Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COS(O)(=O)=O.COCOC.C[C:13]([O:15][CH2:16][C:17]1[CH2:26][S:25][C@@H:20]2[C@H:21]([NH2:24])[C:22](=[O:23])[N:19]2[C:18]=1[C:27]([OH:29])=[O:28])=O>C(OC)(=O)CCC(OC)=O>[NH2:24][CH:21]1[C:22](=[O:23])[N:19]2[C:18]([C:27]([OH:29])=[O:28])=[C:17]([CH2:16][O:15][CH3:13])[CH2:26][S:25][C@H:20]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: COC(=O)CCC(=O)OC
Agent: COS(=O)(=O)O
Solvent: COCOC
Product: COCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Temperature: 15 °C
Reaction time: 1.5 h
Yield: 83 %

Procedure:
17.94 g of a methanolic solution of methoxysulfonic acid (prepared as described in Preparation 1) and 6.12 g of methylal (prepared as described in Preparation 5) were added to 30 ml of dimethyl succinate. The mixture was cooled to 15° C., and 2.74 g of 7-ACA were added thereto, followed by stirring at 15° C. for 1.5 hours. After completion of the reaction, the reaction mixture was treated following the procedures described in Example 2 to give 2.04 g (yield 83%) of the desired compound with a high purity.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:11])=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[N+:12]([O-])([OH:14])=[O:13]>>[Br:1][C:2]1[C:3]([F:11])=[C:4]2[C:10]([N+:12]([O-:14])=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Fc1c(Br)cnc2[nH]ccc12
Reactant: O=[N+]([O-])O
Product: O=[N+]([O-])c1c[nH]c2ncc(Br)c(F)c12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridine (10 g, 47 mmol) was added to fuming nitric acid (50 mL) at 0° C., and the reaction was stirred at 0° C. for 30 minutes. Ice (300 mL) was added, and the reaction was allowed to warm to room temperature. The resulting suspension was filtered and dried under high vacuum to provide 5-bromo-4-fluoro-3-nitro-1H-pyrrolo[2,3-b]pyridine (9.2 g, 76% yield) as a solid. 1H NMR (400 MHz, (CD3)2SO) δ 13.63 (br s, 1H), 8.85 (s, 1H), 8.56 (d, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:39]=[CH:38][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]3[CH:24]=[C:25]([C:27]([NH:29][CH2:30][CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])=[O:28])[S:26][C:19]=23)=[CH:15][CH:14]=1)=[O:11].[OH-].[Na+].O.Cl>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]3[CH:24]=[C:25]([C:27]([NH:29][CH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:28])[S:26][C:19]=23)=[CH:38][CH:39]=1)=[O:11]
Reactant: CCOC(=O)CCCNC(=O)c1cc2nccc(Oc3ccc(NC(=O)Nc4cc(C)ccc4F)cc3)c2s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc4cc(C(=O)NCCCC(=O)O)sc34)cc2)c1
Temperature: 60 °C

Procedure:
To a stirred solution of ethyl 4-[({7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]butanoate (110 mg, 0.20 mmol) in 10 ml of THF was added 1M NaOH (2.0 ml, 2.0 mmol). The mixture was heated at 60° C. for 3 hours, cooled to room temperature and poured into 100 ml of water with vigorous stirring. 2M HCl was added dropwise until pH=4. The precipitates were filtered, washed with water and dried in vacuo to give 4-[({7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]butanoic acid as white solid. Yield: 100 mg, 96%.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1I.C(=O)([O-])O.[Na+].[Br:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.CCOCC>C1(C)C=CC=CC=1.C(O)C.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>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:31]1[CH:32]=[CH:33][C:28]([Br:27])=[CH:29][CH:30]=1
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1I
Reactant: OB(O)c1ccc(Br)cc1
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: CCOCC
Solvent: O
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1-c1ccc(Br)cc1
Reaction time: 8 h

Procedure:
To a rapidly stirred solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-iodopyrazole (0.25 g) in toluene (2 ml) containing tetrakis(triphenylphosphine)palladium(0) (0.02 g) was added saturated aqueous sodium hydrogen carbonate solution (1 ml) and a solution of 4-bromophenylboronic acid (0.25 g) in ethanol (1 ml). The mixture was heated under reflux for 1 hour, then left at room temperature overnight and then poured into ether (25 ml) and water (25 ml). The organic layer was separated, dried (MgSO4) and evaporated. The residue was taken up the minimum amount of ethyl acetate and purified by column chromatography on silica gel (20 g) eluted with dichloromethane:hexane (1:1). Combination and evaporation of suitable fractions followed by recrystallisation from ether/hexane gave the title compound as an off-white solid, m.p. 242-4° C.
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2.[CH3:19][CH:20]([C:24]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)=[O:25])[C:21](O)=[O:22]>>[Cl:34][C:31]1[CH:32]=[CH:33][C:28]([CH2:27][NH:26][C:24](=[O:25])[CH:20]([CH3:19])[C:21]([NH:1][CH:2]2[C:8](=[O:9])[N:7]([CH3:10])[C:6]3[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=3[C:4]3[CH:15]=[CH:16][CH:17]=[CH:18][C:3]2=3)=[O:22])=[CH:29][CH:30]=1
Reactant: CC(C(=O)O)C(=O)NCc1ccc(Cl)cc1
Reactant: CN1C(=O)C(N)c2ccccc2-c2ccccc21
Product: CC(C(=O)NCc1ccc(Cl)cc1)C(=O)NC1C(=O)N(C)c2ccccc2-c2ccccc21

Procedure:
The title compound, MS: m/e=462.2 (M+H+), was prepared in analogy to example 16 from 7-amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one and 2-methyl-N-(4-chloro-benzyl)-malonamic acid.
Reaction SMILES: [CH3:1][NH:2][C:3](=[S:6])[NH:4][NH2:5].[F:7][C:8]([F:13])([F:12])[C:9](O)=O>>[CH3:1][N:2]1[C:9]([C:8]([F:13])([F:12])[F:7])=[N:5][NH:4][C:3]1=[S:6]
Reactant: CNC(=S)NN
Reactant: O=C(O)C(F)(F)F
Product: Cn1c(C(F)(F)F)n[nH]c1=S
Yield: 95.5 %

Procedure:
257 g (2.44 mol) of 4-methyl-thiosemicarbazide are added to 1.2 liters of trifluoroacetic acid, and the mixture is refluxed for 16 hours. It is then concentrated under a water pump vacuum, the residue is triturated with diethyl ether/petroleum ether (5:100 by volume), and the product, which is obtained as crystals, is isolated by filtration. 444.5 g (95.5% of theory) of 4-methyl-5-trifluoromethyl-2,4-dihydro-3H-1,2,4-triazole-3-thione of melting point 115° C. are obtained.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:12]([NH2:13])=[CH:11][C:10]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[CH:9][N:8]=2)[CH2:3][CH2:2]1.Cl[C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=[C:23]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=2)[C:22]=1[CH3:37].Cl.O1CCOCC1.CN1C(=O)CCC1>>[N:4]1([C:7]2[C:12]([NH:13][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]=[C:23]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=4)[C:22]=3[CH3:37])=[CH:11][C:10]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)=[CH:9][N:8]=2)[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1
Reactant: Cc1c(-c2ccccn2)nc2ccccc2c1Cl
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: C1COCCO1
Product: Cc1c(-c2ccccn2)nc2ccccc2c1Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Temperature: 165 °C

Procedure:
Prepared according to Procedure K, method 2 using 2,5-dimorpholinopyridin-3-amine (63.5 mg, 0.24 mmol; described herein), 4-chloro-3-methyl-2-(pyridin-2-yl)quinoline (61.2 mg, 0.24 mmol; described herein), 4.0M hydrogen chloride in 1,4-dioxane (60 μL, 0.24 mmol), and NMP (280 μL, 2.9 mmol), and heating in a microwave at 165° C. for 3 h. Purification afforded N-(2,5-di-4-morpholinyl-3-pyridinyl)-3-methyl-2-(2-pyridinyl)-4-quinolinamine as a yellow solid. 1H NMR (400 MHz, chloroform-d) δ ppm 8.74 (1H, d, J=4.7 Hz), 8.19 (1H, d, J=8.2 Hz), 7.85-7.95 (2H, m), 7.81 (1H, dd, J=8.2, 0.8 Hz), 7.71 (1H, td, J=7.6, 1.2 Hz), 7.59 (1H, d, J=2.7 Hz), 7.47-7.55 (1H, m), 7.34-7.45 (1H, m), 6.78 (1H, s), 6.24 (1H, d, J=2.7 Hz), 3.93 (4H, t, J=4.7 Hz), 3.73 (4H, ddd, J=4.3, 2.7, 2.3 Hz), 3.13-3.36 (4H, m), 2.87-3.01 (4H, m), 2.39 (3H, s). Mass Spectrum (ESI) m/e=483.2 (M+1).
Reaction SMILES: Cl.Cl[C:3]1[N:12]=[C:11]([N:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH3:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.CC(C)([O-])C.[K+].C1OCCOCCOCCOCCOCCOC1.[CH3:47][N:48]([CH3:52])[CH2:49][CH2:50][OH:51]>>[CH3:47][N:48]([CH3:52])[CH2:49][CH2:50][O:51][C:3]1[N:12]=[C:11]([N:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH3:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: COc1ccc(N(C)c2nc(Cl)nc3ccccc23)cc1
Reactant: CN(C)CCO
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: Cl
Product: COc1ccc(N(C)c2nc(OCCN(C)C)nc3ccccc23)cc1
Temperature: 100 °C
Yield: 52 %

Procedure:
To a solution of (2-chloroquinazolin-4-yl)-(4-methoxyphenyl)-methylamine hydrochloride (120 mg, 0.36 mmol) in 2 mL of N,N-dimethylethanolamine were added potassium tert-butoxide (121 mg, 1.07 mmol) and 18-crown-6 (95 mg, 0.36 mmol). The resulting solution was heated at 100° C. overnight with stirring. The mixture was concentrated and purified by silica gel column chromatography to give the title compound (66 mg, 52%). 1H NMR (CDCl3, 400 MHz) δ 7.59 (d, 1H, J=8.4 Hz), 7.45 (t, 1H, J=6.8 Hz), 7.10 (d, 2H, J=8.8 Hz), 6.92 (m, 3H), 6.83 (t, 1H, J=6.8 Hz), 4.60 (t, 2H, J=6.4 Hz), 3.83 (s, 3H), 3.57 (s, 3H), 2.84 (t, 2H, J=6.4 Hz), 2.38 (s, 6H); ESI-MS m/z 353 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]#[N:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.C1(C)C=CC=CC=1.C([O-])(=[O:26])C.[K+].[OH-].[Na+]>O>[OH:26][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]#[N:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1
Reactant: CC(=O)[O-]
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: N#Cc1ccccc1-c1ccc(CO)cc1
Temperature: 90 °C
Reaction time: 5 h

Procedure:
A 750 ml flask is charged with 54.4 g (0.2 mol) of 4′-bromomethyl-biphenyl-2-carbonitrile and 250 ml of toluene. To this suspension is added a solution of 30 g (0.3 mol) of potassium acetate in 15 ml of water. The heterogeneous mixture is heated up to an internal temperature of 90° C. to become a clear biphasic solution. After 12 hours at an internal temperature of 90° C. the conversion to the OAc derivative is complete. The biphasic mixture is cooled down to internal temperature of about 50° C. followed by addition of 150 ml NaOH (2N). The mixture is heated up to an internal temperature of ca. 70° C. (extern. temp. 80° C.). After 5 hours at this temperature the PTC saponification is complete (100% conversion, HPLC). Additional 150 ml toluene is added and the warm reaction solution (ca. 50° C.) is washed three times with 50 ml of hot water until the pH is around 7. The toluene phase is evaporated under reduced pressure and the resulting crystalline residue is dried at 50° C. over 24 hours in vacuum to give the white crystalline product with 98% purity (HPLC) and a water content of 0.23%.
Reaction SMILES: O1CCCCC1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]3[CH:19]=[N:20][C:21]([NH:24][C:25]4[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=4)=[N:22][CH:23]=3)=[CH:13][CH:14]=2)[C:9]([C:36]([F:39])([F:38])[F:37])=[N:8]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:35][C:32]([F:33])([F:34])[O:31][C:28]1[CH:29]=[CH:30][C:25]([NH:24][C:21]2[N:22]=[CH:23][C:18]([CH2:17][O:16][C:12]3[CH:11]=[C:10]4[C:15](=[CH:14][CH:13]=3)[NH:7][N:8]=[C:9]4[C:36]([F:38])([F:39])[F:37])=[CH:19][N:20]=2)=[CH:26][CH:27]=1
Reactant: FC(F)(F)Oc1ccc(Nc2ncc(COc3ccc4c(c3)c(C(F)(F)F)nn4C3CCCCO3)cn2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)Oc1ccc(Nc2ncc(COc3ccc4[nH]nc(C(F)(F)F)c4c3)cn2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 39.5 %

Procedure:
To a solution of 5-(((1-(tetrahydro-2H-pyran-2-yl)-3-(trifluoromethyl)-1H-indazol-5-yl)oxy)methyl)-N-(4-(trifluoromethoxy)phenyl)pyrimidin-2-amine (0.03 g, 0.054 mmol) in DCM (5 mL) at 0° C., TFA (2 mL, 26.0 mmol) was added. The reaction mixture was stirred at room temperature for 5 h. Solvent was removed under vacuum and the crude product was purified by preparative HPLC on an Inertsil ODS column (19×250 mm, 5μ) using 0-65% mobile phase B (ACN) in mobile phase A (0.1% TFA) over 6 min to give N-(4-(trifluoromethoxy)phenyl)-5-(((3-(trifluoromethyl)-1H-indazol-5-yl)oxy)methyl)pyrimidin-2-amine as an off-white solid (10 mg, 39%). 1HNMR 400 MHz, DMSO-d6: δ ppm 5.11 (s, 1H), 7.22-7.22 (m, 1H), 7.29-7.30 (m, 3H), 7.65 (d, J=9.20 Hz, 1H), 7.86-7.87 (m, 2H), 8.67 (s, 2H), 10.00 (s, 1H), 13.90-0.00 (m, 1H). LCMS: R.T.=2.13 min; [M+H]+=468.0.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.II.[F:14]F>[Na]>[F:14][C:3]1[C:2]([Br:1])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: FF
Reactant: Brc1cnc2ccccc2c1
Agent: II
Agent: [Na]
Product: Fc1nc2ccccc2cc1Br
Yield: 32.3 %

Procedure:
A solution containing 3-bromoquinoline (1.0 g, 4.8 mmol) and iodine (1.22 g, 4.8 mmol) in CF2ClCFCl2 (30 ml) was placed in a fluorination apparatus fitted with a drying tube filled with soda lime. Elemental fluorine (5 mmol) as a 10% mixture in dry nitrogen was then passed through the stirred solution using narrow bore PTFE tubing at ca. 15 ml/min. After the fluorine had been added the solution was poured into 10% aqueous sodium metaisulfite solution (30 ml) and extracted with dichloromethane. The organic extracts were dried and evaporated to a brown oil (0.92 g). GC/MS analysis showed a 43% conversion of starting material. Column chromatography on silica gel with dichloromethane as eluant gave 2-fluoro-3-bromoquinoline (0.35 g, 74%); m.p. 75°-76° C. (vacuum sublimation oil bath temp. 50° C./<1 mmHg) as white needles; RF 0.69 (CH2Cl2); (Found: C, 47.5; H, 2.1; N, 6.2. C9H5NBrF requires: C, 47.8; H, 2.2; N, 6.2%); δH (400 MHz, CDCl3, Me4Si) 7.55 ppm (1H, d d, JH5,H6 =JH6,H7 8.0, H-6), 7.74 (1H, d d d, JH7,H8 8.4, JH6,H7 7.2, JH5,H7 1.2, H-7), 7.76 (1H, d, JH5,H6 8.0, H-5), 7.91 (1H, d d, JH7,H8 8.4, JH6,H8 0.8, H-8), 8.42 (1H, d, JH4,F 8.4, H-4); δC (100 MHz, CDCl3, Me4Si) 104.0 (d, 2J 43.2, C-3), 126.6 (s, C-6), 127.0 (d, 4J 2.7, C-8), 128.0 (d, 5J 1.9, C-5) 128.0 (d, 4J 2.2, C-4a), 130.9 (d, 5J 1.1, C-7), 143.5 (d,3J 3.7, C-4), 144.2 (d, 3J15.1, C-8a), 157.3 (d 1J 238.1, C-2); δF (235 MHz, CDCl3, CFCl3) -60.8 ppm (s); m/z (E1+) 225 (M+, 100%), 227 (M+, 74), 146 (56), 126 (23), 101 (18), 75 (14).
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17](=[O:38])[CH:18]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([O:31][C:32]([F:37])([F:36])[CH:33]([F:35])[F:34])[CH:26]=3)[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:13][CH:12]=2)=[CH:6][C:5]=1[CH2:39][CH3:40].Cl.O>C(OCC)C.[Cl-].[Zn+2].[Cl-]>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:12]=[CH:13][C:14]([CH:17]([OH:38])[CH:18]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([O:31][C:32]([F:37])([F:36])[CH:33]([F:35])[F:34])[CH:26]=3)[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:15][CH:16]=2)=[CH:6][C:5]=1[CH2:39][CH3:40]
Reactant: CCOC(=O)C(Cc1cccc(OC(F)(F)C(F)F)c1)C(=O)c1ccc(Oc2ccc(Cl)c(CC)c2)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)C(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(Oc2ccc(Cl)c(CC)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.1 %

Procedure:
To a solution of zinc chloride (4.44 g, 32.6 mmol) in diethyl ether (100 ml) was added sodium borohydride (2.46 g, 65.1. mmol), and the mixture was stirred at room temperature for 30 min. Insoluble material was filtered off, a solution of ethyl 3-(4-((4-chloro-3-ethylphenyl)oxy)phenyl)-3-oxo-2-((3-((1,1,2,2-tetrafluoroethyl)oxy)phenyl)methyl)propionate (9.0 g, 16.3 mmol) in diethyl ether (50 ml) was added to the filtrate, and the mixture was stirred at room temperature for 30 min. 1N Hydrochloric acid was added to the reaction solution under ice-cooling to quench the reaction. Then, water (150 ml) was added and the mixture was extracted with ethyl acetate (200 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give ethyl (2RS,3RS)-3-(4-((4-chloro-3-ethylphenyl)oxy)phenyl)-3-hydroxy-2-((3-((1,1,2,2-tetrafluoroethyl)oxy)phenyl)methyl)propionate (6.79 g, 75%) as a colorless oil.
Reaction SMILES: Br[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[O:3]1.[Cl:12][C:13]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:14]=1[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][C:23]([O-:25])=[O:24].[Na+]>CN(C)C=O>[Cl:12][C:13]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:14]=1[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][C:23]([O:25][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[O:3]1)=[O:24]
Reactant: O=C1OC(Br)c2ccccc21
Reactant: O=C([O-])Cc1ccccc1Nc1c(Cl)cccc1Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Cc1ccccc1Nc1c(Cl)cccc1Cl)OC1OC(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 70 %

Procedure:
To a stirred solution of 10.65 g of 3-bromophthalide in 120 ml of dimethylformamide at room temperature is added 15.9 g of sodium 2-(2,6-dichloroanilino)-phenylacetate. The reaction mixture is stirred 24 hours at the room temperature, and then poured into 500 ml of ice water. After extraction with chloroform, the aqueous phase is washed with an aqueous solution of sodium bicarbonate, then with water and finally it is dried on anhydrous sodium sulfate and evaporated to dryness to yield the phthalidyl 2-(2,6-dichloroanilino)-phenylacetate; yield 70%.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][CH2:7][CH2:8][O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])=[CH:4][C:3]=1[F:19].C([N-]C(C)C)(C)C.[Li+].CN(C)[CH:30]=[O:31].C(O)(=O)C>O1CCCC1.O>[Br:1][C:2]1[C:3]([F:19])=[C:4]([C:5]([O:6][CH2:7][CH2:8][O:9][Si:10]([C:13]([CH3:15])([CH3:14])[CH3:16])([CH3:11])[CH3:12])=[CH:17][CH:18]=1)[CH:30]=[O:31]
Reactant: CN(C)C=O
Reactant: CC(C)(C)[Si](C)(C)OCCOc1ccc(Br)c(F)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCOc1ccc(Br)c(F)c1C=O
Yield: 64.5 %

Procedure:
In a manner similar to the method described in example 52a, 1 [2-(4-bromo-3-fluoro-phenoxy)-ethoxy]-tert-butyl-dimethyl-silane (17.2 g, 49.3 mmol) prepared in example 183a was reacted with lithium diisopropyl amide (32.8 mL, 2.0 M in THF, 59.1 mmol), N,N-dimethyl-formamide (4.57 mL, 59.1 mmol) and quenched with acetic acid (12.1 g, 197.2 mmol) and water (61.8 mL) in tetrahydrofuran to give 3-bromo-6-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-2-fluoro-benzaldehyde as white solid (Yield: 12 g, 67%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:17]=[C:18]([CH3:20])[CH:19]=1)[O:6][CH2:7][CH2:8][O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].[N+](C(C)C)([O-])=[O:22].[O-]CC.[Na+]>C(OCC)(=O)C>[C:13]([Si:10]([CH3:12])([CH3:11])[O:9][CH2:8][CH2:7][O:6][C:5]1[CH:4]=[C:3]([CH:19]=[C:18]([CH3:20])[CH:17]=1)[CH:2]=[O:22])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)[N+](=O)[O-]
Reactant: Cc1cc(CBr)cc(OCCO[Si](C)(C)C(C)(C)C)c1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cc1cc(C=O)cc(OCCO[Si](C)(C)C(C)(C)C)c1
Temperature: 90 °C

Procedure:
To a solution of [2-(3-bromomethyl-5-methyl-phenoxy)-ethoxy]-tert-butyl-dimethyl-silane (2.17 g, 6.04 mmol) under nitrogen in 2-nitropropane (2.0 mL, 20 mmol) was added sodium ethoxide (0.620 g, 9.06 mmol). The resulting mixture was heated at 90° C. for 15 hours, and was then diluted with ethyl acetate and quenched with saturated aqueous ammonium chloride. The aqueous layer was extracted with ethyl acetate and the combined organic layers were backwashed with water and brine, dried over sodium sulfate, and concentrated. The crude material (1.81 g) was purified by column chromatography (silica gel 230-400 mesh; 1/0 to 4/1 hexanes/EtOAc as eluent) to give 3-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-methyl-benzaldehyde as a yellow oil. Yield: 0.97 g (55%).
Reaction SMILES: [CH3:1][CH:2]([CH3:13])[CH2:3][CH:4]([C:9](=[O:12])[NH:10][CH3:11])[CH2:5][C:6]([OH:8])=[O:7].[F:14][C:15]1[C:20](O)=[C:19]([F:22])[C:18]([F:23])=[C:17]([F:24])[C:16]=1[F:25].C(Cl)CCl>ClCCl>[F:14][C:15]1[C:16]([F:25])=[C:17]([F:24])[C:18]([F:23])=[C:19]([F:22])[C:20]=1[O:7][C:6](=[O:8])[CH2:5][CH:4]([C:9](=[O:12])[NH:10][CH3:11])[CH2:3][CH:2]([CH3:13])[CH3:1]
Reactant: CNC(=O)C(CC(=O)O)CC(C)C
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Solvent: ClCCl
Solvent: ClCCCl
Product: CNC(=O)C(CC(=O)Oc1c(F)c(F)c(F)c(F)c1F)CC(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.5 %

Procedure:
To an ice-cooled solution of 5-methyl-3-methylcarbamoyl-hexanoic acid (0.40 g, 2.13 mmol) in dichloromethane (10 ml) was added pentafluorophenol (0.43 g, 2.35 mmol) and EDC (0.45 g, 2.35 mmol). The mixture was stirred at room temperature for 2 h, diluted with more dichloromethane and washed successively with 1 M Na2CO3 solution, 1M HCl and brine. The organic phase was dried (anhydrous MgSO4), filtered and evaporated to leave the title compound as an oil (0.38 g, 56%), which was used in Step D without further purification. 1H-NMR; δ (CDCl3), 5.77 (1H, m), 3.10 (1H, m), 2.83 (3H, d, J=4.7 Hz), 2.75 (2H, m), 1.70 (1H, m), 1.59 (1H, m), 1.31 (1H, m), 0.95 (3H, d, J=4.9 Hz) and 0.93 (3H, d, J=4.8 Hz).
Reaction SMILES: [OH:1][CH:2]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)[C:3]#[C:4][C:5]1([OH:11])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1>ClCCl.[O-2].[O-2].[Mn+4]>[OH:11][C:5]1([C:4]#[C:3][C:2]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)=[O:1])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: Cc1ccc(C(O)C#CC2(O)CCCCC2)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: Cc1ccc(C(=O)C#CC2(O)CCCCC2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 90.9 %

Procedure:
To a solution of 1-(3-hydroxy-3-(p-tolyl)propyn-1-yl)cyclohexanol (Reference Example 2) (593 mg, 2.42 mmol) in dichloromethane (20 mL), manganese dioxide (1.15 g, 13.2 mmol) was added, and the obtained solution was stirred at room temperature for 5 hours. The reaction solution was filtered through Celite and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, n-hexane/ethyl acetate) to obtain the captioned compound (534 mg, 2.20 mmol, 91%) as a light yellow oily product.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Cl)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH2:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1>>[Si:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][NH:17][C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=2)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CCl)cc1
Reactant: N#Cc1ccc(N)cc1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CNc2ccc(C#N)cc2)cc1
Yield: 25.2 %

Procedure:
The procedure of Preparation Example 7 was repeated, except that 2.058 g of 4-(tert-butyldimethylsilyloxy)benzyl chloride was used in place of 4-benzyloxybenzyl chloride, and 0.946 g of 4-aminobenzonitrile was used in place of 4-aminophenol. The resulting crude product was purified by silica gel column chromatography (using a 3:1 mixture of hexane and ethyl acetate as the eluent) to obtain 0.682 g of 4-[N-(4-tert-butyldimethylsilyloxybenzyl)amino]benzonitrile.