Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7](=[C:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:16]>C(O)C.[Pd]>[Cl-:16].[C:1]1([CH:7]([CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH2:8][NH3+:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cl
Reactant: N#CC(=C1CCOCC1)c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: [Cl-]
Product: [NH3+]CC(c1ccccc1)C1CCOCC1

Procedure:
To phenyl(tetrahydro-4H-pyran-4-ylidene)acetonitrile (450 mg, 2.258 mmol) in ethanol (11 ml) was added HCl (12.1 M, 1.867 ml, 22.58 mmol) then 10% Pd/C (48.1 mg, 0.045 mmol) as a slurry in ethanol. The reaction mixture was put under H2 balloon pressure for 21 hours. The reaction was filtered through a 0.45 um syringe-tip filter, then concentrated in vacuo. The product was used without further purification.
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][C:7]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:13]([N+:19]([O-:21])=[O:20])=[CH:12][C:8]=1[C:9]([OH:11])=[O:10].[C:22]1(C)C=CC=CC=1.[OH-].[Na+]>CO.C(OCC)(=O)C.O>[CH3:22][O:10][C:9](=[O:11])[C:8]1[CH:12]=[C:13]([N+:19]([O-:21])=[O:20])[CH:14]=[C:15]([N+:16]([O-:18])=[O:17])[C:7]=1[CH3:6]
Reactant: Cc1ccccc1
Reactant: Cc1c(C(=O)O)cc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: COC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1C
Reaction time: 8 h
Yield: 84 %

Procedure:
Concentrated sulfuric acid (0.5 mL) was added slowly at ambient temperature with stirring to 2-methyl-3,5-dinitro-benzoic acid (5.22 g, 23.06 mmol) in anhydrous methanol (200 mL). After refluxing overnight under an argon atmosphere, the reaction was determined to be about 50% complete. Toluene (100 mL) was used to azeotrope the H2O generated from the reaction, and fresh anhydrous methanol (300 mL) and H2SO4 (0.5 mL) were added and the mixture was again refluxed overnight under an argon atmosphere at which point the volatile components were reduced in vacuo. Ethyl acetate and 5% aqueous NaOH were added with stirring, and the product was extracted into the ethyl acetate. The ethyl acetate was then washed twice each with 5% aqueous NaOH and saturated aqueous NaHCO3, once with brine and dried with Na2SO4 to give Intermediate 2(a) (4.65 g, 19.37 mmol) as a white solid in 84% yield.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:27])[C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[N:13][C:12]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=2)[CH2:5][CH2:4]1.C(N(CC)CC)C.[CH3:35][C:36]1([C:39](O)=[O:40])[CH2:38][CH2:37]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[F:17][C:15]1[CH:14]=[N:13][C:12]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=2)=[C:11]([CH:16]=1)[C:10]([NH:9][C@H:6]1[CH2:7][CH2:8][C@@H:3]([NH:2][C:39]([C:36]2([CH3:35])[CH2:38][CH2:37]2)=[O:40])[CH2:4][CH2:5]1)=[O:27]
Reactant: CC1(C(=O)O)CC1
Reactant: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@@H](N)CC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@@H](NC(=O)C3(C)CC3)CC2)c1
Temperature: 25 °C
Reaction time: 64 h
Yield: 98 %

Procedure:
N-(cis-4-Amino-cyclohexyl)-5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinamide hydrochloride (100 mg, 0.243 mmol) was dissolved in dimethylformamide (1 ml) and triethylamine (100 μl, 0.729 mmol) was added followed by 1-methylcyclopropanecarboxylic acid (29 mg, 0.291 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (56 mg, 0.291 mmol) and 1-hydroxybenzotriazole (39 mg, 0.291 mmol). The reaction was stirred under nitrogen at room temperature for 64 h and the solvent was removed under reduced pressure. The residue was partitioned between sat. sodium bicarbonate solution (5 ml) and ethyl acetate (10 ml) and the aqueous phase was extracted with ethyl acetate (3×10 ml). The combined organic extracts were washed with water (2×5 ml), brine (5 ml), dried over MgSO4 and the solvent was removed under reduced pressure. The residue was triturated with diethylether (5 ml) to give 5-Fluoro-N-{cis-4-[(1-methyl-cyclopropanecarbonyl)-amino]-cyclohexyl}-2-(3-methylsulfanyl-phenoxy)-nicotinamide (109 mg) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[N:14]=[CH:13][C:12]([NH:15][C:16](=[O:22])[C@:17]([CH3:21])([CH2:19][CH3:20])[NH2:18])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[O:23][CH3:24].Cl[C:26](Cl)([O:28]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[CH2:19]([C@@:17]1([CH3:21])[NH:18][C:26](=[O:28])[N:15]([C:12]2[CH:13]=[N:14][C:9]([O:8][C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([O:23][CH3:24])[CH:4]=3)=[CH:10][CH:11]=2)[C:16]1=[O:22])[CH3:20]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC[C@](C)(N)C(=O)Nc1ccc(Oc2ccc(C)c(OC)c2)nc1
Solvent: ClCCl
Product: CC[C@@]1(C)NC(=O)N(c2ccc(Oc3ccc(C)c(OC)c3)nc2)C1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 118.5 %

Procedure:
To a solution of N1-(6-{[4-methyl-3-(methyloxy)phenyl]oxy}-3-pyridinyl)-D-isovalinamide (Intermediate 99, 42 mg) in dry dichloromethane (6 mL), TEA (0.089 mL, 0.638 mmol) was added. The mixture was cooled down to 0° C. and a solution of triphosgene (17.03 mg, 0.057 mmol) in dry dichloromethane (1.500 mL) was added dropwise. The mixture was stirred at that temperature for 1 hour, then a solution of triphosgene (17.03 mg, 0.057 mmol) in dry dichloromethane (DCM) (1.500 mL) was added dropwise again. The reaction was stirred for 30 minutes, it was maintained in the ice-bath and quenched with water (10 mL). The mixture was allowed to reach the room temperature then it was extracted with dichloromethane (3×7 mL). The combined organic layers were dried over sodium sulphate, filtered and evaporated. The residue obtained was purified by flash chromatography on silica gel using a 10 g SNAP column and cyclohexane/ethyl acetate as eluents from 80/20 to 50/50 (Biotage system). This afforded the title compound as a white solid (24 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:21]=O.[CH:23]([S:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]([F:37])([F:36])[F:35])(=[O:27])=[O:26])=[CH2:24]>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH2:21][CH:23]([S:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]([F:35])([F:37])[F:36])(=[O:26])=[O:27])[CH2:24][CH:15]2[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)CNC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: C=O
Reactant: C=CS(=O)(=O)c1ccccc1C(F)(F)F
Product: CCOC(=O)C1CC(S(=O)(=O)c2ccccc2C(F)(F)F)CN1C1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
In analogy to the procedure described in example 343d, 4-(ethoxycarbonylmethyl-amino)-piperidine-1-carboxylic acid tert-butyl ester (CAS Reg. No. 177276-49-2) was reacted with paraformaldehyde and 1-ethenesulfonyl-2-trifluoromethyl-benzene (example 243c) to give the title compound.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:18](=O)[CH3:19])=[N:4][N:5]([CH3:17])[C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1.[N+:21]([C:24]1[CH:33]=[C:32]([C:34]([NH:36][NH2:37])=[O:35])[CH:31]=[CH:30][C:25]=1[C:26]([O:28][CH3:29])=[O:27])([O-:23])=[O:22].O.S(C1C=CC(C)=CC=1)(O)(=O)=O>>[OH:1][C:2]1[C:3]([C:18](=[N:37][NH:36][C:34]([C:32]2[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[C:24]([N+:21]([O-:23])=[O:22])[CH:33]=2)=[O:35])[CH3:19])=[N:4][N:5]([CH3:17])[C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:14])([F:16])[F:15])=[CH:9][CH:8]=1
Reactant: COC(=O)c1ccc(C(=O)NN)cc1[N+](=O)[O-]
Reactant: CC(=O)c1nn(C)c(-c2ccc(C(F)(F)F)cc2)c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: COC(=O)c1ccc(C(=O)NN=C(C)c2nn(C)c(-c3ccc(C(F)(F)F)cc3)c2O)cc1[N+](=O)[O-]
Yield: 60.7 %

Procedure:
From 1-[4-hydroxy-1-methyl-5-(4-trifluoromethylphenyl)-1H-pyrazol-3-yl]ethanone (0.70 mmol, 200 mg) synthesized in Synthetic Example 11, methyl 2-nitro-4-hydrazinocarbonylbenzoate (0.70 mmol, 168.3 mg) of Reference Synthetic Example 40 and tosylic acid monohydrate (36.4 mg, 0.21 mmol), 214.7 mg of the desired product was obtained in the same manner as in Synthetic Example 58 as a yellow solid (yield 60%).
Reaction SMILES: [F:1][C:2]([F:12])([C:7]1[CH:11]=[CH:10][NH:9][N:8]=1)[C:3]([F:6])([F:5])[F:4].[N+]([O-])([O-])=O.[NH4+].[Ce].[Ce].[I:20]I>C(#N)C>[I:20][C:11]1[C:7]([C:2]([F:1])([F:12])[C:3]([F:6])([F:5])[F:4])=[N:8][NH:9][CH:10]=1
Reactant: II
Reactant: FC(F)(F)C(F)(F)c1cc[nH]n1
Agent: O=[N+]([O-])[O-]
Agent: [Ce]
Agent: [NH4+]
Solvent: CC#N
Product: FC(F)(F)C(F)(F)c1n[nH]cc1I
Yield: 162.7 %

Procedure:
An acetonitrile solution (20 ml) of 3-pentafluoroethyl-1H-pyrazole (2.0 g), dicerium ammonium nitrate (3.0 g) and iodine (1.6 g) was refluxed for 3 hours. After cooling, the reaction solution was washed with saturated aqueous solution of sodium thiosulfate and saturated aqueous solution of sodium chloride. After drying the organic layer with magnesium sulfate, the solvent was distilled off under the reduced pressure to obtain 4-iodo-3-pentafluoroethyl-1H-pyrazole (3.2 g).
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([C:18]([O:20]CC)=O)[C:7]2[CH:12]=[N:11][N:10]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:8]=2[N:9]=1.[NH2:23][CH2:24][C:25]1[C:26](=[O:33])[NH:27][C:28]([CH3:32])=[CH:29][C:30]=1[CH3:31].C1CN([P+]([O:50]N2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CCO.CCOC(C)=O.O>[Br:3][C:4]1[CH:5]=[C:6]([C:18]([NH:23][CH2:24][C:25]2[C:26](=[O:33])[NH:27][C:28]([CH3:32])=[CH:29][C:30]=2[CH3:31])=[O:20])[C:7]2[CH:12]=[N:11][N:10]([CH:13]3[CH2:14][CH2:15][O:50][CH2:16][CH2:17]3)[C:8]=2[N:9]=1
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Reactant: CCOC(=O)c1cc(Br)nc2c1cnn2C1CCCC1
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1cc(C)c(CNC(=O)c2cc(Br)nc3c2cnn3C2CCOCC2)c(=O)[nH]1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
Aqueous NaOH (5 equivalent) was added to a solution of ethyl 6-bromo-1-cyclopentyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (1 equivalent) in EtOH (10 times by volume) and stirred at 60° C. for 1 h. After completion of the reaction, ethanol was removed under reduced pressure and it was acidified using 10% citric acid solution. Extraction was carried out using EtOAc; the combined organic layers were washed with water, brine and dried over anhydrous Na2SO4; filtered and concentrated under reduced pressure. The residue was then dissolved in DMSO (10 times by volume) and 3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-one (2 equivalents) was added to it. The reaction mixture was stirred at room temperature for 15 min before PYBOP (1.5 equivalents) was added to it and stirring was continued for 5 to 16 h. After completion of the reaction, water was added to it and extraction was carried out using EtOAc. The combined organic layers were washed with water; brine; dried over anhydrous Na2SO4; filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography followed by ether wash to provide the desired intermediate.
Reaction SMILES: [Cl-].[Li+].C(OP([CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])(OCC)=O)C.O=[C:20]1[CH2:25][CH2:24][CH:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:22][CH2:21]1>CC#N>[C:15]([O:14][C:12](=[O:13])[CH:11]=[C:20]1[CH2:25][CH2:24][CH:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:22][CH2:21]1)([CH3:16])([CH3:17])[CH3:18]
Reactant: CCOP(=O)(CC(=O)OC(C)(C)C)OCC
Reactant: CCOC(=O)C1CCC(=O)CC1
Agent: [Cl-]
Agent: [Li+]
Solvent: CC#N
Product: CCOC(=O)C1CCC(=CC(=O)OC(C)(C)C)CC1
Reaction time: 0.5 h
Yield: 62.1 %

Procedure:
To a suspension of anhydrous lithium chloride (1.9 g, 45 mmol) in MeCN (100 ml) was added tert-butyl 2-(diethoxyphosphoryl)acetate (7.6 g, 30 mmol) at room temperature. The mixture was stirred for 30 min. TEA (6.4 ml, 45 mmol) was added and the mixture was stirred for another 30 min. Ethyl 4-oxocyclohexanecarboxylate (5.1 g, 30 mmol) was added and the mixture was stirred overnight. The precipitate was filtered off and the filtrate was concentrated to afford brown oil, which was purified by silica gel column (PE:EtOAc=10:1) to afford product (5 g, 62%).
Reaction SMILES: [S:1]([O-:5])([OH:4])(=[O:3])=[O:2].[NH3+:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>[OH-].[Na+]>[NH2:6][C:7]1[C:8]([S:1]([OH:5])(=[O:3])=[O:2])=[CH:9][CH:10]=[CH:11][CH:12]=1.[NH2:13][C:14]1[C:19]([S:1]([OH:4])(=[O:3])=[O:2])=[CH:18][C:17]([S:1]([OH:5])(=[O:4])=[O:3])=[CH:16][CH:15]=1
Reactant: O=S(=O)([O-])O
Reactant: [NH3+]c1ccccc1
Reactant: Nc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: Nc1ccc(S(=O)(=O)O)cc1S(=O)(=O)O
Product: Nc1ccccc1S(=O)(=O)O
Yield: 0.02 %
Yield: 0.7 %

Procedure:
439.7 g of powdered anilinium hydrogensulphate were heated for 7 hours at 200° C. in a closed autoclave. After cooling, the autoclave was opened and the solid was dissolved in 1N NaOH (pH 7.2), deposited aniline was separated off, residual aniline was removed by extraction with methylene chloride (2×100 ml) and the aqueous phase was evaporated to dryness. The analysis of the powdery product showed a yield of p-sulphanilic acid Na salt of 68.5%, based on employed aniline. 0.7% of aniline-2-sulphonic acid and 0.02% of aniline-2,4-disulphonic acid were formed.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C:13](=O)[C:14]([O:16]CC)=O.[CH3:20]/[C:21](/[NH2:24])=[N:22]/[NH2:23].Cl>CCO>[CH3:20][C:21]1[NH:24][C:14](=[O:16])[C:13]([CH2:12][N:3]2[C:4](=[O:11])[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:2]2=[O:1])=[N:23][N:22]=1
Reactant: CCOC(=O)C(=O)CN1C(=O)c2ccccc2C1=O
Reactant: C/C(N)=N/N
Agent: Cl
Solvent: CCO
Product: Cc1nnc(CN2C(=O)c3ccccc3C2=O)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73 %

Procedure:
A solution of ethyl 3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-2-oxopropanoate [J. Org. Chem.,(1985), 50 (1), 91](4.29 g, 16.4 mmol), acetamidrazone hydrochloride (1.80 g, 16.4 mmol) in anhydrous EtOH (85.8 mL) was heated to 80° C. for 3 h then cooled to rt and stirred for an additional 16 h. The reaction mixture was filtered through a fritted funnel resulting in 3.28 g, (73% yield) of the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.28 (s, 3H), 4.73 (s, 2H) and 7.74-8.12 (m, 4H); MS (ES+): m/z 271.08 [MH+].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.S([O-])([O-])=O.[Na+].[Na+].C(=O)(O)[O-].[Na+].Br[CH2:24][Cl:25]>O>[Cl:25][CH2:24][S:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: ClCBr
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=S(=O)(CCl)c1ccc(F)cc1
Temperature: 100 °C

Procedure:
A stirred mixture of 4-fluoro-benzenesulfonyl chloride (10.16 g, 52.2 mmol), sodium sulfite (12.25 g, 97.1 mmol) and sodium bicarbonate (8.02 g, 95.5 mmol) in water (55 mL) is heated at 100° C. for 1 h. The crude sodium sulfinate solution is allowed to cool for 30 min and then treated with bromochloromethane (60 mL) and tetra-N-butyl ammonium bromide (1.68 g, 5.22 mmol). The resulting mixture is heated at 75° C. overnight. The organic layer was separated. The aqueous solution was extracted with CH2Cl2 (×2). The combined organics were washed with water and brine, and dried over anhydrous MgSO4. The filtration through Celite-silica gel pad and concentration in vacuo gave the desired product without further purification. 1H NMR (300 MHz, CDCl3) 8.00 (m, 2H), 7.30 (m, 2H), 4.53 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.Cl[C:24](Cl)([O:26]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:35][CH2:36][CH:37]([OH:41])[CH2:38][CH2:39][CH3:40].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:24](=[O:26])[O:41][CH:37]([CH2:36][CH3:35])[CH2:38][CH2:39][CH3:40])=[CH:18][CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: CCCC(O)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCCC(CC)OC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)cc1
Yield: 90.7 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (100 mg) was added to toluene (10 ml) and triethylamine (1 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (151 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 3-hexanol (52 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (130 mg, yield 83%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:13]([OH:15])=O)[CH:10]([CH3:12])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:17][O:18][C:19]([CH2:21][CH:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20].C(N(CC)CC)C.O.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[CH3:17][O:18][C:19]([CH2:21][CH:22]([NH:29][C:13](=[O:15])[C@@H:9]([CH:10]([CH3:11])[CH3:12])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:20]
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)CC(N)c1ccccc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COC(=O)CC(NC(=O)[C@H](NC(=O)OC(C)(C)C)C(C)C)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
N-tert-butoxycarbonyl-D-valine (5.34 g, 24.6 mmols) and 5.31 g (24.6 mmols) of (RS)-α-methoxycarbonylmethylbenzylamine hydrochloride (S:R=2:1) were suspended in 100 ml of methylene chloride, and the suspension was maintained at 0° C. Triethylamine (3.78 ml, 27.1 mmols), 5.20 g (27.1 mmols) of water-soluble carbodiimide hydrochloride and 3.66 g (27.1 mmols) of HOBt were added thereto, and the mixture was stirred for 1 hour while being cooled and then overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and 150 ml of water were then added to the residue. The solution was extracted twice with 100 ml of ethyl acetate. The organic layer was washed twice with 100 ml of a 5% citric acid aqueous solution, with 100 ml of a saturated aqueous solution of sodium chloride, twice with a 5% sodium hydrogencarbonate aqueous solution and with 100 ml of a saturated aqueous solution of sodium chloride. The organic layer was dried over anhydrous magnesium sulfate, and magnesium sulfate was then removed by filtration. The filtrate was concentrated under reduced pressure to obtain 9.27 g (24.5 mmols) of N-tert-butoxycarbonyl-D-valine (RS)-α-methoxycarbonylmethylbenzylamide as a solid.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Br:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][C:28]=1[Br:29])[N:25](COCC[Si](C)(C)C)[N:24]=[C:23]2[NH:38][C:39](=[O:43])[CH2:40][CH2:41][CH3:42].C(OCC)(=O)C>O1CCCC1>[Br:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][C:28]=1[Br:29])[NH:25][N:24]=[C:23]2[NH:38][C:39](=[O:43])[CH2:40][CH2:41][CH3:42]
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(Br)c(Br)cc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCC(=O)Nc1n[nH]c2cc(Br)c(Br)cc12
Yield: 62.6 %

Procedure:
12.2 cm3 of tetrabutylammonium fluoride as a 1M solution in tetrahydrofuran are added to 1 g of N-[5,6-dibromo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide, described previously, in 60 cm3 of tetrahydrofuran, and the mixture is refluxed for 18 hours; after cooling, 75 cm3 of ethyl acetate are added and the organic phase is washed successively with 100 cm3 of saturated sodium hydrogen carbonate solution and then with 75 cm3 of saturated sodium chloride solution. The organic phase is separated out after settling of the phases has taken place, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2 kPa; 50° C.) to give 1.6 g of crude product, which is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 3.5 cm), eluting with a cyclohexane/ethyl acetate mixture (50/50 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.) and the residue is taken up in 20 cm3 of diisopropyl ether, filtered off, washed with 2×10 cm3 of diisopropyl ether and dried (90 Pa; 45° C.) to give 460 mg of N-[5,6-dibromo-1H-indazol-3-yl]butanamide in the form of bluish crystals melting at 250° C.
Reaction SMILES: C(C1C=NC(C2C=CC(O[CH2:22][CH2:23][CH2:24][O:25][CH2:26][C:27]([O:30][C:31]([F:48])([F:47])[C:32]([F:46])([F:45])[O:33][C:34]([F:44])([F:43])[C:35]([F:42])([F:41])[O:36][C:37]([F:40])([F:39])[F:38])([F:29])[F:28])=CC=2)=NC=1)CCCCCCC.[CH2:49]([O:54][C:55]1[CH:56]=[N:57][C:58]([C:61]2[CH:66]=[CH:65][C:64]([OH:67])=[CH:63][CH:62]=2)=[N:59][CH:60]=1)[CH2:50][CH2:51][CH2:52][CH3:53]>CN(C)C=O>[CH2:49]([O:54][C:55]1[CH:60]=[N:59][C:58]([C:61]2[CH:62]=[CH:63][C:64]([O:67][CH2:22][CH2:23][CH2:24][O:25][CH2:26][C:27]([O:30][C:31]([F:47])([F:48])[C:32]([F:45])([F:46])[O:33][C:34]([F:43])([F:44])[C:35]([F:41])([F:42])[O:36][C:37]([F:40])([F:39])[F:38])([F:29])[F:28])=[CH:65][CH:66]=2)=[N:57][CH:56]=1)[CH2:50][CH2:51][CH2:52][CH3:53]
Reactant: CCCCCOc1cnc(-c2ccc(O)cc2)nc1
Reactant: CCCCCCCCc1cnc(-c2ccc(OCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)OC(F)(F)F)cc2)nc1
Solvent: CN(C)C=O
Product: CCCCCOc1cnc(-c2ccc(OCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)OC(F)(F)F)cc2)nc1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
The title compound was prepared essentially as in Example 1 by combining 3-(2-(2-(2-(trifluoromethoxy)tetrafluoroethoxy)tetrafluoroethoxy)-2,2-difluoroethoxy)-1-chloropropane (6.1 g, 28.0 mmol, Example 24) with 5-pentyloxy-2-[4-hydroxyphenyl]pyrimidine (3 g, 11.6 mmol) in dimethylformamide and stirring at 120° C. overnight to provide product boiling at 185°-190° C. at 0.3 torr (yield of 5.5 g).
Reaction SMILES: [OH:1][C@H:2]1[CH2:16][CH:15]=[C:14]2[C@:4]([CH3:17])([CH2:5][C:6]3[C:7](=[CH:13]2)[O:8][C:9](=[O:12])[C:10]=3[CH3:11])[C@H:3]1[CH3:18].[C:19](Cl)(=[O:23])[CH2:20][CH2:21][CH3:22]>>[C:19]([O:1][C@H:2]1[CH2:16][CH:15]=[C:14]2[C@:4]([CH3:17])([CH2:5][C:6]3[C:7](=[CH:13]2)[O:8][C:9](=[O:12])[C:10]=3[CH3:11])[C@H:3]1[CH3:18])(=[O:23])[CH2:20][CH2:21][CH3:22]
Reactant: CCCC(=O)Cl
Reactant: CC1=C2C[C@@]3(C)C(=CC[C@H](O)[C@@H]3C)C=C2OC1=O
Product: CCCC(=O)O[C@H]1CC=C2C=C3OC(=O)C(C)=C3C[C@]2(C)[C@H]1C

Procedure:
The title compound was prepared in the same manner as in Example B2, except that the compound prepared in Example B1 was reacted with butyryl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:40])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[NH:11][C:10]([C:21]3[CH:26]=[C:25]([S:27]([N:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)(=[O:29])=[O:28])[C:24]([O:35][CH3:36])=[CH:23][C:22]=3[O:37][CH2:38][CH3:39])=[N:9]2)=[CH:4][CH:3]=1.[C:41](Cl)([Cl:43])=[O:42]>C(N(CC)CC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:40])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:41]([Cl:43])=[O:42])[C:10]([C:21]3[CH:26]=[C:25]([S:27]([N:30]4[CH2:31][CH2:32][CH2:33][CH2:34]4)(=[O:28])=[O:29])[C:24]([O:35][CH3:36])=[CH:23][C:22]=3[O:37][CH2:38][CH3:39])=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)Cl
Reactant: CCOc1cc(OC)c(S(=O)(=O)N2CCCC2)cc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1
Solvent: CCN(CC)CC
Product: CCOc1cc(OC)c(S(=O)(=O)N2CCCC2)cc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl

Procedure:
In a manner analogous to the method described in example 3, rac-(4S*,5R*)-4,5-bis-(4-chlorophenyl)-2-[2-ethoxy-4-methoxy-5-(pyrrolidine-1-sulfonyl)phenyl]-4,5-dimethyl-4,5-dihydro-1H-imidazole was reacted with phosgene in the presence of triethylamine to give the title compound.