Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[C:5](=[O:14])[CH:4]=1.[CH2:15]([NH2:20])[CH2:16][CH2:17][CH2:18][CH3:19]>C(O)C>[CH2:15]([NH:20][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[C:5](=[O:14])[CH:4]=1)[CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: COC1=CC(=O)C(=O)c2ccccc21
Reactant: CCCCCN
Solvent: CCO
Product: CCCCCNC1=CC(=O)C(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 49 %

Procedure:
To a stirred suspension of 650 mg (3.45 mmol) of 4-methoxy-1,2-naphthoquinone in 20 mL of ethanol was added 0.80 mL (6.90 mmol) of pentylamine. The reaction mixture was stirred at room temperature for 60 min. The resulting red precipitate was collected by filtration and then triturated with 20 mL of ethyl acetate to afford 411.7 mg (49%) of 4-pentylamino-1,2-naphthoquinone, which was recrystallized from ethyl acetate: mp>215° C.; 1H NMR (300 MHz, CDCl3, TMS) δ 8.21 (dd, J=7.5, 1.6 Hz, 1H), 7.69 (td, J=7.7, 1.6 Hz, 1H), 7.61 (t, J=7.5 Hz, 1H), 7.49 (d, J=7.9 Hz, 1H), 5.86 (s, 1H), 5.76 (br s, 1H), 3.4-3.3 (m, 2H), 1.8-1.7 (m, 4H), 1.5-1.4 (m, 4H), 0,95 (t, J=7 Hz, 3H); 13C NMR (75.5 MHz, d6 -DMSO, TMS) δ 182.0, 174.7, 154.8, 134.1, 131.2, 130.8, 127.8, 123.3, 98.0, 43.1, 28.7, 27.4, 21.8, 13.9. Analysis calculated for C15H17NO2 : C=74.04, H=7.06, N=5.7; Found: C=73.88, H=7.01, N=5.73.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](O)=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.Cl.[CH2:30]([O:32][C:33](=[O:38])[C@H:34]([CH2:36][OH:37])[NH2:35])[CH3:31].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH2:30]([O:32][C:33](=[O:38])[C@@H:34]([NH:35][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:28])([F:26])[F:27])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:12])[CH2:36][OH:37])[CH3:31]
Reactant: CCOC(=O)[C@@H](N)CO
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@H](CO)NC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C
Yield: 83.1 %

Procedure:
(S)-3-Hydroxy-2-{[1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-propionic acid ethyl ester (213 mg) was prepared by following General Procedure F starting from 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (200 mg), L-serine ethyl ester hydrochloride (91 mg), HBTU (223 mg), and DIEA (128 uL).
Reaction SMILES: [O:1]=[C:2]1[CH:9](C(OCC)=O)[C:8](=[O:15])[C:5]2([CH2:7][CH2:6]2)[CH2:4][NH:3]1.O>C(#N)C>[CH2:6]1[C:5]2([C:8](=[O:15])[CH2:9][C:2](=[O:1])[NH:3][CH2:4]2)[CH2:7]1
Reactant: CCOC(=O)C1C(=O)NCC2(CC2)C1=O
Solvent: O
Solvent: CC#N
Product: O=C1CC(=O)C2(CC2)CN1
Temperature: 90 °C
Yield: 45.5 %

Procedure:
Ethyl 6,8-dioxo-5-azaspiro[2.5]octane-7-carboxylate (4.0 g, 18.95 mmol) was taken up in ACN containing 1% v/v water (40 mL) and the resulting solution was heated at 90° C. for 3 h. The mixture was cooled to RT and concentrated in vacuo. The residue was diluted with water (40 mL) and extracted with EtOAc (2×50 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 80% EtOAc/petroleum ether) furnished 5-azaspiro[2.5]octane-6,8-dione (1.2 g, 8.62 mmol, 46% yield) as a pale pink solid: 1H NMR (400 MHz, CDCl3): δ 8.24 (br s, 1H), 3.41 (s, 2H), 3.33-3.31 (m, 2H), 1.11-1.05 (m, 2H), 0.98-0.96 (m, 2H). m/z (ESI, +ve) 140.3 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.Cl[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: ClCCN1CCOCC1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccc(OCCN2CCOCC2)cc1
Yield: 54 %

Procedure:
A mixture of 4-nitrophenol (3.5 g, 25 mmol), N-(2-chloroethyl)morpholine hydrochloride (4.7 g, 25 mmol), and potassium carbonate (13.2 g, 125 mmol) in acetone (100 mL) was heated to reflux for 18 hours. The solvent was removed under vacuum. The residue was partitioned between water (150 mL) and ethyl acetate (150 mL), and the aqueous phase was extracted with ethyl acetate (100 mL). The combined organic layers were washed with water (3×100 mL) and extracted with dilute aqueous HCl (2×125 mL). These extracts were washed with CH2Cl2 (2×125 mL), made basic (NaOH), and extracted into ethyl acetate (3×75 mL). These organic extracts were washed with water (3×75 mL), dried (MgSO4), and evaporated, providing 3.4 g as a pale yellow solid, in 54% yield; 1H NMR (CDCl3) δ 2.59 (t, J=4.7 Hz, 4H), 2.84 (t, J=5.7 Hz, 2H), 3.74 (t, J=4.7 Hz, 4H), 4.20 (t, J=5.7 Hz, 2H), 6.97 (d, J=9.0 Hz, 2H), 8.20 (d, J=9.0 Hz, 2H).
Reaction SMILES: [CH:1]1([N:7]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:8](=[O:18])[NH:9][C:10]2[S:11][CH:12]=[C:13]([C:15](O)=[O:16])[N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[CH:1]1([N:7]([CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]2)[C:8]([NH:9][C:10]2[S:11][CH:12]=[C:13]([C:15]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:16])[N:14]=2)=[O:18])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: O=C(O)c1csc(NC(=O)N(C2CCCCC2)C2CCCCC2)n1
Product: O=C(c1csc(NC(=O)N(C2CCCCC2)C2CCCCC2)n1)N1CCOCC1
Yield: 24 %

Procedure:
Prepared in 24% yield (61 mg) as described in general procedure (K) from 2-(3,3-dicyclohexylureido)-thiazole-4-carboxylic acid (210 mg, 0.60 mmol) and morpholine (52 mg, 0.60 mmol).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13](Cl)[CH:12]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.C([O-])(=[O:20])C.[NH4+]>C(O)=O.O>[Cl:1][C:2]1[C:3]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][NH:14][C:13](=[O:20])[CH:12]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(=O)[O-]
Reactant: Clc1cnc(COc2ccnc(Cl)c2)c(Cl)c1
Agent: [NH4+]
Solvent: O=CO
Solvent: O
Product: O=c1cc(OCc2ncc(Cl)cc2Cl)cc[nH]1
Yield: 83.3 %

Procedure:
3,5-Dichloro-2-((2-chloropyridin-4-yloxy)methyl)pyridine (1.15 g, 4.03 mmol) and ammonium acetate (1.55 g, 20.0 mmol) were heated to 110° C. in a mixture of formic acid (20 mL) and water (20 mL) for 5 days. The mixture was concentrated to remove most of the liquid and then adjusted to pH 8 with NaHCO3 solution. The solid was filtered off to provide the title compound (910 mg, 82%) as a tan solid: 1H NMR (300 MHz, DMSO-d6) δ 11.1 (br s, 1H), 8.66 (d, J=2.1 Hz, 1H), 8.34 (d, J=2.1 Hz, 1H), 7.25 (d, J=7.3 Hz, 1H), 5.90-5.87 (dd, J=7.3, 2.8 Hz, 1H), 5.82 (d, J=2.6 Hz, 1H), 5.20 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([NH:6][C:7](=[O:21])[C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([N:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:24](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([NH:6][C:7](=[O:21])[C:8]2[CH:9]=[CH:10][C:11]([N:14]([CH3:24])[S:15]([N:18]([CH3:20])[CH3:19])(=[O:16])=[O:17])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: CN(C)S(=O)(=O)Nc1ccc(C(=O)Nc2ccc(Cl)cc2)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: CN(C)S(=O)(=O)N(C)c1ccc(C(=O)Nc2ccc(Cl)cc2)cc1
Yield: 96.2 %

Procedure:
A mixture of 300 mg of 4'-chloro-4-[(dimethylaminosulfonyl)amino]benzanilide 7, 140 mg of potassium carbonate, 130 mg of dimethyl sulfate 8, and 10 ml of dried acetone is refluxed for 30 minutes. Acetone is distilled off from the reaction mixture, the residue is basified with 10% sodium hydroxide solution and extracted with methylene chloride. The organic layer is washed with water, dried over anhydrous sodium sulfate, and concentrated. The residue is crystallized from ethyl acetate-isopropyl ether to give 300 mg of 4'-chloro-4-[methyl(dimethylaminosulfonyl)amino]benzanilide 9 as crystals, m.p. 155°-156° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]1[CH2:21][CH:20]([OH:22])[C:19]2[N:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.C(OCC)(=O)C>[CH2:1]([O:8][C:9]([NH:11][CH:12]1[CH2:21][C:20](=[O:22])[C:19]2[N:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:13]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NC1Cc2cccnc2C(O)C1)OCc1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(NC1CC(=O)c2ncccc2C1)OCc1ccccc1
Reaction time: 2 h
Yield: 31 %

Procedure:
To a stirred solution of 6-benzyloxycarbonylamino-8-hydroxy-5,6,7,8-tetrahydroquinoline, cis-trans mixture (1.02 g, 3.42 mmol) in methylene chloride (34 mL) at room temperature under nitrogen was added Dess-Martin periodinane (1.73 g, 4.45 mmol). After 2 h, the reaction mixture was diluted with ethyl acetate. The organic layer was washed sequentially with saturated aqueous sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, and evaporated under vacuum to yield a residue. The residue was purified by reverse phase preparative HPLC to obtain the title compound (319 mg, 31%) as a brown oil. 13C NMR (400 MHz, CDCl3) δ 194.1, 155.4, 149.8, 147.6, 138.3, 137.2, 136.0, 128.6, 128.3, 128.2, 127.5, 67.0, 46.7, 45.4, 35.4. 1H NMR (400 MHz, CDCl3) δ 8.66 (d, J=4.4 Hz, 1H), 7.61 (d, J=7.9 Hz, 1H), 7.36 (dd, J=4.4, 7.9 Hz, 1H), 7.26 (m, 5H), 5.02 (s, 2H), 4.34 (s, 1H), 3.29 (d, J=15.4 Hz, 1H), 3.04 (d, J=4.0 Hz, 1H), 2.99 (d, J=4.0 Hz, 1H), 2.80 (dd, J=9.2, 11.4 Hz, 1H). HPLC/MS [M+H]+, 297.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH2:12]([S:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]2=[N:25][N:26]=[C:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:17]2[N:16]=1)[CH3:13]>C(Cl)Cl>[CH2:12]([S:14]([C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]2=[N:25][N:26]=[C:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:17]2[N:16]=1)=[O:9])[CH3:13]
Reactant: CCSc1nn2c(-c3ccccc3)nnc2c2ccccc12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCS(=O)c1nn2c(-c3ccccc3)nnc2c2ccccc12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
m-Chloroperbenzoic acid (3.1 g) is added to a solution of the compound of example 109 (4.6 g) in methylene chloride (50 ml) and the reaction mixture is stirred at room temperature for five hours. The mixture is washed first with diluted sodium metabisulfite and then with aqueous sodium bicarbonate.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].[H-].[Na+].[Cl:9][C:10]1[CH:11]=[C:12]([CH:23]=[C:24]([Cl:26])[CH:25]=1)[O:13][C:14]1[C:15]([CH2:21][CH3:22])=[N:16][NH:17][C:18]=1[CH2:19][CH3:20]>CN(C=O)C>[CH3:6][O:5][C:3](=[O:4])[CH2:2][N:16]1[C:15]([CH2:21][CH3:22])=[C:14]([O:13][C:12]2[CH:23]=[C:24]([Cl:26])[CH:25]=[C:10]([Cl:9])[CH:11]=2)[C:18]([CH2:19][CH3:20])=[N:17]1
Reactant: COC(=O)CBr
Reactant: CCc1n[nH]c(CC)c1Oc1cc(Cl)cc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1nn(CC(=O)OC)c(CC)c1Oc1cc(Cl)cc(Cl)c1
Temperature: 0 °C
Yield: 23.9 %

Procedure:
Methyl bromoacetate (984 μL, 10 mmol) and then sodium hydride (60% dispersion in oil, 801 mg, 20.1 mmol) were added to a stirred solution of the pyrazole (2.6 g, 9.12 mmol) of Example 3 in dry N,N′-dimethylformamide (25 ml) at 0° C. under nitrogen. After stirring for 1 hour at 0° C. ice-water (100 ml) was added and the mixture was extracted with ether (3×50 ml). The combined ether layers were dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate:pentane (20:80, by volume) to provide the title compound (780 mg) as a yellow oil which partly crystallised on standing.
Reaction SMILES: [S:1](Cl)(=[O:4])(=[O:3])[NH2:2].[CH3:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=1)[O:10][CH2:11][CH2:12][OH:13]>>[CH3:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=1)[O:10][CH2:11][CH2:12][O:13][S:1](=[O:4])(=[O:3])[NH2:2]
Reactant: Cc1cccc(OCCO)c1
Reactant: NS(=O)(=O)Cl
Product: Cc1cccc(OCCOS(N)(=O)=O)c1
Yield: 47 %

Procedure:
The title compound was prepared by procedures of Example 4 from sulfamoyl chloride and 2-(3-methylphenoxy)ethanol in 47% yield [recrystallizing ethyl ether-petroleum ether (30°-60° C.)]. A white solid, mp 76°-78° C., was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:10])=[C:6]([CH:9]=1)[CH:7]=O.[S:11]1[CH:15]=[CH:14][C:13]2[S:16][CH:17]=[CH:18][C:12]1=2>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:10])=[C:6]([CH2:7][C:15]2[S:11][C:12]3[CH:18]=[CH:17][S:16][C:13]=3[CH:14]=2)[CH:9]=1
Reactant: O=Cc1cc(Br)ccc1Cl
Reactant: c1cc2sccc2s1
Product: Clc1ccc(Br)cc1Cc1cc2sccc2s1

Procedure:
The above 5-bromo-2-chlorobenzaldehyde and thieno[3,2-b]thiophene (see Fuller, L.; Iddon, B.; Smith, K. A. J. Chem. Soc. Perkin Trans 1 1997, 3465-3470) were treated in a manner similar to Reference Example 9 to give 5-bromo-2-chloro-1-(2-thieno[3,2-b]thienylmethyl)benzene as colorless oil. APCI-Mass m/Z 343/345 (M+H).
Reaction SMILES: [CH:1]1([C:4](=O)/[CH:5]=[CH:6]/N(C)C)[CH2:3][CH2:2]1.[C:11]1([NH:17][NH2:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(O)C>[CH:1]1([C:4]2[CH:5]=[CH:6][N:17]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:18]=2)[CH2:3][CH2:2]1
Reactant: CN(C)/C=C/C(=O)C1CC1
Reactant: NNc1ccccc1
Solvent: CCO
Product: c1ccc(-n2ccc(C3CC3)n2)cc1
Temperature: 150 °C
Reaction time: 0.5 h

Procedure:
(2E)-1-cyclopropyl-3-(dimethylamino)prop-2-en-1-one (327 mg, 2.35 mmol) and phenylhydrazine (0.35 ml, 3.5 mmol) were added to ethanol (5 ml). The reaction mixture was heated to 150° C. in the Biotage Initiator Series microwave reactor. After 30 minutes, the reaction mixture was cooled and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate/hexanes gradient) to afford 3-cyclopropyl-1-phenyl-1H-pyrazole (faster eluting isomer) and 5-cyclopropyl-1-phenyl-1H-pyrazole (slower eluting isomer).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[C:11]([O:19][CH:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])[CH3:21])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[OH-].[K+].CO>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([OH:15])=[O:14])=[C:11]([O:19][CH:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])[CH3:21])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(OCc2ccccc2)cc1OC(C)c1ccccc1C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccccc1C(C)Oc1cc(OCc2ccccc2)ccc1C(=O)O

Procedure:
A solution of methyl 4-benzyloxy-2-(1-o-tolylethoxy)benzoate (2.8 g) in 15% KOH in MeOH (50 mL) is refluxed for 3 hours. The solution is evaporated, the residue treated with water, brought to pH 1 with concentrated HCl, extracted with dichloromethane. The extract is dried and evaporated to give 4-benzyloxy-2-(1-o-tolylethoxy)benzoic acid as a colourless solid, m.p. 110-113° C.
Reaction SMILES: O[C:2](=[C:4]1[C:9](=[O:10])[CH2:8][CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH2:6][C:5]1=O)[CH3:3].O.[NH2:20][NH2:21]>C(O)C>[CH3:3][C:2]1[C:4]2[C:9](=[O:10])[CH2:8][CH:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[CH3:17])[CH2:6][C:5]=2[NH:21][N:20]=1
Reactant: NN
Reactant: CC(O)=C1C(=O)CC(c2ccccc2C)CC1=O
Solvent: O
Solvent: CCO
Product: Cc1ccccc1C1CC(=O)c2c(C)n[nH]c2C1
Yield: 90.4 %

Procedure:
A solution of 2-(1-hydroxyethylidene)-5-(2-methylphenyl)cyclohexane-1,3-dione (0.45 g) and hydrazine hydrate (0.1 g) in ethanol (10 ml) was refluxed for 15 minutes. Under reduced pressure, the solvent was evaporated, and the residue was recrystallized from ethyl acetate-hexane to give colorless crystals of 3-methyl-6-(2-methylphenyl)-4,5,6,7-tetrahydroindazol-4-one (0.40 g).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[S:8]1(=[O:24])=[O:23].[CH3:25][NH:26][CH3:27]>>[F:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[N:9]1[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:7]([CH2:6][CH2:5][O:4][CH2:3][CH2:2][N:26]([CH3:27])[CH3:25])[S:8]1(=[O:24])=[O:23]
Reactant: O=S1(=O)N(CCOCCBr)c2ccccc2N1c1ccccc1F
Reactant: CNC
Product: CN(C)CCOCCN1c2ccccc2N(c2ccccc2F)S1(=O)=O
Yield: 95 %

Procedure:
In an analogous manner as described in general procedure V, 1-[2-(2-bromoethoxy)ethyl]-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.07 g, 0.16 mmol) was treated with dimethylamine (10 mL) to provide 0.05 g (95%) of 2-{2-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethoxy}-N,N-dimethylethanamine. MS (ES) m/z 380.0; HRMS: calculated for C18H22FN3O3S+H+, 380.14387; found (ESI, [M+H]+), 380.1443; HPLC purity 98.1% at 210-370 nm, 9.1 minutes; Xterra RP18, 3.5 u, 150×4.6 mm column, 1.2 mL/minutes 85/15-5195 (Ammon. Bicarb Buff. pH=9.5/ACN+MeOH) for 10 minutes hold 4 minutes.
Reaction SMILES: CO[CH:3](OC)[CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12]N(C(OC(C)(C)C)=O)CC1.[C:23]([O-])([O-])=O.[K+].[K+]>S(=O)(=O)(O)O>[NH:8]1[C:7]2[C:6](=[CH:5][CH:4]=[CH:3][CH:23]=2)[CH:12]=[CH:13]1
Reactant: O=C([O-])[O-]
Reactant: COC(CCCCN1CCN(C(=O)OC(C)(C)C)CC1)OC
Agent: O=S(=O)(O)O
Agent: [K+]
Product: c1ccc2[nH]ccc2c1
Yield: 44 %

Procedure:
A mixture of Intermediate 1 (5.0 g, 28.6 mmol) and 5-[4-(tert-butyloxycarbonyl)piperazin-1-yl]pentanal dimethylacetal (9.03 g, 28.6 mmol) in 4% sulphuric acid (150 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 purified by chromatography on silica gel eluting with CH2Cl2 /MeOH/NH3 (30:8:1) to give the title-indole (3.9 g, 44%). The 3.5 hydrogen oxalate salt was prepared using 200 mg of free base: mp 90-92° C. (Found: C, 45.97; H, 4.76; N, 13.77. C17H22N6.3.5(C2H2O4) requires C, 46.08; H, 4.76; N, 13.43%); δ(360 MHz, D2O) 2.12-2.24 (2H, m, CH2); 2.93 (2H, t, J=7 Hz, CH2); 3.46-3.76 (8H, m, 4 of CH2); 7.37 (1H, dd, J=1.9 and 8.7 Hz, Ar--H); 7.39 (1H, s, Ar--H); 7.66 (1H, d, J=8.7, Ar--H); 7.82 (1H, d, J=1.9 Hz, Ar--H); 9.13 (2H, s, Triazole-H).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:5]=1[CH2:11]Br.[CH3:14][NH2:15]>C1COCC1>[Br:10][C:8]1[CH:9]=[C:4]2[C:5]([CH2:11][N:15]([CH3:14])[C:3]2=[O:2])=[CH:6][CH:7]=1
Reactant: CN
Reactant: COC(=O)c1cc(Br)ccc1CBr
Solvent: C1CCOC1
Product: CN1Cc2ccc(Br)cc2C1=O
Temperature: 50 °C
Yield: 100 %

Procedure:
To a solution of 5-bromo-2-bromomethyl-benzoic acid methyl ester (1.00 g, 3.25 mmol) in THF (6.5 mL) was a solution of methylamine in THF (2M, 8.12 mL, 16.24 mmol). The reaction mixture was heated at 50° C. for 4 hours and then concentrated under vacuum. The residue was taken up in EtOAc and the organic layer was then washed with an aqueous 1M HCl solution, brine, dried (Na2SO4), filtered, concentrated under vacuum to give the title compound (0.73 g, 100%) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([NH:15][NH2:16])=[O:14].[CH2:17]([O:24][C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27](O)=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([O:24][C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27]1[O:14][C:13]([C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:15][N:16]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(O)c1ccccc1OCc1ccccc1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)NN
Product: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccccc2OCc2ccccc2)o1
Yield: 29 %

Procedure:
As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylic acid hydrazide (200 mg, 0.92 mmol) was converted using 2-benzyloxybenzoic acid instead of o-toluic acid to the title compound (SiO2, heptane:ethyl acetate:dichloromethane=70:10:20 to 40:40:20, 109 mg, 29%) which was obtained as a white solid. MS: m/e=410.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([CH:21]=[N:22][CH:23]=2)[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[C:6]([C:8](N(OC)C)=[O:9])[CH:7]=1.[CH3:24][Mg]Br.Cl.C(=O)(O)[O-].[Na+]>O1CCCC1.O>[Cl:1][C:2]1[C:3]2[N:4]([CH:21]=[N:22][CH:23]=2)[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[C:6]([C:8](=[O:9])[CH3:24])[CH:7]=1
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)c1cc(Cl)c2cncn2c1-c1cccc(F)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1cc(Cl)c2cncn2c1-c1cccc(F)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 92.4 %

Procedure:
8-Chloro-5-(3-fluorophenyl)-N-methoxy-N-methylimidazo[1,5-a]pyridine-6-carboxamide (0.15 g, 0.45 mmol) was stirred in tetrahydrofuran (0.73 mL) and cooled to 0° C. A solution of 3.0 M methylmagnesium bromide (0.52 mL, 1.57 mmol) was added dropwise. The mixture was stirred at 0° C. for 30 minutes and at room temperature for 1 hour. The mixture was cooled to 0° C. and a solution of 1.0 M hydrogen chloride in water (1.8 mL) was added. The mixture was poured into saturated sodium bicarbonate and extracted into ethyl acetate 3×. The ethyl acetate extracts were combined and washed with water, dried over sodium sulfate, filtered, concentrated and purified by flash column chromatography with ethyl acetate in hexanes (0-80%) to give the desired compound (0.12 g, 93%). LCMS calculated for C15H11ClFN2O (M+H)+: m/z=289.1. found: 288.9. 1H NMR (300 MHz, DMSO-d6): δ 7.89 (s, 1H), 7.62 (m, 2H), 7.50 (m, 2H), 7.40 (m, 2H), 2.10 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:17]([CH3:18])[C:16]3[C:19](Br)=[C:20]([F:23])[CH:21]=[CH:22][C:15]=3[N:14]=2)[CH3:12])[N:5]=[CH:4][N:3]=1.[N:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.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>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:17]([CH3:18])[C:16]3[C:19]([C:28]4[CH:29]=[CH:30][N:25]=[CH:26][CH:27]=4)=[C:20]([F:23])[CH:21]=[CH:22][C:15]=3[N:14]=2)[CH3:12])[N:5]=[CH:4][N:3]=1
Reactant: OB(O)c1ccncc1
Reactant: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)c(Br)c2n1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)c(-c3ccncc3)c2n1C
Temperature: 140 °C
Yield: 65.4 %

Procedure:
A mixture of 4-Amino-6-[(S)-1-(7-bromo-6-fluoro-1-methyl-1H-benzoimidazol-2-yl)ethylamino]pyrimidine-5-carbonitrile, (0.10 g, 0.26 mmol), 4-pyridyl boronic acid (0.041 g, 0.33 mmol), tetrakis(triphenylphosphine)palladium(0) (0.015 g, 0.01 mmol) and caesium carbonate (0.17 g, 0.51 mmol) in dioxane (3 mL) and water (1.5 mL) was placed in a sealed tube and degassed with nitrogen for 5 minutes, then heated for 40 minutes at 140° C. by microwave irradiation. The resulting mixture was loaded onto an Isolute® SCX-2 cartridge then washed with MeOH and the product eluted with 2M NH3/MeOH then concentrated in vacuo. The residue was purified by chromatography eluting with (SiO2, 0-10% (2M ammonia in methanol) in DCM) then by preparative HPLC (Phenomenex Gemini 5 μm C18 on a 78 min gradient 20-98% 0.1% HCO2H in acetonitrile/water). The relevant fractions were concentrated to approximately ⅓ volume then partitioned between DCM (3×) and saturated aqueous NaHCO3. The combined DCM extracts were dried (Na2SO4) and concentrated in vacuo to give 429 as a white solid (0.066 g, 66%). LCMS (Method K): RT 2.32 min [M+H]+ 389.1. 1H NMR (DMSO-d6, 400 MHz): δ 8.72 (2H, d, J=5.05 Hz), 8.03 (1H, s), 7.71-7.70 (2H, m), 7.53 (2H, d, J=13.97 Hz), 7.31 (2H, s), 7.18 (1H, dd, J=10.45, 8.79 Hz), 5.64 (1H, m), 3.21 (3H, s), 1.58 (3H, d, J=6.74 Hz)