Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][C:7]=1[N+:12]([O-])=O.CO.[ClH:21]>C(OCC)(=O)C>[NH2:12][C:7]1[C:8]([Cl:21])=[N:9][CH:10]=[CH:11][C:6]=1[NH:5][CH2:4][C:3]1[CH:15]=[CH:16][CH:17]=[CH:18][C:2]=1[F:1]
Reactant: O=[N+]([O-])c1cnccc1NCc1ccccc1F
Reactant: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1c(NCc2ccccc2F)ccnc1Cl
Reaction time: 0.5 h

Procedure:
A mechanically stirred solution of 4-[(2-fluorobenzyl)amino]-3-nitropyridine (12.31 g, 49.8 mmol) in concentrated hydrochloric acid (118 ml) was heated to 90° under a nitrogen atm. Stannous chloride dihydrate (55.56 g, 246 mmol) was added in small portions over a 5 min period (the oil bath was removed until the reaction subsided). After an additional 30 min at 90°, the reaction mixture was cooled, diluted with water (200 ml) and spin evaporated in vacuo. The residue was diluted with water (200 ml) and cooled in an ice-bath, while concentrated ammonium hydroxide was added to adjust the pH to 7-8. The solids were collected and allowed to air dry overnight. The solid was treated with ethyl acetate and filtered (12×200 ml), the combined extracts were washed with water, dried (sodium sulphate) and spin evaporated in vacuo. The residue was combined with the product from a separate reaction (12 g, 48.5 mmoles) and dissolved in ethyl acetate. This solution was added to Silica Gel 60 and spin evaporated in vacuo. The residual solids were introduced to a column (5 cm×30 cm) of Silica Gel 60 wetted with ethyl acetate. The column was eluted with ethyl acetate using flash chromatography. The appropriate fractions were combined and spin evaporated in vacuo to give 20.8 g (84%) of 3-amino-2-chloro-4-[2-fluorobenzyl)amino]pyridine as a white solid, mp.=185°-187°; UV (0.1M hydrochloric acid+5% methanol), λmax 233 nm (ξ17900), 302 nm (ξ14900); (pH 7.0 buffer+5% methanol), λmax 262 nm (ξ11200), (0.1N sodium hydroxide+5% methanol), λmax 262 nm (ξ10700), 1H nmr (DMSO-d6): δ7.36-7.15 (complex m, 5H,Ar+pyridine H-6), 6.35-6.30 (d,1H,pyridine H-5), 6.27-6.33 (overlapping,1H,NH). 4.84 (2,2H,NH2), 4.41 (d,2H,J=5 Hz, CH2Ar).
Reaction SMILES: [N:1]1[C:14]2[C:5](=[C:6]3[C:11](=[CH:12][CH:13]=2)[CH2:10][CH2:9][CH:8]([CH2:15][OH:16])[O:7]3)[CH:4]=[CH:3][CH:2]=1.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[N:1]1[C:14]2[C:5](=[C:6]3[C:11](=[CH:12][CH:13]=2)[CH2:10][CH2:9][CH:8]([CH2:15][O:16][S:23]([C:20]2[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=2)(=[O:25])=[O:24])[O:7]3)[CH:4]=[CH:3][CH:2]=1
Reactant: OCC1CCc2ccc3ncccc3c2O1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2CCc3ccc4ncccc4c3O2)cc1
Reaction time: 120 h
Yield: 45.8 %

Procedure:
(7,8-Dihydro-6H-5-oxa-1-aza-phenanthren-6-yl)-methanol (0.27 g, 1.3 mmole) was dissolved in 75 mL of methylene chloride and p-toluenesulfonyl chloride (0.60 g, 3.1 mmole) added. The mixture was placed in an ice/isopropanol bath and first N,N-diisopropylethylamine (0.55 mL, 3.1 mmole) and then N,N-dimethyaminopyridine added. The mixture was allowed to stir under nitrogen for 5 days. It was washed with 150 mL portions of 2 N aqueous HCl, saturated aqueous sodium bicarbonate and saturated brine, dried over magnesium sulfate, filtered and concentrated in vacuum to an orange oil. Column chromatography on silica gel with 0–5% methanol/methylene chloride gave 0.22 g of the title compound. 1H-NMR (CDCl3): doublet 8.8 δ (1 H); doublet 8.25 δ (1 H); doublet 7.8 δ (2 H); doublet 7.6 δ (1 H); multiplet 7.3 δ (4 H); multiplet 4.4 δ (1 H); doublet 4.3 δ (2 H); multiplet 2.9 δ (2 H); singlet 2.4 δ (3 H); multiplet 2.0 δ (2 H).
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].[Li]CCCC.CON(C)[C:16](=[O:28])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=1.CC(O)=O>C1(C)C=CC=CC=1.O>[CH3:4][O:3][P:2]([CH2:1][C:16](=[O:28])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:26])([F:25])[F:27])[CH:19]=1)(=[O:7])[O:5][CH3:6]
Reactant: COP(C)(=O)OC
Reactant: CON(C)C(=O)Cc1cccc(C(F)(F)F)c1
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: COP(=O)(CC(=O)Cc1cccc(C(F)(F)F)c1)OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of dimethyl methylphosphonate (9.4 g, 75.8 mmol) in toluene (80 mL) at −78° C. was slowly added n-BuLi (2.5M in hexanes, 28 mL, 70 mmol). The reaction mixture was stirred for 1 h and a solution of N-methoxy-N-methyl-2-(3-trifluoromethyl-phenyl)-acetamide (14.39 g) in toluene (50 mL) was slowly added. The reaction mixture was stirred for 2.5 h and AcOH (40 mL) was added. The reaction mixture was warmed to room temperature and water was added. The organic layer was washed with water followed by brine. The organic solution was dried (MgSO4), filtered and concentrated in vacuo. Medium pressure chromatography (CH2Cl2 to 2% MeOH in CH2Cl2) provided the title compound of Preparation 10 (9.37 g). 1H NMR (CDCl3) δ7.52 (m, 1H), 7.44 (m, 2H), 7.37 (m, 1H), 3.96 (s, 2H), 3.87 (s, 3H), 3.76 (s, 3H), 3.12 (d, 2H).
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[C:15]3[N:17](C4CCCCO4)[N:18]=[C:19]([CH3:20])[C:14]3=[C:13]([CH2:27][N:28]3[CH2:33][C:32]([CH3:35])([CH3:34])[N:31]([CH2:36][CH2:37][C:38]([F:41])([F:40])[F:39])[CH2:30][C:29]3([CH3:43])[CH3:42])[CH:12]=2)=[CH:7][CH:6]=1.Cl>O1CCOCC1>[CH3:20][C:19]1[C:14]2[C:15](=[N:16][C:11]([C:8]3[CH:9]=[CH:10][C:5]([OH:4])=[CH:6][CH:7]=3)=[CH:12][C:13]=2[CH2:27][N:28]2[CH2:33][C:32]([CH3:34])([CH3:35])[N:31]([CH2:36][CH2:37][C:38]([F:41])([F:40])[F:39])[CH2:30][C:29]2([CH3:43])[CH3:42])[NH:17][N:18]=1
Reactant: COCOc1ccc(-c2cc(CN3CC(C)(C)N(CCC(F)(F)F)CC3(C)C)c3c(C)nn(C4CCCCO4)c3n2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1n[nH]c2nc(-c3ccc(O)cc3)cc(CN3CC(C)(C)N(CCC(F)(F)F)CC3(C)C)c12
Reaction time: 16 h
Yield: 47.1 %

Procedure:
167 mg of 6-(4-methoxymethoxy-phenyl)-3-methyl-1-(tetrahydro-pyran-2-yl)-4-[2,2,5,5-tetramethyl-4-(3,3,3-trifluoro-propyl)-piperazin-1-ylmethyl]-1H-pyrazolo[3,4-b]pyridine were dissolved in 2 ml of 1,4-dioxane and treated with 1.5 ml of hydrochloric acid (4M in dry dioxane). After standing at rt for 16 h the volatiles were removed in vacuo. The residue was purified by preparative HPLC (C18 column, acetonitrile/water gradient) and 62 mg (47%) of the title compound were obtained.
Reaction SMILES: Cl[CH:2]([NH:7][C:8](=[O:16])[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)[C:3]([F:6])([F:5])[F:4].[S-:17][C:18]#[N:19].[K+]>CC(C)=O>[CH3:15][C:12]1[CH:13]=[CH:14][C:9]([C:8]([NH:7][CH:2]([N:19]=[C:18]=[S:17])[C:3]([F:6])([F:5])[F:4])=[O:16])=[CH:10][CH:11]=1
Reactant: Cc1ccc(C(=O)NC(Cl)C(F)(F)F)cc1
Reactant: N#C[S-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1ccc(C(=O)NC(N=C=S)C(F)(F)F)cc1
Reaction time: 12 h
Yield: 61.1 %

Procedure:
A stirred solution of Example 1B (2.00 g, 8.00 mmol) in acetone (35 mL) at ambient temperature was treated with potassium thiocyanate (1.60 g, 16.0 mmol). The reaction mixture was stirred for 12 hours, concentrated, and the crude residue was purified by flash chromatography (elution with 40% ethyl acetate/hexanes) to provide 1.34 g of the desired product as an off-white solid.
Reaction SMILES: [CH3:1][CH:2]([CH3:8])[C:3](=O)[CH2:4][C:5]#[N:6].Cl.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][NH2:19])=[CH:14][CH:13]=1>CCO>[CH:2]([C:3]1[CH:4]=[C:5]([NH2:6])[N:18]([C:15]2[CH:16]=[CH:17][C:12]([O:11][CH3:10])=[CH:13][CH:14]=2)[N:19]=1)([CH3:8])[CH3:1]
Reactant: COc1ccc(NN)cc1
Reactant: CC(C)C(=O)CC#N
Agent: Cl
Solvent: CCO
Product: COc1ccc(-n2nc(C(C)C)cc2N)cc1
Temperature: 80 °C
Yield: 48 %

Procedure:
Using the procedure described in Example 308A Step 1, to a solution of 4-methyl-3-oxopentanenitrile (514 mg, 4.5 mmol) prepared as described in Example 122A Step 1, in anhydrous EtOH (15 ml) was added (4-methoxyphenyl)hydrazine hydrochloride (524 mg, 3.0 mmol) and the reaction mixture was heated at 80° C. overnight. The residue was purified by silica gel chromatography (DCM/EtOAc 1:1) to afford 3-isopropyl-1-(4-methoxyphenyl)-1H-pyrazol-5-amine (333 mg, 48%) as a solid. 1H NMR (300 MHz, CDCl3) δ 1.26 (d, J=7 Hz, 6H), 2.92 (m, 1H), 3.66 (s, 2H), 3.83 (s, 3H), 5.46 (s, 1H), 6.96 (d, J=9 Hz, 2H), 7.44 (d, J=9 Hz, 2H); LC-MS (ESI) m/z 232 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=1.Cl[CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>CN(C)C=O>[C:21]([O:20][C:18]([CH2:17][O:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=1)=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: O=Cc1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1ccc(C=O)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 54.3 %

Procedure:
366 g of dimethylformamide and 165.9 g (1.2 mol) of potassium carbonate were placed in a flask, followed by dropwise addition of 122 g (1 mol) of 4-hydroxybenzaldehyde. 181.2 g (1.2 mol) of t-butyl chloroacetate were added dropwise to the mixture at a temperature of 50° C. for two hours. After the addition, the mixture was stirred for two hours at a temperature of 50° C. and then another seven hours at a temperature of 70° C. The resulting reaction mixture was washed with 122 g of toluene and 662 g of water. 100 g of the solvent was removed from the mixture by distillation under reduced pressure and then 236 g of n-heptane were added to the distillation residue to effect crystallization. The resulting crystals were collected by filtration to provide 128.4 g of 4-t-butoxycarbonylmethoxybenzaldehyde having a purity of 99.9% as white crystals. FIG. 2 is an infrared absorption spectrum of the compound. The yield was 54%.
Reaction SMILES: [Li]CCCC.Br[C:7]1[C:20]2[C:21]3=[C:22]4[C:17](=[CH:18][CH:19]=2)[CH:16]=[CH:15][CH:14]=[C:13]4[CH:12]=[CH:11][C:10]3=[CH:9][CH:8]=1.C1COCC1.[Si:28](Cl)([Cl:31])([Cl:30])[Cl:29]>C1COCC1.CCOCC>[Cl:29][Si:28]([Cl:31])([Cl:30])[C:7]1[C:20]2[C:21]3=[C:22]4[C:17](=[CH:18][CH:19]=2)[CH:16]=[CH:15][CH:14]=[C:13]4[CH:12]=[CH:11][C:10]3=[CH:9][CH:8]=1
Reactant: Brc1ccc2ccc3cccc4ccc1c2c34
Reactant: Cl[Si](Cl)(Cl)Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cl[Si](Cl)(Cl)c1ccc2ccc3cccc4ccc1c2c34
Temperature: -60 °C
Reaction time: 2 h
Yield: 48 %

Procedure:
Under a dry nitrogen atmosphere, n-BuLi (10.6 mL, 1.6 M) in hexanes was added drop-wise to a cooled (−60° C.) solution of 1-bromopyrene (5.01 g, 0.018 mol) in THF/Et2O (1:1) (80 mL) and stirred for 2 hours at −60° C. The solution was cooled to −90° C. and a THF solution of SiCl4 (8.66 g, 0.051 mol) (10 mL) was added slowly and stirred for 24 hours at room temperature. The reaction mixture was evaporated to dryness, washed in Et2O (100 mL), and filtered to remove any unreacted 1-bromopyrene and LiBr. The filtrate was collected and evaporated to dryness to give a 48% yield of 1-trichlorosilylpyrene, a yellow powder. 1HNMR (CDCl3, ppm) 8.66 (d, J=9.3 Hz, 1H), 8.59 (d, J=8.1 Hz, 1H), 8.30 (m, 5H), 8.11 (m, 2H). 13C {1H}NMR (CDCl3, ppm) 136.18 (C), 135.85 (C), 133.13 (CH), 132.06 (C), 131.30 (C), 131.22 CH), 130.31 (CH), 127.96 (CH), 127.67 (CH), 127.61 (CH), 126.65 (CH), 125.61 (C), 125.01 (CH), and 124.39 (C). 29Si{1H} (CDCl3, ppm) −1.64 (s).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:3]12[CH3:4])[C@:16]1([CH3:17])[C@H:11]([CH2:12][C:13](=[O:22])[C@@H:14]2[CH2:21][C@@H:15]21)[CH2:10][CH2:9]3.[O:23]1[CH:28]=[CH:27][CH2:26][CH2:25][CH2:24]1>O1CCCC1.P(Cl)(Cl)(Cl)=O.C(OCC)C>[CH2:21]1[C@H:14]2[C:13](=[O:22])[CH2:12][C@H:11]3[C@:16]([CH3:17])([C@@H:15]12)[C@@H:18]1[C@H:8]([C@H:5]2[C@@:3]([CH2:20][CH2:19]1)([CH3:4])[C@@H:2]([O:1][CH:24]1[CH2:25][CH2:26][CH2:27][CH2:28][O:23]1)[CH2:7][CH2:6]2)[CH2:9][CH2:10]3
Reactant: C[C@]12CC[C@H]3[C@@H](CC[C@H]4CC(=O)[C@@H]5C[C@@H]5[C@@]43C)[C@@H]1CC[C@@H]2O
Reactant: C1=COCCC1
Solvent: CCOCC
Solvent: O=P(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: C[C@]12CC[C@H]3[C@@H](CC[C@H]4CC(=O)[C@@H]5C[C@@H]5[C@@]43C)[C@@H]1CC[C@@H]2OC1CCCCO1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 8.0 g of 17β-hydroxy-1α,2α-methylene-5α-androstan-3-one in 40 ml of tetrahydrofuran is combined with 8 ml of 3,4-dihydro-2H-pyran and 3 drops of phosphorus oxychloride and stirred at room temperature for 30 minutes. Subsequently the mixture is diluted with diethyl ether, washed with sodium bicarbonate solution and water, dried, and evaporated, yielding 9.0 g of 1α,2α-methylene-17β-(tetrahydropyran-2-yloxy)-5α-androstan-3-one.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][O:11][CH3:12])=[CH:4][C:3]=1[CH3:13].[Br:14]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:14][CH2:13][C:3]1[CH:4]=[C:5]([O:8][CH2:9][CH2:10][O:11][CH3:12])[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: COCCOc1ccc(Cl)c(C)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COCCOc1ccc(Cl)c(CBr)c1

Procedure:
To a solution of 1-chloro-4-(2-methoxyethoxy)-2-methylbenzene from the previous step (1 eq.) in carbon tetrachloride (0.02 M) was added N-bromosuccinimide (1 eq.) and a few crystals of AIBN (1.1 eq.). The resulting mixture was irradiated with sunlamp at reflux for 1 h. The insolubles were removed via filtration and the filtrate was concentrated in vacuo to furnish the title compound.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[CH2:19](O)[CH3:20]>>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:19][CH3:20])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CCCCc1ccccc1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)CCCCc1ccccc1
Temperature: 0 °C
Yield: 97.5 %

Procedure:
250 g (1.4 mols) of 5-phenylvaleric acid are dissolved in 450 ml of absolute ethanol. 114 ml of concentrated sulphuric acid are added to the clear colourless solution and the reaction mixture is refluxed for 48 hours. The reaction mixture, which initially is two-phase, becomes almost homogeneous and separates into two phases again on cooling. The cold two-phase reaction mixture is poured onto diethyl ether and about 1 kg of ice. The aqueous phase is extracted with ether twice more. The ether phases are washed twice with 2 N sodium carbonate solution and twice with NaCl solution. The combined ether phases are dried over MgSO4 and the solvent is removed on a rotary evaporator. After drying under a high vacuum at room temperature, 281.7 g of a colourless oil (97.5% of theory) are obtained.
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[C:14]([C:22]([F:25])([F:24])[F:23])[CH2:15]P(=O)(OC)OC)=[CH:9][CH:8]=1.[CH:33]([CH:35]1[O:40][C:39](C)(C)[O:38][CH:37]([CH2:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:36]1)=O>O1CCCC1>[F:32][C:29]1[CH:30]=[CH:31][C:26]([C:13]([C:10]2[CH:9]=[CH:8][C:7]([F:6])=[CH:12][CH:11]=2)=[C:14]([C:22]([F:23])([F:25])[F:24])[CH:15]=[CH:33][CH:35]2[O:40][CH2:39][O:38][CH:37]([CH2:43][C:44]([O:46][C:47]([CH3:48])([CH3:50])[CH3:49])=[O:45])[CH2:36]2)=[CH:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)CC1CC(C=O)OC(C)(C)O1
Reactant: COP(=O)(CC(=C(c1ccc(F)cc1)c1ccc(F)cc1)C(F)(F)F)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC1CC(C=CC(=C(c2ccc(F)cc2)c2ccc(F)cc2)C(F)(F)F)OCO1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Butyl lithium(1.2 mL of 2.5M solution, 3.0 mmol) was added to a solution of dimethyl [3,3-bis(4-fluorophenyl)-2-trifluoromethyl-2-propen-1-yl]phosphonate in 20 mL tetrahydrofuran at -70° C. followed by immediate addition of 1,1-dimethylethyl 6-formyl-2,2-dimethyl-1,3-dioxane-4-acetate (0.9 g, 3.6 mmol). The solution was allowed to gradually warm to room temperature and then stirred for 14 hours. The reaction was quenched with saturated ammonium chloride solution and the mixture extracted with diethyl ether. The extracts were dried and concentrated in vacuo. The residue was purified by chromatography on silica eluting with 10% ethyl acetate in hexane to give 0.7 g of the title compound as an oil. MS(CI): m/e =538 for M+ of C29H31F4O4.
Reaction SMILES: Br[C:2]1[S:3][C:4]([S:17]([N:20]2[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]2)(=[O:19])=[O:18])=[CH:5][C:6]=1[C:7]1[S:11][C:10]([NH:12][C:13](=[O:15])[CH3:14])=[N:9][C:8]=1[CH3:16].C([Li])CCC>C1COCC1>[CH3:16][C:8]1[N:9]=[C:10]([NH:12][C:13](=[O:15])[CH3:14])[S:11][C:7]=1[C:6]1[CH:5]=[C:4]([S:17]([N:20]2[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]2)(=[O:19])=[O:18])[S:3][CH:2]=1
Reactant: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)N3CCN(C)CC3)sc2Br)s1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(C)c(-c2csc(S(=O)(=O)N3CCN(C)CC3)c2)s1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
N-{5-[2-Bromo-5-(4-methyl-piperazine-1-sulfonyl)-thiophen-3-yl]-4-methyl-thiazol-2-yl}-acetamide obtained in Step I as described above (400 mg; 0.83 mmol; 1 eq), is dissolved in anhydrous THF (50 ml). The reaction mixture is cooled down to −70° C. and put under nitrogen. n-Butyllithium (4.2 ml; 1.6 M; 6.67 mmol; 8 eq) is added dropwise. After 1 hour the reaction is complete and quenched with water. Solvents are evaporated and the crude product is dissolved in EtOAc. The resulting organic phase is washed with water (2 times), brine and dried over MgSO4. After evaporation of the solvents, the resulting product is precipitated in an ether/DCM mixture, affording Compound (29) as a white-off solid (125 mg; 37%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]#[N:5].Br[CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12].[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>C(OCC)C.CN(C)C=O>[CH2:7]([N:5]([CH2:12][CH2:11][CH2:10][CH2:9][CH:8]=[CH2:7])[CH2:4][CH2:3][C:2]#[N:1])[CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12]
Reactant: N#CCCN
Reactant: C=CCCCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C=CCCCCN(CCC#N)CCCCC=C
Temperature: 25 °C
Yield: 67 %

Procedure:
N,N-Dimethylformamide (28 ml) was added to 3-aminopropionitrile (0.98 g, 14 mmol), and the mixture was stirred at room temperature. 6-Bromo-1-hexene (5.0 g, 31 mmol), sodium iodide (11 g, 73 mmol) and potassium carbonate (5.8 g, 42 mmol) were added to the mixture, and the whole was stirred overnight. The reaction mixture was diluted with diethyl ether (100 ml), and the whole was washed with water (100 ml, twice) and saturated brine (50 ml) successively. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 2.2 g (66%) of 3-(di-5-hexenyl)aminopropionitrile as a colorless oily matter.
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[OH-].[Na+].C([O:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14](Cl)=[O:15])(=O)C.[OH-].[K+].Cl>>[NH2:4][C:3]1[O:11][C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14](=[O:15])[C:2]=1[C:1]#[N:5]
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Reactant: N#CCC#N
Agent: Cl
Agent: [K+]
Agent: [Na+]
Product: N#Cc1c(N)oc2ccccc2c1=O
Temperature: 40 °C
Reaction time: 0.17 h

Procedure:
-- A mixture of 6.6 g (0.1 mole) of malononitrile, 50 g of ice, 5 ml of 20% sodium hydroxide and 9.9 g (0.5 mole) of 2-acetoxy benzoyl chloride is stirred vigorously for 10 minutes. Second portions of malononitrile and 20% sodium hydroxide are added, the mixture is stirred another 10 minutes, then warmed to 40°C. With stirring, there is added 50% potassium hydroxide solution in 5 ml increments until the solution becomes clear. The solution is cooled, acidified with conc. HCl, and the solid filtered and washed with water and air dried, mp 315°-20°C.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][S:8][C:7]2[CH:11]=[CH:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][C:6]1=2)=[O:4].[CH2:18]([N:20](CC)CC)[CH3:19].Cl.C(N)C>O1CCOCC1.O>[CH2:18]([NH:20][CH2:2][C:3]([N:5]1[CH2:10][CH2:9][S:8][C:7]2[CH:11]=[CH:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][C:6]1=2)=[O:4])[CH3:19]
Reactant: O=C(CCl)N1CCSc2ccc([N+](=O)[O-])cc21
Reactant: CCN(CC)CC
Agent: CCN
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: CCNCC(=O)N1CCSc2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Yield: 87.7 %

Procedure:
To a stirred solution of 2-chloro-1-(6-nitro-2H-benzo[b][1,4]thiazin-4(3H)-yl)ethanone (855 mg, 3.14 mmol) in dioxane (15 mL) and triethylamine (0.881 mL, 6.27 mmol) was added ethanamine hydrochloride (1.278 g, 15.68 mmol) as a solution in water (7.50 mL). The resulting mixture was stirred vigorously at room temperature over the weekend. The mixture was then diluted with water and extracted with dichloromethane (2×). The combined organics were dried, filtered, concentrated, and then chromatographed in 1:9 (2M NH3 in methanol):ethyl acetate, giving the desired product (775 mg, 88%). 1H NMR (DMSO-d6) δ 8.37 (d, J=2.4 Hz, 1H), 7.93 (dd, J=8.7, 2.4 Hz, 1H), 7.50 (d, J=8.7 Hz, 1H), 3.97-3.90 (m, 2H), 3.52 (s, 2H), 3.37-3.33 (m, 2H), 2.58-2.50 (m, 2H), 2.07 (brs, 1H), 1.00 (t, J=7.0 Hz, 3H); ESI-MS (m/z, %): 282 (MH+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[N+:20]([O-])([OH:22])=[O:21].O>C(OC(=O)C)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][C:13]=2[N+:20]([O-:22])=[O:21])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(NS(=O)(=O)c2ccc(Cl)cc2)cc1
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: N#Cc1ccc(NS(=O)(=O)c2ccc(Cl)cc2)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 92.3 %

Procedure:
To a suspension of 4-chloro-4′-cyanobenzenesulfonanilide (4.03 g (13.8 mmol)) in 15 ml of acetic anhydride, 97% fuming nitric acid (0.61 ml (14.3 mmol)) was added dropwise with stirring at room temperature. After one hour's stirring at 50° C. the reaction mixture was poured into water to give crystals, which were then collected by filtration and washed with water to give 4.30 g (93%) of 4-chloro-4′-cyano-2′-nitrobenzenesulfonanilide as pale yellow crystals.
Reaction SMILES: C[O:2][C:3](=[O:39])[C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([O:11][CH2:12][CH:13]([C:20]2[N:21]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)[N:22]=[C:23]3[C:28]=2[CH:27]=[C:26]([F:29])[C:25]([F:30])=[CH:24]3)[CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:6]([CH3:38])[CH:5]=1.[OH-].[Li+]>C1COCC1.CO>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([N:21]2[C:20]([CH:13]([CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:12][O:11][C:7]3[C:6]([CH3:38])=[CH:5][C:4]([C:3]([OH:39])=[O:2])=[CH:9][C:8]=3[CH3:10])=[C:28]3[C:23]([CH:24]=[C:25]([F:30])[C:26]([F:29])=[CH:27]3)=[N:22]2)=[CH:32][CH:33]=1
Reactant: COC(=O)c1cc(C)c(OCC(c2c3cc(F)c(F)cc3nn2-c2ccc(Cl)cc2)C2CCCCC2)c(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(C(=O)O)cc(C)c1OCC(c1c2cc(F)c(F)cc2nn1-c1ccc(Cl)cc1)C1CCCCC1

Procedure:
In analogy to the procedure described in example 7.2, [rac]-4-{2-[2-(4-chloro-phenyl)-5,6-difluoro-2H-indazol-3-yl]-2-cyclohexyl-ethoxy}-3,5-dimethyl-benzoic acid methyl ester was treated with 1 N aqueous lithium hydroxide solution in THF and MeOH to give the title compound as off-white solid. MS: m/e=539.3 [M+H+].
Reaction SMILES: [CH3:1][C:2]([O:14][Si](C)(C)C)([CH3:13])[C:3]#[C:4][C:5]([C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:6].CC1C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[OH:14][C:2]([CH3:13])([CH3:1])[C:3]#[C:4][C:5]([C:7]1[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=1)=[O:6]
Reactant: CC(C)(C#CC(=O)c1ccncc1)O[Si](C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CC(C)(O)C#CC(=O)c1ccncc1
Reaction time: 2 h
Yield: 96.6 %

Procedure:
To a stirred solution of 4-methyl-1-(pyridin-4-yl)-4-(trimethylsilyloxy)pent-2-yn-1-one (0.5 g, 1.915 mmol) in DCM (10 mL) was added PTSA (0.47 g, 2.49 mmol) at RT and the reaction mixture was stirred for 2 h. The reaction mixture was diluted with DCM (50 mL). The organic layers were washed with a saturated NaHCO3 solution and water, dried over Na2SO4, filtered and then concentrated in vacuo to afford 4-hydroxy-4-methyl-1-(pyridin-4-yl)pent-2-yn-1-one (0.35 g, 96%) as an oil.