Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([CH:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][C:12]2=[O:20])[N:4]=1.CN1C=CN=C1.[F:27][CH:28]([F:33])[S:29](Cl)(=[O:31])=[O:30].O>ClCCl>[F:27][CH:28]([F:33])[S:29]([N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]([C:5]2[N:4]=[C:3]([O:2][CH3:1])[N:8]=[C:7]([O:9][CH3:10])[N:6]=2)[C:12]1=[O:20])(=[O:31])=[O:30]
Reactant: O=S(=O)(Cl)C(F)F
Reactant: COc1nc(OC)nc(C2C(=O)Nc3ccccc32)n1
Agent: Cn1ccnc1
Solvent: ClCCl
Solvent: O
Product: COc1nc(OC)nc(C2C(=O)N(S(=O)(=O)C(F)F)c3ccccc32)n1
Temperature: -5 °C

Procedure:
3-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-1,3-dihydro-2H-indol-2-one (10 g) and 1-methyl-1H-imidazole (5.4 g) are introduced as initial charge in 100 ml of dichloromethane and cooled to −5° C. under nitrogen. With stirring, difluoromethanesulfonyl chloride (7.03 g) is added dropwise at −5° C. to 0° C. over the course of 20 minutes, and the mixture is after-stirred at this temperature for 2.5 hours. The reaction mixture is admixed with 50 ml of water and mixed thoroughly. The organic solvent is largely distilled off in vacuo and the residue is filtered. The solid product is washed with water and acetonitrile and dried in a vacuum drying cabinet. This gives the title compound as a solid in an HPLC purity of 93% (12.5 g, 92% of theory). The UV absorption (maximum at 360 nm) verifies the N-sulfonylation of the product.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])=[C:8]([OH:10])[CH:9]=1)([O-:3])=[O:2].Cl[CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.C(C1C=CC([N+]([O-])=O)=CC=1OCCN1CCCCC1)(C)(C)C>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:11]([F:16])([F:17])[C:12]([F:13])([F:14])[F:15])=[C:8]([CH:9]=1)[O:10][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)([O-:3])=[O:2]
Reactant: ClCCN1CCCCC1
Reactant: O=[N+]([O-])c1ccc(C(F)(F)C(F)(F)F)c(O)c1
Agent: CC(C)(C)c1ccc([N+](=O)[O-])cc1OCCN1CCCCC1
Product: O=[N+]([O-])c1ccc(C(F)(F)C(F)(F)F)c(OCCN2CCCCC2)c1

Procedure:
1-[2-(5-Nitro-2-pentafluoroethyl-phenoxy)-ethyl]-piperidine was prepared from 5-nitro-2-pentafluoroethylphenol and 1-(2-chloroethyl)piperidine by a procedure similar to that described in the preparation of 1-[2-(2-tert-butyl-5-nitro-phenoxy)-ethyl]-piperidine.
Reaction SMILES: [C:1]([O:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([OH:16])[CH2:12][C@@H:11]1[C:17]1[N:21]([CH3:22])[N:20]=[CH:19][CH:18]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])(=O)=O.O>ClCCl>[C:1]([O:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([O:16][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])[CH2:12][C@@H:11]1[C:17]1[N:21]([CH3:22])[N:20]=[CH:19][CH:18]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: Cn1nccc1[C@H]1C[C@@H](O)CC[C@@H]1OC(=O)c1ccccc1
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Solvent: O
Product: Cn1nccc1[C@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@@H]1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.7 %

Procedure:
To a solution of the (1S*,2R*,4S*)-4-hydroxy-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl benzoate (293 mg, 0.976 mmol) prepared in Example 162d and 2,6-lutidine (0.136 mL, 1.17 mmol) in dichloromethane (5.0 mL), tert-butyl(dimethyl)silyl trifluoromethanesulfonate (0.269 mL, 1.17 mmol) was added, and the mixture was stirred at room temperature for 1 hour. To the reaction solution, water (10 mL) was added, followed by extraction with dichloromethane (50 mL). The thus obtained organic layer was dried over anhydrous sodium sulfate. After vacuum concentration, the residue was purified with silica gel chromatography (hexane/ethyl acetate=4:1) to yield the title compound (367 mg, 91%) as a colorless solid.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:14][OH:15].O>C(O)C>[C:1]1([CH:7]2[CH2:12][CH2:11][C:10](=[N:14][OH:15])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NO
Reactant: O=C1CCC(c2ccccc2)CC1
Solvent: O
Solvent: CCO
Product: ON=C1CCC(c2ccccc2)CC1
Temperature: 25 °C
Yield: 61.38 %

Procedure:
To a solution of 4-phenylcyclohexanone (1.50 g, 8.609 mmol) in 95% ethanol (20 ml) was added 50% hydroxylamine in water (5.276 ml, 86.09 mmol), and the reaction was heated to reflux for 1 hour. The reaction was allowed to cool to ambient temperature, and the product was precipitated by the slow addition of water. The solids were collected via filtration to yield 1.0 g of the title compound (61.38% yield).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7](OS(C(F)(F)F)(=O)=O)[C:8](=[O:15])[N:9]2[C:13]=1[CH2:12][CH2:11][CH:10]2[CH3:14])=[O:4].[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>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.CCO>[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:7]1[C:8](=[O:15])[N:9]2[C:13](=[C:5]([C:3]([OH:2])=[O:4])[CH:6]=1)[CH2:12][CH2:11][CH:10]2[CH3:14]
Reactant: COC(=O)c1cc(OS(=O)(=O)C(F)(F)F)c(=O)n2c1CCC2C
Reactant: OB(O)c1ccccc1F
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: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC1CCc2c(C(=O)O)cc(-c3ccccc3F)c(=O)n21
Yield: 53.6 %

Procedure:
To a microwave tube was added methyl-3-methyl-5-oxo-6-(trifluoromethylsulfonyloxy)-1,2,3,5-tetrahydroindolizine-8-carboxylate (94 mg, 0.26 mmol), 2-fluorophenylboronic acid (37 mg, 0.26 mmol, Aldrich), and 2 M sodium carbonate (0.65 mL, 1.30 mmol). To this was added 4 mL of toluene, 0.25 mL of EtOH, and Pd(PPh3)4 (20 mg, 0.17 mmol, Aldrich). The tube was sealed and treated in Emry's optimizer for 15 min at 160° C. The aqueous phase was separated and acidified to pH 2 with 2 N HCl and extracted with EtOAc (3×). The combined EtOAc layers were washed with brine, dried over MgSO4, and concentrated in vacuo to give 40 mg (53%) of the title compound as a light brown residue. MS m/z: 288.1(M+1).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].S(=O)(=O)(O)O.[CH3:18]O>>[Br:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:18])=[O:8]
Reactant: Cc1cc(O)c(C(=O)O)cc1Br
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(Br)c(C)cc1O
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a solution of 5-bromo-2-hydroxy-4-methylbenzoic acid (6.78 g) in methanol (200 mL) was added dropwise sulfuric acid (6.77 mL), and the mixture was stirred overnight at 70° C. The reaction mixture was concentrated under reduced pressure, the residue was neutralized with saturated aqueous sodium bicarbonate solution under ice-cooling, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (6.56 g).
Reaction SMILES: [OH-].[Li+].[C:3]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([P:33]([O:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)(=[O:42])[O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[P:15]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)(=[O:24])[O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:9][CH:8]=1)([O:5]C)=[O:4].Cl>O.O1CCOCC1>[C:3]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([P:33]([O:43][CH2:44][C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)(=[O:42])[O:34][CH2:35][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[P:15]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)(=[O:24])[O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:9][CH:8]=1)([OH:5])=[O:4]
Reactant: COC(=O)c1ccc(CC(P(=O)(OCc2ccccc2)OCc2ccccc2)P(=O)(OCc2ccccc2)OCc2ccccc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1ccc(CC(P(=O)(OCc2ccccc2)OCc2ccccc2)P(=O)(OCc2ccccc2)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 52.2 %

Procedure:
A solution of lithium hydroxide (84 mg, 2.0 mmol) in water (1.0 mL) is added to a solution of methyl ester 2 (455 mg, 0.6 mmol) in 1,4-dioxane (1.0 mL) at room temperature. The mixture is stirred at room temperature for 5 hours and a 1N solution of HCl (10 mL) is added. Dioxane is evaporated under reduced pressure and the mixture is diluted with EtOAc (20 mL). The separated aqueous layer is extracted with EtOAc (3×50 mL) and the combined organic layers are washed (brine), dried (MgSO4 anh.), filtered and evaporated. Flash-chromatography (HOAc:EtOH:EtOAc (0.1:1:9)) of the residue gives carboxylic acid 4 (210 mg, 48%). 1H NMR (CDCl3): δ 9.65 (1H, br. s), 7.98 (2H, d, J=8.1 Hz), 7.26 (20H, s), 7.13 (2H, d, J=8.1 Hz), 4.95 (8H, m), 3.31 (2H, td, J=16.7, 6.4 Hz), 2.82 (1H, tt, J=24.0, 6.4 Hz). 13C NMR (CDCl3): δ 170.0, 144.6 (t, J=7.6 Hz), 135.9, 135.8, 130.1, 129.0, 128.6, 128.5, 128.4, 128.3, 128.2, 128.1, 68.3 (dd, J=19.6, 6.5 Hz), 39.4 (t, J=133.2 Hz), 31.2 (br. s).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([CH3:19])([CH3:18])[C:15]([OH:17])=O)[N:5]=[C:4]([CH3:20])[C:3]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22].[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][NH2:35])=[CH:30][CH:29]=1>>[CH2:24]([O:23][C:21]([C:3]1[C:4]([CH3:20])=[N:5][C:6]2[C:11]([C:2]=1[NH2:1])=[C:10]([O:12][CH2:13][C:14]([CH3:18])([CH3:19])[C:15]([NH:35][CH2:34][C:31]1[CH:32]=[CH:33][C:28]([O:27][CH3:26])=[CH:29][CH:30]=1)=[O:17])[CH:9]=[CH:8][CH:7]=2)=[O:22])[CH3:25]
Reactant: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)C(=O)O)c2c1N
Reactant: COc1ccc(CN)cc1
Product: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)C(=O)NCc3ccc(OC)cc3)c2c1N

Procedure:
Prepared as in Example 24a from 3-((4-amino-3-(ethoxycarbonyl)-2-methylquinolin-5-yl)oxy)-2,2-dimethylpropanoic acid (Example 47b) and (4-methoxyphenyl)methanamine as a yellow solid (100%). MS 466 (MH+).
Reaction SMILES: CN(C)C(=O)C.[C:7]([C:9]1[NH:10][N:11]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:12](=[O:31])[C:13]=1[N:14]=[N:15][C:16]1[CH:21]=[C:20]([S:22](O)(=[O:24])=[O:23])[C:19]([O:26][CH2:27][CH2:28][O:29][CH3:30])=[CH:18][CH:17]=1)#[N:8].P(Cl)(Cl)([Cl:40])=O>CC(C)=O>[C:7]([C:9]1[NH:10][N:11]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:12](=[O:31])[C:13]=1[N:14]=[N:15][C:16]1[CH:21]=[C:20]([S:22]([Cl:40])(=[O:24])=[O:23])[C:19]([O:26][CH2:27][CH2:28][O:29][CH3:30])=[CH:18][CH:17]=1)#[N:8]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COCCOc1ccc(N=Nc2c(C#N)[nH]n(-c3ccccc3)c2=O)cc1S(=O)(=O)O
Solvent: CC(=O)N(C)C
Solvent: CC(C)=O
Product: COCCOc1ccc(N=Nc2c(C#N)[nH]n(-c3ccccc3)c2=O)cc1S(=O)(=O)Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
50 ml of N,N-dimethylacetamide was added dropwise at 50° C. or lower to a mixture of 51.0 g of 3-cyano-4-[4-(2-methoxyethoxy)-5-sulfophenylazo]-1-phenyl-5-pyrazolone prepared as described in Step (a) of Reference Synthesis Example 1 above, and then 250 ml of acetone and 50 ml of phosphorous oxychloride was added. After completion of the dropwise addition, the reaction mixture was stirred for about 1 hour, and was then gradually poured into 1.0 l of ice water. The crystals thus-precipitated were recovered by filtration, washed with 100 ml of acetonitrile and air-dried.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([S:20][CH3:21])=[CH:16][CH:15]=2)[C:5]([C:10]([NH2:12])=[O:11])=[N:6][C:7]=1[CH2:8][CH3:9].C(O)(=O)C.OO.[OH-:28].[Na+].[OH2:30]>O.O.[O-][W]([O-])(=O)=O.[Na+].[Na+].C(OCC)(=O)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:21])(=[O:30])=[O:28])=[CH:16][CH:15]=2)[C:5]([C:10]([NH2:12])=[O:11])=[N:6][C:7]=1[CH2:8][CH3:9]
Reactant: [OH-]
Reactant: CCc1nc(C(N)=O)c(Nc2ccc(SC)cc2)nc1Cl
Reactant: O
Agent: O=[W](=O)([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCc1nc(C(N)=O)c(Nc2ccc(S(C)(=O)=O)cc2)nc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 5-chloro-6-ethyl-3-{[4-(methylsulfanyl)phenyl]amino}pyrazine-2-carboxamide (Preparation Example 394) (92 mg) and acetic acid (2.5 mL), sodium tungstate dihydrate (29 mg) and 30% hydrogen peroxide solution (0.15 mL) were added and stirred at room temperature for 30 minutes. After water and ethyl acetate were added to the reaction liquid, 1M aqueous sodium hydroxide was added and stirred for 30 minutes, and the reaction liquid was partitioned. After drying over anhydrous sodium sulfate, the organic layer was filtered and concentrated. The resulting residue was washed with ethyl acetate to give 5-chloro-6-ethyl-3-{[4-(methylsulfonyl)phenyl]amino}pyrazine-2-carboxamide (103 mg).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([C:7]([CH3:10])=[CH:8][CH:9]=1)[NH2:6].CC1C=CC(C)=CC=1N.[C:20](OC(=O)C)(=[O:22])[CH3:21].C([O-])(=O)C.[K+]>C(Cl)(Cl)Cl>[OH:1][CH2:2][C:3]1[CH:4]=[C:5]([C:7]([CH3:10])=[CH:8][CH:9]=1)[NH:6][C:20]([CH3:21])=[O:22]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(CO)cc1N
Agent: CC(=O)[O-]
Agent: Cc1ccc(C)c(N)c1
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1cc(CO)ccc1C
Yield: 114.1 %

Procedure:
To a solution of an approximately 1:1 mixture of 3-(hydroxymethyl)-6-methylaniline, (8.05 g, 58.8 mmol) (2) and 2,5-dimethylaniline in chloroform (290 mL), was added acetic anhydride (20 mL, 206 mmol) and potassium acetate (20 g, 202 mmol). The resulting mixture was heated to its reflux temperature for 2 hours. The mixture was then concentrated and purified by a flash column chromatography (1:1 of hexane-ethyl acetate) which also removed the by-product from Example 61 to give the title compound (12.02 g, 92%). TLC Rf: 0.52 (ethyl acetate); MS (electrospray) 222 (M+1); 1H N MR (CDCl3) δ2.09 (s, 3H), 2.21 (s, 3H), 2.25 (s, 3H), 5.06 (s, 2H), 7.00 (br s, 1H, NH), 7.08 (d, 1H, J=7.6 Hz), 7.18 (d, 1H, J=7.6 Hz), 7.81 (s, 1H).
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH2:9][CH2:10][O:11]C2CCCCO2)=[CH:6][CH:5]=[CH:4][N:3]=1.[OH:18][CH2:19][C@@H:20]1[CH2:24][CH2:23][CH2:22][N:21]1[CH3:25].CC(C)([O-])C.[K+].C(O)(C)(C)C>C1(C)C=CC=CC=1>[CH3:25][N:21]1[CH2:22][CH2:23][CH2:24][C@H:20]1[CH2:19][O:18][C:2]1[C:7]([O:8][CH2:9][CH2:10][OH:11])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CN1CCC[C@H]1CO
Reactant: Clc1ncccc1OCCOC1CCCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: Cc1ccccc1
Product: CN1CCC[C@H]1COc1ncccc1OCCO
Temperature: 50 °C
Reaction time: 48 h
Yield: 79.5 %

Procedure:
A solution of 2-chloro-3-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]pyridine (from Example 4; 100 mg, 0.39 mmol), (S)-(−)-2-hydroxymethyl-1-methylpyrrolidine (69 μl, 0.58 mmol) and 1.0 M potassium tert-butoxide in tert-butanol (0.8 mL, 0.80 mmol) in 4 mL of toluene was heated at 100° C. for 1 day. The organic phase was washed with 3×2 mL of water and 2 mL of brine. The organic phase was shaken at 50° C. with 4 mL of 2.0 M acetic acid for 2 days. The aqueous phase was washed with 3×3 mL of ethyl acetate, made basic by addition of potassium hydroxide, saturated with sodium chloride and extracted with 3×2 mL of ethyl acetate. The organic phase was dried (MgSO4) and concentrated under reduced pressure to give 78 mg (0.31 mmol, 79%) of the title compound as a colorless oil. LC-UV purity 95%. MS m/z 253 (M+1)+, calc. 253 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.[Cl:9][C:10]1[C:11]([CH:21]=O)=[C:12]([CH:18]=[CH:19][CH:20]=1)[O:13][CH2:14][C:15]([NH2:17])=[O:16].[CH3:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:25]=1[N+:31]#[C-:32].Cl(O)(=O)(=O)=O>C(O)C>[NH2:17][C:15]([CH2:14][O:13][C:12]1[CH:18]=[CH:19][CH:20]=[C:10]([Cl:9])[C:11]=1[C:21]1[N:1]=[C:2]2[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]2[C:32]=1[NH:31][C:25]1[C:26]([CH3:30])=[CH:27][CH:28]=[CH:29][C:24]=1[CH3:23])=[O:16]
Reactant: [C-]#[N+]c1c(C)cccc1C
Reactant: NC(=O)COc1cccc(Cl)c1C=O
Reactant: Nc1ccc(F)cn1
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CCO
Product: Cc1cccc(C)c1Nc1c(-c2c(Cl)cccc2OCC(N)=O)nc2ccc(F)cn12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
3.2 0.177 g of 2-amino-5-fluoropyridine 4 and 0.288 g of the aldehyde 10 are dissolved successively in 30 ml of ethanol at RT under an inert gas. 0.205 g of 2,6-dimethylphenylisocyanide 5 is then added, 64.1 μl of 70% perchloric acid are added dropwise, and the mixture is stirred at RT for a further 20 h. The mixture is subsequently subjected to conventional work-up, giving 0.286 g (43%) of “A3”; m.p. 186-187°; MS-EI (M+)=438.
Reaction SMILES: OC1[C:11]2[C:6](=[C:7]3[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:8]3=[CH:9][CH:10]=2)[O:5][C:4](=O)C=1.[CH2:18](OCC)C>COCCOCCOCCOC.[Pd]>[CH3:4][O:5][C:6]1[C:7]2[C:8](=[C:12]([CH2:16][CH3:18])[CH:13]=[CH:14][CH:15]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: CCOCC
Reactant: Cc1cccc2c1ccc1c(O)cc(=O)oc12
Agent: [Pd]
Solvent: COCCOCCOCCOC
Product: CCc1cccc2c(OC)cccc12
Yield: 8.5 %

Procedure:
5-Methoxy-1-tetralone (5) (4 g, 22.6 mmol) was dissolved in 50 mL anhydrous diethyl ether, stirred, and cooled down on ice to 0° C. Ethylmagnesium bromide (19 mL, 56.8 mmol) was added dropwise to the solution, producing copious precipitation. The mixture was then heated to reflux and stirred for 10 h. After cooling, cold water was added slowly to the reaction mixture, which was then extracted with diethyl ether three times. The organic layer was evaporated to afford crude product 6. Without purification, zinc chloride (15 g, 114 mmol) was added to a solution of 6 in benzene (35 mL), then concentrated hydrochloride acid (12 mL) was added to the solution at room temperature. The reaction mixture was heated to reflux for 5 h, cooled, extracted with diethyl ether three times, and the organic layer was evaporated to afford crude product. Purification by column chromatography gave 7 (2 g). To a solution of 7 (2 g) in triglyme (15 mL) was added 10% Pd/C (2 g) and the mixture was heated to reflux for 3 days. After cooling, diethyl ether was added to the mixture and it was filtered on Celite, then washed with diethyl ether to provide compound 8.50% yield; 1H NMR δ1.37 (3H, t, J=7.8 Hz, CH3CH2—), 3.10 (2H, q, J=7.8 Hz, CH3CH2—), 4.01 (3H, s, OCH3), 6.82 (1H, d, J=7.8 Hz, H-2), 7.36-7.44 (3H, m, H-3, 6, 7), 7.64 (1H, d, J=8.7 Hz, H-4), 815 (1H, d, J=8.4 Hz, H-8).
Reaction SMILES: CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][N:29]([C:32](Cl)=[O:33])[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].[F:35][C:36]([F:47])([F:46])[O:37][C:38]1[CH:45]=[CH:44][C:41]([CH2:42][OH:43])=[CH:40][CH:39]=1>C(#N)C>[F:35][C:36]([F:46])([F:47])[O:37][C:38]1[CH:45]=[CH:44][C:41]([CH2:42][O:43][C:32]([N:29]2[CH2:30][CH2:31][N:26]([C:24]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:25])[CH2:27][CH2:28]2)=[O:33])=[CH:40][CH:39]=1
Reactant: OCc1ccc(OC(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)Cl)CC1
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccc(OC(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
652 mg (1.5 mmol) PS-BEMP and 373 mg (1.5 mmol) 4-chlorocarbonyl-piperazine-1-carboxylic acid tert-butyl ester was added to a solution of 192 mg (1.0 mmol) 4-trifluoromethoxybenzyl alcohol in 5 ml acetonitrile. The mixture was heated to reflux for 24 h then cooled to rt, diluted with 5 ml acetonitrile, 666 mg (4.5 mmol) PS-NH2 added and shaken at rt for 16 h. After filtration and evaporation the crude product is purified by flash chromatography on silica gel with hexane/AcOEt 50:50: 180 mg colourless crystalline solid. 1H-NMR (CDCl3): 1.45 s, 9H, 3.35–3.55 m, 8H, 5.14 s, 2H, 7.20 d, 2H and 7.40 d, 2H, AB-system.
Reaction SMILES: [Li][Li].[Cl-:3].[Ti+4:4].[Cl-].[Cl-].[Cl-].[C:8]1([CH3:14])[CH:13]=[CH:12][CH:11]=CC=1>>[Cl-:3].[Cl-:3].[CH-:11]1[CH:12]=[CH:13][CH:8]=[CH:14]1.[CH-:11]1[CH:12]=[CH:13][CH:8]=[CH:14]1.[Ti+2:4]
Reactant: Cc1ccccc1
Reactant: [Ti+4]
Agent: [Cl-]
Agent: [Li][Li]
Product: [Ti+2]
Product: c1cc[cH-]c1
Temperature: -78 °C
Reaction time: 30 h
Yield: 13 %

Procedure:
A suspension of 5.46 g (17.5 mmol) of the dilithium etherate (Example 2) in 200 ml of toluene is cooled to -78° C., and 3.3 g (17.5 mmol) of titanium chloride are added. The reaction solution immediately becomes a dark red color. The mixture is stirred at room temperature for 30 hours, insoluble constituents are removed by filtration through a frit, and the dark-red toluene phase is evaporated to dryness in an oil-pump vacuum. Repeated washing with pentane gives 1.85 g of the titanocene dichioride as a brown-beige powder. The crude product is subsequently extracted for several days with pentane in a circulation frit, giving, after removal of the solvent, the titanocene dichloride as a brown solid in a yield of 13% (780 mg): m.p. 259° C. (decomp.,DSC).
Reaction SMILES: [K].[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:9])=[N:7][CH:8]=1.[Br:10][C:11]1[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=1>CC(N(C)C)=O.CO>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([O:2][C:3]2[CH:4]=[CH:5][C:6]([CH3:9])=[N:7][CH:8]=2)=[CH:13][CH:12]=1
Reactant: Cc1ccc(O)cn1
Reactant: Brc1ccc(Br)cc1
Agent: [K]
Solvent: CO
Solvent: CC(=O)N(C)C
Product: Cc1ccc(Oc2ccc(Br)cc2)cn1

Procedure:
2.84 g of a potassium salt of 5-hydroxy-2-methylpyridine, 4.7 g of p-dibromobenzene and 400 mg of cuprous oxide were suspended in 10 ml of dimethylacetamide, and the mixture was allowed to react in a nitrogen gas stream at 150° C. for 15 hours. The reaction mixture was diluted with 30 ml of methanol and then filtered. The filtrate was immediately dried, and the residue was taken into 100 ml of chloroform and washed successively with a 3% aqueous sodium carbonate solution and 50 ml of water. The chloroform layer was dried with anhydrous sodium sulfate and immediately concentrated to dryness to obtain 2.1 g of oily 5-(p-bromophenoxy)-2-methylpyridine.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:18][C:19]#[N:20].C(Cl)Cl.CCOC(C)=O>C(#N)C>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:18][C:19]#[N:20])[CH2:13][CH2:12]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)n[nH]c2c1
Reactant: N#CCCl
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: ClCCl
Product: N#CCN1CCC(c2n[nH]c3cc(F)ccc23)CC1
Temperature: 25 °C
Yield: 89.1 %

Procedure:
To a stirred suspension of 4-(6-fluoro-1H-indazol-3-yl)piperidine (4.95 g, 22.6 mmol) and NaHCOa (2.1 g, 24.9 mmol) in dry acetonitrile (110 ml) was added chloroacetonitrile (1.6 ml, 24.9 mmol) at room temperature, under nitrogen. The suspension was warmed to reflux for 22.5 hours, cooled to room temperature, and subsequently filtered. The remaining solids were washed with DCM and the combined filtrates were concentrated. The resulting brown oil was dissolved into EtOAc and washed with water. The organic phase was dried (MgSO4), filtered and concentrated to give a brown solid which was re-dissolved into DCM/EtOAc and flushed through alumina with DCM. The eluent was concentrated to give 5.2 g of the desired product as a solid, m.p. 149°-151° C. ANALYSIS: Calculated for C14H15FN4 : 65.10%C 5.85%H 21.69%N Found: 64.84%C 5.90%H 21.74%N