Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].[C:12](Cl)(=[O:14])[CH3:13]>ClCCl.N1C=CC=CC=1>[C:12]([O:11][C:10]1[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=1[Br:1])(=[O:14])[CH3:13]
Reactant: CC(=O)Cl
Reactant: O=C(O)c1ccc(O)c(Br)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Oc1ccc(C(=O)O)cc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.5 %

Procedure:
To a solution of 3-bromo-4-hydroxy-benzoic acid (3.0 g, 13.83 mmol) in dichloromethane (100 mL) and pyridine (20 mL) was added acetyl chloride (1.1 mL, 15.20 mmol) and the resulting mixture was stirred at rt for 1 h. The reaction was quenched with water (50 mL) and acidified with HCl (1 N) to adjust pH=1˜2. The mixture was extracted with dichloromethane (3×100 mL) and concentrated to afford 4-acetoxy-3-bromo-benzoic acid (3.6 g, 100%). To a solution of 4-acetoxy-3-bromo-benzoic acid (3.60 g, 13.83 mmol) in dichloromethane (100 mL) at rt was added oxalyl chloride (1.8 mL, 20.75 mmol) and DMF (0.5 mL), sequentially. The resulting mixture was stirred at rt for 1 h. The mixture was concentrated to afford the acid chloride. To a solution of the freshly prepared acid chloride in dichloromethane (100 mL) were added 2′-hydroxyacetophenone (2.5 mL, 20.75 mmol) and triethylamine (3.9 mL, 27.66 mmol). This mixture was stirred at rt for 2 h. The reaction was quenched with water (100 mL) and extract with dichloromethane (3×150 mL). The combined organic layers were concentration to afford an oily residue, which was purified by column chromatography using 30% EtOAc in hexane to give the phenol ester (4.5 g, 86%). A solution of the phenol ester (4.0 g, 10.61 mmol) in THF (100 mL) was mixed with potassium t-butoxide (1.6 g, 14.32 mmol) and stirred at 60° C. for 1.5 h. This mixture was cooled to rt, diluted with water (100 mL) and acidified with HCl (1 N) to adjust pH=5-6. The mixture was extract with dichloromethane (3×100 mL) and the combined organic layers were concentration to give a yellow solid residue. The residue was purified by column chromatography using 30% EtOAc in hexane to give the diketone (2.3 g, 58%). A solution of the diketone (1.50 g, 3.98 mmol) in AcOH (100 mL) and HCl (conc., 2 mL) was stirred at reflux for 16 h. This mixture was cooled to rt, diluted with water (100 mL), extracted with dichloromethane (3×100 mL) and concentrated. The residue was purified by column chromatography using 50% EtOAc in hexane to give the flavone acetate (0.4 g, 28%). A solution of the flavone acetate (0.53 g, 1.48 mmol) in MeOH (80 mL) and water (20 mL) was mixed with potassium carbonate (1.10 g, 8.00 mmol) and was stirred at rt for 1 h. The solid was filtered off, washed with water, hexanes, and dichloromethane sequentially to give 390 mg of product (83%) as a light yellow solid. MS (ES) m/z: 318.84+316.84 (two isotopes of M); Mp. 273.5-274.9° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[O:11])[C:7]([O:9][CH3:10])=[O:8].C1OCCOCCOCCOCCOCCOC1.CC([O-])(C)C.[K+].[CH2:36](Br)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>CCOCC>[CH2:36]([N:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[O:11])[C:7]([O:9][CH3:10])=[O:8])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: COC(=O)C(=O)c1ccc[nH]1
Reactant: BrCc1ccccc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Product: COC(=O)C(=O)c1cccn1Cc1ccccc1
Reaction time: 0.5 h
Yield: 42.4 %

Procedure:
A suspension of 10 g (65 mmol) of methyl pyrrol-2-ylglyoxylate in 100 ml of ether is added to a solution of 1.7 g (6.5 mmol) of 18-crown-6 with 7.3 g (65 mmol) of potassium tert-butylate in 100 ml of ether, stirring is carried out for 30 minutes and 11.1 g (65 mmol) of benzylbromide in 50 ml of ether are then added dropwise. Stirring is carried out overnight at room temperature, the mixture is poured onto water and extracted with ether and the organic phase is dried and evaporated down. Chromatography over silica gel with hexane/ethyl acetate gives 6.7 g (42%) of the title compound as a reddish brown oi.
Reaction SMILES: C(O)(=O)C[CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7].C[O:12][C:13]([O:16][CH3:17])([CH3:15])C.[CH3:18]O>>[CH3:17][O:16][C:13](=[O:12])[CH2:15][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH3:18])=[O:7]
Reactant: CO
Reactant: O=C(O)CCCCC(=O)O
Reactant: COC(C)(C)OC
Product: COC(=O)CCCCC(=O)OC
Yield: 94 %

Procedure:
According to a process described in J. Org. Chem. 24, 261 (1959), methyl esters of carboxylic acid are obtained by the reaction of carboxylic acids with methanol in the presence of acetone dimethyl acetal, the dimethyl acetal acting as a hydrophilic agent and supplier of methanol. If adipic acid, methanol and acetone dimethyl acetal are reacted in a molar ratio of 4:5:8, a 94% yield of dimethyladipate is obtained. The economy of this procedure is impaired by the fact that the use of acetone dimethyl acetal increases the raw material costs, and the formation of acetone during the course of the reaction increases the amount of distillation required.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][S:10][C:9]=2[CH2:13][OH:14])=[CH:4][CH:3]=1.CN(C)C=O.C1C(=O)N([Br:27])C(=O)C1>CC(=O)OCC>[Br:27][C:11]1[S:10][C:9]([CH2:13][OH:14])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:12]=1
Reactant: OCc1sccc1-c1ccc(Cl)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: OCc1sc(Br)cc1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 100-mL round-bottom flask, was placed [3-(4-chlorophenyl)thiophen-2-yl]methanol (3.6 g, 16.02 mmol, 1.00 equiv), N,N-dimethylformamide (20 mL). This was followed by the addition of NBS (2.85 g, 16.01 mmol, 1.00 equiv) portions at −5° C. The resulting solution was stirred for 2 h at room temperature (20 degree C.). The resulting solution was diluted with 100 mL of EA. The resulting mixture was washed with 3×30 mL of brine. The mixture was dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5). This resulted in 4.8 g (99%) of [5-bromo-3-(4-chlorophenyl)thiophen-2-yl]methanol as a yellow solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]([N+:12]([O-:14])=[O:13])=[N:4][CH:3]=1.[NH2:15][CH2:16][CH:17]([OH:20])[CH2:18][OH:19].C(N(CC)CC)C>C(O)(C)C>[OH:20][CH:17]([CH2:18][OH:19])[CH2:16][NH:15][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]([N+:12]([O-:14])=[O:13])=[N:4][CH:3]=1
Reactant: NCC(O)CO
Reactant: COC(=O)c1nc(Cl)cnc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: COC(=O)c1nc(NCC(O)CO)cnc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 1.0 g (0.004 mol) 9 in 15 ml isopropanol is added 0.36 g (0.004 mol) 10 and 0.4 g (0.004 mol) triethylamine at room temperature. The reaction mixture becomes reddish in color and is stirred at room temperature for 16 hours. The solvent is removed on the rotary evaporator and the residue is purified by flash chromatography on silica gel followed by elution with 10% methanol/chloroform. Pure 15 has Rf 0.4 and is obtained as a yellow solid, m.p 107°-9°.
Reaction SMILES: C(O[CH:4]=[C:5]([C:11]#[N:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[Cl:13][C:14]1[C:15]([NH:21][NH2:22])=[N:16][CH:17]=[C:18]([Cl:20])[CH:19]=1>C(OC(O)C)C>[NH2:12][C:11]1[N:21]([C:15]2[C:14]([Cl:13])=[CH:19][C:18]([Cl:20])=[CH:17][N:16]=2)[N:22]=[CH:4][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC=C(C#N)C(=O)OCC
Reactant: NNc1ncc(Cl)cc1Cl
Agent: CCOC(C)O
Product: CCOC(=O)c1cnn(-c2ncc(Cl)cc2Cl)c1N
Reaction time: 2 h
Yield: 98.3 %

Procedure:
16.9 g (0.1 mole) of ethyl ethoxymethylenecyanoacetate and 17.8 g (0.1 mole) of 3,5-dichloro-pyrid-2-ylhydrazine in 150 ml of ethoxyethanol are stirred at 80° C. for 5 hours and then at 120° C. for a further 2 hours. For working up, the solvent is removed in vacuo. 29.6 g (98% of theory) of 5-amino-1-(3,5-dichloro-pyrid-2-yl)-4-ethoxycarbonyl-pyrazole of melting point 98°-101° C. are obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]=1Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:26]/[C:27](/B(O)O)=[CH:28]/[CH3:29].O>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]=1/[C:27](/[CH3:26])=[CH:28]\[CH3:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C/C=C(/C)B(O)O
Reactant: COC(=O)c1ccc(OCc2ccccc2)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: O
Product: C/C=C(/C)c1cc(C(=O)OC)ccc1OCc1ccccc1
Yield: 40.5 %

Procedure:
Methyl 4-benzyloxy-3-bromobenzoate (1.61 g, 5.0 mmol), caesium carbonate (4.89 g, 15.0 mmol), (E)-2-buten-2-yl boronic acid (600 mg, 6.0 mmol) and [1,1′-bis(diphenylphosphino)ferrocenyl]palladium (II) chloride (204 mg, 0.25 mmol) were dissolved in anhydrous tetrahydrofuran (100 ml), water (10 ml) was added and the mixture was stirred and held at reflux under an atmosphere of nitrogen for 16 hours. Upon cooling the solvent was removed in vacuo and the mixture partitioned between dichloromethane and water. The organic layer was separated, the solvent removed in vacuo and the residue subjected to column chromatography on silica. Elution with 5% ethyl acetate in petroleum ether afforded methyl(Z)-4-benzyloxy-3-(1-methyl-propenyl)-benzoate (600 mg, 41%) as a colourless solid. 1H NMR (DMSO-d6) 7.88 (1H, dd), 7.59 (1H, d), 7.40 (4H, m), 7.34 (1H, m), 7.23 (1H, d), 5.57 (1H, q), 5.21 (2H, s), 3.82 (3H, s), 1.94 (3H, s), 1.38 (3H, d).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[CH:9]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[C:12](=[O:26])[CH:11]([CH3:27])[CH2:10]1.[F:28][CH2:29][CH2:30]I.C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:30][CH2:29][F:28])[C:3]=1[CH:9]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:23])([F:24])[F:25])=[CH:17][CH:16]=2)[C:12](=[O:26])[CH:11]([CH3:27])[CH2:10]1
Reactant: CC1CC(c2c(O)cccc2F)N(Cc2ccc(OC(F)(F)F)cc2)C1=O
Reactant: FCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1CC(c2c(F)cccc2OCCF)N(Cc2ccc(OC(F)(F)F)cc2)C1=O
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of 5-(2-fluoro-6-hydroxyphenyl)-3-methyl-1-(4-(trifluoromethoxy)benzyl)pyrrolidin-2-one (preparation described in example 413; 50 mg; 0.13 mmol), 1-fluoro-2-iodoethane (23 mg; 0.13 mmol), potassium carbonate (36 mg; 0.26 mmol), and cesium carbonate (8.5 mg; 0.026 mmol) in anh. DMF (0.7 ml) was stirred at rt, under nitrogen, for 17 h. Subsequent filtration and purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.92 min.; [M+H]+: 429.96 g/mol.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]([O:14][C:15]([NH:17][C@@H:18]([CH2:22][CH:23]=[CH2:24])[C:19]([OH:21])=O)=[O:16])([CH3:13])([CH3:12])[CH3:11].Cl.[CH:26]([C@H:28]1[CH2:33][CH2:32][CH2:31][CH2:30][NH:29]1)=[CH2:27].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[O:21]=[C:19]([N:29]1[CH2:30][CH2:31][CH2:32][CH2:33][C@@H:28]1[CH:26]=[CH2:27])[C@@H:18]([NH:17][C:15](=[O:16])[O:14][C:10]([CH3:11])([CH3:12])[CH3:13])[CH2:22][CH:23]=[CH2:24]
Reactant: C=C[C@H]1CCCCN1
Reactant: C=CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCCC[C@@H]1C=C
Temperature: 25 °C
Reaction time: 72 h
Yield: 69.7 %

Procedure:
DIPEA (1.801 gm, 13.94 mmol) was slowly added to a 0° C. mixture of (S)-2-(tert-butoxycarbonylamino)pent-4-enoic acid (1.00 gm, 4.65 mmol), (R)-2-vinylpiperidine hydrochloride (0.720 gm, 4.88 mol), EDC (1.02 gm, 5.34 mmol) and HOBt (0.818 gm, 5.34 mmol) in DCM (19 mL). The yellow reaction mixture was then stirred at rt for 3 days. The reaction mixture was concentrated to remove the DCM and the residue was partitioned between EtOAc and 0.5 N aqueous HCl. The organic phase was isolated, washed with saturated aqueous NaHCO3 and saturated aqueous NaCl, dried over MgSO4, filtered and concentrated. The crude product was purified using silica gel chromatography (ISCO system) eluting with a gradient of 0-100% EtOAc/Hex to give tert-butyl (S)-1-oxo-1-((R)-2-vinylpiperidin-1-yl)pent-4-en-2-ylcarbamate (1.00 gm, 3.24 mmol, 69.8% yield) as a colorless oil. Anal. Calcd. for C17H28N2O3 m/z 308.3. found: 309.0 (M+H)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:7](=[O:32])[CH2:8][CH:9]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[CH:19]=1)[C:10]#[C:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[H-].[Na+].[CH3:35]I>C1COCC1.C(OCC)(=O)C>[CH3:35][N:6]([C:2]1[S:1][CH:5]=[CH:4][N:3]=1)[C:7](=[O:32])[CH2:8][CH:9]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[CH:19]=1)[C:10]#[C:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CI
Reactant: COc1ccc(C(C#Cc2ccccc2)CC(=O)Nc2nccs2)cc1OC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(C(C#Cc2ccccc2)CC(=O)N(C)c2nccs2)cc1OC1CCCC1
Temperature: 80 °C

Procedure:
To a solution of the compound from Example 22 (0.07 g, 0.16 mmol) in THF (2 mL) under an argon atmosphere was added 60% NaH/mineral oil suspension (0.008 g, 0.19 mmol), followed by methyl iodide (0.012 mL, 0.19 mmol). After heating at 80° C. for 0.25 h, the mixture was cooled to room temperature, was diluted with ethyl acetate, was washed with brine, was dried (MgSO4) and was evaporated. Purification by flash chromatography, eluting with 1:1 hexanes/ethyl acetate provided the title compound as a yellow resin (0.025 g, 34%). Anal. (C27H28N2SO3 ·0.375 H2O) calcd: C, 69.39; H, 6.20; N, 5.99. found: C, 69.52; H, 6.22; N, 5.78.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1.Cl.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH:19]N.[CH3:21][N:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1>C(N(CC)CC)C>[Cl:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][N:19]2[C:14]3[C:13]([Cl:12])=[CH:18][CH:17]=[CH:16][C:15]=3[C:24]3[CH2:23][N:22]([CH3:21])[CH2:27][CH2:26][C:25]2=3)=[CH:5][CH:6]=1
Reactant: CN1CCC(=O)CC1
Reactant: Clc1ccc(CCBr)cc1
Reactant: NNc1ccccc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Product: CN1CCc2c(c3cccc(Cl)c3n2CCc2ccc(Cl)cc2)C1

Procedure:
The title compound is prepared by following Method 8 by using 1-(2-bromoethyl)-4-chlorobenzene, 2-chlorophenylhydrazine hydrochloride, triethylamine and N-methyl-4-piperidone
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[C:3]=1[C:4](Cl)=[O:5].[F:13][C:14]1[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=1[C:21]1[CH:22]=[C:23]2[C:29]([NH2:30])=[N:28][NH:27][C:24]2=[N:25][N:26]=1>N1C=CC=CC=1>[F:13][C:14]1[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=1[C:21]1[CH:22]=[C:23]2[C:29]([NH:30][C:4](=[O:5])[C:3]3[C:2]([CH3:1])=[CH:10][C:9]([CH3:11])=[CH:8][C:7]=3[CH3:12])=[N:28][NH:27][C:24]2=[N:25][N:26]=1
Reactant: Cc1cc(C)c(C(=O)Cl)c(C)c1
Reactant: Nc1n[nH]c2nnc(-c3cccc(F)c3F)cc12
Solvent: c1ccncc1
Product: Cc1cc(C)c(C(=O)Nc2n[nH]c3nnc(-c4cccc(F)c4F)cc23)c(C)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2,4,6-Trimethylbenzoyl chloride (0.594 g, 3.24 mmol) was added to a solution of 5-(2,3-Difluorophenyl)-1H-pyrazolo[3,4-c]pyridazin-3-ylamine (Description 14; 0.400 g, 1.62 mmol) in pyridine (2 mL). The solution was heated at reflux for 72 hours, and the solvent then evaporated in vacuo. Piperidine (50 mL) was added and the solution stirred at room temperature for 16 hours. The mixture was evaporated and the residue azeotroped with ethanol. The crude product was purified firstly by chromatography on silica gel using a gradient elution with 5–20% v/v methanol in dichloromethane, and subsequently by further chromatography on silica gel using diethyl ether as eluent to afford the title compound, a solid.
Reaction SMILES: C([N:8]1[C@@H:13]2[CH2:14][CH2:15][C@@:9]1([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C@H:10]([O:16][CH2:17][C:18]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([C:28]([F:31])([F:30])[F:29])[CH:19]=1)[CH2:11][CH2:12]2)C1C=CC=CC=1.C(O)(=O)C>C(OCC)(=O)C.[OH-].[Pd+2].[OH-]>[F:26][C:24]([F:25])([F:27])[C:22]1[CH:23]=[C:18]([CH2:17][O:16][C@@H:10]2[CH2:11][CH2:12][C@@H:13]3[NH:8][C@@:9]2([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:15][CH2:14]3)[CH:19]=[C:20]([C:28]([F:31])([F:29])[F:30])[CH:21]=1
Reactant: FC(F)(F)c1cc(CO[C@@H]2CC[C@H]3CC[C@]2(c2ccccc2)N3Cc2ccccc2)cc(C(F)(F)F)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: FC(F)(F)c1cc(CO[C@@H]2CC[C@H]3CC[C@]2(c2ccccc2)N3)cc(C(F)(F)F)c1
Yield: 80 %

Procedure:
(1R*,2R*,5R*)-8-Benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-1-phenyl-8-azabicyclo[3.2.1]octane (Example 59; 1.21 g, 2.33 mmol) was dissolved in ethyl acetate (20 ml) then 10% palladium hydroxide(0.13 mg) added. Glacial acetic acid (2 ml) was added and the mixture hydrogenated at room temperature at 40 psi overnight. The reaction mixture was filtered then concentrated in vacuo. The yellow oil was basified (saturated sodium hydrogen carbonate solution), and the solution extracted with dichloromethane (×3), dried (MgSO4) and concentrated in vacuo to give a yellow oil. The reaction mixture was purified by flash column chromatography [5%-15% methanol in dichloromethane] to give the title compound as a yellow oil (0.80 g, 80%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:25])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:23][CH3:24])=[C:16]([CH2:19][NH:20][CH2:21][CH3:22])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.CC[O:28][C:29]([C@H:31](OS(C(F)(F)F)(=O)=O)[CH3:32])=[O:30]>>[Cl:1][C:2]1[C:3]([F:25])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:23][CH3:24])=[C:16]([CH2:19][N:20]([CH2:21][CH3:22])[C@H:31]([C:29]([OH:28])=[O:30])[CH3:32])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)[C@@H](C)OS(=O)(=O)C(F)(F)F
Reactant: CCNCc1cc2c(Nc3cccc(Cl)c3F)ncnc2cc1OC
Product: CCN(Cc1cc2c(Nc3cccc(Cl)c3F)ncnc2cc1OC)[C@@H](C)C(=O)O

Procedure:
N-(3-Chloro-2-fluorophenyl)-6-[(ethylamino)methyl]-7-methoxyquinazolin-4-amine was coupled with ethyl O-trifluoromethanesulfonyl-D-lactate and hydrolysed using analogous methods to those described for the equivalent steps in Example 46 to give N-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)-N-ethyl-L-alanine; 1H NMR Spectrum: (DMSO-d6) 1.03 (t, 3H); 1.29 (d, 3H); 2.71 (q, 2H); 3.56 (q, 1H); 3.86 (d, 1H); 3.94 (m, 4H); 7.19 (s, 1H); 7.28 (t, 1H); 7.48 (m, 1H); 7.56 (m, 1H); 8.41 (m, 2H); 9.76 (brs, 1H); Mass Spectrum: (M+H)+ 433.
Reaction SMILES: Cl[CH2:2][Si:3]([O:10][CH2:11][CH3:12])([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6].[C:13]([O-:18])(=[O:17])[C:14]([CH3:16])=[CH2:15].[K+]>C(P(CCCC)CCCC)CCC.C1C2NC3C(=CC=CC=3)SC=2C=CC=1>[C:13]([O:18][CH2:2][Si:3]([O:10][CH2:11][CH3:12])([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6])(=[O:17])[C:14]([CH3:16])=[CH2:15]
Reactant: CCO[Si](CCl)(OCC)OCC
Reactant: C=C(C)C(=O)[O-]
Agent: CCCCP(CCCC)CCCC
Agent: [K+]
Agent: c1ccc2c(c1)Nc1ccccc1S2
Product: C=C(C)C(=O)OC[Si](OCC)(OCC)OCC
Reaction time: 3 h
Yield: 93.3 %

Procedure:
Using a method analogous to Example 4, 212.7 g (1 mol) of chloromethyltriethoxysilane are reacted in the presence of 11.1 g (0.03 mol) of tri-n-butylphosphine and 0.1 g of phenothiazine with 130.4 g (1.05 mol) of potassium methacrylate at 90° C. The reaction is complete 3 hours after all the potassium methacrylate has been introduced. Work-up gives 244.7 g (93%) of methacryloxymethyltriethoxysilane having a purity of 99.2%.
Reaction SMILES: [CH2:1]1[O:17][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[NH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][NH2:25]>>[CH2:24]([NH:25][CH2:1][CH:2]([OH:17])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][NH:18][CH2:1][CH:2]([OH:17])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: NCCCCCCN
Reactant: CCCCCCCCCCCCCCC1CO1
Product: CCCCCCCCCCCCCCC(O)CNCCCCCCNCC(O)CCCCCCCCCCCCCC

Procedure:
Condensation of 1-hexadecene oxide and hexamethylenediamine affords N,N'-(1,6-hexylene)-bis[2-hydroxyhexadecylamine] (I: R= CH3 (CH2)13, R' = H, X= (CH2)6, Z= H).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH3:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH3:12][C:13]1[CH:19]=CC(N)=[C:15]([O:20][CH2:21]CC(C)C)[CH:14]=1.[NH2:26][C:27]1[S:28][CH:29]=[CH:30][N:31]=1>CC(C)CCO>[CH3:12][CH:13]([CH3:19])[CH2:14][CH2:15][O:20][C:2]1[CH:3]=[C:4]([CH3:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[S:28]1[CH:29]=[CH:30][N:31]=[C:27]1[NH:26][C:21](=[O:20])[NH2:8]
Reactant: Nc1nccs1
Reactant: Cc1ccc(N)c(OCCC(C)C)c1
Reactant: Cc1ccc([N+](=O)[O-])c(F)c1
Solvent: CC(C)CCO
Product: Cc1ccc([N+](=O)[O-])c(OCCC(C)C)c1
Product: NC(=O)Nc1nccs1
Yield: 80 %
Yield: 76 %

Procedure:
3-(3-Methyl-butoxy)-4-nitrotoluene (0.89 g, 80%) was prepared from 3-methylbutanol and 3-fluoro-4-nitrotoluene (0.77 g, 5.0 mmol) following the general procedure G. This was reduced to 4-methyl-2-(3-methylbutoxy)aniline (0.55 g, 72%) following general procedure C. 1-[4-Methyl-2-3-methyl-butoxy)-phenyl]-3-thiazol-2-yl-urea (240 mg, 76%) was prepared from 4-methyl-2-(3-methyl-butoxy)aniline (193 mg, 1.0 mmol) and 2-aminothiazole (100 mg, 1.0 mmol) following the general procedure D.
Reaction SMILES: Cl[C:2]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:3]=1[NH2:4].C([O:15][CH:16]=[C:17]([C:23](OCC)=O)[C:18]([O:20]CC)=[O:19])C.C1(C)C=CC=CC=1>CCCCCC>[O:15]=[C:16]1[C:5]2[C:3](=[CH:2][CH:8]=[CH:7][C:6]=2[C:9]([F:12])([F:11])[F:10])[NH:4][CH:23]=[C:17]1[C:18]([OH:20])=[O:19]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1cc(C(F)(F)F)ccc1Cl
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: O=C(O)c1c[nH]c2cccc(C(F)(F)F)c2c1=O
Temperature: 140 °C
Yield: 133 %

Procedure:
2-Chloro-5-(trifluoromethyl)aniline 2 (200 g, 1.023 mol), diethyl 2-(ethoxymethylene)malonate 3 (276 g, 1.3 mol) and toluene (100 mL) were combined under a nitrogen atmosphere in a three-neck, 1-L round bottom flask equipped with Dean-Stark condenser. The solution was heated with stirring to 140° C. and the temperature was maintained for 4 h. The reaction mixture was cooled to 70° C. and hexane (600 mL) was slowly added. The resulting slurry was stirred and allowed to warm to room temperature. The solid was collected by filtration, washed with 10% ethyl acetate in hexane (2×400 mL) and then dried under vacuum to provide a white solid (350 g, 94% yield) as the desired condensation product diethyl 2-((2-chloro-5-(trifluoromethyl)phenylamino) methylene) malonate 4. 1H NMR (400 MHz, DMSO-d6) δ 11.28 (d, J=13.0 Hz, 1H), 8.63 (d, J=13.0 Hz, 1H), 8.10 (s, 1H), 7.80 (d, J=8.3 Hz, 1H), 7.50 (dd, J=1.5, 8.4 Hz, 1H), 4.24 (q, J=7.1 Hz, 2H), 4.17 (q, J=7.1 Hz,2H),1.27 (m, 6H).
Reaction SMILES: [CH:1]1([CH:7]([C:18]2[CH:22]=[C:21]([CH2:23][CH:24]([CH3:26])[CH3:25])[S:20][C:19]=2[CH2:27][CH3:28])[O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:29][NH:30][CH2:31][CH2:32][C:33]([O:35]CC)=[O:34]>>[CH:1]1([CH:7]([C:18]2[CH:22]=[C:21]([CH2:23][CH:24]([CH3:25])[CH3:26])[S:20][C:19]=2[CH2:27][CH3:28])[O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([N:30]([CH3:29])[CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:14])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCNC
Reactant: CCc1sc(CC(C)C)cc1C(Oc1ccc(C(=O)O)cc1)C1CCCCC1
Product: CCc1sc(CC(C)C)cc1C(Oc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Yield: 51.2 %

Procedure:
An operation similar to that in Example 69 (9) was performed using 4-{cyclohexyl[2-ethyl-5-(2-methylpropyl)thiophen-3-yl]methoxy}benzoic acid (256 mg) synthesized in Example 81 (4) and ethyl 3-(methylamino)propanoate (101 mg) to give the title compound (159 mg, 51%).