Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=1.[C:12]1([C:18]#[CH:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(NC(C)C)(C)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I.C(OCC)(=O)C>[N+:9]([C:5]1[CH:4]=[CH:3][C:2]([C:19]#[C:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][C:6]=1[NH2:8])([O-:11])=[O:10]
Reactant: Nc1cc(Br)ccc1[N+](=O)[O-]
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Product: Nc1cc(C#Cc2ccccc2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.6 %

Procedure:
A flame-dried flask was charged with the 5-bromo-2-nitroaniline (2, 300 mg, 1.38 mmol) (scheme 1, Example 1), phenylacetylene (155 mg, 1.52 mmol) and ethyl acetate (13.8 mL). The solution was degassed under vacuum and put under N2 atmosphere. Then, dichlorobis(triphenylphosphine)palladium (48 mg, 0.069 mmol) and copper iodide (26 mg, 0.138 mmol) were added. The yellow solution was degassed again (3 cycles) N,N-diisopropylamine (231 μl, 1.68 mmol) was added and the solution rapidly turned dark. It was degassed twice again and allowed to stir under N2 atmosphere at r.t. over 16 h. Then it was passed through celite and the filtrate was successively washed with dilute aqueous ammonia (NH4OH), saturated NaHCO3, saturated NH4Cl, brine, dried over MgSO4, filtered and concentrated. The resulting dark solid was purified by flash chromatography on silica gel using EtOAc/hexanes as the eluent with increasing polarity (10:90 to 15:85) affording the title compound 124 (242 mg, 74% yield) as a deep yellow solid. 1H NMR: (400 MHz, CD3OD) δ(ppm): 8.04 (dd, J=8.8, 0.4 Hz, 1H), 7.54-7.51 (m, 2H), 7.40-7.37 (m, 3H), 7.11 (dd, J=1.8, 0.4 Hz, 1H), 6.73 (dd, J=8.8, 1.8 Hz, 1H). LRMS: (m/z): 239.3 (MH+).
Reaction SMILES: [C:1]([C:4]1[CH:17]=[CH:16][C:7]2[CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[S:10][C:6]=2[CH:5]=1)(=O)[CH3:2].[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH:25][CH:1]([C:4]2[CH:17]=[CH:16][C:7]3[CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[S:10][C:6]=3[CH:5]=2)[CH3:2])=[CH:22][CH:21]=1
Reactant: CCOC(=O)c1cc2ccc(C(C)=O)cc2s1
Reactant: COc1ccc(CN)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCOC(=O)c1cc2ccc(C(C)NCc3ccc(OC)cc3)cc2s1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
Ethyl 6-acetyl-1-benzothiophene-2-carboxylate (0.3 g, 1.21 mmol) was dissolved in DCE (3.0 mL). 4-methoxybenzyl amine was then added to the reaction followed by acetic acid (0.1 mL, 1.69 mmol) and NaBH(OAc)3 (0.41 g, 1.93 mmol). The reaction was allowed to stir for 5 d at room temperature before it was quenched with saturated sodium bicarbonate solution. The reaction mixture was then extracted with ethyl acetate (3×) and the combined organic layers was dried over Na2SO4. After concentrating in vacuo, the crude reaction mixture was purified by flash column chromatography to provide the amine. 1H (600 MHz, CDCl3) δ 8.03 (s, 1H), 7.84 (s, 1H), 7.82 (s, 1H), 7.41 (d, J=8.9 Hz, 1H), 7.18 (d, J=8.5 Hz, 2H), 6.85 (d, J=8.5 Hz, 2H), 4.40 (q, J=7.1 Hz, 2H), 3.93 (q, J=6.5 Hz, 1H), 3.79 (s, 3H), 3.57 (dd, J=21.0, 12.9 Hz, 2H), 1.42-1.26 (m, 6H). MS: cal'd (MH+) 370, exp (MH+): 370.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[O:18][CH3:19])[N:14]([S:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:22])=[O:21])[CH:13]=[CH:12]2)C1C=CC=CC=1.C1CCCCC=1.Cl>CCO.[Pd]>[CH3:19][O:18][C:17]1[CH:16]=[C:15]2[C:11]([CH:12]=[CH:13][N:14]2[S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:22])=[O:21])=[CH:10][C:9]=1[OH:8]
Reactant: COc1cc2c(ccn2S(=O)(=O)c2ccccc2)cc1OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: C1=CCCCC1
Product: COc1cc2c(ccn2S(=O)(=O)c2ccccc2)cc1O
Temperature: 150 °C
Yield: 97 %

Procedure:
To a suspension of 5-(benzyloxy)-6-methoxy-1-(phenylsulfonyl)-1H-indole (Intermediate 14, 6.6 g, 17 mmol) and Pd/C 10 wt. % (2.0 g, 1.9 mmol) in EtOH (30 mL) were cyclohexene (9 mL) and conc. HCl (9 mL) added. The reaction mixture was heated at 150° C. for 5 minutes in a microwave heater. The Pd/C was filtered off and the solvent was removed under reduced pressure to afford the title compound (5.0 g) as a black gum. MS m/z 304 [M+H]+.
Reaction SMILES: [N:1]([C@H:4]1[C:7](=[O:8])[NH:6][C@H:5]1[CH2:9][CH:10](OC)[O:11]C)=[N+:2]=[N-:3]>Cl.O1CCOCC1.O>[N:1]([C@H:4]1[C:7](=[O:8])[NH:6][C@H:5]1[CH2:9][CH:10]=[O:11])=[N+:2]=[N-:3]
Reactant: COC(C[C@@H]1NC(=O)[C@@H]1N=[N+]=[N-])OC
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: [N-]=[N+]=N[C@H]1C(=O)N[C@H]1CC=O
Reaction time: 0.5 h

Procedure:
A mixture of 500 mg (2.5 mmole) of cis-3-azido-2-(2,2-dimethoxyethyl)-4-oxoazetidine in 10 ml of 5% HCl and 10 ml of dioxane was stirred at 35° for 1/2 hour. The mixture was diluted with water and extracted with 50 ml of benzene. The aqueous phase was saturated with brine and extracted 10 times with 50 ml of ethyl acetate. The ethyl acetate extract was dried over magnesium sulfate and evaporated to dryness. The residue was titurated with ether to give the desired aldehyde, 235 mg (60%), mp 73°-78°.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1Cl)=[O:4].C(=O)([O-])[O-].[Cs+].[Cs+].[F:18][C:19]([F:30])([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)[CH2:20][CH2:21][SH:22]>CN(C=O)C.O>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[S:22][CH2:21][CH2:20][C:19]([F:30])([F:18])[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)=[O:4]
Reactant: Fc1ccc(C(F)(F)CCS)cc1
Reactant: COC(=O)c1ccncc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccncc1SCCC(F)(F)c1ccc(F)cc1
Temperature: 90 °C
Reaction time: 1 h
Yield: 34 %

Procedure:
To a solution of 3-chloro-pyridine-4-carboxylic acid methyl ester (0.28 g, 1.65 mmol) in DMF (10 ml) are added cesium carbonate (2.68 g, 8.25 mmol) and 3,3-difluoro-3-(4-fluorophenyl)-propane-1-thiol (synthesized according to the methods described in sections a) and b) of example 3) (0.34 g, 1.65 mmol) in a sealed tube. The reaction mixture is stirred at 90° C. for 1 h. After completion of the reaction, the mixture is diluted with water (15 ml) and extracted with EtOAc (3×20 ml). The organic layer is washed with water (20 ml), brine (20 ml), dried over anhydrous sodium sulfate and evaporated to get the crude product, which is purified by column chromatography (silica gel, 10% acetone/hexane) to yield 3-[[3,3-difluoro-3-(4-fluorophenyl)-propyl]sulfanyl]-pyridine-4-carboxylic acid methyl ester (0.19 g, 0.56 mmol, 34%).
Reaction SMILES: C(O)C.[Cl-].[NH4+].[N+:6]([C:9]1[C:10]([NH:15][C:16]2[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=2)=[N:11][CH:12]=[CH:13][CH:14]=1)([O-])=O>[Fe].O>[NH2:6][C:9]1[C:10]([NH:15][C:16]2[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=2)=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: CCOC(=O)c1ccc(Nc2ncccc2[N+](=O)[O-])cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1ccc(Nc2ncccc2N)cc1
Yield: 91.8 %

Procedure:
To phenol (22.92 g) were added 2-chloro-3-nitropyridine (13.22 g) and potassium iodide (0.42 g), and the mixture was stirred at 100° C. for 10 min. Ethyl 4-aminobenzoate (13.2 g) were added, and the mixture was stirred at 100° C.-150° C. for 6 hr. The reaction mixture was poured into ice water, and 4N aqueous sodium hydroxide solution (63 mL) and ethyl acetate (100 mL) were added. The precipitated solid was collected by filtration, and recrystallized from ethanol to give ethyl 4-(3-nitropyridin-2-ylamino)benzoate (15.48 g). Then, to a solution of ethanol (186 mL) and water (46 mL) were added ammonium chloride (1.12 g) and iron (8.1 g), the mixture was stirred at 60° C.-70° C., and the obtained ethyl 4-(3-nitropyridin-2-ylamino)benzoate (10.67 g) was added. After completion of the reaction, the insoluble material was collected by filtration, and the filtrate was concentrated. To the residue was added aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate, and the solvent was evaporated to give ethyl 4-(3-aminopyridin-2-ylamino)benzoate (8.77 g). To the obtained ethyl 4-(3-aminopyridin-2-ylamino)benzoate (8.77 g) was added triethyl orthoformate (87 mL), and the mixture was stirred with heating under reflux for 4 hr. The solvent was evaporated from the reaction mixture, and toluene (35 mL) and a small amount of p-toluenesulfonic acid hydrate were added to the residue, and the mixture was stirred with heating under reflux for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The solvent was evaporated from the organic layer, and to the residue were added ethylether and hexane, and the precipitated solid was collected by filtration to give the title compound (7.926 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[S:16])[NH2:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:17][CH2:18][C:19]([CH2:21]Cl)=O.[O-]S([O-])(=O)=O.[Mg+2]>CC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[S:16][CH:21]=[C:19]([CH2:18][Cl:17])[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(C(N)=S)CC1
Reactant: O=C(CCl)CCl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2nc(CCl)cs2)CC1

Procedure:
To a solution of 4-thiocarbamoyl-piperidine-1-carboxylic acid tert-butyl ester (4.9 g, 20 mmol) in acetone (80 mL) was added 1,3-dichloroacetone (3.3 g, 26 mmol), MgSO4 (3.6 g, 30 mmol) and MgCO3 (1.68 g, 20 mmol). The mixture was heated under reflux overnight, cooled and filtered through celite. The solvent was removed in vacuo and the residue was redissolved with EtOAc (150 mL). The resulting solution was washed successively with 5% NaHSO3, saturated NaHCO3, and brine. After drying (Na2SO4), the solvent was removed to afford the desired product. 1H NMR (CDCl3): δ 7.20 (1H, s), 4.67 (2H, s), 4.20 (2H, br), 3.16 (1H, m), 2.87 (2H, m), 2.09 (2H, m), 1.72 (2H, m), 1.47 (9H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:24][CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[C:13]([NH:15][C:16]2[CH:21]=[N:20][C:19]([CH:22]=O)=[CH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[NH:30]1[CH2:36][C:34](=[O:35])[NH:33][C:31]1=[O:32].N1CCCCC1.C(O)(=O)C1C=CC=CC=1>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:24][CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29]2)[C:13]([NH:15][C:16]2[CH:21]=[N:20][C:19]([CH:22]=[C:36]3[C:34](=[O:35])[NH:33][C:31](=[O:32])[NH:30]3)=[CH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: O=C1CNC(=O)N1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2cnc(C=O)cn2)cc1Cl
Agent: O=C(O)c1ccccc1
Solvent: CCO
Solvent: C1CCNCC1
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2cnc(C=C3NC(=O)NC3=O)cn2)cc1Cl
Temperature: 25 °C
Yield: 32.4 %

Procedure:
A solution of 2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(5-formyl-pyrazin-2-yl)-propionamide (prepared as in Example 18, 217 mg, 0.5 mmol), hydantoin (75 mg, 0.75 mmol), piperidine (10 μL, 0.10 mmol), and benzoic acid (6.1 mg, 0.05 mmol) in anhydrous ethanol (30 mL) was heated under reflux for 2 d. The reaction mixture was allowed to cool to 25° C. and then was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 10%–65% ethyl acetate/hexanes) afforded the 2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[5-(2,5-dioxo-imidazolidin-4-ylidenemethyl)-pyrazin-2-yl]-propionamide (84 mg, 33%) as a white solid: LC-MS m/e 518 (MH+).
Reaction SMILES: N[C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N:9]=O)=[C:4](N)[N:3]=1.N[C:13]1[N:18]=[C:17](N)[CH:16]=[C:15](O)[N:14]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)(=O)C>[N:14]1[C:15]2[C:16](=[N:9][C:5]3[CH:4]=[N:3][CH:2]=[N:7][C:6]=3[N:8]=2)[CH:17]=[N:18][CH:13]=1
Reactant: Nc1cc(O)nc(N)n1
Reactant: Nc1nc(N)c(N=O)c(N)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(=O)O
Product: c1ncc2nc3cncnc3nc2n1
Temperature: 113 °C
Reaction time: 20 h

Procedure:
A suspension of 6.20 g of commercial 2,4,6-triamino-5-nitrosopyrimidine (Chemie Uetikon, Lahr, Germany), 5.15 g of commercial 2,4-diamino-6-hydroxypyrimidine (Fluka, Buchs, Switzerland) and 11.52 g of commercial toluene-4-sulfonic acid monohydrate in 110 ml of glacial acetic acid (100%) is stirred for 20 hours at 113° C. The reaction mixture is filtered off over a laminated paper filter while still hot, and the residue is washed with hot water (approx. 60° C.) until the pH of the washing water has reached a value of at least 4. The washed residue, moist with water, is dried in vacuo at 110° C. to yield a greenish-yellow powder of the pyrimido[5,4-g]pteridine salt of formula VI
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:13]1([O:19][CH3:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(=S)=S.O>[CH3:20][O:19][C:13]1[CH:18]=[CH:17][C:16]([C:8]([C:7]2[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[O:9])=[CH:15][CH:14]=1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: COc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: S=C=S
Product: COc1ccc(C(=O)c2ccc([N+](=O)[O-])cc2)cc1
Reaction time: 0.5 h

Procedure:
The compound of formula 3a was prepared according to the procedure of Shani, J. etal., J. Med. Chem, 1985, 28, 1504. Thus, a mixture of 4-nitrobenzoyl chloride (90 g, 0.48 mol) and anisole (57.24 g, 0.53 mol) in carbon disulfide (450 mL) was stirred in a three neck round bottom flask equipped with nitrogen inlet, condenser and mechanical stirrer that was being cooled in an ice bath. Aluminum chloride (84.0 g, 0.63 mol) was added in portions and stirring continued at ice bath temperature for 30 minutes, then at room temperature for an additional 1 hour. The reaction mixture was cooled, treated with concentrated hydrochloric acid (150 mL), diluted with cold water (250 mL). The product was collected, filtered, washed, dried, and crystallized from ethyl acetate to give 4-(4-methoxybenzoyl)-nitrobenzene as an off-white solid, m.p. 120-122° C.; Analysis for C14H11NO4: Calc.: C, 65.3; H, 4.31; N, 5.44; Found: C, 65.22; H, 4.16; N, 5.69.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([O:15]CC1C=CC=CC=1)[CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2]>CO.C(Cl)Cl.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([OH:15])[CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2c(OCc3ccccc3)cccc2[nH]1
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)c1cc2c(O)cccc2[nH]1
Reaction time: 24 h

Procedure:
To a solution of 4-Benzyloxy-1H-indole-2-carboxylic acid ethyl ester (29 g, 98.2 mmol) in a mixture of MeOH (750 ml) and DCM (500 ml) is added 1 gram of Pd/C (10%). It is hydrogenated under normal pressure for 24 hours. After filtration and evaporation a white powder is obtained.
Reaction SMILES: C1(C)C=CC=CC=1.[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[O:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.Cl[CH2:30][CH2:31][CH2:32][O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[N+:40]([O-:42])=[O:41]>C(N(CC)CC)C>[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[O:16][CH:17]1[CH2:18][CH2:19][N:20]([CH2:30][CH2:31][CH2:32][O:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[N+:40]([O-:42])=[O:41])[CH2:21][CH2:22]1
Reactant: O=[N+]([O-])c1ccccc1OCCCCl
Reactant: Clc1ccccc1C(OC1CCNCC1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccccc1OCCCN1CCC(OC(c2ccccc2)c2ccccc2Cl)CC1
Reaction time: 15 h
Yield: 73.8 %

Procedure:
Into 50 ml of toluene were dissolved 3.02 g of 4-[(2-chlorophenyl)-phenylmethoxy]piperidine, 2.59 g of 1-chloro-3-(2-nitrophenoxy)propane and 3.04 g of triethylamine, and the resultant solution was heated under reflux with stirring for 15 hours. After cooling, the reaction solution was washed with water, and the solvent was removed under reduced pressure. The residue was eluted with methanol-chloroform (1:50) by silica gel column chromatography to give 3.55 g of oily 4-[(2-chlorophenyl)-phenylmethoxy]-1-[3-(2-nitrophenoxy)propyl]piperidine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][C:3]=1[CH:10]([CH3:24])[C:11]([C:17]1[CH:22]=[CH:21][N:20]=[C:19]([Cl:23])[CH:18]=1)([OH:16])[C:12]([F:15])([F:14])[F:13].[CH3:25][O:26][C:27]([C:29]1[N:30]=[N:31][C:32](Cl)=[CH:33][CH:34]=1)=[O:28]>>[CH3:25][O:26][C:27]([C:29]1[N:30]=[N:31][C:32]([O:9][CH2:8][C:6]2[CH:5]=[CH:4][C:3]([CH:10]([CH3:24])[C:11]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([Cl:23])[CH:18]=3)([OH:16])[C:12]([F:15])([F:14])[F:13])=[C:2]([Cl:1])[CH:7]=2)=[CH:33][CH:34]=1)=[O:28]
Reactant: CC(c1ccc(CO)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Reactant: COC(=O)c1ccc(Cl)nn1
Product: COC(=O)c1ccc(OCc2ccc(C(C)C(O)(c3ccnc(Cl)c3)C(F)(F)F)c(Cl)c2)nn1

Procedure:
The title compound was prepared in analogy to Example 93, step 7 from 3-(2-chloro-4-hydroxymethyl-phenyl)-2-(2-chloro-pyridin-4-yl)-1,1,1-trifluoro-butan-2-ol (obtained in Example 120, stepl) by alkylation with methyl-6-chloropyridazine-3-carboxylate [CAS Reg. No. 65202-50-8]. MS (m/e)=516.1 [MH+].
Reaction SMILES: [CH3:1][NH:2][S:3]([CH3:6])(=[O:5])=[O:4].C(#N)C.[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:21]([CH:27]([CH3:29])[CH3:28])[N:20]=[C:19](OS(C3C=CC(C)=CC=3)(=O)=O)[N:18]=2)=[CH:13][CH:12]=1>O>[F:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:21]([CH:27]([CH3:29])[CH3:28])[N:20]=[C:19]([N:2]([CH3:1])[S:3]([CH3:6])(=[O:5])=[O:4])[N:18]=2)=[CH:15][CH:16]=1
Reactant: COC(=O)c1c(-c2ccc(F)cc2)nc(OS(=O)(=O)c2ccc(C)cc2)nc1C(C)C
Reactant: CNS(C)(=O)=O
Solvent: CC#N
Solvent: O
Product: COC(=O)c1c(-c2ccc(F)cc2)nc(N(C)S(C)(=O)=O)nc1C(C)C
Temperature: 81.5 °C
Yield: 74.8 %

Procedure:
In a 25 mL-volume glass flask equipped with a stirrer, a thermometer and a reflux condenser were placed 196 mg (1.8 mmol.) of N-methylmethanesulfonamide, 198 mg (1.8 mmol.) of sodium t-pentoxide, 7.5 mL of acetonitrile, and 667 mg (1.5 mmol.) of 4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-(p-toluenesulfonyloxy)pyrimidine. The mixture was heated to 81-82° C. for 1.5 hours under refluxing, to carry out reaction. After the reaction was complete, the reaction mixture was cooled to room temperature. To the cooled mixture was added 10 mL of water, and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate portion was separated, and dried over anhydrous magnesium sulfate. The dried ethyl acetate portion was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (column: Wako Gel C-200, eluent: hexane/ethyl acetate (2:1, volume ratio)). There was obtained 428 mg of 4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-(N-methyl-N-methanesul-fonylamino)-pyrimidine. The yield was 75% (based on the amount of 4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-(p-toluenesulfonyloxy)pyrimidine).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([F:10])[CH:3]=1.[CH3:11][CH:12](O)[CH3:13].OS(O)(=O)=O>>[Br:1][C:2]1[CH:3]=[C:4]([F:10])[C:5]([O:8][CH3:9])=[C:6]([CH:12]([CH3:13])[CH3:11])[CH:7]=1
Reactant: COc1ccc(Br)cc1F
Reactant: CC(C)O
Agent: O=S(=O)(O)O
Product: COc1c(F)cc(Br)cc1C(C)C
Temperature: 80 °C
Yield: 38.4 %

Procedure:
To a mixture of 4-bromo-2-fluoroanisole (2.0 g, 9.70 mmol) and 2-propanol (1.2 g, 19.4 mmol) at room temperature was added 80% H2SO4 (10.0 mL). The reaction mixture was heated at 80° C. for 12 h, cooled to room temperature, quenched with ice (50 g) and extracted with ether (20 mL×2). The combined organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with 5% ethyl acetate in hexanes to afford 4-bromo-6-fluoro-2-iso-propylanisole (0.92 g, 38%): 1H NMR (300 MHz, CD3OD): δ 7.36 (d, J=10.5 Hz, 1 H), 7.22 (d, J=10.5 Hz, 1 H), 3.91 (s, 3 H), 3.24 (m, 1 H), 1.26 (d, J=6.6 Hz, 6 H); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=ethyl acetate-hexanes (5:95); Rf=0.50.
Reaction SMILES: [CH2:1]([C:4]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:5]=1[CH2:6][CH:7]1[CH2:11][C:10](=[O:12])[N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:8]12)[CH:2]=[CH2:3].C(O[CH:29](N(C)C)[N:30]([CH3:32])[CH3:31])(C)(C)C>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([C:4]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:5]=1[CH2:6][CH:7]1[CH:8]2[N:9]([C:13]([O:15][C:16]([CH3:18])([CH3:19])[CH3:17])=[O:14])[C:10](=[O:12])/[C:11]/1=[CH:29]\[N:30]([CH3:32])[CH3:31])[CH:2]=[CH2:3]
Reactant: C=CCc1cccc2c1CC1CC(=O)N(C(=O)OC(C)(C)C)C21
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=CCc1cccc2c1CC1/C(=C/N(C)C)C(=O)N(C(=O)OC(C)(C)C)C21
Yield: 93 %

Procedure:
A solution of the tert-butyl 5-allyl-2-oxo-3,3a,4,8b-tetrahydroindeno[1,2-b]pyrrole-1-carboxylate (Step 4, 0.21 g, 0.7 mmol) in tert-butoxybis(dimethylamino)methane (0.415 mL, 2.0 mmol) in toluene (3 ml) was heated at 110° C. overnight. The solution was diluted with ethyl acetate and washed twice with water, brine, dried over magnesium sulphate and concentrated to give tert-butyl (3Z)-5-allyl-3-(dimethylaminomethylene)-2-oxo-4,8b-dihydro-3aH-indeno[1,2-b]pyrrole-1-carboxylate D1 (colourless solid, 0.24 g, 97%). This compound was used without extra purification. LC-MS (Method C) RT 1.05 min, 369 (M+H+). This method was used to prepare compound D2 to D13 (table D).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([F:9])=[C:5]([CH3:10])[CH:4]=1)#[CH:2].C(N(CC)CC)C.[Cl:18][C:19]1[CH:20]=[C:21](OS(C(F)(F)F)(=O)=O)[CH:22]=[N:23][CH:24]=1>C(OCC)(=O)C.[Cu]I.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:18][C:19]1[CH:24]=[N:23][CH:22]=[C:21]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][C:6]([F:9])=[C:5]([CH3:10])[CH:4]=2)[CH:20]=1
Reactant: O=S(=O)(Oc1cncc(Cl)c1)C(F)(F)F
Reactant: C#Cc1ccc(F)c(C)c1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1cc(C#Cc2cncc(Cl)c2)ccc1F
Temperature: 70 °C
Yield: 43.9 %

Procedure:
Add 4-ethynyl-1-fluoro-2-methylbenzene (0.56 g, 4.21 mmol), triethylamine (2.2 mL, 15 mmol), copper (I) iodide (36 mg, 0.19 mmol), and bis(triphenylphosphine)palladium (II) dichloride (110 mg, 0.15 mmol) to a solution of trifluoromethanesulfonic acid 5-chloropyridin-3-yl ester, (prepared as described in PREPARATION 25), (1.0 g, 3.8 mmol) in ethyl acetate (5 mL) under nitrogen. Heat the at 70° C. for 16 h and concentrate. Purify by silica gel chromatography, eluting with 100% dichloromethane, followed by a second silica gel chromatography eluting with 50:50 to 60:40 dichloromethane:hexanes, to give the title compound as a light yellow solid (410 mg, 44%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][C:10]([O:15][CH3:16])=[CH:11][CH:12]=2)[NH:7][C:6]1=[O:17].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH3:1][O:2][C:3](=[O:18])[CH2:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][C:10]([O:15][CH3:16])=[CH:11][CH:12]=2)[N:7]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:6]1=[O:17]
Reactant: COC(=O)CC1Cc2ccc(OC)cc2NC1=O
Reactant: BrCc1ccccc1
Product: COC(=O)CC1Cc2ccc(OC)cc2N(Cc2ccccc2)C1=O
Yield: 88 %

Procedure:
The title compound (4.3 g, 88% yield) was prepared using the conditions of Example 124 using (7-methoxy-2-oxo-1,2,3,4-tetrahydro-quinolin-3-yl)-acetic acid methyl ester in place of (7-methoxy-2-oxo-1,2-dihydro-quinolin-3-yl)acetic acid methyl ester and benzyl bromide in place of ethyl iodide.