Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][CH:6]([O:8][CH:9]([C:13]([F:16])([F:15])[F:14])[CH2:10][CH2:11][OH:12])[CH3:7])[CH3:4].Cl[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1.O>C1COCC1.CN(C=O)C>[N+:24]([C:21]1[CH:22]=[CH:23][C:18]([O:12][CH2:11][CH2:10][CH:9]([O:8][CH:6]([O:5][CH2:3][CH3:4])[CH3:7])[C:13]([F:14])([F:15])[F:16])=[CH:19][CH:20]=1)([O-:26])=[O:25]
Reactant: CCOC(C)OC(CCO)C(F)(F)F
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(C)OC(CCOc1ccc([N+](=O)[O-])cc1)C(F)(F)F
Reaction time: 0.5 h
Yield: 78 %

Procedure:
To a suspension of 2.4 g (0.049 mol) of 50% NaH in 50 ml of THF, is slowly added a solution of 10.6 g (0.049 mol) of 3-(1-ethoxyethoxy)-4,4,4-trifluoro-1-butanol in 15 ml of THF. When no more gas evolves, a solution of 6.5 g (0.041 mol) of 4-chloronitrobenzene in 65 ml of DMF is added. After 30 min., the reaction medium is poured on iced water. The reaction medium is extracted with ether. The organic phase is washed with water, dried over Na2SO4 and concentrated. The aimed product is obtained with a 78% yield after recrystallization from isopropanol. m.p.: 81° C.;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])=O)=[CH:5][CH:4]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:29])=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([C:7](=[S:29])[NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)Nc2ccccc2OC)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(C(=S)Nc2ccccc2OC)cc1
Yield: 153.2 %

Procedure:
4-Methoxy-2'-methoxybenzanilide (29.5 g) [Bull. Soc. Chim. France, 1964, (5), 924-935] was dissolved in 150 ml of toluene, and 25.6 g of Lawesson's reagent was added. The mixture was refluxed for 4.5 hours. After the reaction, the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography [eluted with cyclohexane/ethyl acetate (7/1, v/v)] to give 26.5 g of 4-methoxy-2'-methoxybenzothioanilide.
Reaction SMILES: [CH2:1]([PH:7](=[O:9])[OH:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]>C(O)CCC>[CH2:1]([PH:7](=[O:8])[O:9][CH2:1][CH2:2][CH2:3][CH3:4])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCC[PH](=O)O
Solvent: CCCCO
Product: CCCCCC[PH](=O)OCCCC

Procedure:
The title compound was prepared from n-hexylphosphinic acid and n-butanol according the the method described in Procedure 43. The compound was used without further purification.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[N:11][C:12]=2[NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:23]=[N:24][C:25]([CH3:28])=[CH:26][CH:27]=3)=[C:17]([CH3:29])[CH:16]=2)[NH:7][N:6]=1.[NH:30]1[CH2:35][CH2:34][NH:33][CH2:32][C:31]1=[O:36]>>[CH3:29][C:17]1[CH:16]=[C:15]([NH:14][C:12]2[N:11]=[CH:10][N:9]=[C:8]3[NH:7][N:6]=[C:5]([O:4][CH2:3][CH2:2][N:33]4[CH2:34][CH2:35][NH:30][C:31](=[O:36])[CH2:32]4)[C:13]=23)[CH:20]=[CH:19][C:18]=1[O:21][C:22]1[CH:23]=[N:24][C:25]([CH3:28])=[CH:26][CH:27]=1
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4[nH]nc(OCCCl)c34)cc2C)cn1
Reactant: O=C1CNCCN1
Product: Cc1ccc(Oc2ccc(Nc3ncnc4[nH]nc(OCCN5CCNC(=O)C5)c34)cc2C)cn1
Yield: 25 %

Procedure:
The procedure described in Example 23 was repeated using 3-(2-chloroethoxy)-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine and piperazinone to give the title compound in 25% yield; NMR Spectrum: 2.19 (s, 3H), 2.44 (s, 3H), 2.71 (t, 2H), 2.90 (t, 2H), 3.12 (s, 2H), 3.14 (br s, 1H), 4.47 (t, 2H), 6.95 (d, 1H), 7.18-7.25 (m, 2H), 7.63 (br s, 1H), 7.64 (s, 1H), 7.74 (br s, 1H), 8.17 (s, 1H), 8.31 (s, 1H); Mass Spectrum: 475 (MH+).
Reaction SMILES: [CH3:1][C:2](=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3](O)=[O:4].S(Cl)([Cl:15])=O>CN(C=O)C>[CH3:1][C:2](=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([Cl:15])=[O:4]
Reactant: O=S(Cl)Cl
Reactant: CC(=Cc1ccccc1)C(=O)O
Solvent: CN(C)C=O
Product: CC(=Cc1ccccc1)C(=O)Cl
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
α-methylcinnamic acid (45 g) and thionyl chloride (50 g) was stirred at 20-30° C. After 5 min, 0.3 ml of DMF was added and kept stirring at 20-30° C. for 1 hour to give crude of α-methylcinnamoyl chloride (solution A)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:8]([C:15]2[C:24]3[C:19](=[CH:20][C:21]([OH:25])=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)=[C:9]2[CH2:14][CH2:13][CH2:12][N:10]2[N:11]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:45]1[CH:50]=[CH:49][C:48]([CH2:51]O)=[CH:47][CH:46]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1(C)C=CC=CC=1.O1CCCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:8]([C:15]2[C:24]3[C:19](=[CH:20][C:21]([O:25][CH2:51][C:48]4[CH:49]=[CH:50][N:45]=[CH:46][CH:47]=4)=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)=[C:9]2[CH2:14][CH2:13][CH2:12][N:10]2[N:11]=1
Reactant: Oc1ccc2c(-c3c(-c4ccccn4)nn4c3CCC4)ccnc2c1
Reactant: OCc1ccncc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: c1ccc(-c2nn3c(c2-c2ccnc4cc(OCc5ccncc5)ccc24)CCC3)nc1
Temperature: 75 °C

Procedure:
4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-ol (0.100 g, 0.305 mmol), triphenylphosphine (0.080 g, 0.305 mmol), and 4-pyridylcarbinol (0.033 g, 0.305 mmol) are combined in toluene (1.0 mL) and treated with diisopropylazodicarboxylate (0.062 g, 0.305 mmol). The resulting mixture is heated at 75° C. for 18 hours. The mixture is diluted with tetrahydrofuran and heated at 75° C. for 24 h. The mixture is placed on a 10 g SCX resin column which is washed sequentially with dichloromethane (120 mL), methanol (60 mL), and 4:1 dichloromethane/2 N ammonia in methanol (125 mL). The latter fraction is concentrated in vacuo and the residue chromatographed on SiO2 (9:1 ethyl acetate:2N ammonia in methanol) to yield the desired product as a tan solid, 0.035 g (27%).
Reaction SMILES: [CH2:1]([C:3]1([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21]C)[CH:16]=2)[CH2:9][CH2:8][CH2:7][CH2:6][N:5]([CH2:10][CH2:11][CH2:12][OH:13])[C:4]1=[O:14])[CH3:2].B(Br)(Br)Br>C(Cl)Cl>[CH2:1]([C:3]1([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=2)[CH2:9][CH2:8][CH2:7][CH2:6][N:5]([CH2:10][CH2:11][CH2:12][OH:13])[C:4]1=[O:14])[CH3:2]
Reactant: CCC1(c2cccc(OC)c2)CCCCN(CCCO)C1=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCC1(c2cccc(O)c2)CCCCN(CCCO)C1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3-ethyl-1-(3-hydroxy-propyl)-3-(3-methoxy-phenyl)-azepan-2-one (as described above in Step B) (0.12 g, 0.393 mmol) in CH2Cl2 (20 mL) at −78° C. was added BBr3 (1M, 0.786 mL, 0.786 mmol). The reaction mixture was stirred for 3 hr at 25° C. then quenched with H2O and extracted with EtOAc. The organic layer was separated, washed with brine and dried (MgSO4). Filtration and concentration to dryness gave the title compound after purification by preparative RP HPLC.
Reaction SMILES: [NH:1]1[C:5]([C:6]([OH:8])=[O:7])=[N:4][N:3]=[N:2]1.[C:9]([C:11](OCC)=O)#N.[N-]=[N+]=[N-].[Na+].[Cl-].[NH4+]>>[NH:1]1[C:5]([C:6]([O:8][CH2:9][CH3:11])=[O:7])=[N:4][N:3]=[N:2]1
Reactant: O=C(O)c1nnn[nH]1
Reactant: CCOC(=O)C#N
Agent: [Cl-]
Agent: [N-]=[N+]=[N-]
Agent: [NH4+]
Product: CCOC(=O)c1nnn[nH]1

Procedure:
Tetrazole-5-carboxylic acid can be prepared by treating ethyl cyanoformate with sodium azide and ammonium chloride to form ethyl tetrazole-5-carboxylate, which is hydrolyzed with alkali (e.g., KOH) to give alkali tetrazole-5-carboxylate, according to the method described in J. Med. Chem. 19, 289(1976) and Ibid, 29, 538(1986).
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[N:3]1[CH2:12][C:13]([OH:15])=O.[Br:16][C:17]1[C:18]([C:23]2[O:24][CH:25]=[CH:26][N:27]=2)=[C:19]([NH2:22])[S:20][CH:21]=1>>[Br:16][C:17]1[C:18]([C:23]2[O:24][CH:25]=[CH:26][N:27]=2)=[C:19]([NH:22][C:13](=[O:15])[CH2:12][N:3]2[C:4]3[C:9](=[N:8][CH:7]=[CH:6][CH:5]=3)[CH2:10][CH2:11][C:2]2=[O:1])[S:20][CH:21]=1
Reactant: O=C(O)CN1C(=O)CCc2ncccc21
Reactant: Nc1scc(Br)c1-c1ncco1
Product: O=C(CN1C(=O)CCc2ncccc21)Nc1scc(Br)c1-c1ncco1

Procedure:
The title compound was prepared from 2-(2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)acetic acid (85 mg, 0.416 mmol) and 4-bromo-3-(oxazol-2-yl)thiophen-2-amine (51 mg, 0.208) mmol) according to protocol A. Retention time (min)=3.245, method [7], MS(ESI) 433.0 (M+H); 1H NMR (300 MHz, CDCl3) δ 8.39 (dd, J=5.1, 1.0 Hz, 1H), 7.72 (s, 1H), 7.55 (d, J=7.0 Hz, 1H), 7.45 (dd, J=8.4, 5.5 Hz, 1H), 7.17 (s, 1H), 6.94 (s, 1H), 4.93 (s, 2H), 3.51-3.46 (m, 2H), 3.05-3.00 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:22](Cl)[CH3:23])[C:5]2[O:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7][C:6]=2[C:19]=1[C:20]#[N:21].[CH3:25][C:26]1[C:34]2[C:29](=[N:30][CH:31]=[N:32][C:33]=2[NH2:35])[NH:28][N:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[NH2:35][C:33]1[N:32]=[CH:31][N:30]=[C:29]2[N:28]([CH:22]([C:4]3[C:5]4[O:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7][C:6]=4[C:19]([C:20]#[N:21])=[C:2]([Cl:1])[CH:3]=3)[CH3:23])[N:27]=[C:26]([CH3:25])[C:34]=12
Reactant: CC(Cl)c1cc(Cl)c(C#N)c2c1OCCN(C(=O)OC(C)(C)C)C2
Reactant: Cc1n[nH]c2ncnc(N)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1nn(C(C)c2cc(Cl)c(C#N)c3c2OCCN(C(=O)OC(C)(C)C)C3)c2ncnc(N)c12
Temperature: 90 °C

Procedure:
The crude tert-butyl 7-chloro-9-(1-chloroethyl)-6-cyano-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (0.090 g, 0.26 mmol) was dissolved in N,N-dimethylformamide (3 mL), and 3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.076 g, 0.51 mmol) and cesium carbonate (0.17 g, 0.51 mmol) were added. The reaction was heated to 90° C. for 18 hrs and then allowed to cool to room temperature. The reaction was diluted with ethyl acetate and then decanted from the solids. The organic layer was washed with water, brine, dried over magnesium sulfate, and concentrated to give tert-butyl 9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-cyano-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate as an oil. LCMS calculated for C23H27ClN7O3 (M+H)+: m/z=484.1; found: 484.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O.[C:14]1([CH:22]=C(O)[CH:19]=[C:17]([OH:18])[CH:16]=1)[OH:15]>>[OH:15][C:14]1[C:22]2[C:5](=[O:7])[C:4]3[C:3](=[C:11]([O:12][CH3:13])[CH:10]=[CH:9][CH:8]=3)[O:2][C:1]=2[CH:19]=[C:17]([OH:18])[CH:16]=1
Reactant: COc1cccc(C(=O)O)c1OC
Reactant: Oc1cc(O)cc(O)c1
Product: COc1cccc2c(=O)c3c(O)cc(O)cc3oc12
Temperature: 80 °C
Reaction time: 4 h
Yield: 94.5 %

Procedure:
2,3-dimethoxybenzoic acid (0.91 g, 5 mmol), phloroglucinol (0.95 g, 7.5 mmol), ZnCl□ (4.69 g, 30 mmol) and POCl□ (20 mL) were charged to a dry round-bottom flask, followed by stirring at 80° C. for 4 hours. After the reaction was completed, the reaction mixture was cooled to room temperature and was very slowly added to 500 mL of ice water. When the reaction liquid was poured in ice water, ice was added portionwise to prevent overheating. The resulting precipitate was allowed to stand at 4° C. overnight, combined, washed with water and ether, and then dried under reduced pressure to give the title compound (1.22 g, 94.8%) as a reddish brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].[Br:12]Br>O>[Br:12][C:9]1[CH:10]=[N:11][C:3]([O:2][CH3:1])=[C:4]([CH:8]=1)[C:5]([OH:7])=[O:6]
Reactant: BrBr
Reactant: COc1ncccc1C(=O)O
Solvent: O
Product: COc1ncc(Br)cc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.5 %

Procedure:
To a solution of 2-methoxynicotinic acid (20 g, 130.60 mmol) in H2O (1500 mL), Br2 (20 mL, 375.45 mmol) was added at room temperature. The mixture was stirred at room temperature overnight. The reaction mixture was filtered, washed with water and dried to provide 5-bromo-2-methoxynicotinic acid (25 g, yield: 82%). 1H-NMR (DMSO, 400 MHz) δ 13.33 (br s, 1H), 8.47 (d, J=2.4 Hz, 1H), 8.21 (d, J=2.4 Hz, 1H), 3.90 (s, 3H). MS (M+H)+: 232/234.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15]2[S:16][CH:17]=[C:18]([CH2:20][O:21]C(=O)C)[N:19]=2)=[N:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C.O>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15]2[S:16][CH:17]=[C:18]([CH2:20][OH:21])[N:19]=2)=[N:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OCc1csc(Nc2ccc(Oc3ccccc3)cn2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: OCc1csc(Nc2ccc(Oc3ccccc3)cn2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
Acetic acid 2-(5-phenoxy-pyridine-2-ylamino)-thiazole-4-ylmethyl ester (0.44 mmol) is suspended in ethanol (1.5 ml) and 1 M NaOH (1.5 ml) is added. The solution is stirred at RT for 3 h. The reaction solution is diluted with water. The precipitate is filtered, washed with water and dried 16 h in vacuo at 40° C. “A10” is obtained as a beige powder in yield of 88%; mp. 130.0-131.0° C.; HPLC (method C): 1.64 min; LC-MS (method A): 1.430 min, 300.15 (M+H+); 1H-NMR (DMSO-d6, 400 MHz): δ [ppm] 11.221 (s, 1H), 8.102 (d, 1H, J=2.8 Hz), 7.515 (dd, 1H, J=8.9 Hz, J=2.8 Hz), 7.389-7.349 (m, 2H), 7.125-7.083 (m, 2H), 6.996-6.972 (s, 2H), 6.687 (s, 1H), 5.105 (t, 1H, J=5.3 Hz), 4.442 (d, 2H, J=5.3 Hz).
Reaction SMILES: [CH2:1](OC(=O)C(NC1C=CC(=O)C(O)=CC=1)=O)C.[CH2:18]([O:20][C:21](=[O:34])[C:22]([NH:24][C:25]1[C:26](=[O:33])[C:27]([OH:32])=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:23])C>>[CH3:18][O:20][C:21](=[O:34])[C:22]([NH:24][C:25]1[C:26](=[O:33])[C:27]([O:32][CH3:1])=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:23]
Reactant: CCOC(=O)C(=O)Nc1ccc(O)c(=O)cc1
Reactant: CCOC(=O)C(=O)Nc1ccccc(O)c1=O
Product: COC(=O)C(=O)Nc1ccccc(OC)c1=O

Procedure:
In the same manner but replacing [(5-hydroxy-4-oxo-2.5,7-cycloheptatrien-1-yl)amino]oxo-acetic acid ethyl ester with an equivalent amount of [(3-hydroxy-2-oxo-3,5,7-cycloheptatrien-1-yl)amino]oxo-acetic acid ethyl ester (described in Example 5), [(3-methoxy-2-oxo-3,5,7-cycloheptatrien-1-yl)amino]oxo-acetic acid methyl ester is obtained.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1.[CH3:12][O:13][C:14]1[N:19]=[CH:18][C:17]([NH:20][C:21]2[N:30]=[CH:29][CH:28]=[CH:27][C:22]=2[C:23](OC)=[O:24])=[CH:16][CH:15]=1.[OH-].[Na+]>C(OCC)(=O)C>[CH3:12][O:13][C:14]1[N:19]=[CH:18][C:17]([NH:20][C:21]2[C:22]([CH2:23][OH:24])=[CH:27][CH:28]=[CH:29][N:30]=2)=[CH:16][CH:15]=1
Reactant: COC(=O)c1cccnc1Nc1ccc(OC)nc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(Nc2ncccc2CO)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.9 %

Procedure:
Under a nitrogen gas stream, 2.1 g (56 mmol) of lithium aluminum hydride was added to tetrahydrofuran (100 mL) under ice cooling, and a tetrahydrofuran (60 mL) solution of 6.8 g (28 mmol) of methyl 2-(6-methoxy-3-pyridinyl)aminonicotinate was added dropwise to the above solution. The resulting mixture was stirred for 2 hours at room temperature. Ethyl acetate was added to the reaction mixture, and 23 mL of a 10% aqueous solution of sodium hydroxide was further added thereto. Insoluble materials were filtered off. The filtrate was concentrated, and the residue was dissolved in ethyl acetate, dried, filtered, and concentrated. 6.6 g of the title compound was obtained as a yellow viscous product (yield: quantitative).
Reaction SMILES: [NH:1]1[C:5]2[C:6]3[CH:7]=[CH:8][N:9]=[CH:10][C:11]=3[CH2:12][CH2:13][C:4]=2[C:3]([C:14]([OH:16])=O)=[CH:2]1.C1C=CC2N(O)N=[N:23]C=2C=1.N.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH:1]1[C:5]2[C:6]3[CH:7]=[CH:8][N:9]=[CH:10][C:11]=3[CH2:12][CH2:13][C:4]=2[C:3]([C:14]([NH2:23])=[O:16])=[CH:2]1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1c[nH]c2c1CCc1cnccc1-2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: N
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1c[nH]c2c1CCc1cnccc1-2
Yield: 30 %

Procedure:
A mixture of 4,5-dihydro-1H-pyrrolo[2,3-f]isoquinoline-3-carboxylic acid E6 (0.093 mmol), HOBT.NH3 (0.374 mmol), TBTU (0.186 mmol) and DIEA (0.374 mmol) in DMF (5 mL) was stirred 4 h at rt. The solvent was evaporated and the crude residue was purified by preparative HPLC (Phase A: 0.05% NH4OH pH10/AN 95/5, Phase B: AN; gradient phase B 0—50% 8 min, yield 30%). ESI (+) MS: m/z 214 (MH+). 1H NMR: 2.83 (t, J=7.93, 2H), 2.98 (t, J=8.05, 2H), 6.61-7.28 (m, 2H), 7.33 (d, J=5.00, 1H), 7.56 (d, J=2.80, 1H), 8.28-8.38 (m, 2H), 11.85 (bs, 1H).
Reaction SMILES: [CH2:1]([O:4][C:5]([NH:7][C:8]1[CH:16]=[C:15]2[C:11]([CH:12]=[C:13]([C:17]([O:19]CC)=[O:18])[NH:14]2)=[CH:10][CH:9]=1)=[O:6])[CH:2]=[CH2:3].[OH-].[Li+]>CO.O>[CH2:1]([O:4][C:5]([NH:7][C:8]1[CH:16]=[C:15]2[C:11]([CH:12]=[C:13]([C:17]([OH:19])=[O:18])[NH:14]2)=[CH:10][CH:9]=1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)Nc1ccc2cc(C(=O)OCC)[nH]c2c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C=CCOC(=O)Nc1ccc2cc(C(=O)O)[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.5 %

Procedure:
To 134 mg (0.465 mmol) of ethyl 6{[(allyloxy)carbonyl]amino}-1H-indole-2-carboxylate dissolved in 5 mL methanol was added 43 mg (1.023 mmol) lithium hydroxide dissolved in 1 mL water. The mixture was stirred at room temperature overnight, partitioned between ethyl acetate and 1 N HCl until neutral, dried over magnesium sulfate and concentrated to provide 118 mg 6-{[(allyloxy)carbonyl]amino}-1H-indole-2-carboxylic acid, as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[N:5][N:6]=1.[Li]CCCC.[CH2:12]([O:14][CH2:15][C:16](OCC)=[O:17])[CH3:13]>C1COCC1.C1(C)C=CC=CC=1>[CH3:1][C:2]1[O:3][C:4]([C:16]([CH2:15][O:14][CH2:12][CH3:13])=[O:17])=[N:5][N:6]=1
Reactant: Cc1nnco1
Reactant: CCOCC(=O)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOCC(=O)c1nnc(C)o1
Temperature: -40 °C
Reaction time: 1 h

Procedure:
To a stirred solution of the 2-methyl-1,3,4-oxadiazole (5.0 g, 59.5 mmol) in THF (100 mL) was added dropwise n-BuLi (23.79 mL, 59.5 mmol) in toluene under N2 at −78° C. After 1 h, ethyl ethoxyacetate (10.22 g, 77 mmol) was added. The reaction mixture was then allowed to warm to −40° C. and stirred for 2 h. The reaction mixture was then quenched with 65 mL of LON HCl and extracted with EtOAc. The organic layer was washed with water and then brine, dried over anhydrous Na2SO4, and concentrated. The resulting residue was purified on a flash chromatography column (Biotage™-40M) using a gradient of 0-100% of n-hexane/Et2O to give the desired product. 1H NMR (500 MHz, CD3OD): δ 1.27 (t, 3H), 2.64 (s, 3H), 3.69 (q, 2H), 4.88 (s, 2H).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=1[N:19]1[N:23]=[CH:22][CH:21]=[N:20]1)=[O:11].F[C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=1>>[F:18][C:14]1[C:13]([N:19]2[N:23]=[CH:22][CH:21]=[N:20]2)=[C:12]([C:10]([N:4]2[CH2:5][CH2:6][CH2:7][C@@H:8]([CH3:9])[C@H:3]2[CH2:2][NH:1][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=2)=[O:11])[CH:17]=[CH:16][CH:15]=1
Reactant: Fc1ccc(C(F)(F)F)cn1
Reactant: C[C@@H]1CCCN(C(=O)c2cccc(F)c2-n2nccn2)[C@@H]1CN
Product: C[C@@H]1CCCN(C(=O)c2cccc(F)c2-n2nccn2)[C@@H]1CNc1ccc(C(F)(F)F)cn1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(3-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 2-fluoro-5-(trifluoromethyl)pyridine. ESI-MS (m/z): 463 [M+1]+. 1H NMR (300 MHz, DMSO-d6) δ 8.40-6.55 (m, 9H), 4.75-2.70 (m, 5H), 1.70-0.75 (m, 8H).
Reaction SMILES: [N:1]([N:3]1[CH:8]([CH:9]2[CH2:14][CH2:13][CH:12]([Cl:15])[CH2:11][N:10]2C(=O)C(F)(F)F)[C:7](=[O:22])[N:6]([N:23]=[O:24])[CH:5]([CH:25]2[CH2:30][CH2:29][CH:28]([Cl:31])[CH2:27][N:26]2C(=O)C(F)(F)F)[C:4]1=[O:38])=[O:2].[OH-].[Na+]>C(Cl)(Cl)Cl>[N:23]([N:6]1[CH:5]([CH:25]2[CH2:30][CH2:29][CH:28]([Cl:31])[CH2:27][NH:26]2)[C:4](=[O:38])[N:3]([N:1]=[O:2])[CH:8]([CH:9]2[CH2:14][CH2:13][CH:12]([Cl:15])[CH2:11][NH:10]2)[C:7]1=[O:22])=[O:24]
Reactant: O=NN1C(=O)C(C2CCC(Cl)CN2C(=O)C(F)(F)F)N(N=O)C(=O)C1C1CCC(Cl)CN1C(=O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: O=NN1C(=O)C(C2CCC(Cl)CN2)N(N=O)C(=O)C1C1CCC(Cl)CN1

Procedure:
A 1 mmole portion of 1,4-dinitroso-3,6-bis-(1-trifluoracetyl-5-chloro-2-piperidinyl)-2,5-piperazinedione is stirred in a 2-phase system of 10ml. of chloroform and 10 ml. of 0.2 N sodium hydroxide with ice-bath cooling for 4 hours. The solvents are then removed in vacuo and the residue is chromatographed on silica gel tic plates to afford 1,4-dinitroso-3,6-bis-(5-chloro-2-piperdinyl)-2,5-piperazinedione.
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][C:13]([NH2:16])=[N:12]2)[O:6]CCO1.[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=1/[CH:25]=[CH:26]/[C:27](O)=[O:28]>>[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=1/[CH:25]=[CH:26]/[C:27]([NH:16][C:13]1[CH:14]=[CH:15][N:11]([CH2:10][CH2:9][CH2:8][CH2:7][C:2](=[O:6])[CH3:1])[N:12]=1)=[O:28]
Reactant: O=C(O)/C=C/c1c(F)cccc1Cl
Reactant: CC1(CCCCn2ccc(N)n2)OCCO1
Product: CC(=O)CCCCn1ccc(NC(=O)/C=C/c2c(F)cccc2Cl)n1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[4-(2-methyl-[1,3]dioxolan-2-yl)-butyl]-1H-pyrazol-3-ylamine and (E)-3-(2-chloro-6-fluoro-phenyl)-acrylic acid.
Reaction SMILES: [Br-].[CH3:2]P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.[F:27][C:28]1[CH:36]=[CH:35][C:34]2[C:33](=O)[CH2:32][CH2:31][C:30]=2[C:29]=1[C:38]#[N:39].[NH4+].[Cl-]>C1COCC1.CCOC(C)=O>[F:27][C:28]1[CH:36]=[CH:35][C:34]2[C:33](=[CH2:2])[CH2:32][CH2:31][C:30]=2[C:29]=1[C:38]#[N:39]
Reactant: N#Cc1c(F)ccc2c1CCC2=O
Reactant: C[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=C1CCc2c1ccc(F)c2C#N
Temperature: -20 °C
Reaction time: 0.33 h

Procedure:
Methyl triphenylphosphine bromide (816 mg, 2.28 mmol) was dissolved in THF (10 mL) and placed in a cool bath at −20° C. The mixture was then treated with n-butyl lithium (913 μl, 2.28 mmol), and stirred for 20 min. at −20° C. To the mixture was then added 5-fluoro-1-oxo-2,3-dihydro-1H-indene-4-carbonitrile (200 mg, 1.14 mmol) via cannula and subsequently stirred for 20 min at −20° C.; LC as well as TLC (hexanes/EtOAc=1/0.3) indicated that reaction was half complete. To the mixture was poured NH4Cl, and the solution was transferred into separatory funnel, diluted with EtOAc, washed with NH4Cl, NaCl, dried over Na2SO4, filtered and concentrated to dryness. The residue was then absorbed into silica gel and separated over a silica column with the solvent systems of hexanes/EtOAc (1/0.3) to give 5-fluoro-1-methylidene-2,3-dihydro-1H-indene-4-carbonitrile. LC-MS (IE, m/z): 174 [M+1]+; tR=2.10 min.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[CH:13][N:14]([C:16]3[CH:21]=[CH:20][C:19](I)=[CH:18][CH:17]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1.[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][C:24]1=[O:29].OC1C=CC=C2C=1N=CC=C2.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.[Cu]I>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[CH:13][N:14]([C:16]3[CH:21]=[CH:20][C:19]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][C:24]4=[O:29])=[CH:18][CH:17]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1
Reactant: O=C1COCCN1
Reactant: O=C(NCc1cn(-c2ccc(I)cc2)cn1)c1ccc(Cl)s1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Product: O=C(NCc1cn(-c2ccc(N3CCOCC3=O)cc2)cn1)c1ccc(Cl)s1
Temperature: 130 °C

Procedure:
A mixture of 5-chloro-N-((1-(4-iodophenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide 1-6 prepared in Example 1 (33 mg, 0.074 mmol), 3-morpholinone prepared above (22 mg, 0.218 mmol), 8-hydroxyquinoline (7 mg, 0.048 mmol) and K2CO3 (30 mg, 0.217 mmol) in DMSO (0.5 mL) was degassed before being charged with CuI (14 mg, 0.073 mmol). The mixture in a sealed tube was heated at 130° C. overnight. The mixture was then purified by HPLC to give the title compound (3 mg). MS 417.0 and 419.0 (M+H, Cl pattern).