Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:6](=O)[C:5](=[O:8])[NH:4][C:3]2[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:15](=[O:16])[C:2]1=2.O.[CH2:18]([SH:21])[CH2:19][SH:20].B(F)(F)F.CCOCC>C1(C)C=CC=CC=1>[CH2:18]1[S:21][C:6]2([C:5](=[O:8])[NH:4][C:3]3[C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=4[C:15](=[O:16])[C:2]=3[NH:1]2)[S:20][CH2:19]1
Reactant: SCCS
Reactant: O=C1c2ccccc2-c2[nH]c(=O)c(=O)[nH]c21
Agent: FB(F)F
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1C2=C(NC(=O)C3(N2)SCCS3)c2ccccc21
Temperature: 25 °C

Procedure:
A suspension of 9H-indeno[1,2-b]pyrazine-2,3,9(1H, 4H)-trione. 0.9 H2O (2.0 g, 8.68 mmol) in toluene (50 ml), 1,2-ethanedithiol (2.19 ml, 26.04 mmol) and boron trifluoride etherate (1.07 ml, 8.68 mmol) was refluxed for 20 hours. The reaction mixture was cooled to room temperature, and the precipitate was filtered off and washed with toluene, ethanol-water (2:1) and ethanol. The crude material (2.40 g) was recrystallized from DMF-water to give 2.09 g (83%) of the title, compound. M.p.>300° C. 1H-NMR (DMSO-d6, δ): 3.68 (m, 2H), 3.91 (m, 2H), 7.2 (t, 1H), 7.3 (t, 1H), 7.51 (d, 1H), 7.59 (d, 1H), 12.05 (s, 1H), 12.38 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[CH:9][C:10]([OH:12])=O)=[N:6][CH:7]=1.Cl.[CH3:14][NH:15][O:16][CH3:17].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.C(N(CC)CC)C>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[CH:9][C:10]([N:15]([O:16][CH3:17])[CH3:14])=[O:12])=[N:6][CH:7]=1
Reactant: CNOC
Reactant: O=C(O)C=Cc1ccc(Br)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)C=Cc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.1 %

Procedure:
3-(5-Bromo-pyridin-2-yl)-acrylic acid (1.3 g, 5.7 mmol) prepared in Step 1, N,O-dimethylhydroxylamine hydrochloride (0.7 g, 6.8 mmol), HOBT (1.5 g, 11.4 mmol), EDAC (2.2 g, 11.4 mmol) and triethylamine (1.6 mL, 11.4 mmol) were added to dichloromethane (42.0 mL). The reaction mixture was stirred at room temperature for 18 hours, quenched with a saturated solution of ammonium chloride, and then extracted with dichloromethane. The extract was washed with brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/9) to give 1.3 g of the titled compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:16][C:17]([N+:24]#[C-:25])([CH3:23])[CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20].[CH:26](=O)[CH3:27]>Cl(O)(=O)(=O)=O>[CH2:9]([O:8][C:7]1[C:2]2[N:3]([C:25]([NH:24][C:17]([CH3:23])([CH3:16])[CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[C:26]([CH3:27])[N:1]=2)[CH:4]=[CH:5][CH:6]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Nc1ncccc1OCc1ccccc1
Reactant: [C-]#[N+]C(C)(C)CC(C)(C)C
Reactant: CC=O
Agent: [O-][Cl+3]([O-])([O-])O
Product: Cc1nc2c(OCc3ccccc3)cccn2c1NC(C)(C)CC(C)(C)C

Procedure:
Compound (29) was prepared according to the general synthesis instructions from 1.0 ml of 2-amino-3-benzyloxypyridine solution (0.1 M, DCM), 0.575 ml of 1,1,3,3-tetramethylbutyl isocyanide solution (0.2 M, DCM), 0.500 ml of acetaldehyde solution (0.3 M, DCM), and 10 μl of perchloric acid (w=20%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:14]([OH:16])=O)[CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:17](N(CC)CC)C.CN(C(ON1N=N[C:34]2[CH:35]=[CH:36][CH:37]=[N:38][C:33]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:17][C@@H:37]1[CH2:36][CH2:35][C@H:33]([CH3:34])[N:38]1[C:14]([C:9]1([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10][CH2:11][CH2:12][CH2:13]1)=[O:16]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: C[C@@H]1CC[C@H](C)N1C(=O)C1(NC(=O)OC(C)(C)C)CCCC1
Temperature: 23 °C
Reaction time: 4 h
Yield: 69.4 %

Procedure:
To a suspension of 1-(tert-butoxycarbonylamino)cyclopentanecarboxylic acid (500 mg, 2.181 mmol), (2R,5S)-2,5-dimethylpyrrolidine, HCl (296 mg, 2.181 mmol), and triethylamine (0.912 mL, 6.54 mmol) in DMF (5 mL) was added HATU (829 mg, 2.181 mmol). The mixture was stirred at 23° C. for 4 h then concentrated. The residue was taken up in EtOAc (25 mL) then washed successively with 0.5 M HCl (2×25 mL), saturated NaHCO3 (2×25 mL), and brine (2×25 mL). The combined organic layers were dried (MgSO4), filtered, then concentrated under reduced pressure. The residue was purified by silica gel flash chromatography to give the title compound (0.47 g) as a white solid. LCMS m/z=311.3 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:29])=[C:4]([C:8]2[C:20]3[C:19]4[C:14](=[CH:15][C:16]([O:21][CH2:22][CH2:23][O:24][CH3:25])=[CH:17][CH:18]=4)[NH:13][C:12]=3[C:11]([C:26]([NH2:28])=[O:27])=[N:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[F:30][C:31]1[CH:32]=[CH:33][C:34]([CH:40]=O)=[C:35]([CH:39]=1)[C:36]([OH:38])=[O:37].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClC(Cl)C.O1CCCC1>[C:26]([C:11]1[C:12]2[NH:13][C:14]3[C:19]([C:20]=2[C:8]([C:4]2[C:3]([CH3:29])=[C:2]([NH:1][CH2:40][C:34]4[CH:33]=[CH:32][C:31]([F:30])=[CH:39][C:35]=4[C:36]([OH:38])=[O:37])[CH:7]=[CH:6][CH:5]=2)=[CH:9][N:10]=1)=[CH:18][CH:17]=[C:16]([O:21][CH2:22][CH2:23][O:24][CH3:25])[CH:15]=3)(=[O:27])[NH2:28]
Reactant: COCCOc1ccc2c(c1)[nH]c1c(C(N)=O)ncc(-c3cccc(N)c3C)c12
Reactant: O=Cc1ccc(F)cc1C(=O)O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Solvent: C1CCOC1
Product: COCCOc1ccc2c(c1)[nH]c1c(C(N)=O)ncc(-c3cccc(NCc4ccc(F)cc4C(=O)O)c3C)c12
Temperature: 25 °C
Reaction time: 16 h
Yield: 31.2 %

Procedure:
A mixture of 4-(3-amino-2-methylphenyl)-7-(2-methoxyethoxy)-9H-pyrido[3,4-b]indole-1-carboxamide (60.0 mg, 0.154 mmol), 5-fluoro-2-formylbenzoic acid (64.6 mg, 0.384 mmol), sodium triacetoxyborohydride (98 mg, 0.461 mmol), and acetic acid (0.022 mL, 0.384 mmol) in dichloroethane (3 mL) and tetrahydrofuran (2 mL) was stirred at room temperature for 16 hr and then quenched with water (3 mL). The resulting mixture was diluted with ethyl acetate (50 mL) and washed with water (25 mL). The aqueous solution was extracted with ethyl acetate (2×30 mL). The combined extract was washed with brine (25 mL) and dried over anhydrous MgSO4. The organic solution was concentrated under vacuum to dryness. The residue was dissolved with minimum amount of DMF, diluted with MeOH (3 mL), divided into 2 portions, and purified by reverse phase HPLC. The correct fractions were combined, concentrated under vacuum, and lyophilized to afford the desired product (TFA salt) (31.6 mg, 0.048 mmol, 31.3% yield) as a white powder.
Reaction SMILES: OC[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=O)[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[C:39](OCC)(=[O:41])C.O>O1CCCC1>[CH2:18]([O:17][C:14]1[CH:13]=[CH:12][C:11]([CH2:10][NH:9][C:6]2[CH:5]=[CH:4][CH:3]=[CH:8][C:7]=2[CH2:39][OH:41])=[CH:16][CH:15]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCOC(C)=O
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)Nc2ccc(CO)cc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCCCCCCCOc1ccc(CNc2ccccc2CO)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 13 g of N-[4-(hydroxymethyl)phenyl]-4-(tetradecyloxy)benzamide in 250 ml of tetrahydrofuran is added dropwise with stirring under argon 59.14 ml of 1 molar lithium aluminum hydride in tetrahydrofuran. The mixture is stirred at room temperature for 0.5 hours and refluxed for 5 hours. Ethyl acetate is added dropwise followed by water. The mixture is filtered and the cake washed with ether. The filtrate is evaporated to a residue which is purified by chromatography on silica gel with 2:1 chloroform:hexane to give the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:9][CH:8]=[CH:7][CH:6]=2.[OH:17][C:18]([CH3:23])([CH3:22])[C:19](O)=O>O>[CH3:22][C:18]([CH3:23])([C:19]1[N:12]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1)[OH:17]
Reactant: CC(C)(O)C(=O)O
Reactant: CC(C)CNc1c(N)cnc2ccccc12
Solvent: O
Product: CC(C)Cn1c(C(C)(C)O)nc2cnc3ccccc3c21
Temperature: 160 °C
Yield: 22.8 %

Procedure:
3-Amino-4-(2-methylpropyl amino) quinoline (28.7 g; 0.133 mol) and 2-hydroxyisobutyric acid (27.8 g; 0.267 mol) were mixed and the mixture was heated at 160° C. for 5 hrs. Water was added to the dark mixture and a green oil formed. The oil was extracted with ether to yield 8.6 g of an oil which contained two products. The mixture was purified by silica gel column chromatography to yield 3.2 g of the intended product. A small amount was recrystallized from ethyl acetate for analysis and characterization. m.p. 156°-164° C.
Reaction SMILES: [CH:1]([NH:3][CH:4]([CH2:7][CH2:8][O:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1)[CH2:5][OH:6])=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:1][NH:3][CH:4]([CH2:7][CH2:8][O:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1)[CH2:5][OH:6]
Reactant: O=CNC(CO)CCOc1cccc2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CNC(CO)CCOc1cccc2ccccc12
Temperature: 45 °C

Procedure:
A solution of 2-(formylamino)-4-(1-naphthyloxy)butanol (7.1 g), prepared as described in Example 3, in dry THF (150 ml) is added dropwise to a suspension of LiAlH4 (5.0 g) in THF (150 ml). The mixture is heated at 45° C. for 3 hours and cooled. Excess LiAlH4 is destroyed by the careful addition of THF/water (9:1). The mixture is filtered through diatomaceous earth (Celite). The filtrate is dried and evaporated. The residue is crystallized from diethyl ether to give the title compound, γmaxCHCl3 3650, 3352, 1595 and 1580 cm-1.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(O)(=O)C.[C:23]([O:26][CH2:27][C:28]1[CH:45]=[CH:44][C:43]([CH2:46][O:47][Si](C(C)(C)C)(C)C)=[CH:42][C:29]=1[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1)=[O:31])(=[O:25])[CH3:24]>O1CCCC1>[C:23]([O:26][CH2:27][C:28]1[CH:45]=[CH:44][C:43]([CH2:46][OH:47])=[CH:42][C:29]=1[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1)=[O:31])(=[O:25])[CH3:24]
Reactant: COc1ccc(COC(=O)c2cc(CO[Si](C)(C)C(C)(C)C)ccc2COC(C)=O)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1ccc(COC(=O)c2cc(CO)ccc2COC(C)=O)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 73.7 %

Procedure:
Tetrabutylammonium fluoride (1N tetrahydrofuran solution; 9.9 ml, 9.9 mmol) and acetic acid (592.9 mg, 9.87 mmol) were added to a solution of 4-methoxybenzyl 2-(acetoxymethyl)-5-[(tert-butyldimethylsilyl)oxymethyl]benzoate (905 mg, 1.97 mmol) obtained from Example 1-(8) in tetrahydrofuran (5 ml). The mixture was stirred at 50° C. for 1 hour, and then the solvent was distilled off under reduced pressure. The oily residue was subjected to chromatography on a silica gel (25 g) column (eluent; ethyl acetate:hexane=1:1) to give the title compound (500.1 mg, 74% yield) as a colorless amorphous solid.
Reaction SMILES: C(O/C(=[C:6]1/[C:7]([CH2:18][C:19]([O:21][CH3:22])=[O:20])=[N:8][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]/1=[O:11])/C)C.C(OC(=O)C)(=O)C.CC(OCC)(OCC)OCC>>[OH:11][C:10]1[N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:8]=[C:7]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH:6]=1
Reactant: CCO/C(C)=C1\C(=O)N(c2ccccc2)N=C1CC(=O)OC
Agent: CCOC(C)(OCC)OCC
Solvent: CC(=O)OC(C)=O
Product: COC(=O)Cc1cc(O)n(-c2ccccc2)n1

Procedure:
Methyl [(4Z)-4-(1-ethoxyethylidene)-5-oxo-1-phenyl-4,5-dihydro-1H-pyrazol-3-yl]acetate (Compound of Formula (VII), Scheme 1). The mixture of the above obtained methyl (5-hydroxy-1-phenyl-1H-pyrazol-3-yl)acetate (Compound of Formula (IV), 1.85 g), acetic anhydride (1.00 ml) and MeC(OEt)3 (2.50 ml) was refluxed for 1 h. and left overnight at an ambient temperature. Resulting precipitate was collected by filtration and washed with ethyl ether (10 ml) in order to obtain crude product methyl [(4Z)-4-(1-ethoxyethylidene)-5-oxo-1-phenyl-4,5-dihydro-1H-pyrazol-3-yl]acetate (1.20 g, 80% purity) in 50% yields. 1HNMR (400 MHz, CDCl3, ppm): 1.42 (3H, t, 7.1 Hz), 2.78 (3H, s), 3.73 (3H, s), 3.76 (2H, s), 4.31 (2H, q, 6.9 Hz), 7.16 (1H, t, 7.2 Hz), 7.37 (2H, t, 7.6 Hz), 7.97 (2H, d, 8.0 Hz). MS (ESI+): 303.3; MS (ESI−): 301.2.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[Cl-:14].[Al+3].[Cl-].[Cl-].[CH:18]#[CH:19]>ClCCCl>[Cl:14][CH:18]=[CH:19][C:4]([C:3]1[CH:7]=[C:8]([F:13])[C:9]([F:12])=[C:10]([F:11])[C:2]=1[F:1])=[O:5]
Reactant: [Cl-]
Reactant: C#C
Reactant: O=C(Cl)c1cc(F)c(F)c(F)c1F
Agent: [Al+3]
Solvent: ClCCCl
Product: O=C(C=CCl)c1cc(F)c(F)c(F)c1F

Procedure:
53.2 g of 2,3,4,5-tetrafluorobenzoyl chlorde are added dropwise to a suspension of 36.5 g of anhydrous aluminum chloride in 100 ml of 1,2-dichloroethane at 0°14 10° C., while cooling with ice and stirring. Acetylene is then passed in at 40°-50° C. for 7 hours and the mixture is poured onto ice. The phases are separated, subsequent extraction with methylene chloride is carried out and the extract is washed with water and dried with sodium sulphate. The solvent is distilled off in vacuo and the residue is distilled under a high vacuum. 49.2 g of 2,3,4,5-tetrafluorophenyl 2-chlorovinyl ketone pass over at 92°-105° C./1.5 mbar.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([C:7]1[C:12]([OH:13])=[CH:11][CH:10]=[CH:9][N:8]=1)=O.Cl.[C:18]([O:22][NH2:23])([CH3:21])([CH3:20])[CH3:19].C(O)C>O>[Br:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)/[C:5](/[C:7]1[C:12]([OH:13])=[CH:11][CH:10]=[CH:9][N:8]=1)=[N:23]\[O:22][C:18]([CH3:21])([CH3:20])[CH3:19].[Br:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)/[C:5](/[C:7]1[C:12]([OH:13])=[CH:11][CH:10]=[CH:9][N:8]=1)=[N:23]/[O:22][C:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: O=C(c1cccc(Br)c1)c1ncccc1O
Reactant: CC(C)(C)ON
Agent: Cl
Solvent: CCO
Solvent: O
Product: CC(C)(C)O/N=C(/c1cccc(Br)c1)c1ncccc1O
Product: CC(C)(C)O/N=C(\c1cccc(Br)c1)c1ncccc1O

Procedure:
A mixture of 2-(3-bromobenzoyl)-3-hydroxypyridine (1.78 g), O-t-butylhydroxylamine hydrochloride (1.19 g) and ethanol (50 mL) was refluxed for 5 hours. The reaction mixture was poured into water, and subjected to extraction with ethyl acetate. The extract was washed with water and a saturated aqueous saline solution, successively, and dried (sodium sulfate), followed by evaporating the solvent under reduced pressure. The residue was purified by means of a silica gel column (ethyl acetate--hexane) to afford (E)-2-(3-bromo-α-t-butoxyiminobenzyl)-3-hydroxypyridine (0.83 g) and (Z)-2-(3-bromo-α-t-butoxyiminobenzyl)-3-hydroxypyridine (0.83 g) and (Z)-2-(3-bromo-α-t-butoxyiminobenzyl)-3-hydroxypyridine (1.12 g) (compounds 2 and 1). In substantially the same manner as above, compounds 5, 6, 10, 13, 14, 18 to 24 were produced. Physical properties and spectrum data of these compounds and those produced in the following Examples are shown in Table 7 to Table 11.
Reaction SMILES: [Br:1][C:2]1[N:10]2[C:5]([CH:6]=[N:7][C:8](O)=[N:9]2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.CN(C=O)C.C1C=CC(N(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O)=CC=1.[C:47]([O:51][C:52]([N:54]1[CH2:59][CH2:58][CH:57]([C:60]2[CH:65]=[CH:64][C:63]([NH2:66])=[CH:62][CH:61]=2)[CH2:56][CH2:55]1)=[O:53])([CH3:50])([CH3:49])[CH3:48]>>[C:47]([O:51][C:52]([N:54]1[CH2:59][CH2:58][CH:57]([C:60]2[CH:65]=[CH:64][C:63]([NH:66][C:8]3[N:7]=[CH:6][C:5]4=[CH:4][CH:3]=[C:2]([Br:1])[N:10]4[N:9]=3)=[CH:62][CH:61]=2)[CH2:56][CH2:55]1)=[O:53])([CH3:50])([CH3:48])[CH3:49]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cc2)CC1
Reactant: Oc1ncc2ccc(Br)n2n1
Agent: O=S(=O)(N(c1ccccc1)S(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc4ccc(Br)n4n3)cc2)CC1
Temperature: 25 °C

Procedure:
To a round bottom flask, 7-Bromo-pyrrolo[2,1-f][1,2,4]triazin-2-ol (0.593 g, 0.00277 mol), DIEA (1.50 mL, 0.0086 mol) and DMF (25 mL, 0.32 mol) were added. The mixture was stirred at room temperature and N-Phenylbis(trifluoromethanesulfonimide) (1.14 g, 0.00320 mol) was added. The mixture was stirred at room temperature for 1 h then 4-(4-Amino-phenyl)-piperidine-1-carboxylic acid tert butyl ester (0.995 g, 0.00361 mol) was added and the mixture stirred at 60° C. for 4 h. The solvent was removed under vacuum. The product was isolated via ISCO column chromatography with a 2:1 Hexane/DCM and Methanol as eluant (0 to 10% Methanol). The collected fractions gave 4-[4-(7-Bromo-pyrrolo[2,1-f][1,2,4]-triazin-2ylamino)-phenyl]-piperidine-1-carboxylic acid tert butyl ester as a pale solid (˜2:1 P: SM by NMR). LCMS (E/I+) 472 (M+H). ii) To a round bottom flask, Palladium Acetate (0.083 g, 0.000368 mol) and Triphenylphosphine (0.144 g, 0.000551 mol) and THF (6 mL, 0.070 mol) were added and purged under an atmosphere of Nitrogen for 10 minutes. A solution of 4-[4-(7-Bromo-pyrrolo[2,1-f][1,2,4]-triazin-2ylamino)-phenyl]-piperidine-1-carboxylic acid tert butyl ester (70% pure, 1.24 g, 0.00184 mol) in THF (4 mL, 0.050 mol) was added and the reaction was stirred for a further 10 minutes. 4-(Methylsulfonylphenyl)boronic acid (0.735 g, 0.00368 mol), Ethanol (10 mL, 0.20 mol) and 0.90 M Sodium carbonate in Water (6.12 mL, 0.00551 mol) were added and the mixture was heated at 80° C. overnight. The reaction was partitioned with aqueous Sodium Carbonate and EtOAc. The organic was separated, washed with Brine, and dried over Sodium Sulfate. The solid was filtered and washed with EtOAc. The solvent was removed under vacuum. The product was isolated via ISCO column chromatography with DCM and MeOH as eluant (0 to 10%). The collected fractions afforded 4-{4-[7-(4-Methanesulfonyl-phenyl)-pyrrolo[2,1-f][1,2,4]-triazin-2ylamino)-phenyl}-piperidine-1-carboxylic acid tert butyl ester as a yellow solid (0.762 g, 75% pure by NMR). LCMS (E/I+) 570 (M+Na).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH:10]1[N:15]2[CH:16]=[N:17][CH:18]=[C:14]2[CH2:13][CH2:12][CH2:11]1)[C:5]#[N:6].[CH2:19]1[CH2:21][CH2:20]1>>[CH:19]1([C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=2[CH:10]2[N:15]3[CH:16]=[N:17][CH:18]=[C:14]3[CH2:13][CH2:12][CH2:11]2)[C:5]#[N:6])[CH2:21][CH2:20]1
Reactant: N#Cc1ccc(C2CCCc3cncn32)c(Br)c1
Reactant: C1CC1
Product: N#Cc1ccc(C2CCCc3cncn32)c(C2CC2)c1

Procedure:
3-Bromo-4-(5,6,7,8-tetrahydro-imidazo[1,5-a]pyridin-5-yl)benzonitrile, prepared above, is converted to the corresponding cyclopropane by the method outlined in Tet. Lett. 2002, 43, 6987. MS (ESI) m/z 264.1 (M+H); 1H NMR (400 MHz, MeOD) δ ppm 0.69-0.80 (m, 2 H), 0.94-1.06 (m, 2 H), 1.69-1.80 (m, 2 H), 1.93-2.04 (m, 2 H), 2.24-2.34 (m, 1 H), 2.76-2.86 (m, 2 H), 5.95 (d, J=6.1 Hz, 1 H), 6.64-6.72 (m, 2 H), 7.15 (s, 1 H), 7.35 (s, 1 H), 7.39 (d, J=8.1 Hz, 1 H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:14])=[C:4]([C:9]([Br:13])=[C:10]([Cl:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[N:15]([O-])=O.[Na+]>C(O)(=O)C.O>[Br:13][C:9]1[C:10]([Cl:12])=[CH:11][C:2]2[NH:1][N:15]=[CH:14][C:3]=2[C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=N[O-]
Reactant: COC(=O)c1c(C)c(N)cc(Cl)c1Br
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1c(Br)c(Cl)cc2[nH]ncc12
Reaction time: 24 h
Yield: 76.4 %

Procedure:
To a solution of methyl 3-amino-6-bromo-5-chloro-2-methylbenzoate (500 mg, 1.80 mmol) in acetic acid (9 mL) was added a solution of sodium nitrite (137 mg, 1.99 mmol) in water (0.9 mL) at room temperature, and the mixture was stirred for 24 hr. The organic solvent was evaporated under reduced pressure. The residual aqueous solution was diluted with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate) to give the title compound (398 mg, yield 76%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:18])=[C:6]([C:8](=[O:17])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])[CH:7]=1.[C:19](OC(=O)CC)(=O)[CH2:20][CH3:21].Cl>C(N(CC)CC)C>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:18][C:19]([CH2:20][CH3:21])=[C:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:16])[C:8]2=[O:17]
Reactant: CCC(=O)OC(=O)CC
Reactant: Cc1ccccc1CC(=O)c1cc(Br)ccc1O
Agent: Cl
Solvent: CCN(CC)CC
Product: CCc1oc2ccc(Br)cc2c(=O)c1-c1ccccc1C
Temperature: 25 °C
Yield: 20.7 %

Procedure:
Intermediate 11 (3.0 g, 9.83 mmoles) was taken in a RB flask and to this triethylamine (25 ml) and propionic anhydride (4.00 g, 30.76 mmoles) were added and the mixture was refluxed for 24 h. After cooling to RT, the reaction mixture was acidified by the addition of 1N HCl solution, extracted with ethyl acetate, washed with sodium bicarbonate solution, dried with sodium sulphate and concentrated. The crude product was purified by column chromatography with ethyl acetate:petroleum ether to afford the title compound as colourless liquid (0.700 g, 20% yield). 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 7.73(d, J=2.5Hz, 1H), 7.63(dd, J=8.7, 2.5 Hz, 1H), 7.34(t, J=4.8Hz, 1H), 7.22-7.14(m, 4H), 2.63(q, J=7.5Hz, 2H), 0.94(t, J=7.5Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1O[C:5](=[O:7])[NH:4][N:3]=1.[NH2:8][CH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1>CO>[CH3:1][C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[C:5](=[O:7])[NH:4][N:3]=1
Reactant: Cc1n[nH]c(=O)o1
Reactant: NC1CCOCC1
Solvent: CO
Product: Cc1n[nH]c(=O)n1C1CCOCC1
Temperature: 100 °C
Reaction time: 2 h
Yield: 43.7 %

Procedure:
After dissolving 5-methyl-3H-[1,3,4]oxadiazol-2-one (CAS 3069-67-8) (500 mg) in methanol (5 ml), 4-aminotetrahydropyran (1.01 g) was added and the mixture was heated to reflux for 15 hours. The reaction mixture was concentrated under reduced pressure, and then a 1N aqueous solution of sodium hydroxide (5.5 ml) was added to the residue and the mixture Was stirred at 100° C. for 2 hours. After then adding 5N hydrochloric acid (1.1 ml) to the reaction mixture, it was stirred at room temperature for 3 hours. The precipitate was collected by filtration and washed with water and ethyl acetate in that order to obtain the title compound (400 mg).