Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:38])([CH3:37])[C@H:3]([NH:8][C:9]([C:11]1[N:12]=[C:13]([C:28]2[CH:33]=[C:32]([F:34])[C:31]([F:35])=[CH:30][C:29]=2[F:36])[N:14]2[CH2:19][CH2:18][N:17]([CH2:20][C:21]([O:23]C(C)(C)C)=[O:22])[CH2:16][C:15]=12)=[O:10])[C:4]([NH:6][CH3:7])=[O:5].[OH-].[K+]>CO.O>[CH3:1][C:2]([CH3:38])([CH3:37])[C@H:3]([NH:8][C:9]([C:11]1[N:12]=[C:13]([C:28]2[CH:33]=[C:32]([F:34])[C:31]([F:35])=[CH:30][C:29]=2[F:36])[N:14]2[CH2:19][CH2:18][N:17]([CH2:20][C:21]([OH:23])=[O:22])[CH2:16][C:15]=12)=[O:10])[C:4]([NH:6][CH3:7])=[O:5]
Reactant: CNC(=O)[C@@H](NC(=O)c1nc(-c2cc(F)c(F)cc2F)n2c1CN(CC(=O)OC(C)(C)C)CC2)C(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CNC(=O)[C@@H](NC(=O)c1nc(-c2cc(F)c(F)cc2F)n2c1CN(CC(=O)O)CC2)C(C)(C)C
Temperature: 100 °C
Yield: 14 %

Procedure:
To compound 69B (20 mg, 0.037 mmol) in 1 mL of a 3:1 mixture of MeOH/water was added KOH (6.3 mg, 0.112 mmol). The reaction vessel was capped and heated in the microwave at 100° C. for 10 minutes. The reaction mixture was quenched with 1N HCl and evaporated to dryness. The residue was purified by automated preparative LC/MS to provide 2.5 mg (13% yield) of a white solid. LCMS (+ESI) m/z 482.6 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16]([C:21]#[N:22])=[N:17][N:18]([CH3:20])[CH:19]=2)=[CH:11][CH:10]=1)#[N:2].C([Li])CCC.Cl[C:29]([O:31][CH2:32][CH3:33])=[O:30]>C1COCC1>[CH2:32]([O:31][C:29]([C:19]1[N:18]([CH3:20])[N:17]=[C:16]([C:21]#[N:22])[C:15]=1[C:12]1[CH:11]=[CH:10][C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:1]#[N:2])=[CH:14][CH:13]=1)=[O:30])[CH3:33]
Reactant: Cn1cc(-c2ccc(-c3ccccc3C#N)cc2)c(C#N)n1
Reactant: CCOC(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1c(-c2ccc(-c3ccccc3C#N)cc2)c(C#N)nn1C
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
Prepare a solution of 4-(2′-cyano-biphenyl-4-yl)-1-methyl-1H-pyrazole-3-carbonitrile (101 mg, 0.355 mmol, prepared in preparation 46) in 3 mL of anhydrous THF and cool to −70° C. Add n-butyl lithium (1.6M in hexanes, 0.2 mL, 0.32 mmol) dropwise, keeping the internal temperature less than −65° C. Stir the orange solution for 30 minutes at −70° C. Next, add ethyl chloroformate (0.1 mL, 1.02 mmol) and allow the reaction to warm to room temperature over one hour. Quench with 2 mL of saturated NH4Cl and dilute with 50 mL of EtOAc. Wash the organic layer with water (1×10 mL) and brine (1×10 mL) and dry over anhydrous Na2SO4. Filter, evaporate and chromatograph over silica gel (100/0-7/3 toluene/EtOAc) to give the title compound, 37 mg (29%) along with 38 mg of recovered starting material.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[C:10]3[CH2:18][N:19]([CH3:22])[CH2:20][CH2:21][C:9]2=3)[CH:5]=[CH:6][CH:7]=1.[CH3:23][C:24]1[CH:29]=[CH:28][C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][N:25]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.O.CCOC(C)=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>[CH3:22][N:19]1[CH2:20][CH2:21][C:9]2[N:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([C:27]4[CH:26]=[N:25][C:24]([CH3:23])=[CH:29][CH:28]=4)[CH:3]=3)[C:16]3[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[C:10]=2[CH2:18]1
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cc1ccc2c(c1)c1c(n2-c2cccc(Br)c2)CCN(C)C1
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: [K+]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: Cc1ccc2c(c1)c1c(n2-c2cccc(-c3ccc(C)nc3)c2)CCN(C)C1
Temperature: 90 °C
Reaction time: 0.75 h

Procedure:
To a de-aerated solution of 5-(3-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.281 mmol), 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (124 mg, 0.564 mmol) and K2CO3 (116 mg, 0.845 mmol) in DME-water (2:1) was added Pd(PPh3)4 (16 mg, 0.013 mmol). The reaction mixture was stirred at 90° C. for 45 min. The reaction mixture was concentrated under reduced pressure. The residue obtained was dissolved in EtOAc (50 mL) and washed with water (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to yield 2,8-dimethyl-5-(3-(6-methylpyridin-3-yl)phenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (TFA salt, CD3OD) δ (ppm): 8.84 (s, 1H), 8.56 (d, 1H), 7.83 (d, 1H), 7.75-7.8 (m, 3H), 7.57 (d, 1H), 7.38 (s, 1H), 7.18 (d, 1H), 7.04 (d, 1H), 4.7 (m, 1H), 4.4 (m, 1H), 3.8 (m, 1H), 3.6 (m, 1H), 3.0-3.22 (m, 5H), 2.77 (s, 3H), 2.4 (s, 3H).
Reaction SMILES: C[O:2][C:3]1[C:8]2[O:9][C:10]([CH3:12])=[CH:11][C:7]=2[C:6]([CH:13]=[O:14])=[CH:5][CH:4]=1.CN(P(N(C)C)(N(C)C)=O)C.O>C1(C)C=CC=CC=1>[OH:2][C:3]1[C:8]2[O:9][C:10]([CH3:12])=[CH:11][C:7]=2[C:6]([CH:13]=[O:14])=[CH:5][CH:4]=1
Reactant: COc1ccc(C=O)c2cc(C)oc12
Solvent: Cc1ccccc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: Cc1cc2c(C=O)ccc(O)c2o1
Reaction time: 4.5 h
Yield: 95 %

Procedure:
To a freshly prepared solution of sodium-4-methyl benzene thiolate (prepared from 42 g of 4-methyl benzene thiol and 14 g of sodium hydroxide) in toluene (700 mL) was added 7-methoxy-2-methylbenzo[b]furan-4-carboxaldehyde (50.0 g) at reflux. Then HMPA (62.0 g) was added slowly and reaction mixture was stirred at the same temperature for 4-5 hr. reaction mixture was then bring to 50-60° C., water (500 mL) was added and layers were separated. The aqueous layer was acidified (pH 4-5). The solid separated was filtered, washed with water (3×200 mL) and dried to get light yellow solid product (44.0 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][N:13]2C(=O)C3=CC=CC=C3C2=O)[CH2:7]1)=[O:5])[CH3:2].O.NN>C(O)C>[NH2:13][CH2:12][CH:8]1[O:9][CH2:10][CH2:11][N:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:7]1
Reactant: CCOC(=O)N1CCOC(CN2C(=O)c3ccccc3C2=O)C1
Agent: NN
Solvent: CCO
Solvent: O
Product: CCOC(=O)N1CCOC(CN)C1
Reaction time: 0.17 h
Yield: 98.1 %

Procedure:
A mixture of N-[(4-ethoxycarbonyl-2-morpholinyl)methyl]phthalimide (10.0 g), 85% hydrazine hydrate (2.9 g), and ethanol (10 ml) is refluxed with stirring for 10 minutes. The reaction mixture is filtered and the filtrate is extracted with chloroform. The organic layer is washed successively with water and saturated aqueous sodium chloride solution, and dried over magnesium sulfate. Removal of the solvent under reduced pressure gives the title compound (5.8 g) as an oil.
Reaction SMILES: C([BH3-])#[N:2].[Na+].[CH2:5]([N:7]([CH2:22][CH3:23])[CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=O)[CH2:18][CH2:19][CH3:20])=[CH:13][CH:12]=1)[CH3:6].C([O-])(=O)C.[NH4+]>CO.C(OCC)(=O)C>[CH2:5]([N:7]([CH2:22][CH3:23])[CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([NH2:2])[CH2:18][CH2:19][CH3:20])=[CH:13][CH:12]=1)[CH3:6]
Reactant: [BH3-]C#N
Reactant: CCCC(=O)c1ccc(OCCN(CC)CC)cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCC(N)c1ccc(OCCN(CC)CC)cc1
Temperature: 40 °C
Yield: 59.4 %

Procedure:
Sodium cyanoborohydride (155 mg, 3.5 mmol) was added to a suspension of 1-(4-(2-(diethylamino)ethoxy)phenyl)butan-1-one (21; 186 mg, 0.7 mmol) and ammonium acetate (1.63 g, 21.2 mmol) in methanol (2 mL). The resulting mixture was then heated at 40° C. for 72 hours. The reaction mixture was diluted with ethyl acetate, washed with sat. aqueous NaHCO3 (2×) and sat. brine, dried over sodium sulfate and concentrated to give crude 25 (110 mg, 59%) as a yellow oil: MS (ES+) m/z 265.1 (M+H)+. This material was taken to the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[NH:12][C:5]2[CH:6]=[N:7][N:8]([CH3:11])[C:9](=[O:10])[C:4]=2[C:3]=1[Cl:13].[H-].[Na+].[Cl:16][C:17]1[CH:32]=[CH:31][C:20]([C:21]([C:23]2[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=2)[CH2:26]Br)=[O:22])=[CH:19][CH:18]=1.O>CN(C=O)C>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([C:21]([C:23]2[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=2)[CH2:26][N:12]2[C:5]3[CH:6]=[N:7][N:8]([CH3:11])[C:9](=[O:10])[C:4]=3[C:3]([Cl:13])=[C:2]2[Cl:1])=[O:22])=[CH:31][CH:32]=1
Reactant: Cn1ncc2[nH]c(Cl)c(Cl)c2c1=O
Reactant: O=C(c1ccc(Cl)cc1)c1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ncc2c(c(Cl)c(Cl)n2Cc2cccc(C(=O)c3ccc(Cl)cc3)c2)c1=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 16.8 %

Procedure:
A solution of 2,3-dichloro-5-methyl-1H-pyrrolo [2,3-d]pyridazin-4(5H)-one (303 mg) in DMF (50 ml) was dripped into a suspension of 60% sodium hydride-oil (72 mg) in DMF (10 ml) on an ice-water bath. The mixture was stirred at room temperature for 2.5 hours, after which a solution of 3-(4-chlorobenzoyl) benzyl bromide (511 mg) in DMF (10 ml) was added and the mixture was further stirred at room temperature for 17 hours. The reaction was stopped by adding water and the reaction mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (developer; n-hexane: ethyl acetate=1:1) to provide the title compound as white powder (104 mg, yield 16%).
Reaction SMILES: [CH2:1]([C:3]1[C:11](I)=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1)[CH3:2].[O:13]1[CH2:18][CH2:17][CH:16]([C:19]([NH2:21])=[O:20])[CH2:15][CH2:14]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(N)CCCCC1N>[Cu](I)I.C1(C)C(C)=CC=CC=1>[CH2:1]([C:3]1[C:11]([NH:21][C:19]([CH:16]2[CH2:17][CH2:18][O:13][CH2:14][CH2:15]2)=[O:20])=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1)[CH3:2]
Reactant: NC(=O)C1CCOCC1
Reactant: CCc1nn2ccccc2c1I
Agent: I[Cu]I
Agent: NC1CCCCC1N
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1C
Product: CCc1nn2ccccc2c1NC(=O)C1CCOCC1
Temperature: 120 °C
Reaction time: 8 h
Yield: 79.4 %

Procedure:
A mixture of 2-ethyl-3-iodopyrazolo[1,5-a]pyridine (350 g, 1.29 mol), tetrahydro-2H-4-pyrancarboxamide (249 g, 1.93 mol), copper iodide (49.0 g, 258 mmol), tripotassium phosphate (hydrate) (546 g, 2.57 mol), 1,2-cyclohexanediamine (mixture of cis and trans) (58.7 g, 514 mmol) and xylene (3500 mL) was stirred while heating at an external temperature of 120° C. (oil bath). The reaction mixture was heated and stirred for 6 hours, and then heating was terminated and upon reaching an internal temperature of 61.5° C., hot water (58° C., 3500 mL) was added to the reaction mixture and stirring was continued overnight. After adding 28% aqueous ammonia (1050 mL) to the reaction mixture and stirring for 1 hour, the precipitate was filtered out and washed with water (1750 mL) and ethyl acetate (1050 mL) and then dried under aeration at 60° C. overnight to afford 280 g of the title compound (major conformer:minor conformer=6:1) (79.6% yield).
Reaction SMILES: [CH3:1][CH:2]([CH2:9][CH:10]([CH3:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:3][C:4]([O:6]CC)=[O:5].CO.[OH-].[Na+]>O>[CH3:1][CH:2]([CH2:9][CH:10]([CH3:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: CCCCCCCC(C)CC(C)CC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCCCCC(C)CC(C)CC(=O)O
Temperature: 65 °C
Reaction time: 2 h

Procedure:
In a nitrogen atmosphere, the crude product (1.22 g, 0.00452 mol) of ethyl 3,5-dimethyldodecanoate (7Et) produced in the method of Example 3-1, methanol (1 ml), a 25% by weight aqueous sodium hydroxide solution (3 ml) were placed in a reaction vessel and stirred at 65° C. for 2 hours. After addition of water, the resulting mixture was washed with a hexane-tetrahydrofuran mixture. The aqueous phase was made acidic in addition of 20% by weight hydrochloric acid, followed by extraction with a hexane-tetrahydrofuran mixture. The organic phase thus obtained was dried over magnesium sulfate and then concentrated under reduced pressure. The concentrate thus obtained was distilled under reduced pressure (bp: from 130 to 140° C./2 mmHg) to obtain 3,5-dimethyldodecanoic acid (5) (1.03 g, 0.00452 mol). A total yield of the three steps from the 2-methylnonyl chloride (1 Cl) was 60%.
Reaction SMILES: N#N.[CH3:3][O:4][C:5]([C:7]1[CH:11]=[C:10](Br)[O:9][C:8]=1[CH3:13])=[O:6].CC1(C)C(C)(C)OB([C:22]2[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=2)O1.C(=O)(O)[O-].[Na+]>COCCOC.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>[CH3:3][O:4][C:5]([C:7]1[CH:11]=[C:10]([C:22]2[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=2)[O:9][C:8]=1[CH3:13])=[O:6]
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: COC(=O)c1cc(Br)oc1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])O
Solvent: COCCOC
Product: COC(=O)c1cc(-c2ccc(N)cc2)oc1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 46.7 %

Procedure:
(The following reaction is carried out in a N2 atmosphere.) Dissolve Pd(PPh3)4 (1.26 g, 1.09 mmol) and 5-Bromo-2-methyl-furan-3-carboxylic acid methyl ester (101) (4.77 g, 21.77 mmol) in DME (116 mL) and stir for 15 min at rt. Add 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (5.25 g, 23.96 mmol) followed by an aqu. 1M sodium bicarbonate solution (65.4 mL, 65.3 mmol). Degas the reaction mixture carefully, flush with N2 (5 times) and stir for 4 h at 95° C. (reflux). Cool reaction mixture to rt, remove organic solvent under reduced pressure and partition the residue between water and EtOAc. Extract the aqu. layer with EtOAc (3 times), wash the combined organic layer with water and brine and dry it with Na2SO4. Purify the obtained crude product by flash chromatography (silica gel, EtOAc/CyH 1+2) to obtain 5-(4-Amino-phenyl)-2-methyl-furan-3-carboxylic acid methyl ester (102) (2.35 g, 46%) as a yellow-brown solid. 1H NMR (400 MHz, CDCl3): 2.60 (s, 3H); 3.74 (br.s, 2H); 3.82 (s, 3H); 6.64 (s, 1H); 6.67 (dt, 1H, J1=8.6 Hz, J2=2.3 Hz); 7.42 (dt, 2H, J1=8.8 Hz, J2=2.3 Hz).
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[C:19]2[C:18]3[CH:20]=[C:21]([N+:24]([O-])=O)[CH:22]=[CH:23][C:17]=3[O:16][C:15]=2[C:14]([O:27][CH3:28])=[CH:13][CH:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[OH-].[K+]>C(O)C.[Fe]>[CH2:1]([NH:8][C:9]([C:11]1[C:19]2[C:18]3[CH:20]=[C:21]([NH2:24])[CH:22]=[CH:23][C:17]=3[O:16][C:15]=2[C:14]([O:27][CH3:28])=[CH:13][CH:12]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=O)NCc2ccccc2)c2c1oc1ccc([N+](=O)[O-])cc12
Agent: [Fe]
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: COc1ccc(C(=O)NCc2ccccc2)c2c1oc1ccc(N)cc12
Yield: 78.7 %

Procedure:
N1-benzyl-4-methoxy-8-nitro-dibenzo[b,d]furan-1-carboxamide (125 mg, 0.33 mmol) (from step 1) and iron powder (56 mg, 1.0 mmol) was suspended in 50% aqueous ethanol (10 ml) and reflux for 10 min. To this was added a solution of concentrated HCl (7 ul in 5 ml 50% aqueous ethanol) and refluxed for 4 h. The reaction mixture was flitered hot through celite and the filterate was basified with 15% ethanolic KOH, filtered and the filterate was concentrated in vaccuo. The residue was triturated with water, to obtain a solid which-was filtered dried to give the product as white solid (90 mg) mp: 228° C.
Reaction SMILES: [OH:1][C:2]1[N:6]=[CH:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=2[Cl:14])[N:3]=1.C[O-].[Na+].Br[CH:19]([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21]>CS(C)=O>[CH2:23]([O:22][C:20]([CH:19]([O:1][C:2]1[N:6]=[CH:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=2[Cl:14])[N:3]=1)[CH3:25])=[O:21])[CH3:24]
Reactant: Oc1ncn(-c2ccc(Cl)cc2Cl)n1
Reactant: CCOC(=O)C(C)Br
Agent: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)C(C)Oc1ncn(-c2ccc(Cl)cc2Cl)n1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Thirteen g of 3-hydroxy-1-(2,4-dichlorophenyl)-1,2,4-1H-triazole was added to a solution of sodium methoxide (prepared from 1.3 g of sodium and excess methanol) in 200 ml of dimethylsulfoxide. The solution was heated on a steam bath for 2 hours, and then 10 g of ethyl 2-bromopropionate was added and heating was continued for 1.5 hours more. The mixture was then cooled, poured over ice-water, and extracted with 200 ml of diethyl ether. The ether extract was washed with 1N hydrochloric acid, with saturated aqueous sodium bicarbonate, and finally with saturated brine, and was dried with sodium sulfate and phase separation paper. The solvent was removed under vacuum to obtain 16 g of the desired product, an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:3]=1[C:4]([NH:6][C:7]([N:9]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([C:26]([O:28][CH3:29])=[O:27])[CH:19]=1)[NH:10]C(OC(C)(C)C)=O)=[O:8])=O.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:3]=1[C:4]1[NH:6][C:7](=[O:8])[N:9]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([CH:19]=2)[C:26]([O:28][CH3:29])=[O:27])[N:10]=1
Reactant: COC(=O)c1cc(N(NC(=O)OC(C)(C)C)C(=O)NC(=O)c2c(F)cccc2Cl)ccc1OC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1cc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)ccc1OC
Yield: 87.4 %

Procedure:
The title compound was prepared according to the procedure described in step-2 of Intermediate-9 by using tert-butyl 2-[(2-chloro-6-fluorobenzoyl)carbamoyl]-2-[4-methoxy-3-(methoxycarbonyl)phenyl]hydrazinecarboxylate (3.0 g, 6.06 mmol), DCM (30 mL) and trifluoro acetic acid (3.0 mL) to afford 2.0 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 3.80 (s, 3H), 3.84 (s, 3H), 7.28 (d, J=9.3 Hz, 1H), 7.49 (t, J=8.7 Hz, 1H), 7.57 (d, J=8.4 Hz, 1H), 7.65-7.73 (m, 1H), 8.06 (d, J=9.0 Hz, 1H), 8.18 (s, 1H), 12.62 (s, 1H); MS (m/z): 376.27 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[C:7]3[CH:13]=[C:12]([CH3:14])[N:11]([CH2:15][C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-])=O)[CH:17]=4)[C:8]=3[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[H][H]>CO.[Pd]>[CH3:1][C:2]1[N:6]2[C:7]3[CH:13]=[C:12]([CH3:14])[N:11]([CH2:15][C:16]4[CH:17]=[C:18]([CH:19]=[CH:20][CH:21]=4)[NH2:22])[C:8]=3[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1
Reactant: [H][H]
Reactant: Cc1cc2c(ccc3nnc(C)n32)n1Cc1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: Cc1cc2c(ccc3nnc(C)n32)n1Cc1cccc(N)c1

Procedure:
1,7-Dimethyl-6-(3-nitrobenzyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine (0.16 g, 0.50 mmol, from Example 25, Step 1) in methanol (100 mL) was hydrogenated for 6.5 hours under 1 atmosphere of hydrogen provided by a balloon, over 10% palladium on activated carbon (100 mg, 0.10 mmol, Degussa type, Aldrich). The reaction mixture was filtered through celite and concentrated to afford product as light yellow solid, which was used without further purification (0.14 g, 96%).
Reaction SMILES: Br[C:2]1[C:11]2[O:10][CH2:9][C@H:8]([N:12]([CH:16]([CH3:18])[CH3:17])[CH2:13][CH2:14][CH3:15])[CH2:7][C:6]=2[C:5]([O:19][CH3:20])=[CH:4][CH:3]=1.[Li]CCCC.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:36])(=O)=O)=CC=1.[NH4+].[Cl-].NO.Cl.C([O-])([O-])=O.[Na+].[Na+].N>C1COCC1.O>[F:36][C:2]1[C:11]2[O:10][CH2:9][C@H:8]([N:12]([CH:16]([CH3:18])[CH3:17])[CH2:13][CH2:14][CH3:15])[CH2:7][C:6]=2[C:5]([O:19][CH3:20])=[CH:4][CH:3]=1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: CCCN(C(C)C)[C@H]1COc2c(Br)ccc(OC)c2C1
Agent: Cl
Agent: N
Agent: NO
Solvent: O
Solvent: C1CCOC1
Product: CCCN(C(C)C)[C@H]1COc2c(F)ccc(OC)c2C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 52.9 %

Procedure:
(R)-8-Bromo-3(N-isopropyl-N-propylamino)-5-methoxy-3,4-dihydro-2H-1-benzopyran (2.3 g, 6.72 mmol) was dissolved in anhydrous THF (25 mL) and cooled to -78° C. To this was a 1.6M n-BuLi solution (4.83 mL, 7.73 mmol) added dropwise and allowed to stir at -78° C. for 1 h. N-Fluorobenzenesulfonimide (2.55 g, 8.06 mmol), dissolved in anhydrous THF (15 mL), was added dropwise under 20-30 min and allowed to stir at -78° C. for 4 h. The reaction was stopped by adding 1 mL of a saturated aqueous NH4Cl solution followed by 3 mL of a solution comprised of 2 g of NH2OH×HCl and 8 g of Na2CO3 in 100 mL of H2O and allowing the reaction to warm to room temperature. A 2M NH3 solution was added and the reaction was extracted, twice, with diethyl ether, treated with brine, dried (Na2SO4), filtered, and evaporated in vacuo to give the crude product. Chromatography on silica (eluent: chloroform) gave 1.0 g (53% yield) of the title compound as a clear oil. [α]21D =89.2° (C=0.1, CHCl3). GC-MS (70 eV) M=281 (32%).
Reaction SMILES: [F:1][C:2]([F:29])([C:25]([F:28])([F:27])[F:26])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23]Br)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[CH3:30][N:31]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[N:33]=[C:32]1[N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>>[F:1][C:2]([F:29])([C:25]([F:28])([F:27])[F:26])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:43]2[CH2:44][CH2:45][N:40]([C:32]3[N:31]([CH3:30])[C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=4[N:33]=3)[CH2:41][CH2:42]2)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: O=C(NCC(F)(F)C(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: Cn1c(N2CCNCC2)nc2ccccc21
Product: Cn1c(N2CCN(CCCCC3(C(=O)NCC(F)(F)C(F)(F)F)c4ccccc4-c4ccccc43)CC2)nc2ccccc21

Procedure:
Prepared analogously to Example 1 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,3,3,3-pentafluoro-propyl)-amide and 1-methyl-2-piperazin-1-yl-1H-benzimidazole.
Reaction SMILES: [CH2:1]([SnH:5]([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[C:14]([OH:20])(=[O:19])[CH2:15][CH2:16][C:17]#[CH:18]>>[CH2:10]([Sn:5]([CH2:1][CH2:2][CH2:3][CH3:4])([CH2:6][CH2:7][CH2:8][CH3:9])[CH:18]=[CH:17][CH2:16][CH2:15][C:14]([O:20][Sn:5]([CH2:6][CH2:7][CH2:8][CH3:9])([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:1][CH2:2][CH2:3][CH3:4])=[O:19])[CH2:11][CH2:12][CH3:13]
Reactant: C#CCCC(=O)O
Reactant: CCCC[SnH](CCCC)CCCC
Product: CCCC[Sn](C=CCCC(=O)O[Sn](CCCC)(CCCC)CCCC)(CCCC)CCCC
Temperature: 60 °C

Procedure:
A mixture of tri-n-butyltinhydride (b 2.0 equiv.) (Aldrich) and 4-pentynoic acid (1.0 equiv.) (Aldrich) is warmed to 60° C. for six hours. Kugelrohr distillation of the crude product gives tri-n-butylstannyl 5-(tri-n-butylstannyl)-4-pentenoate acid.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[Cl:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:24])[CH2:18]2>CO>[C:1]([C:22]1[CH:23]=[C:15]([Cl:14])[CH:16]=[C:17]2[C:21]=1[NH:20][C:19](=[O:24])[CH2:18]2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1Cc2cc(Cl)ccc2N1
Reactant: O=C(Cl)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CO
Product: O=C1Cc2cc(Cl)cc(C(=O)c3ccccc3)c2N1

Procedure:
A mixture of 162.5 g. (1.08 mole) of benzoyl chloride and 260 g. of aluminum chloride (1.80 mole) heated to 200° C. with stirring was treated with 65 g. (.360 mole) of recrystallized 5-chloroindolin-2-one. This mixture was stirred 15 min. and poured over ice. The resulting precipitate was triturated with boiling water and then chloroform. The chloroform solution was washed with 5% sodium bicarbonate, water, dried over sodium sulfate, and stripped to yield approximately 55 g. of a glossy solid. This material was then triturated with hot methanol and the methanol evaporated under vacuum to yield approximately 20 g. of a solid yellow material. Extraction of a benzene solution of this material removed any starting 5-chloroindoline-2-one present and after washing with water and drying the benzene yielded on evaporation 3 g. of a blue-gray material. Trituration of this material with room temperature methanol gave a residue which on recrystallization from methanol yielded 2.5 g. of a tan solid identified as product, m.p. 186°-187° C.