Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:23][C:8]23[CH2:9][CH2:10][CH:11]4[CH:20]([CH:7]2[CH2:6][CH2:5][CH:4]3[CH:3]1[CH3:24])[CH2:19][CH:18]=[C:17]1[C:12]4([CH3:22])[CH2:13][CH2:14][CH:15]([OH:21])[CH2:16]1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33](O)=[O:34])=[CH:28][CH:27]=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C1COCC1>[CH3:1][N:2]1[CH2:23][C:8]23[CH2:9][CH2:10][CH:11]4[CH:20]([CH:7]2[CH2:6][CH2:5][CH:4]3[CH:3]1[CH3:24])[CH2:19][CH:18]=[C:17]1[C:12]4([CH3:22])[CH2:13][CH2:14][CH:15]([O:21][C:33](=[O:34])[CH2:32][C:29]2[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=2)[CH2:16]1
Reactant: O=C(O)Cc1ccc(F)cc1
Reactant: CC1C2CCC3C4CC=C5CC(O)CCC5(C)C4CCC32CN1C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CC1C2CCC3C4CC=C5CC(OC(=O)Cc6ccc(F)cc6)CCC5(C)C4CCC32CN1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.5 %

Procedure:
A mixture of compound 130A (20 mg, 0.06 mmol), 4-fluorophenylacetic acid (14 mg, 0.09 mmol), 1,3-dicyclohexylcarbodiimide (25 mg, 0.12 mmol), 4(dimethylamino) pyridine (2 mg, 0.016 mmol) and THF (1 mL) was stirred at room temperature overnight. The crude reaction mixture was loaded directly onto silica gel column and eluted with 0.2% ammonium hydroxide and 2% methanol in dichloromethane to give the pure desired product (25 mg, 87% yield).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[CH3:7][O:8][CH:9]([O:12][CH3:13])[CH2:10][NH2:11].[OH-].[Na+]>C1(C)C=CC=CC=1.O>[CH3:7][O:8][CH:9]([O:12][CH3:13])[CH2:10][NH:11][C:2](=[O:3])[O:4][CH2:5][CH3:6]
Reactant: CCOC(=O)Cl
Reactant: COC(CN)OC
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)NCC(OC)OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
214 g (2 mol) of ethyl chloroformate are added dropwise to 214 g (2 mol) of aminoacetaldehyde dimethyl acetal in 1 l of toluene and 90 g of NaOH in 500 ml of water at 10° C. The mixture is stirred at room temperature for a further 2 hours and the aqueous phase is separated off, saturated with sodium chloride and extracted with toluene. The toluene solutions are dried over magnesium sulphate and concentrated and the residue is distilled.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([CH2:15][CH2:16][CH3:17])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:18][CH2:19][CH2:20][CH2:21]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:2]1([O:1][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:21][CH2:20][CH2:19][Br:18])=[C:10]([CH2:15][CH2:16][CH3:17])[CH:9]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrCCCBr
Reactant: CCCc1cc(Oc2ccccc2)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCc1cc(Oc2ccccc2)ccc1OCCCBr

Procedure:
A solution of 4-phenoxy-2-propylphenol (12.0 g, 52.60 mmol), 1,3-dibromopropane (31.86 g, 157.81 mmol) and cesium carbonate (18.0 g, 55.23 mmol) in dry DMF (110 mL) was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and 0.2N HCl. The organic was washed twice with water, then dried over sodium sulfate. The organic was filtered and evaporated to an oil which was chromatographed over silica gel with methylene chloride/hexane (1:1) to afford the title compound.
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: CO[C:3](=[O:15])[NH:4][C:5]1[NH:9][C:8]2[CH:10]=[C:11]([OH:14])[CH:12]=[CH:13][C:7]=2[N:6]=1.[CH3:16][O:17][CH2:18][CH2:19][NH2:20].O>CN1CCCC1=O>[OH:14][C:11]1[CH:12]=[CH:13][C:7]2[N:6]=[C:5]([NH:4][C:3]([NH:20][CH2:19][CH2:18][O:17][CH3:16])=[O:15])[NH:9][C:8]=2[CH:10]=1
Reactant: COC(=O)Nc1nc2ccc(O)cc2[nH]1
Reactant: COCCN
Solvent: CN1CCCC1=O
Solvent: O
Product: COCCNC(=O)Nc1nc2ccc(O)cc2[nH]1

Procedure:
A solution of (6-hydroxy-1H-benzoimidazol-2-yl)-carbamic acid methyl ester (300 mg, example 61) and 2-methoxy-ethylamine (630 IA) in N-methylpyrrolidinone (8 ml) was heated at 90° C. in a sealed tube for 20 hours. The reaction mixture was poured into water (160 ml) and extracted three times with ethyl acetate (40 ml). The combined extracts were dried over magnesium sulfate and then evaporated. The residue was subjected to flash chromatography on silica eluting with a mixture of dichloromethane and methanol (95 C:5 C, v/v) to 1-(6-hydroxy-1H-benzoimidazol-2-yl)-3-(2-methoxy-ethyl)-urea as a yellow solid (180 mg). Mass spectrum: 251 [M+H]+; retention time=0.55 minutes.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[OH-].[K+].Cl[C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=1[N+:20]([O-:22])=[O:21].Cl>CS(C)=O>[OH:2][C:1]1[CH:8]=[CH:7][C:5]([O:6][C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=2[N+:20]([O-:22])=[O:21])=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Oc1ccc(O)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: N#Cc1ccc(Oc2ccc(O)cc2)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 38.8 %

Procedure:
A solution of hydroquinone (1.21 g, 0.011 mol) and potassium hydroxide (0.894 g, 0.0159 mol) in anhydrous dimethylsulfoxide (8 mL) was heated at 90° C. for 30 minutes under a nitrogen atmosphere. A solution of 4-chloro-3-nitrobenzonitrile (1.806 g, 0.0099 mol) in dimethylsulfoxide (8 mL) was added dropwise over a 30 minute period at 90°, then let the reaction stir for 1 hour at the same temperature. The reaction was then cooled in an ice bath and poured into 30 mL of ice-water. The mixture was acidified with concentrated hydrochloric acid to pH 3 and extracted with ethyl ether (3×100 mL). The combined ethereal extracts were washed with water (3×150 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation under vacuum. Purification by silica gel chromatography using 4% ethyl acetate/methylene chloride as eluent provided the product as an orange solid (0.984 g, 39%).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[S:15][CH:16]=[CH:17][C:11]=2[N:10]=[C:9]1[CH:18](Br)[CH2:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25][NH2:26]>CCO.CCOC(C)=O>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[S:15][CH:16]=[CH:17][C:11]=2[N:10]=[C:9]1[CH:18]([NH:26][CH2:25][CH2:24][N:23]([CH3:27])[CH3:22])[CH2:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(Br)c1nc2ccsc2c(=O)n1Cc1ccccc1
Reactant: CN(C)CCN
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCC(NCCN(C)C)c1nc2ccsc2c(=O)n1Cc1ccccc1
Reaction time: 24 h

Procedure:
3-Benzyl-2-(1-bromopropyl)thieno[3,2-d]pyrimidin-4(3H)-one (1-6, 0.032 g, 0.088 mmol) was dissolved in EtOH (2.0 mL) and treated with N,N-dimethyl ethylenediamine (0.03 mL, 0.26 mmol). The reaction was to 80° C. for 24 h. The reaction was diluted with EtOAc (20 mL), washed with 5% NH4Cl, and dried over MgSO4. The organics were concentrated under reduced pressure to provide 3-benzyl-2-(1-{[2-(dimethylamino)ethyl]amino}propyl)thieno[3,2-d]pyrimidin-4(3H)-one (1-7). MS 371.1 found 370.5 required.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=2)=[C:14]2[C:19](=[CH:20][C:21]=1[CH3:22])[N:18]=[C:17]([CH2:23][N:24]([CH3:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:16]=[CH:15]2)[C:7](OCC)=[O:8])([CH3:4])([CH3:3])[CH3:2].C(O[C@@H](C1C(C2C=CC(Cl)=CC=2)=C2C(=CC=1C)[N+]([O-])=C(C)C=C2)C[O:46][C:47](=O)[C:48]([CH3:51])([CH3:50])[CH3:49])(C)(C)C>>[C:47]([O:8][CH2:7][C@@H:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[C:12]1[C:13]([C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=2)=[C:14]2[C:19](=[CH:20][C:21]=1[CH3:22])[N:18]=[C:17]([CH2:23][N:24]([CH3:31])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH:16]=[CH:15]2)(=[O:46])[C:48]([CH3:51])([CH3:50])[CH3:49]
Reactant: Cc1cc2c(ccc(C)[n+]2[O-])c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(CN(C)c3ccccc3)ccc2c1-c1ccc(Cl)cc1
Product: Cc1cc2nc(CN(C)c3ccccc3)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C

Procedure:
(S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-((methyl(phenyl)amino)methyl)quinolin-6-yl)ethyl pivalate was prepared following the procedure used to prepare compound (S)-ethyl 2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-((methyl(phenyl)amino)methyl)quinolin-6-yl)acetate of Example 14, except that (S)-6-(1-tert-butoxy-2-(pivaloyloxy)ethyl)-5-(4-chlorophenyl)-2,7-dimethylquinoline 1-oxide was used instead of (S)-6-(1-tert-butoxy-2-ethoxy-2-oxoethyl)-5-(4-chlorophenyl)-2,7-dimethylquinoline 1-oxide. LCMS-ESI+ (m/z): 573.3, 575.4 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7][CH2:6]2.[B-](F)(F)(F)[F:15].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C(#N)C>[F:15][C:4]1[C:3]([O:2][CH3:1])=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][CH2:8][C:9]2=[O:13]
Reactant: F[B-](F)(F)F
Reactant: COc1ccc2c(c1)CCCC2=O
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Product: COc1ccc2c(c1F)CCCC2=O
Temperature: 40 °C
Reaction time: 8 h
Yield: 42.1 %

Procedure:
To a solution of 6-methoxy-1-tetralone (200 mg, 1.1 mmol) in ACN (20 mL) was added Selectfluor (603 mg, 1.7 mmol) at rt, and the reaction was stirred at 40° C. overnight. The reaction was filtered and concentrated. The residue was dissolved in EtOAc (40 mL), filtered, and concentrated. Purification by silica gel chromatography (PE/EtOAc/DCM=20:1:2) gave 90 mg (41%) of the title compound as a yellow solid. [M+H] Calc'd for C11H1FO2, 195. Found, 195.
Reaction SMILES: [C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][C:4]([C:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)=[CH:8][CH2:9][NH2:10])=[CH:3][CH:2]=1.[C:29](OC(=O)C)(=[O:31])[CH3:30]>C(O)(=O)C>[C:14]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:16][C:11]([C:7]([C:4]2[CH:3]=[CH:2][C:1]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[CH:6][CH:5]=2)=[CH:8][CH2:9][NH:10][C:29](=[O:31])[CH3:30])=[CH:12][CH:13]=1
Reactant: NCC=C(c1ccc(-c2ccccc2)cc1)c1ccc(-c2ccccc2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)NCC=C(c1ccc(-c2ccccc2)cc1)c1ccc(-c2ccccc2)cc1

Procedure:
1, 1-di(4-biphenyl)-3 (1g) was added to a mixture of anhydrous sodium acetate (1g), acetic acid (10 ml.) and acetic anhydride (1 ml) and the mixture was refluxed for 1 hour then evaporated in vacuo. The residue was washed with water and dried and recrystallised from n- propanol to give 1, 1-di(4-biphenylyl)- 3 -acetamido-prop-1-ene. (m.p. 246° - 249° C). This compound was reduced in a similar manner to the method described in Example 43 to yield 1,1-di(4-biphenyly;0- 3 -ethylamino-prop-1-ene.
Reaction SMILES: Br[CH2:2][C:3]1[CH:11]=[CH:10][C:6]2=[N:7][S:8][N:9]=[C:5]2[CH:4]=1.C(=O)([O-])[O-:13].[Ca+2]>O1CCOCC1.O>[OH:13][CH2:2][C:3]1[CH:11]=[CH:10][C:6]2=[N:7][S:8][N:9]=[C:5]2[CH:4]=1
Reactant: BrCc1ccc2nsnc2c1
Reactant: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Solvent: C1COCCO1
Product: OCc1ccc2nsnc2c1
Yield: 76.4 %

Procedure:
5-Bromomethylbenzo-2,1,3-thiadiazole (4.8 g) and calcium carbonate (10 g) were heated at reflux in 1:1 dioxane/water (120 mL) for 3 hours. The solvents were evaporated and the residue was partitioned between 2N hydrochloric acid and methylene 6 3 chloride. The organic layers were dried (magnesium sulfate), evaporated and chromatographed on silica gel eluting with 1:1 ethyl acetate/hexane to provide 2.66 g of the title compound.
Reaction SMILES: [CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[CH:7](Cl)([Cl:9])[Cl:8].[OH-].[Na+].CCCCCCCC>ClCCl>[Cl:8][C:7]1([Cl:9])[CH:6]2[CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]2
Reactant: ClC(Cl)Cl
Reactant: C1=CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCCCCCCC
Product: ClC1(Cl)C2CCCCC21
Temperature: 40 °C

Procedure:
In a flask provided with a one-blade paddle mixer, a mixture of 1.64 grams of cyclohexene, 23.7 grams of chloroform, 20 milliliters of 50%w aqueous sodium hydroxide, 5 milliliters of dichloromethane, 1 milliliter of n-octane (to serve as a GLC marker) and 0.010 gram of the catalyst indicated in Table I was stirred vigorously at 40° C. Samples were taken after stirring had been started at the times indicated in Table I. Table I presents the yields of 7,7-dichloronorcarane. The selectivity to the latter compound was 100% in all cases. A dash indicates that no analysis was effected.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:16][CH2:15][C:14]2[S:17][C:18]([NH2:20])=[N:19][C:13]=2[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH3:21]I>C1COCC1>[C:3]([O:7][C:8]([N:10]1[CH2:16][CH2:15][C:14]2[S:17][C:18]([NH:20][CH3:21])=[N:19][C:13]=2[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCc2nc(N)sc2CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CNc1nc2c(s1)CCN(C(=O)OC(C)(C)C)CC2
Temperature: 25 °C

Procedure:
104 mg 60% sodium hydrid was added to 700 mg 2-amino-4,5,7,8-tetrahydro-thiazolo (4,5-d) azepine-6-carboxylic acid tert-butyl ester in 1.5 mL THF at 0° C. Then, 162 μL methyliodide was dropped to the mixture. The reaction was stirred over night at RT. The solvent was removed and the residue was purified by HPLC and 121 mg of the desired product was obtained.
Reaction SMILES: C([O:4][C@H:5]([CH2:10]Br)[CH2:6][C:7]([OH:9])=[O:8])(=O)C.[C:12]([NH2:16])([CH3:15])([CH3:14])[CH3:13]>O>[C:12]([NH2:16])([CH3:15])([CH3:14])[CH3:13].[O:4]1[CH2:10][C@@H:5]1[CH2:6][C:7]([OH:9])=[O:8]
Reactant: CC(=O)O[C@H](CBr)CC(=O)O
Solvent: O
Solvent: CC(C)(C)N
Product: O=C(O)C[C@H]1CO1
Reaction time: 2 h

Procedure:
A solution of distilled water (10 ml), (S)-3-acetoxy-4-bromobutyric acid (0.9 g, 0.004 mol) and t-butylamine (0.08 g, 0.012 mol) was charged to 100 ml flask equipped with a thermometer, pH meter and agitator, and stirred at 0˜5° C. for 2 hours to give (S)-3,4-epoxybutyric acid t-butylamine salt. It was confirmed by a NMR analysis that more than 99% (S)-3,4-epoxybutyric acid t-butylamine salt was converted.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:44])[C@H:16]([NH:24][C:25]([C@@H:27]2[CH2:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:29][N:28]2C(OC(C)(C)C)=O)=[O:26])[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:11][CH2:10]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:29]1[C:30]2[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:36][C@@H:27]([C:25]([NH:24][C@H:16]([CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:15]([N:12]2[CH2:13][CH2:14][CH:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[CH2:10][CH2:11]2)=[O:44])=[O:26])[NH:28]1
Reactant: COc1ccccc1C1CCN(C(=O)[C@@H](Cc2ccccc2)NC(=O)[C@@H]2Cc3ccccc3CN2C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccccc1C1CCN(C(=O)[C@@H](Cc2ccccc2)NC(=O)[C@@H]2Cc3ccccc3CN2)CC1
Reaction time: 0.5 h
Yield: 42.9 %

Procedure:
The title compound was prepared according to the procedure described in Example 3 (Step b) from tert-butyl (3S)-3-(N-((1R)-2-[4-(2-methoxyphenyl)piperidyl]-2-oxo-1-benzylethyl]carbamoyl)-1,2,3,4-tetrahydro-isoquinoline-2-carboxylate (Step b) (1.4 g, 2.34 mmol) and 50% TFA in CH2Cl2 (80 mL). Purification by reverse phase preparative HPLC [Phenomenex; 5 μm 250×21.2 mm, 5% to 95% CH3CN (0.1% TFA) in H2O (0.1% TFA) over 30 min, then 10U % CH3CN (0.1% TFA) for 2 min] provided the title compound (TFA salt) as a white foam (0.5 g). MS (ESI, pos. ion) m/z: 498 (M+1). Calc'd for C31H35N3O3: 497.27.
Reaction SMILES: [C:1]1([N:7]2[C:11]([NH2:12])=[CH:10][C:9]([C:13]([F:16])([F:15])[F:14])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].Cl[C:24]([O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:25]>C1COCC1>[C:1]1([N:7]2[C:11]([NH:12][C:24](=[O:25])[O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:10][C:9]([C:13]([F:15])([F:16])[F:14])=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1cc(C(F)(F)F)nn1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(Nc1cc(C(F)(F)F)nn1-c1ccccc1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.7 %

Procedure:
To a suspension of 1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-amine (1.136 g, 5 mmol) and K2CO3 (1.035 g, 7.5 mmol) in THF (20 mL) was dropped a solution of phenyl chloroformate (0.939 g, 6 mmol) in THF (10 mL). After stirred at room temperature overnight, the mixture was quenched with water and extracted with CH2Cl2. Extracts were dried over MgSO4, concentrated under reduced pressure, and dried under vacuum to afford phenyl 1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-ylcarbamate as solid (1.714 g, 99%). 1H NMR (300 MHz, CDCl3) δ 7.55 (m, 5H), 7.39 (m, 2H), 7.28 (m, 2H), 7.14 (m, 2H), 6.86 (m, 1H); LC-MS (ESI) m/z 348 (M+H)+.
Reaction SMILES: [CH2:1]([N:5]([CH2:9][CH2:10][OH:11])[CH2:6][CH2:7][OH:8])[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.Cl[C:20](Cl)([O:22]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[CH2:1]([N:5]1[CH2:6][CH2:7][O:8][C:20](=[O:22])[O:11][CH2:10][CH2:9]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(CCO)CCO
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCN1CCOC(=O)OCC1
Yield: 239.2 %

Procedure:
The procedure of Example 1 was followed using N-butyl diethanolamine (13.5 g, 83.9 mmol), triethylamine (24.0 mL, 167.8 mmol), dry THF (600 mL) and triphosgene (8.3 g, 28.8 mmol). The filtrate was concentrated yielding a yellow/brown oil product (12.9 g, 82%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:8])=[N:4][NH:5][C:6]=1[CH3:7].[H-].[Na+].[Cl:11][C:12]1[CH:13]=[C:14]([C:19]([NH:21][C@H:22]2[CH2:27][CH2:26][C@H:25]([CH2:28]OS(C)(=O)=O)[CH2:24][CH2:23]2)=[O:20])[C:15]([CH3:18])=[N:16][CH:17]=1>C(#N)C.O>[Cl:11][C:12]1[CH:17]=[N:16][C:15]([CH3:18])=[C:14]([CH:13]=1)[C:19]([NH:21][C@H:22]1[CH2:27][CH2:26][C@H:25]([CH2:28][N:4]2[C:3]([CH3:8])=[C:2]([Cl:1])[C:6]([CH3:7])=[N:5]2)[CH2:24][CH2:23]1)=[O:20]
Reactant: Cc1ncc(Cl)cc1C(=O)N[C@H]1CC[C@H](COS(C)(=O)=O)CC1
Reactant: Cc1n[nH]c(C)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Cc1ncc(Cl)cc1C(=O)N[C@H]1CC[C@H](Cn2nc(C)c(Cl)c2C)CC1
Temperature: 120 °C

Procedure:
To a solution of 4-chloro-3,5-dimethyl-1H-pyrazole (step 5a)(37 mg, 0.283 mmol) in dry acetonitrile (4.5 mL) at room temp is added sodium hydride (14 mg of a 60% dispersion in mineral oil, 0.353 mmol). The mixture is stirred at room temp for 10 minutes before trans-methanesulfonic acid 4-[(5-chloro-2-methyl-pyridine-3-carbonyl)-amino]-cyclohexylmethyl ester (step 4) (85 mg, 0.236 mmol) is added in one portion. The mixture is heated at 120° C. for 30 minutes using microwave radiation. After cooling to RT, the reaction mixture is diluted with water (10 mL) and extracted with EtOAc (3×10 mL). The EtOAc extracts are combined, washed with saturated brine (10 mL), dried (MgSO4), filtered and evaporated to give a colourless foam. Purification by chromatography on silica gel using a 12 g pre-packed column eluting with 0-100% EtOAc affords the title compound as a colourless solid. MS m/z 395.3/397.3 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.53 (1H, d), 8.39 (1H, d), 7.78 (1H, d), 3.83 (2H, d), 3.67 (1H, m), 2.47 (3H, s), 2.20 (3H, s), 2.09 (3H, s), 1.89 (2H, m), 1.73 (1H, m), 1.57 (2H, m), 1.16 (4H, m).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:39]=[CH:40][CH:41]=1)[O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([N+:36]([O-])=O)[CH:31]=3)=[CH:25][CH:24]=2)([C:19]([F:22])([F:21])[F:20])[C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)([O-])=O.O.NN>CC(O)C>[NH2:1][C:4]1[CH:5]=[C:6]([CH:39]=[CH:40][CH:41]=1)[O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([NH2:36])[CH:31]=3)=[CH:25][CH:24]=2)([C:19]([F:20])([F:21])[F:22])[C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1
Reactant: O=[N+]([O-])c1cccc(Oc2ccc(C(c3ccc(Oc4cccc([N+](=O)[O-])c4)cc3)(C(F)(F)F)C(F)(F)F)cc2)c1
Agent: NN
Solvent: CC(C)O
Solvent: O
Product: Nc1cccc(Oc2ccc(C(c3ccc(Oc4cccc(N)c4)cc3)(C(F)(F)F)C(F)(F)F)cc2)c1
Temperature: 22.5 °C
Yield: 75 %

Procedure:
In the next step, a 300 ml glass reaction vessel was charged with 20 grams (0.035 mol) of crude 2,2-bis[4-(3-nitrophenoxy)phenyl]-1,1,1,3,3,3-hexafluoropropane, 2 grams of active carbon, 0.2 gram of ferric chloride hexahydrate and 100 ml of IPA. The mixture was refluxed for 30 minutes with stirring and 7 grams (0.14 mol) of hydrazine hydrate was dropwise added at 60-70° C. during 2 hours, and refluxed for further 5 hours with stirring. The resultant reaction mixture was cooled, filtered to remove the catalyst and heated to distill off 60 ml of IPA. To the residue, 80 grams of 17.5% aqueous hydrochloric acid and 10 grams of sodium chloride were added and cooled to 20-25° C. with stirring. The separated crystals were filtered and recrystallized again from 40 ml of IPA and 80 grams of 17.5% aqueous hydrochloric acid. The resulting crystals were dissolved into 50% aqueous IPA solution and neutralized with aqueous ammonia to separate crystals. The crystals were filtered, washed with water, dried and recrystallized from the solvent mixture of benzene and n-hexane. Colorless crystals of 2,2-bis[4-(3-aminophenoxy)phenyl]-1,1,1,3,3,3-hexafluoropropane thus obtained were 13.6 grams (75% yield) and had a melting point of 137-139° C. The analytical results were as follows.