc2ccc(C(=N)NO)cc2)c1
Agent: C1CN=C2CCCN2C1
Solvent: CC#N
Product: COc1ccc(Cl)cc1S(=O)(=O)Nc1cccc(C(=O)Nc2ccc(-c3noc(=S)[nH]3)cc2)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 20.2 %

Procedure:
3-(5-Chloro-2-methoxy-benzenesulfonylamino)-N-[4-(N-hydroxycarbamimidoyl)-phenyl]-benzamide (110 mg, 0.23 mmol) was diluted in acetonitrile (2 ml) under argon. 1,1′-Thiocarbonyldiimidazole (TCDI) (68 mg, 0.38 mmol, 1.65 equiv.) was then added, followed by 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) (114 mg, 3.95 equiv.). The mixture was stirred at room temperature for 6 hours, then the solvents were evaporated. The residue was diluted with water and the pH was adjusted to 4 with HCl 1N. The aqueous phase was extracted with ethyl acetate, and the organic phase evaporated. The residue was dissolved in NaOH 1N, and washed with ether. The aqueous solution was adjusted to pH 4 with HCl 1N and then extracted with ethyl acetate. The organic phase was dried over sodium sulfate and evaporated. Purification via flash chromatography (dichloromethane/methanol) yielded the title compound as a light yellow solid (24 mg, 20%), MS (ISP): m/e=515.1 (M−H).
Reaction SMILES: [C:1]1([CH:7]([NH:12][C:13]([NH:15][CH2:16][CH2:17]Cl)=[O:14])[C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C>O>[F:9][C:8]([F:11])([F:10])[CH:7]([NH:12][C:13]1[O:14][CH2:17][CH2:16][N:15]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(NCCCl)NC(c1ccccc1)C(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Product: FC(F)(F)C(NC1=NCCO1)c1ccccc1
Yield: 95 %

Procedure:
7.6 g of N-(α-phenyl trifluoroethyl) N'-(β-Chloroethyl) Urea are suspended in 60 ml water, then 4.3 ml triethylamine are added and the whole mixture is heated to reflux under stirring for 30 mn. The reaction mixture is let to revert to about 20°, the precipitate is separated which is dried, washed with water until the washings are neutral and dried under vacuum--6.3 g 2-[α-(trifluoromethyl) benzylamino] oxazoline are obtained i.e. a yield of 95%. For analytical purpose the compound is recrystallized from isopropanol with a yield of 73%. The analytical sample melts at 162°-168° (sublim).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:21]([CH3:24])=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([N:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[CH:11]=1.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](Cl)=[O:31]>CN1CCCC1=O>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:3]=[C:2]([NH:1][C:30](=[O:31])[C:29]5[CH:33]=[CH:34][CH:35]=[C:27]([C:26]([F:25])([F:36])[F:37])[CH:28]=5)[CH:23]=[CH:22][C:21]=4[CH3:24])=[CH:11][N:10]3[N:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: Cc1ccc(N)cc1Oc1ccc2nc(NC(=O)C3CC3)nn2c1
Solvent: CN1CCCC1=O
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1Oc1ccc2nc(NC(=O)C3CC3)nn2c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 65.3 %

Procedure:
To a solution of N-[6-(3-amino-6-methylphenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (100 mg, 0.309 mmol) in 1-methylpyrrolidin-2-one (2.0 mL) was added 3-(trifluoromethyl)benzoyl chloride (78 mg, 0.371 mmol), and the mixture was stirred at room temperature for 10 hr. The reaction mixture was concentrated under reduced pressure, the residue was diluted with ethyl acetate (100 mL), washed with 5% aqueous sodium hydrogen carbonate solution (50 mL) and saturated brine (50 mL), and dried over anhydrous sodium sulfate. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH silica gel, hexane/ethyl acetate=50/50→0/100), and the obtained oil was triturated with ethyl acetate and hexane to give the title compound (100 mg, 65%) as a colorless powder.
Reaction SMILES: [CH:1]1([C:4]2[CH:41]=[CH:40][C:7]([CH2:8][O:9][C:10]3[CH:15]=[CH:14][C:13]([CH:16]4[CH2:19][N:18]([C:20]([C:22]5[CH:27]=[C:26]([CH2:28][O:29][CH2:30][C@@H:31]6[CH2:35][O:34]C(C)(C)[O:32]6)[CH:25]=[CH:24][N:23]=5)=[O:21])[CH2:17]4)=[CH:12][C:11]=3[O:38][CH3:39])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.C1(C2C=CC(COC3C=CC(C4CN(C(C5C=C([C@H](C6COC(C)(C)O6)OC)C=CN=5)=O)C4)=CC=3OC)=CC=2)CC1.Cl>O1CCCC1>[CH:1]1([C:4]2[CH:41]=[CH:40][C:7]([CH2:8][O:9][C:10]3[CH:15]=[CH:14][C:13]([CH:16]4[CH2:17][N:18]([C:20]([C:22]5[CH:27]=[C:26]([CH2:28][O:29][CH2:30][C@@H:31]([OH:32])[CH2:35][OH:34])[CH:25]=[CH:24][N:23]=5)=[O:21])[CH2:19]4)=[CH:12][C:11]=3[O:38][CH3:39])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: COc1cc(C2CN(C(=O)c3cc(COC[C@@H]4COC(C)(C)O4)ccn3)C2)ccc1OCc1ccc(C2CC2)cc1
Agent: COc1cc(C2CN(C(=O)c3cc([C@@H](OC)C4COC(C)(C)O4)ccn3)C2)ccc1OCc1ccc(C2CC2)cc1
Agent: Cl
Solvent: C1CCOC1
Product: COc1cc(C2CN(C(=O)c3cc(COC[C@@H](O)CO)ccn3)C2)ccc1OCc1ccc(C2CC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 38 %

Procedure:
To a solution of the crude {3-[4-(4-cyclopropylbenzyloxy)-3-methoxyphenyl]azetidin-1-yl}-[4-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxymethyl)pyridin-2-yl]-methanone prepared in (8) in THF (10 mL) was added 1 N hydrochloric acid (5 mL). The reaction mixture was stirred at RT for 3 hr. The reaction mixture was quenched with aqueous 1 N NaOH and saturated aqueous NaHCO3. The mixture was extracted with ethyl acetate. The organic layer was dried over MgSO4. The solvent was removed under reduced pressure. The residue was purified by preparative thin-layer chromatography (Developing solvent: chloroform/methanol=8/1) to give the title compound (0.30 g, 38%).
Reaction SMILES: N#N.Cl[C:4]1[CH:5]=[C:6]([N+:11]([O-:13])=[O:12])[CH:7]=[C:8]([Cl:10])[CH:9]=1.[S:14]1[CH:18]=[CH:17][N:16]=[CH:15]1.C([O-])(=O)C.[K+]>CN(C=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>[Cl:10][C:8]1[CH:9]=[C:4]([C:18]2[S:14][CH:15]=[N:16][CH:17]=2)[CH:5]=[C:6]([N+:11]([O-:13])=[O:12])[CH:7]=1
Reactant: c1cscn1
Reactant: O=[N+]([O-])c1cc(Cl)cc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: N#N
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(Cl)cc(-c2cncs2)c1
Temperature: 120 °C
Reaction time: 17 h

Procedure:
N2 was bubbled through a solution of 3,5-dichloronitrobenzene (0.384 g, 2.00 mmol), thiazole (0.204 g, 2.40 mmol), potassium acetate (0.294 g, 3.00 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.16 g, 0.14 mol) in DMF (5 mL) for 10 min. The mixture was then heated to 120° C. and stirred for 17 h. The solvents were removed in vacuo. The residue was purified by chromatography on silica gel (MeOH in methylene chloride: 1% to 5%) to afford the title compound. 1H-NMR (CDCl3, 400 MHz): δ=7.88 (t, J=2.0 Hz, 1H), 8.20 (t, J=2.4 Hz, 1H), 8.22 (s, 1H), 8.32 (t, J=2.0 Hz, 1H), 8.90 (s, 1H). MS (ES+): m/z 241.04 (35Cl, MH+), 243.00 (37Cl, MH+). HPLC: tR=3.35 min (ZQ2000, polar—5 min).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[OH-].[K+].Br[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:21]>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:19][C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:21])[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Reactant: O=C(CBr)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CN1CCc2c(c3cc(Cl)ccc3n2CC(=O)c2ccccc2)C1
Reaction time: 8 h
Yield: 17.7 %

Procedure:
8-Chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (220 mg, 10 mmol) was dissolved in NMP (2 mL). KOH (560 mg, 0.010 mol) was then added, followed by addition of 2-bromoacetophenone (199 mg, 0.001 mol). The reaction was kept overnight at RT and was monitored by TLC & LC/MS. The reaction was quenched by adding water, and extracted using EtOAc, which was then washed with water (2-3×). The organic layer was dried over sodium sulfate and then concentrated to yield 60 mg of dark brown crude oil that was purified by column chromatography using 100-200 mesh silica gel with 4% MeOH:DCM as eluent. 1HNMR (CDCl3, TFA salt) d (ppm): 8.0 (m, 2H), 7.70 (m, 1H), 7.60 (m, 2H), 7.40 (d, 1H), 7.20 (m, 1H), 7.05 (m, 1H), 5.60 (m, 1H), 5.38 (m, 1H), 4.80 (m, 1H), 4.20 (m, 1H), 3.90 (m, 1H), 3.40 (m, 2H), 3.05 (s, 3H), 1.90 (m, 1H).
Reaction SMILES: [CH2:1]([C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[C:8]([C:13]([O:15][CH3:16])=[O:14])[CH:7]=2)[CH2:2][CH3:3].ClS([N:21]=[C:22]=O)(=O)=O.CN(C)C=O.O>C(#N)C>[C:22]([C:12]1[C:11]2[C:6](=[CH:7][C:8]([C:13]([O:15][CH3:16])=[O:14])=[CH:9][CH:10]=2)[NH:5][C:4]=1[CH2:1][CH2:2][CH3:3])#[N:21]
Reactant: CCCc1cc2ccc(C(=O)OC)cc2[nH]1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCCc1[nH]c2cc(C(=O)OC)ccc2c1C#N
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 52.7 %

Procedure:
To a stirred solution of methyl 2-propylindole-6-carboxylate (911 mg) in acetonitrile (15 ml) was added chlorosulfonylisocyanate (0.6 g) in acetonitrile (1.5 ml) at 0° C. The mixture was stirred at 0° C. for 30 minutes, then N,N-dimethylformamide (0.35 g) in acetonitrile (15 ml) was added at 0° C. The resultant mixture was stirred at 20° C. for 40 minutes, and then poured into water. The mixture was extracted with methylene chloride three times, and the combined organic phase was dried over sodium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel eluting with a mixture of ethyl acetate and hexane (1:3) to give the crystals which were recrystallized from a mixture or ethyl acetate and hexane to give methyl 3-cyano-2-propylindole-6-carboxylate (535 mg) as colorless crystals.