Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)=[O:5].[C:17]([OH:20])(=O)[CH3:18].[CH:21]1C=CC=CC=1>>[CH3:21][O:20][C:17](=[N:1][C:2]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)=[O:5])[CH3:18]
Reactant: Nc1ccc(Br)cc1C(=O)c1ccccn1
Reactant: CC(=O)O
Reactant: c1ccccc1
Product: COC(C)=Nc1ccc(Br)cc1C(=O)c1ccccn1

Procedure:
A mixture of 8.7 g of 2-(2-amino-5-bromobenzoyl)-pyridine, 5.7 g of ortho-methyl-acetate, 2.8 ml. of acetic acid and 100 ml. of benzene is refluxed, while removing alcohol formed by azeotropic distillation, for 1.5 hours and then cooled. The resultant is washed with saturated aqueous sodium hydrogen carbonate, then with water, and dried over sodium sulfate. Evaporation of the solvent under reduced pressure gives 2-[2-(1-methoxyethylideneamino)-5-bromobenzoyl]-pyridine as oily product. This product is dissolved in 60 ml. methanolic solution and 44 ml. of hydrazine hydrate (100%) and 1.9 ml. of acetic acid are added to the solution. The mixture is stirred at room temperature for 3 hours and the precipitate formed is collected by filtration, washed with methanol and dried to give 3-amino-6-bromo-3,4-dihydro-4-hydroxy-2-methyl-4-(2-pyridyl)quinazoline as crystals. Recrystallization from a mixture of methanol and chloroform gives colorless crystals, melting at 208° to 210° C (decomposition).
Reaction SMILES: [NH3:1].[NH2-].[Na+].Br[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[Cl:12]>>[Cl:12][C:6]1[CH:5]=[C:10]([CH:9]=[C:8]([Cl:11])[CH:7]=1)[NH2:1]
Reactant: N
Reactant: Clc1ccc(Br)c(Cl)c1
Agent: [NH2-]
Agent: [Na+]
Product: Nc1cc(Cl)cc(Cl)c1
Reaction time: 1 h
Yield: 75.5 %

Procedure:
In the second step of Example 1, 500 ml of liquid ammonia, 10 g (0.25 mole) of sodium amide and 11.3 g (0.05 mole) of 1-bromo-2,4-dichlorobenzene were charged and the reaction was carried out for 1 hour to obtain 6.1 g of 3,5-dichloroaniline. (yield: 75.5%).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]3[O:27][CH2:28][O:29][C:23]=3[CH:22]=2)[C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]4[O:27][CH2:28][O:29][C:23]=4[CH:22]=3)[C:10]3[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: O=[N+]([O-])c1cc2c(NCc3ccc4c(c3)OCO4)nc(Cl)nc2s1
Product: O=[N+]([O-])c1cc2c(NCc3ccc4c(c3)OCO4)nc(-n3cncn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-6-nitro-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-6-nitro-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[Cl-].[Al+3].[Cl-].[Cl-].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][CH3:26].Cl>S(Cl)(Cl)=O.ClCCl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([C:22]2[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[C:20]([O:25][CH3:26])[CH:21]=2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1ccccc1OC
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Cc2ccc(Cl)c(Cl)c2)cc1OC
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of (3,4-dichloro-phenyl)-acetic acid (11.14 g, 54.33 mmol) and anhydrous DMF (1.45 ml) in thionyl chloride (137 ml) was stirred at RT, under nitrogen, for 17 h. The excess of thionyl chloride was removed under vacuum. Anhydrous toluene was added to the residue, which was again concentrated in vacuum (repeated two more times). Powdered anhydrous aluminium chloride (11.57 g, 86.72 mmol) was added portionwise (exothermic reaction) to a stirred mixture of 1,2-dimethoxy-benzene (6.92 ml, 54.34 mmol) and the previous acyl chloride in anhydrous dichloromethane (120 ml). An exothermic reaction occurred and the reaction mixture was heated at reflux for 2 h. The reaction mixture was allowed to cool to RT and was then poured into a mixture of ice (67 g) and aqueous 7.5N HCl (64 ml). The layers were separated and the aqueous layer was extracted with dichloromethane. The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and evaporated to dryness to give a brown residue (oil and solid). After a further drying (HV), anhydrous diethylether was added and a beige solid precipitated. The beige solid was filtered and further dried (8.33 g, 47%).
Reaction SMILES: O=C1CCC(=O)N1[O:8][C:9](=O)[CH2:10][CH2:11][CH:12]([NH:20][C:21](=[O:47])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[NH2:49][CH2:50][CH2:51][O:52][CH2:53][CH2:54][O:55][CH2:56][C:57]([NH:59][CH2:60][CH2:61][O:62][CH2:63][CH2:64][O:65][CH2:66][C:67]([OH:69])=[O:68])=[O:58].NCCOCCOCC(O)=O.CCN(C(C)C)C(C)C>C(O)C>[C:43]([O:42][C:40](=[O:41])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][C:21](=[O:47])[NH:20][C@H:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH2:10][C:9](=[O:8])[NH:49][CH2:50][CH2:51][O:52][CH2:53][CH2:54][O:55][CH2:56][C:57](=[O:58])[NH:59][CH2:60][CH2:61][O:62][CH2:63][CH2:64][O:65][CH2:66][C:67]([OH:69])=[O:68])([CH3:46])([CH3:44])[CH3:45]
Reactant: NCCOCCOCC(=O)NCCOCCOCC(=O)O
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCCCC(=O)NC(CCC(=O)ON1C(=O)CCC1=O)C(=O)OC(C)(C)C
Agent: NCCOCCOCC(=O)O
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCCCC(=O)N[C@@H](CCC(=O)NCCOCCOCC(=O)NCCOCCOCC(=O)O)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 96 %

Procedure:
To a solution of 2-(19-tert-Butoxycarbonylnonadecanoylamino)pentanedioic acid 1-tert-butyl ester 5-(2,5-dioxopyrrolidin-1-yl) ester (2.50 g, (prepared similarly as described in WO 2005/012347) and [2-(2-{2-[2-(2-Aminoethoxy)ethoxy]acetylamino}ethoxy)ethoxy]acetic acid (1.47 g, alternative name: 8-amino-3,6-dioxaoctanoic acid dimer, IRIS Biotech GmbH, Cat. No. PEG1221) in ethanol (40 ml) was added DIPEA (1.26 ml). The mixture was stirred at room temperature over night and then concentrated in vacuo. To the residue was added aqueous 0.1 N HCl (150 ml) and ethyl acetate (200 ml). The layers were separated and the aqueous layer was extracted with ethyl acetate (100 ml). The combined organic layers were washed with water and brine, dried (magnesium sulphate) and concentrated in vacuo to give an oil, which crystalised on standing. Yield 96% (3.1 g). LC-MS (electrospray): m/z=874.49.
Reaction SMILES: [CH2:1]([N:8]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C@H:9]([CH2:20][OH:21])[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S([O-])([O-])(=O)=O.[Na+].[Na+].[F:36][C:37]([F:45])(S(F)(=O)=O)C(O)=O>C(#N)C>[CH2:22]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@H:9]([CH2:20][O:21][CH:37]([F:45])[F:36])[C:10]([O:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:11])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=C(O)C(F)(F)S(=O)(=O)F
Reactant: O=C(OCc1ccccc1)[C@@H](CO)N(Cc1ccccc1)Cc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: O=C(OCc1ccccc1)[C@@H](COC(F)F)N(Cc1ccccc1)Cc1ccccc1
Yield: 13.4 %

Procedure:
To a mixture of Benzyl (2R)-2-(dibenzylamino)-3-hydroxypropanoate (22.2 g, 59.2 mmol) and sodium sulfate (2.0 g, 14 mmol) in acetonitrile (200 mL) at 40° C., difluoro(fluorosulfonyl)acetic acid (10.5 g, 59.2 mmol) was added dropwise for 1.5 hrs. The reaction mixture was concentrated to dryness. The residue was mixed with ethyl acetate and silica gel, then concentrated again and purified by column chromatography, eluting with 1.5-2.5% ethyl acetate in hexanes to give benzyl (2R) 2-dibenzylamino-3-difluoromethoxy-propionate (3.375 g, 13.4%) as a colorless oil. 1H NMR (300 MHz, CDCl3): δ(ppm) 7.20-7.40 (m, 15H), 6.17 (wt, 1H), 5.27 (q, 2H), 4.22 (dd, 1H), 4.10 (dd, 1H), 3.88 (d, 2H), 3.74 (t, 1H) and 3.65 (d, 2H).
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][C:7]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:11]([C:12](=[S:15])[NH:13][NH2:14])[N:10]=[C:9]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[F:23])[S:8]1)=[N+:2]=[N-:3].[CH3:30]OC(OC)OC.CC1C=CC(S(O)(=O)=O)=CC=1>>[N:1]([CH2:4][CH2:5][CH2:6][C:7]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:11]([C:12]2[S:15][CH:30]=[N:14][N:13]=2)[N:10]=[C:9]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[F:23])[S:8]1)=[N+:2]=[N-:3]
Reactant: COC(OC)OC
Reactant: [N-]=[N+]=NCCCC1(c2ccccc2)SC(c2cc(F)ccc2F)=NN1C(=S)NN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: [N-]=[N+]=NCCCC1(c2ccccc2)SC(c2cc(F)ccc2F)=NN1c1nncs1
Temperature: 80 °C
Yield: 89.3 %

Procedure:
2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazole-3(2H)-carbothiohydrazide (220 mg, 0.51 mmol) was dissolved in trimethyl-orthoformate (1.62 g, 15.2 mmol) with a few crystals of pTsOH (10 mg, 0.05 mmol), and heated to 80° C. for 20 minutes. The reaction mixture was then concentrated and purified by flash column chromatography, eluting with 4:1 (hexanes/ethyl acetate), to afford the desired product as a light yellow oil (202 mg, 90%).
Reaction SMILES: [CH:1](=[O:5])[CH2:2][CH2:3][CH3:4].[CH:6](=[O:10])/[CH:7]=[CH:8]/[CH3:9]>[Bi](Cl)(Cl)Cl>[CH2:1]([O:5][CH:6]([O:10][CH2:1][CH:2]=[CH:3][CH3:4])[CH2:7][CH2:8][CH3:9])[CH:2]=[CH:3][CH3:4]
Reactant: C/C=C/C=O
Reactant: CCCC=O
Agent: Cl[Bi](Cl)Cl
Product: CC=CCOC(CCC)OCC=CC
Yield: 178.5 %

Procedure:
The general procedure of Example 2 was repeated except that 72 g (1 mole) of n-butanal and 2 mg of bismuth chloride were used instead of 70 g of crotonaldehyde and 3 mg of stannous chloride dihydrate, respectively to give 177.0 g of n-butanal dicrotyl acetal (R1 =an n-propyl group, R2 =a hydrogen atom and R3 =a crotyl group] (boiling point: 116° C./25 mmHg) (yield: 89.4%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25].C(=O)(O)[O-].[Na+]>ClCCl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][N:13]([S:24]([CH3:23])(=[O:26])=[O:25])[CH2:12][CH2:11]2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CS(=O)(=O)Cl
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
1-(4-Nitrophenyl)piperazine (2.79 g, 13.5 mmol) was dissolved in dichloromethane (100 ml). Triethylamine (2.25 ml, 16.2 mmol) was added and the reaction was cooled to 0° C. Methanesulfonyl chloride (1.15 ml, 14.9 mmol) was added dropwise and the reaction was stirred at 0° C. for 1 h. Saturated sodium bicarbonate was added and the reaction was extracted (×3) with dichloromethane, dried (MgSO4), filtered and concentrated in vacuo to give 4-(4 nitrophenyl)-1-methylsulfonylpiperazine as a yellow solid (3.83 g, quantitative yield). GC/MS (EI, M+) m/z=285.
Reaction SMILES: C([O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[CH:7]=1)(C)(C)C.[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32]([OH:35])(=[O:34])=[O:33])=[CH:28][CH:27]=1>C1COCC1>[C:26]1([CH3:36])[CH:27]=[CH:28][C:29]([S:32]([O-:35])(=[O:33])=[O:34])=[CH:30][CH:31]=1.[OH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH+:9]=[C:8]([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(C)(C)Oc1cc(-c2ccc3ccccc3c2)nc2ccccc12
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Product: Oc1cc(-c2ccc3ccccc3c2)[nH+]c2ccccc12
Temperature: 0 °C

Procedure:
A solution of crude compound 4 (6.5 g, 20 mmol) and p-toluenesulfonic acid (6.0 g, 30 mmol) in THF (150 mL) was heated under reflux for 4 h and then cooled to 0° C., the precipitate of 6 was filtered off and crystallized from methanol: yield 8.0 g (93%); mp 223-225° C.; 1H NMR (DMSO-d6) δ2.28 (s, 3), 7.10 (d, J=8 Hz, 2 H), 7.28 (s, 1 H), 7.50 (d, J=8 Hz, 2 H), 7.71 (m, 3 H), 8.0-8.215 (m, 6 H), 8.33 (d, J=8 Hz, 1 H), 8.61 (s, 1 H). Anal. Calcd for C26H21NO4S: C, 70.40; H, 4.77; N, 3.16. Found: C, 70.38; H, 4.73; N, 3.11.
Reaction SMILES: Cl.Cl.[N:3]1([CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:22]=[C:21]3[C:16]([CH2:17][CH2:18][NH:19][CH2:20]3)=[CH:15][CH:14]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.CCN(CC)CC.[C:30]([C:32]1[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1)#[N:31]>>[C:30]([C:32]1[CH:33]=[CH:34][C:35]([S:38]([N:19]2[CH2:18][CH2:17][C:16]3[C:21](=[CH:22][C:13]([O:12][CH2:11][CH2:10][CH2:9][N:3]4[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]4)=[CH:14][CH:15]=3)[CH2:20]2)(=[O:40])=[O:39])=[CH:36][CH:37]=1)#[N:31]
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: c1cc2c(cc1OCCCN1CCCCC1)CNCC2
Agent: Cl
Solvent: CCN(CC)CC
Product: N#Cc1ccc(S(=O)(=O)N2CCc3ccc(OCCCN4CCCCC4)cc3C2)cc1

Procedure:
2-(4-Cyanobenzenesulfonyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinoline is prepared from 7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinoline dihydrochloride (175 mg, 0.5 mmol), NEt3 (0.25 mL, 1.8 mmol), and 4-cyanobenzenesulfonyl chloride (121 mg, 0.60 mmol) via a procedure substantially analogous to Procedure F except that an additional SCX column purification step is performed to give the product (157 mg, 71% yld). MS(ES+) 440.1(M+H)+.
Reaction SMILES: [CH:1]1[C:6](NN)=[CH:5][CH:4]=[C:3]([N:9]2[CH:13]=NN=C2)[CH:2]=1.[C:14]([O-])([O-])=O.[K+].[K+]>S(=O)(=O)(O)O>[NH:9]1[C:3]2[C:4](=[CH:5][CH:6]=[CH:1][CH:2]=2)[CH:14]=[CH:13]1
Reactant: NNc1ccc(-n2cnnc2)cc1
Reactant: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: c1ccc2[nH]ccc2c1
Yield: 17 %

Procedure:
A mixture of intermediates 1 (1.0 g, 5.71 mmol) and 2 (2.07 g, 6.86 mmol) in 4% sulphuric acid (30 ml) was heated at reflux for 48 h. The solution was cooled in an ice-bath, basified with solid K2CO3 and extracted with butan-1-ol (×3). The solvent was removed under vacuum and azeotroped with hexane (×2). The crude product was chromatographed through silica gel eluting with CH2Cl2 /MeOH/NH3 (30:8:1) to give the title-indole (282 mg, 17%). The succinate hemihydrate salt was prepared: mp 227°-228° C. (Found: C, 59.11; H, 6.58; N, 22.54.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].[C-:13]#[N:14].[K+]>CS(C)=O>[C:13]([CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])#[N:14]
Reactant: [C-]#N
Reactant: COC(=O)c1cccc(CBr)c1
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)c1cccc(CC#N)c1

Procedure:
A solution of methyl 3-(bromomethyl)benzoate (2.29 g, 0.01 mol) and potassium cyanide (3.26 g, 0.05 mol) in DMSO (20 mL) was heated to 100° C. for 1 h. The reaction mixture was cooled, partitioned between ether and water, washed with brine, dried (Na2SO4) and concentrated to give the title compound.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:27])=[C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]3[CH:20]=[C:21]([CH3:25])[CH:22]=[CH:23][CH:24]=3)=[CH:14][C:13]=2[Cl:26])=[O:11])[CH:9]=1)=[N+:2]=[N-:3].[CH2:28]([OH:32])[CH2:29][C:30]#[CH:31]>>[Cl:26][C:13]1[CH:14]=[C:15]([NH:18][C:19]2[CH:20]=[C:21]([CH3:25])[CH:22]=[CH:23][CH:24]=2)[CH:16]=[CH:17][C:12]=1[C:10]([C:8]1[CH:9]=[C:4]([N:1]2[CH:31]=[C:30]([CH2:29][CH2:28][OH:32])[N:3]=[N:2]2)[CH:5]=[CH:6][C:7]=1[CH3:27])=[O:11]
Reactant: C#CCCO
Reactant: Cc1cccc(Nc2ccc(C(=O)c3cc(N=[N+]=[N-])ccc3C)c(Cl)c2)c1
Product: Cc1cccc(Nc2ccc(C(=O)c3cc(-n4cc(CCO)nn4)ccc3C)c(Cl)c2)c1

Procedure:
The reaction was carried out similarly as described in the preparation of compound 116, using compound 465 (0.25 mmol) and but-3-yn-1-ol (0.30 mmol). The crude product was purified by flash chromatography using EtOAc/petroleum ether (40-60) 6:1 as the eluent to afford the title compound as light yellow foam. 13C NMR (CDCl3) δ 194.8, 148.9, 146.3, 141.1, 139.7, 139.6, 138.1, 135.6, 134.8, 134.0, 132.5, 129.5, 127.5, 125.2, 122.3, 122.2, 120.7, 119.9, 118.7, 116.3, 112.8, 61.6, 28.7, 21.5, 19.9
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][C:9]([O:10][C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][C:12]=3[F:18])=[C:4]2[CH:3]=[CH:2]1.Cl.N1C2=NC=CC(OC3C=CC(N[C:37]4[C:42]([C:43]([NH:45][C:46]5[CH:51]=[CH:50][C:49]([F:52])=[CH:48][C:47]=5[F:53])=[O:44])=[CH:41][N:40]=[CH:39][CH:38]=4)=CC=3F)=C2C=C1.[Cl:55]C1N=CC=CC=1C(NC1C=CC(F)=CC=1F)=O>>[ClH:55].[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][C:9]([O:10][C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:41]4[N:40]=[CH:39][CH:38]=[CH:37][C:42]=4[C:43]([NH:45][C:46]4[CH:51]=[CH:50][C:49]([F:52])=[CH:48][C:47]=4[F:53])=[O:44])=[CH:13][C:12]=3[F:18])=[C:4]2[CH:3]=[CH:2]1
Reactant: O=C(Nc1ccc(F)cc1F)c1cnccc1Nc1ccc(Oc2ccnc3[nH]ccc23)c(F)c1
Reactant: Nc1ccc(Oc2ccnc3[nH]ccc23)c(F)c1
Reactant: O=C(Nc1ccc(F)cc1F)c1cccnc1Cl
Agent: Cl
Product: O=C(Nc1ccc(F)cc1F)c1cccnc1Nc1ccc(Oc2ccnc3[nH]ccc23)c(F)c1
Yield: 21 %

Procedure:
4-(1H-Pyrrolo[2,3-b]pyridin-4-yloxy)-3-fluorobenzenamine (0.073 g, 0.30 mmol, Compound C of Example 1) was converted to the title compound (0.032 g, 21%) in a manner similar to the preparation of 4-(4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)-3-fluorophenylamino)-N-(2,4-difluorophenyl)nicotinamide hydrochloride salt (Compound D of Example 1), except that 2-chloro-N-(2,4-difluorophenyl)nicotinamide (Maybridge, 0.081 g, 0.30 mmol) was used instead of 4-chloro-N-(2,4-difluorophenyl)nicotinamide. 1H NMR (DMSO-d6) δ 12.83 (s, 1H), 10.75 (s, 1H), 10.52 (s, 1H), 8.28-8.41 (m, 3H), 8.15 (dd, 1H, J=13.6, 2.2 Hz), 7.32-7.56 (m, 5H), 7.09-7.13 (m, 1H), 6.98-7.01 (m, 1H), 6.72 (d, 1H, J=6.5 Hz), 6.48-6.49 (m, 1H); HRMS(ESI+), 476.1334 (M+H)+ calc, 476.1350 (M+H)+ found.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6]([S:10][C:11]([F:14])([F:13])[F:12])=[CH:5][N:4]=1.[CH:15](O)=O>O>[CH3:1][N:2]1[C:3]2=[N:4][CH:5]=[C:6]([S:10][C:11]([F:12])([F:14])[F:13])[CH:7]=[C:8]2[N:9]=[CH:15]1
Reactant: O=CO
Reactant: CNc1ncc(SC(F)(F)F)cc1N
Solvent: O
Product: Cn1cnc2cc(SC(F)(F)F)cnc21

Procedure:
A mixture of 10.0 g of N2-methyl-5-trifluoromethylsulfanylpyridine-2,3-diamine, 41 ml of formic acid and 5 ml of water was stirred under heating and refluxing for 2 hours. The reaction mixture was concentrated under reduced pressure, a saturated aqueous sodium bicarbonate solution was added to the resulting residue, and the mixture was extracted with methyl-tert-butyl ether. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was applied to a silica gel column chromatography to obtain 7.80 g of 3-methyl-6-trifluoromethylsulfanyl-3H-imidazo[4,5-b]pyridine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](I)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:11]([Si:13]([CH3:16])([CH3:15])[CH3:14])#[CH:12].C(N(CC)CC)C>C1COCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([C:12]#[C:11][Si:13]([CH3:16])([CH3:15])[CH3:14])[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: C#C[Si](C)(C)C
Reactant: Cn1cc(Br)cc(I)c1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cn1cc(Br)cc(C#C[Si](C)(C)C)c1=O
Temperature: 60 °C
Yield: 82.8 %

Procedure:
A mixture of 5-bromo-3-iodo-1-methylpyridin-2-one (8.0 g, 25.48 mmol), ethynyltrimethylsilane (2.7 g, 27.52 mmol), CuI (485 mg, 2.55 mmol), Pd(PPh3)2Cl2 (1.79 g, 2.55 mmol) and triethylamine (12.9 g, 127.4 mmol) in dry THF (100 mL) was heated to 60° C. under an atmosphere of nitrogen for 2 h. The mixture was concentrated and the residue was purified by column chromatography on silica gel (PE:EA=5:1) to give the title compound (6 g, 82%) as a yellow solid. 1H NMR (CDCl3, 400 MHz): δ 7.61 (d, J=2.4 Hz, 1H), 7.42 (d, J=2.4 Hz, 1H), 3.54 (s, 3H), 0.25 (s, 9H). LCMS (M+H)+=285.
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]([CH3:15])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[N:7]=1)[CH3:2].[Br:16]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:16][CH2:15][C:5]1[O:4][C:3]([CH2:1][CH3:2])=[N:7][C:6]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1
Reactant: CCc1nc(-c2ccc(Cl)cc2)c(C)o1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCc1nc(-c2ccc(Cl)cc2)c(CBr)o1
Yield: 100 %

Procedure:
2-Ethyl-4-(4-chlorophenyl)-5-methyloxazole (6.6 g) was brominated with N-bromosuccinimide (5.4 g) in carbon tetrachloride (90 ml) in the presence of azobisisobutyronitrile (0.3 g) in the same manner as Example 5-(2). The procedure gave an oil of 5-bromomethyl-4-(4-chlorophenyl)-2-ethyloxazole, yield 100%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[CH:9][NH:8][C:7]=1[CH3:11])=[O:5])[CH3:2].[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16]Br>>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[CH:9][N:8]([CH2:16][C:15]2[CH:18]=[CH:19][CH:20]=[C:13]([F:12])[CH:14]=2)[C:7]=1[CH3:11])=[O:5])[CH3:2]
Reactant: Fc1cccc(CBr)c1
Reactant: CCOC(=O)c1cc[nH]c1C
Product: CCOC(=O)c1ccn(Cc2cccc(F)c2)c1C

Procedure:
Prepared in analogy to that of Example 5(a) from 2-methyl-1H-pyrrole-3-carboxylic acid ethyl ester and 3-fluorobenzyl bromide. The title compound, ESI MS (m/z): 262 (M+H)+.
Reaction SMILES: FC(F)(F)C(O)=O.C(O[C:13](=O)[N:14]([C@@H:16]([C:28](=[O:50])[N:29]([C@H:31]([CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:32]([N:34]1[CH2:38][CH2:37][CH2:36][C@H:35]1[CH2:39][N:40]([CH3:42])[CH3:41])=[O:33])[CH3:30])[CH2:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=1)C)(C)(C)C>ClCCl>[CH2:43]([C@@H:31]([N:29]([CH3:30])[C:28](=[O:50])[C@H:16]([NH:14][CH3:13])[CH2:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=1)[C:32]([N:34]1[CH2:38][CH2:37][CH2:36][C@H:35]1[CH2:39][N:40]([CH3:41])[CH3:42])=[O:33])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: CN(C)C[C@@H]1CCCN1C(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN[C@H](Cc1ccc2ccccc2c1)C(=O)N(C)[C@H](Cc1ccccc1)C(=O)N1CCC[C@H]1CN(C)C
Temperature: 0 °C
Reaction time: 1.25 h

Procedure:
At 0° C., trifluoroacetic acid (10 ml) was added to a solution of N-((1R)-1-{N-[(1R)-1-benzyl-2-((2S)-2-((dimethylamino)methyl)pyrrolidin-1-yl)-2-oxoethyl]-N-methylcarbamoyl}-2-(2-naphthyl)ethyl)-N-methylcarbamic acid tert-butyl ester.(1.37 g, 2.28 mmol) in dichloromethane (10 ml). The reaction mixture was stirred for 75 min at 0° C. The solvent was removed in vacuo. The residue was dissolved in dichloromethane (70 ml) and the solvent was removed in vacuo. The latter procedure was repeated two times. The crude product was purified by flash chromatography on silica (90 g), using dichloromethane/methanol/25% aqueous ammonia (100:10:1) as eluent, to give 692 mg of (2R)-N-[(1R)-1-benzyl-2-((2S)-2-((dimethylamino)methyl)pyrrolidin-1-yl)-2-oxoethyl]-N-methyl-2-(methylamino)-3-(2-naphthyl)propionamide.