Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:6]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[C:7](=[O:23])[CH2:8][NH:9][CH:10]2[CH:15]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:14]=[CH:13][CH:12]=[CH:11]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:32](Cl)(=[O:37])[CH2:33][C:34](Cl)=[O:35]>C1COCC1>[CH:1]1([N:6]([C:24]2[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=2)[C:7](=[O:23])[CH2:8][N:9]2[C:34](=[O:35])[CH2:33][C:32](=[O:37])[N:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(Cl)CC(=O)Cl
Reactant: COc1ccc(N(C(=O)CNC2C=CC=CC2Nc2ccccc2)C2CCCC2)cc1
Solvent: C1CCOC1
Product: COc1ccc(N(C(=O)CN2C(=O)CC(=O)N(c3ccccc3)c3ccccc32)C2CCCC2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
To a stirred solution of 419 mg (1.01 mmol) N-Cyclopentyl-N-(4-methoxy-phenyl)-2-(6-phenylamino-cyclohexa-2,4-dienylamino)-acetamide, prepared as in Part B, in 5 mL THF is added 170 mg (1.21 mmol, 1.2 equiv) Malonyl dichloride dissolved in 2 mL THF dropwise at 0° C. The reaction is stirred 1 h at 0° C. followed by 18 h at ambient temperature. The solvent is removed in vacuo and the residue purified by flash chromatography on 15 g silica gel eluted with EtOAc/Hexanes (1:1, 300 mL). Appropriate fractions were combined and concentrated in vacuo to give 249 mg (0.515 mmol) of N-Cyclopentyl-2-(2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-(4-methoxy-phenyl)-acetamide as a clear glass: 1H NMR (CDCl3, 300 MHz) δ7.43-7.20 (m, 8H), 7.09 (m, 2H), 6.97 (m, 3H), 4.95 (m, 1H), 4.38 (d, 1H, J=16.4), 4.06 (d, 1H, J=16.3), 3.84 (s, 3H), 3.59 (d, 1H, J=12.0), 3.49 (d, 1H, J=11.9), 1.90 (m, 2H), 1.52 (m, 4H), 1.35 (m, 2H); TLC Rf =0.16 (EtOAc/Hexanes, 1:1).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH2:8][N:9]2[CH:15]3[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]3)[CH2:11][CH2:10]2)[CH:5]=[CH:4][CH:3]=1.C1COCC1.[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>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.O.C(O)C>[C:23]1([C:2]2[N:7]=[C:6]([CH2:8][N:9]3[CH:15]4[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]4)[CH2:11][CH2:10]3)[CH:5]=[CH:4][CH:3]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Brc1cccc(CN2CCN3CCC2CC3)n1
Reactant: OB(O)c1ccccc1
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: C1CCOC1
Solvent: CCO
Solvent: O
Product: c1ccc(-c2cccc(CN3CCN4CCC3CC4)n2)cc1
Yield: 27.3 %

Procedure:
To a stirred solution of 4-(6-bromo-pyridin-2-ylmethyl)-1,4-diaza-bicyclo[3.2.2]nonane (17.0 mg, 0.06 mmol) in a solvent mixture of THF, ethanol, and water (6.0 mL of 1:1:1) was added phenylboronic acid (18 mg, 0.15 mmol), potassium carbonate (70 mg), and a catalytic amount of tetrakis(triphenylphosphine)palladium(0). The mixture was heated at reflux temperature for 3 hours, cooled, and concentrated to near dryness. The residue was triturated with chloroform (3×) and the crude product in chloroform subjected silica gel chromatography eluting with a chloroform (ammoniated) to 5% methanollchloroform gradient to give the title compound as an off-white solid (4.8 mg). MS (ES+) 294 (MH+).
Reaction SMILES: [OH-].[Na+].[Si]([O:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:18]=[CH:19][C:20]([C:38]([F:41])([F:40])[F:39])=[C:21]([CH:37]=2)[C:22]([NH:24][C:25]2[C:34]([CH3:35])=[CH:33][C:28]([C:29]([O:31]C)=[O:30])=[CH:27][C:26]=2[CH3:36])=[O:23])[CH2:13][CH2:12]1)(C(C)(C)C)(C)C.CO>C1COCC1>[OH:10][CH:11]1[CH2:12][CH2:13][N:14]([C:17]2[CH:18]=[CH:19][C:20]([C:38]([F:41])([F:39])[F:40])=[C:21]([CH:37]=2)[C:22]([NH:24][C:25]2[C:26]([CH3:36])=[CH:27][C:28]([C:29]([OH:31])=[O:30])=[CH:33][C:34]=2[CH3:35])=[O:23])[CH2:15][CH2:16]1
Reactant: COC(=O)c1cc(C)c(NC(=O)c2cc(N3CCC(O[Si](C)(C)C(C)(C)C)CC3)ccc2C(F)(F)F)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(C(=O)O)cc(C)c1NC(=O)c1cc(N2CCC(O)CC2)ccc1C(F)(F)F
Reaction time: 12 h
Yield: 0.1 %

Procedure:
A solution of aqueous 2N NaOH (1.5.00 ml) is added to a stirred solution of methyl 4-[[5-[4-[tert-butyl(dimethyl)silyl]oxy-1-piperidyl]-2-(trifluoromethyl)benzoyl]amino]-3,5-dimethyl-benzoate (60.0 mg, 133.20 mmoles) in THF:MeOH (5 ml:0.5 ml). After 12 h at ambient temperature, the organic solvent is removed under reduced pressure and the residue is diluted with water, acidified to pH4 with aqueous citric acid, and extracted with ethyl acetate (2×20 ml). The organic layers are combined and dried over anhydrous sodium sulfate. The solvent is removed under reduced pressure and the resulting precipitate is triturated with pentane and diethyl ether and filtered to afford the title compound as an off-white solid (0.04 g, 60%). Mass spectrum (m/z): 437.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:23])=[C:5]([C:19]([O:21][CH3:22])=[O:20])[CH:6]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=O)[C:7]=1[C:8]([O:10][CH3:11])=[O:9].[CH:24]1([N:30]2[CH2:35][CH2:34][N:33]([CH2:36][CH2:37][CH2:38][NH2:39])[CH2:32][CH2:31]2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH3:23][C:4]1[NH:3][C:2]([CH3:1])=[C:7]([C:8]([O:10][CH3:11])=[O:9])[CH:6]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]([NH:39][CH2:38][CH2:37][CH2:36][N:33]2[CH2:32][CH2:31][N:30]([CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[CH2:35][CH2:34]2)=[O:18])[C:5]=1[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1CCCCC(=O)O
Reactant: NCCCN1CCN(C2CCCCC2)CC1
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1CCCCC(=O)NCCCN1CCN(C2CCCCC2)CC1

Procedure:
The compound of Example 4 and 4-(cyclohexyl)-1-piperazinepropanamine were reacted according to the General Procedure of Example 13 to yield 1,4-dihydro-2,6-dimethyl-4-[5-[[3-(4-cyclohexyl-1-piperazinyl) propyl]amino]-5-oxopentyl]-3,5-pyridine dicarboxylic acid, dimethyl ester. 1H NMR (DMSO-d6) δ 8.71 (s, 1 H), 8 7.70 (br. t, 1 H), 3.75 (t, 1 H, J=5.4 Hz), 3.59 (s, 6 H), 3.15 (m, 1 H), 2.99 (m, 2 H), 2.45 (m,4 H),2.15 (s,6 H), 1.94 (t, 2 H, J=7.3 Hz), 1.7 (m, 4 H), 1.4-1.2 (m, 9 H), 1.2-1.0 (m, 11 H); 13C NMR (DMSO-d6) δ 171.8, 167.6, 146.3, 100.5, 62.5, 55.6, 53.4, 50.5, 48.4, 44.8, 36.9, 36.5, 35.6, 34.0, 32.0, 28.4, 26.4, 25.9, 25.6, 18.1. Analysis calculated for C29H48N4O5. 2.0 H2O: C, 61.24; H, 9.22; N, 9.85. Found: C, 61.44; H, 9.30; N, 10.53.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH:16]([CH3:18])[OH:17])=[N:2]1.C(OCC)C>N1C=CC=CC=1.[O-2].[O-2].[O-2].[Cr+6]>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16](=[O:17])[CH3:18])=[N:2]1
Reactant: CC(O)c1ccccc1-c1noc2ccccc12
Agent: [Cr+6]
Agent: [O-2]
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(=O)c1ccccc1-c1noc2ccccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.7 %

Procedure:
In 46 ml of dry pyridine was dissolved 4.6 g of 2-(1,2-benzisoxazol-3-yl)-α-methyl-benzenemethanol. Under an atmosphere of nitrogen, 4.6 g of chromium trioxide was slowly added at room temperature. After stirring at room temperature for 4 h, 200 ml of diethyl ether were added to the reaction mixture. The precipitates were filtered off and washed with diethyl ether. The filtrate was washed with 5 portions of 100 ml of 2N aqueous hydrochloric acid and 2 portions of 200 ml of water, dried over magnesium sulphate and evaporated to dryness to afford 4.5 g of 1-[2-(1,2-benzisoxazol-3-yl)phenyl)-ethanone, melting at 108° C.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([CH2:14]O)[S:12][CH:13]=2)=[CH:5][CH:4]=1.P(Br)(Br)[Br:19].O>C1(C)C=CC=CC=1>[Br:19][CH2:14][C:11]1[S:12][CH:13]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:17])([F:16])[F:1])=[CH:4][CH:5]=2)[N:10]=1
Reactant: OCc1nc(-c2ccc(C(F)(F)F)cc2)cs1
Reactant: BrP(Br)Br
Solvent: O
Solvent: Cc1ccccc1
Product: FC(F)(F)c1ccc(-c2csc(CBr)n2)cc1
Temperature: 120 °C
Yield: 24.8 %

Procedure:
To the solution of [4-(4-Trifluoromethyl-phenyl)-thiazol-2-yl]-methanol (0.13 g, 0.50 mmol) in 2 ml of toluene was added PBr3 (0.072 ml, 0.752 mmol) and the reaction mixture was heated at 120° C. for 20 min under nitrogen atmosphere. After the completion of the reaction mixture (TLC monitoring), water (25 mL) was added and extracted with ethyl acetate (3×50 mL). The combined organics was washed with water, brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified over silica gel (230-400 M, 1% EtOAc-Hexane) to get the desired product (0.04 g, 25%). The other derivatives were also prepared by the same general method.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12]O[C:10]=1[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1C(=O)C=COC=1C)C1C=CC=CC=1.C([N:36]1[CH:41]=[CH:40][C:39](=O)[C:38]([OH:43])=C1C)(=O)C.NCCCCO.OCCN>>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:36]([CH2:41][CH2:40][CH2:39][CH2:38][OH:43])[C:10]=1[CH3:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)n1ccc(=O)c(O)c1C
Reactant: Cc1occc(=O)c1OCc1ccccc1
Agent: NCCCCO
Solvent: NCCO
Product: Cc1c(OCc2ccccc2)c(=O)ccn1CCCCO

Procedure:
3-Benzyloxy-2-methyl-4-pyrone, prepared as described under (J), is reacted with 1-amino-4-hydroxybutane under substantially similar conditions to those described under (K) for reaction with 2-hydroxyethylamine to give 3-benzyloxy-1-(4'-hydroxybutyl)-2-methylpyrid-4-one. This is deprotected using the procedure described under (I) to give 3-hydroxy-1-(4'-hydroxybutyl)-2-methylpyrid-4-one as white crystals, m.p. 126°-128° C.; δmax (nujol) 1630, 3350 cm-1 ; δ(d6DMSO) 1.5 (m, 4H), 2.45 (s, 3H), 3.35 (t, 2H), 4.30 (t, 2H), 7.25 (d 1H), 8.2 (d, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:18]([S:21]([CH3:24])(=[O:23])=[O:22])([CH3:20])[CH3:19])[CH:11]=[C:12]3[C:17]=2[N:16]=[CH:15][CH:14]=[CH:13]3)=[CH:4][C:3]=1[CH2:25][OH:26]>FC1C=CC(B(O)O)=CC=1CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:18]([S:21]([CH3:24])(=[O:23])=[O:22])([CH3:19])[CH3:20])[CH:11]=[C:12]3[C:17]=2[N:16]=[CH:15][CH:14]=[CH:13]3)=[CH:4][C:3]=1[CH:25]=[O:26]
Reactant: CC(C)(c1cc(-c2ccc(F)c(CO)c2)c2ncccc2c1)S(C)(=O)=O
Agent: OCc1cc(B(O)O)ccc1F
Product: CC(C)(c1cc(-c2ccc(F)c(C=O)c2)c2ncccc2c1)S(C)(=O)=O

Procedure:
Prepared according to the oxidation procedure described in Quinoline 14 (Step 1) but using the {2-fluoro-5-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl)}-methanol from Step 2 as the starting material.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:8]2[C:9]([C:13]([O:15]CC)=O)=[CH:10][CH:11]=[CH:12][C:7]2=[N:6][CH:5]=1>CN(C=O)C>[N:6]1[CH:5]=[C:4]2[NH:3][C:13](=[O:15])[C:9]3=[CH:10][CH:11]=[CH:12][C:7]=1[N:8]23
Reactant: CCOC(=O)c1cccc2ncc(N)n12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1[nH]c2cnc3cccc1n32
Temperature: 25 °C
Yield: 14.6 %

Procedure:
To a suspension of 343 mg (8.58 mmol) of 60% sodium hydride (dispersion in oil) in 3 ml of DMF was added, while stirring at room temperature, a solution of 880 mg (4.29 mmol) of 3-amino-5-ethoxycarbonylimidazo[1,2-a]pyridine in 5 ml of DMF. The mixture was stirred for 30 minutes at 100° C. After cooling, the reaction mixture was poured into ice-water, washed with ethyl acetate. The aqueous layer was neutralized by the addition of 6N-HCl. The resulting precipitates were collected by filtration, washed with water, and dried to afford 100 mg of the desired compound (14.7%, a brown solid). The filtrate was extracted with chloroform, dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography (eluent:ethyl acetate/ethanol=10:1) to afford 27 mg of the desired compound (4.0%, a yellow solid)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:12]C(=O)[NH:10][CH:9]2[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]([F:25])([F:24])[F:23])[CH:16]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C.O>[NH2:10][CH:9]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]([F:25])([F:23])[F:24])[CH:16]=1)[CH:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[OH:12]
Reactant: O=C1NC(Cc2cccc(OC(F)(F)F)c2)C(c2ccc(F)cc2)O1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: NC(Cc1cccc(OC(F)(F)F)c1)C(O)c1ccc(F)cc1

Procedure:
(4RS,5SR)-5-(4-Fluorophenyl)-4-[3-(trifluoromethoxy)benzyl]-1,3-oxazolidin-2-one (4.071 g, 11.46 mmol) and sodium hydroxide (1.83 g, 45.8 mmol) were heated under reflux in ethanol (30 ml)—water (2 ml) for 6 hrs. The reaction solution was diluted with water and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel (APS type) column chromatography (hexane/ethyl acetate=3/1-ethyl acetate) to give the objective substance.
Reaction SMILES: [C:1]([CH:3]1[CH2:6][C:5]2([CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7]2)[CH2:4]1)#[N:2]>[Ni]>[NH2:2][CH2:1][CH:3]1[CH2:4][C:5]2([CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7]2)[CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC(C#N)C2)C1
Agent: [Ni]
Product: CC(C)(C)OC(=O)N1CCC2(CC(CN)C2)C1
Yield: 107.7 %

Procedure:
The process is performed according to the procedure described in Example 8 (step 8.2.). Starting with 0.20 g (0.85 mmol) of ter-butyl 2-cyano-6-azaspiro[3.4]octane-6-carboxylate, (isomer 1b), described in Example 8 (step 8.1.) and a catalytic amount of Raney nickel, 0.22 g of product is obtained in the form of a yellow oil, which is used without further purification in the following step.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:28])[C:12]2[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[C:15]([NH:21][CH2:22][C:23]([OH:26])([CH3:25])[CH3:24])=[CH:14][C:13]=2Cl)=[CH:6][CH:5]=1.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.CCN(C(C)C)C(C)C>CC#N>[F:1][C:2]([F:30])([F:29])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:28])[C:12]2[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[C:15]([NH:21][CH2:22][C:23]([OH:26])([CH3:25])[CH3:24])=[CH:14][C:13]=2[N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)=[CH:6][CH:5]=1
Reactant: CC(C)(O)CNc1cc(Cl)c(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1[N+](=O)[O-]
Reactant: C1COCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(O)CNc1cc(N2CCOCC2)c(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1[N+](=O)[O-]

Procedure:
The sub-title compound is prepared in analogy to 103a from N-(4-trifluoromethoxy-phenyl)-2-chloro-4-(2-hydroxy-2-methyl-propylamino)-5-nitro-benzoic acid amide (300 mg, 0.67 mmol), morpholine (233 μL, 2.7 mmol), DIPEA (1.1 mL, 6.7 mmol) and MeCN (3 mL) in a microwave oven at 150° C. (45 min). Yield: 324 mg. HPLC Rt=1.58 min (method H). MS m/z: 499 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[C:16]([Si:20]([CH3:50])([CH3:49])[O:21][CH:22]([C:45]([CH3:48])([CH3:47])[CH3:46])[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([C:36]2[CH:41]=[CH:40][C:39](O)=[C:38]([CH3:43])[CH:37]=2)([CH2:34][CH3:35])[CH2:32][CH3:33])=[CH:27][C:26]=1[CH3:44])([CH3:19])([CH3:18])[CH3:17].N1C=CC=CC=1.[Cl-].[NH4+]>ClCCl.CCCCCC.C(OCC)(=O)C>[C:16]([Si:20]([CH3:50])([CH3:49])[O:21][CH:22]([C:45]([CH3:48])([CH3:47])[CH3:46])[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([C:36]2[CH:41]=[CH:40][C:39]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])=[C:38]([CH3:43])[CH:37]=2)([CH2:32][CH3:33])[CH2:34][CH3:35])=[CH:27][C:26]=1[CH3:44])([CH3:17])([CH3:19])[CH3:18]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CCC(CC)(c1ccc(O)c(C)c1)c1ccc(CCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCC(CC)(c1ccc(CCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1ccc(OS(=O)(=O)C(F)(F)F)c(C)c1
Reaction time: 0.33 h
Yield: 755.6 %

Procedure:
Trifluoromethanesulfonic anhydride (0.51 mL, 3.09 mmol) was added to a solution of 4-(1-{4-[3-(t-Butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methyl-phenyl}-1-ethyl-propyl)-2-methyl-phenol (Example 3-(4); 1.18 g, 2.38 mmol) in dichloromethane (40 mL) and pyridine (0.35 mL, 4.28 mmol) at room temperature, and the mixture was stirred at the same temperature for 20 minutes. A saturated aqueous ammonium chloride solution, ethyl acetate and hexane were added to the mixture. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane only to hexane/ethyl acetate=97/3) to give the title compound (11.31 g, 88%).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[O:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[C:9](=O)[CH2:10][C:4]=2[CH:3]=1.[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[O:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[C:9]([N:22]3[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]3)=[CH:10][C:4]=2[CH:3]=1
Reactant: CN1CCNCC1
Reactant: O=C1Cc2cc(Cl)ccc2Oc2ccccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1C
Product: CN1CCN(C2=Cc3cc(Cl)ccc3Oc3ccccc32)CC1
Yield: 79.9 %

Procedure:
Thirty grams of 2-chlorodibenzo[b,f]oxepin-10(11H)-one, prepared in accordance with the procedure of Example 3, 45 grams of N-methylpiperazine and a solution of 8 grams of p-toluenesulfonic acid monohydrate in 150 ml of xylene are refluxed for a period of 22 hours in a reflux apparatus equipped with a Dean-Stark trap in order to remove the water that forms. The reaction mixture is cooled, treated with a solution of sodium bicarbonate, washed with water until the water washings are neutral, dried over anhydrous sodium sulfate and filtered through a column of neutral aluminum oxide. The filtrate is concentrated to dryness in vacuo and the residue, 46 grams, crystallized from ethanol to yield 32 grams of 1-(2-chlorodibenzo[b,f]oxepin-10-yl)-4-methylpiperazine having an m.p. of 119°-121° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([O:19]C)=O)[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH3:21][NH2:22]>C(O)C.CO>[CH3:21][NH:22][C:17]([C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]2[C:5]1[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH:6]=1)=[O:19]
Reactant: CN
Reactant: COC(=O)c1ccc2[nH]cc(C3=CCN(C)CC3)c2c1
Solvent: CO
Solvent: CCO
Product: CNC(=O)c1ccc2[nH]cc(C3=CCN(C)CC3)c2c1

Procedure:
A solution of the product of stage (i) (0.5 g) in a mixture of methylamine in ethanol (40%, 20 ml) and methanol (10 ml) was heated at reflux for 10 h. The mixture was cooled, and partitioned between water (100 ml) and ethyl acetate (100 ml). The aqueous phase was separated, and extracted with ethyl acetate (50 ml). The organic layers were combined, dried and evaporated in vacuo to give a solid, (0.25 g) which was crystallized twice from ethyl acetate to give the title compound as microcrystals (0.1 g), m.p. 125°-135°.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][CH:20](SCC)[NH:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[CH3:32][O:33][CH2:34][CH2:35][NH:36][CH2:37][CH2:38][O:39][CH3:40]>>[CH3:32][O:33][CH2:34][CH2:35][N:36]([CH2:37][CH2:38][O:39][CH3:40])[C:20]1[S:21][C:17](=[CH:16][C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[N:7]([CH2:6][C:5]2[CH:26]=[CH:27][C:2]([Cl:1])=[CH:3][C:4]=2[C:28]([F:30])([F:31])[F:29])[N:8]=[CH:9]3)[C:18](=[O:25])[N:19]=1
Reactant: CCSC1NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: COCCNCCOC
Product: COCCN(CCOC)C1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1

Procedure:
2-[Bis-(2-methoxy-ethyl)-amino]-5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazolidin-4-one and Bis-(2-methoxy-ethyl)-amine following General Procedure C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([O:10][CH3:11])[CH:3]=1.[C:12]1([S:18]([NH2:21])(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[N:21][S:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:20])=[O:19])=[C:4]([O:10][CH3:11])[CH:3]=1
Reactant: NS(=O)(=O)c1ccccc1
Reactant: COc1cc(O)ccc1C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc(O)ccc1C=NS(=O)(=O)c1ccccc1
Temperature: 25 °C

Procedure:
An equimolar mixture of 27.4 g (0.18 mol) 4-hydroxy-2-methoxybenzaldehyde and 28.3 g (0.18 mol) benzenesulfonamide was placed into toluene. 100 mg p-toluenesulfonic acid was added as a catalyst. The mixture was then heated under reflux on a water separator until the theoretically calculated quantity of water had separated. After cooling to room temperature, the precipitated solid was filtered off and dried under vacuum. Yield: 43.0 g (78.9%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:9](=[O:10])[O:8][CH2:7]2.[C:12]1([CH:19]=[CH:18][CH:17]=[C:15]([OH:16])[CH:14]=1)[OH:13].CC(C)([O-])C.[K+].Cl>CN1CCCC1=O.O>[OH:13][C:12]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[O:16][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH3:7])[C:11]=1[C:9]([OH:10])=[O:8]
Reactant: Oc1cccc(O)c1
Reactant: Cc1cccc2c1C(=O)OC2
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1cccc(COc2cccc(O)c2)c1C(=O)O
Temperature: 140 °C
Reaction time: 21 h
Yield: 77.7 %

Procedure:
7-Methylphthalide (30.1 g, 203 mmol), resorcinol (45.3 g, 407 mmol) and potassium tert-butoxide (47.6 g, 424 mmol) are suspended in 300 ml of N-methylpyrrolidone (NMP) and stirred at 140° C. for 21 h. After this time, a second amount of potassium tert-butoxide (2.4 g, 21.4 mmol) is added and stirring is continued at 140° C. for 2.5 h. The reaction mixture is cooled, 800 ml of water are added, and the mixture is acidified to pH=2 at 20° C. with concentrated hydrochloric acid. After stirring at 3 to 5° C. for 2 hours, the pale beige solid is filtered off with suction, washed with water and then dried. The isolated product contains 2-(3-hydroxyphenoxymethyl)-6-methylbenzoic acid and N-methylpyrrolidone as solvate molecule in a ratio of 1:1. Yield 77.7%, melting point 98 to 99° C.
Reaction SMILES: C[O:2][CH:3]=[C:4]1[CH2:9][CH2:8][CH:7]([C:10]([O:12][CH3:13])=[O:11])[CH2:6][CH2:5]1.CCCCCC>C1COCC1.Cl>[CH:3]([CH:4]1[CH2:5][CH2:6][CH:7]([C:10]([O:12][CH3:13])=[O:11])[CH2:8][CH2:9]1)=[O:2]
Reactant: COC=C1CCC(C(=O)OC)CC1
Agent: Cl
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(=O)C1CCC(C=O)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.1 %

Procedure:
103 g of methyl 4-methoxymethylidene-cyclohexane-carboxylate was dissolved in 350 mL of THF, to which 100 mL of 10% hydrochloric acid was added dropwise at 11 to 13° C. for 10 minutes. The solution was further stirred at room temperature for 3 hours, and then 80 mL of hexane was added. The water phase was extracted with ethyl acetate, and then the organic phases were combined and washed with water and saturated saline in this order. The resultant product was dried over anhydrous magnesium sulfate, and then concentrated, to obtain 92.4 g of methyl 4-formylcyclohexane-carboxylate in the form of an oil-like product. The obtained product was analyzed by gas chromatography, and was found to be a mixture of cis-form: trans-form at a ratio of 64:36.