Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[N:5]=[C:4]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=2)[CH:3]=1.[NH:22]([CH3:24])[CH3:23].Cl.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:23][N:22]([CH3:24])[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[N:5]=[C:4]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=2)[CH:3]=1
Reactant: O=C(O)c1ccc(-c2cc(F)c3cc(O)ccc3n2)cc1
Reactant: CNC
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)c1cc(-c2ccc(C(=O)O)cc2)nc2ccc(O)cc12
Temperature: 160 °C
Yield: 32.2 %

Procedure:
30 mg of 4-(4-fluoro-6-hydroxyquinolin-2-yl)benzoic acid (Compound 26) was mixed with 1 mmol Me2NH.HCl and 0.5 ml DIEA in 3 ml DMF and heated to 160° C. for 30 minutes. The solvent was evaporated to dryness and water was added. The solid was filtered and washed with water and dried. The crude was triturated with acetone to obtain 10.5 mg of Compound 47. 1H NMR (DMSO-d6 300 MHz TMS): δ 13.2 (b, 1H), 10.28 (s, 1H), 8.22 (m, 2H), 8.11 (d, 1H), 7.99 (d, 1H), 7.50 (s, 1H), 7.39 (d, 1H), 7.26 (s, 1H), 3.24 (s, 6H), MS (ESI): m/z=309.30 [M+1]+.
Reaction SMILES: [F:1][C@:2]1([CH3:18])[C@H:6]([OH:7])[C@@H:5]([CH2:8]O)[O:4][C@H:3]1[N:10]1[CH:15]=[CH:14][C:13](=[O:16])[NH:12][C:11]1=[O:17].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N1C=CN=C1.[I:43]I>C1COCC1>[F:1][C@:2]1([CH3:18])[C@H:6]([OH:7])[C@@H:5]([CH2:8][I:43])[O:4][C@H:3]1[N:10]1[CH:15]=[CH:14][C:13](=[O:16])[NH:12][C:11]1=[O:17]
Reactant: C[C@@]1(F)[C@H](O)[C@@H](CO)O[C@H]1n1ccc(=O)[nH]c1=O
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@@]1(F)[C@H](O)[C@@H](CI)O[C@H]1n1ccc(=O)[nH]c1=O
Temperature: 20 °C
Reaction time: 0.33 h
Yield: 93.9 %

Procedure:
Chiral 1-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-hydroxymethyl-3-methyl-tetrahydro-furan-2-yl)-1H-pyrimidine-2,4-dione (6.14 g, 23.6 mmol), PPh3 (9 g, 34.4 mmol), imidazole (2.4 g, 34.4 mmol) and dry THF (100 mL) were added into a 3-neck flask bottle (500 mL), the mixture was stirred at 20° C. under nitrogen atmosphere for 20 min. Then I2 (6.6 g, 26 mmol) dissolved in dry THF (100 mL) was added into the mixture dropwise at 20° C. during 30 min, after addition, the whole mixture was stirred at 20° C. under nitrogen atmosphere for 18 hrs. TLC showed that the SM was consumed, then water (50 mL) was added into it, the mixture was extracted by EA (150 mL×3), organic layer was washed with brine, dried over Na2SO4, removed solvent by reduced pressure, residue was purified by silica gel chromatography column (DCM:MeOH=100:1 to 50:1) to afford the title compound as a white solid (8.2 g, 94%).
Reaction SMILES: [CH2:1]([CH:8]([CH2:13][N:14]([CH3:16])[CH3:15])[C:9](OC)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>CCOCC>[CH2:1]([CH:8]([CH2:13][N:14]([CH3:16])[CH3:15])[CH2:9][OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C(Cc1ccccc1)CN(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: CN(C)CC(CO)Cc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of methyl 2-benzyl-3-dimethylaminopropionate (60.0 g) in ether (300 ml) is added dropwise with stirring under a nitrogen atmosphere to a suspension of lithium aluminum hydride (28.0 g) in ether (700 ml). The reaction mixture is refluxed for 4 hours, then stirred at room temperature for 18 hours. The reaction mixture is cooled to 0°, and water (30 ml) is added cautiously (dropwise initially) followed by 10% NaOH (60 ml). The solid inorganic material is filtered off, and the filtrate dried over magnesium sulfate. The solvent is removed under reduced pressure to give 2-benzyl-3-dimethylaminopropanol as an oil which is used without further purification; NMR(CDCl3): δ7.12 (m, 5H), 5.62 (broad s, 1H), 3.57 (m, 2H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[Li]CCCC.CCCCCC.[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[S:27][C:28]([C:31](=[O:33])[CH3:32])=[CH:29][N:30]=2)=[CH:22][CH:21]=1>C1COCC1>[F:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[S:27][C:28]([C:31]([C:2]3[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=3)([OH:33])[CH3:32])=[CH:29][N:30]=2)=[CH:24][CH:25]=1
Reactant: Ic1ccncc1
Reactant: CC(=O)c1cnc(-c2ccc(F)cc2)s1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(O)(c1ccncc1)c1cnc(-c2ccc(F)cc2)s1
Reaction time: 0.17 h
Yield: 98.2 %

Procedure:
A solution 4-iodopyridine (1 g, 4.88 mmol) in THF (15 mL) was cooled to −78° C. under nitrogen, 1.6 M n-BuLi in hexane (0.565 mL, 8.14 mmol) was slowly added at −78° C. The reaction mixture was stirred for 10 min and 1-(2-(4-fluorophenyl)thiazol-5-yl) ethanone (900 mg, 4.07 mmol) in THF (25 mL) was added. The resulting mixture was stirred at −78° C. for 2 h. The reaction mixture was quenched with saturated NH4Cl solution (160 mL), extracted with ethyl acetate (3×250 mL), the organic layer dried over Na2SO4, filtered and concentrated under reduced pressure to obtain crude product. The crude product was purified by flash chromatography (100-200μ; 70% ethyl acetate in hexane) to afford 1-(2-(4-fluorophenyl)thiazol-5-yl)-1-(pyridin-4-yl)ethanol as off-white solid (1.2 g, 35% yield) in 99.6% HPLC purity. 1H NMR (400 MHz, DMSO-d6): δ 8.51 (d, 2H), 7.88-7.92 (m, 2H), 7.81 (s, 1H), 7.48 (d, 2H), 7.28 (t, 2H), 6.64 (s, 1H), 1.93 (s, 3H); LC-MS m/z calculated for [M+H]+301.07. found 301.1.
Reaction SMILES: C([Li])CCC.[Br:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10](Br)=[CH:9][N:8]=1.[F:15][C:16]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:17]=1[CH:18]=[O:19].[Cl-].[NH4+]>C(OCC)C.CCCCCC>[Br:6][C:7]1[N:8]=[CH:9][C:10]([CH:18]([C:17]2[CH:20]=[C:21]([F:24])[CH:22]=[CH:23][C:16]=2[F:15])[OH:19])=[C:11]([CH3:13])[CH:12]=1
Reactant: O=Cc1cc(F)ccc1F
Reactant: Cc1cc(Br)ncc1Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CCOCC
Product: Cc1cc(Br)ncc1C(O)c1cc(F)ccc1F
Reaction time: 0.5 h
Yield: 33.4 %

Procedure:
In an argon atmosphere, a hexane solution of n-butyllithium M, 8.22 ml, 13.2 mmol) was added to a solution of 2,5-dibromo-4-methylpyridine (3.00 g, 12.0 mmol) in diethyl ether (120 ml) at −78° C. After stirring the reaction mixture for 30 minutes, 2,5-difluorobenzaldehyde (1.34 ml, 12.0 mmol) was added. After stirring for 1 hour at the same temperature, saturated aqueous ammonium chloride was added at room temperature. After the organic layer was separated, the organic layer was dried over anhydrous sodium sulfate and filtered, and then the filtrate was concentrated under reduced pressure. The resulting residue was subjected to flash silica gel chromatography. The fraction obtained from an elution with hexane:ethyl acetate=4:1 was concentrated under reduced pressure, to obtain the title compound (1.26 g, 4.01 mmol, 34%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[CH:4][C:3]=1[N:22]=[C:23]1[N:27]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:26](=[O:34])[CH:25]([CH2:35][C:36](=[O:58])[NH:37][O:38]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[S:24]1.C([SiH](C(C)C)C(C)C)(C)C.CO>FC(F)(F)C(O)=O.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:17])[F:18])[N:11]([CH3:20])[C:10]2=[O:21])=[CH:4][C:3]=1[N:22]=[C:23]1[N:27]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:26](=[O:34])[CH:25]([CH2:35][C:36](=[O:58])[NH:37][OH:38])[S:24]1
Reactant: CCOC(=O)CN1C(=O)C(CC(=O)NOC(c2ccccc2)(c2ccccc2)c2ccccc2)SC1=Nc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Agent: CC(C)[SiH](C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)CN1C(=O)C(CC(=O)NO)SC1=Nc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl

Procedure:
A solution of ethyl 2-{{2-chloro-5-[3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-4-fluorophenyl}imino}-4-oxo-5-{[(trityloxy)carbamoyl]-methyl}-3-thiazolidineacetate (entire sample from Example 23) and triisopropylsilane (1 mL) in trifluoroacetic acid (19 mL) is stirred at room temperature for 4 hours, cooled with an ice-water bath, and filtered. The resultant filtrate is concentrated in vacuo and chased three times with toluene to obtain a solid. Column chromatography of the solid using silica gel and a 7.5% methanol in methylene chloride solution gives the title product as a yellow solid which is identified by 1H NMR spectral analysis.
Reaction SMILES: C[O:2][C:3](=[O:26])/[CH:4]=[C:5](\[CH3:25])/[CH:6]=[CH:7]/[C:8](/[F:24])=[C:9](\[CH3:23])/[CH:10]=[CH:11]/[C:12]1[C:17]([Cl:18])=[CH:16][C:15]([O:19][CH3:20])=[C:14]([CH3:21])[C:13]=1[Cl:22].CO.[OH-].[Na+].C/C(/C=C/C(/F)=C(\C)/C=C/C1C(Cl)=CC(OC)=C(C)C=1Cl)=C\C(O)=O>O>[CH3:25][C:5]([CH:6]=[CH:7]/[C:8](/[F:24])=[C:9](\[CH3:23])/[CH:10]=[CH:11]/[C:12]1[C:17]([Cl:18])=[CH:16][C:15]([O:19][CH3:20])=[C:14]([CH3:21])[C:13]=1[Cl:22])=[CH:4][C:3]([OH:26])=[O:2]
Reactant: COC(=O)/C=C(C)/C=C/C(F)=C(C)/C=C/c1c(Cl)cc(OC)c(C)c1Cl
Agent: COc1cc(Cl)c(/C=C/C(C)=C(F)/C=C/C(C)=C/C(=O)O)c(Cl)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc(Cl)c(/C=C/C(C)=C(\F)C=CC(C)=CC(=O)O)c(Cl)c1C

Procedure:
In a manner similar to that described in Example 24, 1.2 g. (3 mmol) of methyl-(2E,4E,6Z,8E)-3,7-dimethyl-6-fluoro-9-(2,6-dichloro-3-methyl-4-methoxyphenyl)-nonatetraenoate were dissolved in 10 ml. of methanol and treated with a solution of 0.59 g. of sodium hydroxide in 4 ml. of water. The work-up as described in Example 24 afforded 2E,4E,6Z,8E-3,7-dimethyl-6-fluoro-9-(2,6-dichloro-3-methyl-4-methoxyphenyl)-2,4,6,8-nonatetraenoic acid.
Reaction SMILES: [CH3:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5]([C:10]([OH:12])=O)[NH:4][N:3]=1.[CH3:13][C:14]1[C:18]([N+:19]([O-:21])=[O:20])=[C:17]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[NH:16][N:15]=1>>[CH3:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5]([C:10]([NH2:15])=[O:12])[NH:4][N:3]=1.[CH3:13][C:14]1[C:18]([N+:19]([O-:21])=[O:20])=[C:17]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[NH:16][N:15]=1
Reactant: Cc1n[nH]c(C(=O)O)c1[N+](=O)[O-]
Agent: CCOC(=O)c1[nH]nc(C)c1[N+](=O)[O-]
Product: Cc1n[nH]c(C(N)=O)c1[N+](=O)[O-]

Procedure:
In a method for synthesizing 7-alkylamino-3-methylpyrazolo[4,3-d]pyrimidines, including the steps of esterifying 3-methyl-4-nitropyrazole-5-carboxylic acid to ethyl 3-methyl-4-nitropyrazole-5-carboxylate, forming 3-methyl-4-nitropyrazole-5-carboxamide from ethyl 3-methyl-4-nitropyrazole-5-carboxylate, catalytically reducing and formylating ethyl 3-methyl-4-nitropyrazole-5-carboxamide to produce 4-formylamino-3-methylpyrazole-5-carboxamide, closing the ring of 4-formylamino-3-methylpyrazole-5-carboxamide to produce 3-methyl-7-hydroxypyrazolo[4,3-d]pyrimidine, chlorinating said 3-methyl-7-hydroxypyrazolo [4,3-d]pyrimidine to produce 7-chloro-3-methylpyrazolo-[4,3-d], and reacting said 7-chloro-3-methylpyrazolo[4,3-d]pyrimidine with an alkylamine to produce a 7-alkylamino-3-methylpyrazolo[4,3-d]pyrimidine:
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH2:12]([C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1)[CH3:13]>[Cl-].[Zn+2].[Cl-].Cl>[NH2:18][C:17]1[CH:19]=[CH:20][C:14]([CH2:12][CH3:13])=[CH:15][C:16]=1[C:4]([C:3]1[CH:7]=[CH:8][C:9]([F:11])=[CH:10][C:2]=1[F:1])=[O:5]
Reactant: CCc1ccc(N)cc1
Reactant: O=C(Cl)c1ccc(F)cc1F
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Product: CCc1ccc(N)c(C(=O)c2ccc(F)cc2F)c1
Temperature: 200 °C
Reaction time: 2.5 h
Yield: 30.6 %

Procedure:
Zinc chloride (7.2 g) was added portionwise to a stirred mixture of 2,4-difluorobenzoyl chloride (17 g) and 4-ethylaniline (5.3 g) at 180° C. The mixture was stirred for 2.5 hours at 200° C. and cooled to 120° C. To the mixture was added 3N hydrochloric acid (50 ml) and the resulting mixture was refluxed for 1.5 hours, then the supernatant was decanted out. The above procedure was repeated three times. 75% Sulfuric acid (40 ml) was added and the reaction mixture was stirred and heated at 140° C. for 2 hours. The reaction mixture was poured into ice (500 ml) and extracted with dichloromethane. The organic layer was washed with 3N hydrochloric acid (200 ml), 3N sodium hydroxide (200 ml) and water, dried, and evaporated. The oily residue (5.7 g) was purified by column chromatography on silica gel (170 g) eluting with toluene to give crystals of 2-amino-5-ethyl-2',4'-difluorobenzophenone (3.5 g).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([N+:11]([O-])=O)[C:5]=1[CH2:14][N:15]=[N+]=[N-].C(O)(=O)C>C(O)C.[Pd]>[NH2:11][C:6]1[CH:7]=[C:8]([F:10])[CH:9]=[C:4]2[C:5]=1[CH2:14][NH:15][C:3]2=[O:2]
Reactant: COC(=O)c1cc(F)cc([N+](=O)[O-])c1CN=[N+]=[N-]
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: Nc1cc(F)cc2c1CNC2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.86 g (7.32 mmol) of 2-(azidomethyl)-5-fluoro-3-nitrobenzoic acid methyl ester is added in 46 ml of ethanol and 3.4 ml of glacial acetic acid and mixed with 256.6 mg of Pd/C. After stirring overnight at room temperature under a hydrogen atmosphere, the catalyst is suctioned off via a glass fiber filter, and the filtrate is evaporated to the dry state. The residue, 1.18 mg (97.5%) of the desired compound, is further incorporated in crude form.
Reaction SMILES: [C:1]1([CH:7]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](O)([C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][C:26]=3[OH:27])[O:23][CH2:22][CH2:21][CH2:20]4)[C:9]2=[O:29])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C2C=1C(O)(C1C(O)=CC3OCCC=3C=1)C(=O)N2C(C1C=CC=CC=1)C1C=CC=CC=1>>[C:30]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][C:26]=3[OH:27])[O:23][CH2:22][CH2:21][CH2:20]4)[C:9]2=[O:29])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C1(O)c1cc2c(cc1O)OCCC2
Agent: O=C1N(C(c2ccccc2)c2ccccc2)c2cccc(Cl)c2C1(O)c1cc2c(cc1O)OCC2
Product: O=C1C(c2cc3c(cc2O)OCCC3)c2ccccc2N1C(c1ccccc1)c1ccccc1

Procedure:
Following the procedure as described in PREPARATION 4C, and making non-critical variations using 1-(diphenylmethyl)-3-hydroxy-3-(7-hydroxy-3,4-dihydro-2H-chromen-6-yl)-1,3-dihydro-2H-indol-2-one to replace 4-chloro-1-(diphenylmethyl)-3-hydroxy-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one, 1-(diphenylmethyl)-3-(7-hydroxy-3,4-dihydro-2H-chromen-6-yl)-1,3-dihydro-2H-indol-2-one was obtained (81%) as a pale yellow solid: mp 207-210° C. (hexanes): 1H NMR (300 MHz, CDCl3) δ8.43 (br s, 1H), 7.37-7.22 (m, 11H), 7.09-7.03 (m, 2H), 6.99 (s, 1H), 6.58 (s, 1H), 6.56-6.50 (m, 1H), 6.48 (s, 1H), 5.05 (s, 1H), 4.15-4.08 (m, 2H), 2.68-2.51 (m, 2H), 1.97-1.89 (m, 2H); 13C NMR (75 MHz, CDCl3) δ179.1, 155.4, 154.9, 143.4, 137.5, 137.4, 128.8, 128.7, 128.6, 128.5, 128.1, 127.9, 127.3, 125.9, 122.9, 115.8, 114.6, 112.8, 106.7, 66.5, 58.8, 47.3, 24.4, 22.6; MS (ES+) m/z 448.1 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.[CH2:9]([O:11][C:12](=[O:19])[CH:13]=[C:14]([NH2:18])[S:15][CH2:16][CH3:17])[CH3:10]>C(O)C>[CH2:9]([O:11][C:12]([C:13]1[CH:7]([C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)[CH:13]([C:12]([O:11][CH2:9][CH3:10])=[O:19])[C:14]([S:15][CH2:16][CH3:17])=[N:18][C:14]=1[NH2:18])=[O:19])[CH3:10]
Reactant: CCOC(=O)C=C(N)SCC
Reactant: O=Cc1ccncc1
Solvent: CCO
Product: CCOC(=O)C1=C(N)N=C(SCC)C(C(=O)OCC)C1c1ccncc1
Yield: 47 %

Procedure:
Upon boiling a solution of 5.3 g of pyridine-4-aldehyde and 17.5 g of 3-amino-3-ethylmercaptoacrylic acid ethyl ester in 100 ml of ethanol for 5hours, 2-amino-4-(4-pyridyl)-6-ethylmercapto-4,5-dihydropyridine-3,5-dicarboxylicacid diethyl ester of melting point 156° C is obtained.
Reaction SMILES: [CH3:1][C:2]([C:7]1[CH:12]=[CH:11][C:10]([B:13]2[O:17][C:16]([CH3:19])([CH3:18])[C:15]([CH3:21])([CH3:20])[O:14]2)=[CH:9][CH:8]=1)([CH3:6])[C:3](O)=[O:4].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH3:36][CH:37]([CH3:40])[CH2:38][NH2:39]>C(Cl)Cl>[CH2:38]([NH:39][C:3](=[O:4])[C:2]([CH3:6])([C:7]1[CH:8]=[CH:9][C:10]([B:13]2[O:14][C:15]([CH3:20])([CH3:21])[C:16]([CH3:18])([CH3:19])[O:17]2)=[CH:11][CH:12]=1)[CH3:1])[CH:37]([CH3:40])[CH3:36]
Reactant: CC(C)(C(=O)O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: CC(C)CN
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)CNC(=O)C(C)(C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reaction time: 0.08 h
Yield: 99.2 %

Procedure:
2-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoic acid (example 20d) (10 g, 34.46 mmol), EDC (7.26 g, 37.91 mmol) and HOBt (5.12 g, 37.91 mmol) were mixed in DCM (350 mL) and stirred for 5 minutes then 2-methylpropan-1-amine (3.6 mL, 36.19 mmol) was added. The reaction mixture was stirred at room temperature overnight then diluted with dichloromethane and washed successively with aq. HCl (0.5N), water, aq. NaHCO3, water and brine, dried over MgSO4, filtered and evaporated. The residue was crystallized from EtOAc/hexane to give 11.8 g of product as a white solid in 99% yield. 1H NMR (400 MHz, CDCl3): δ 0.76-0.78 (d, 6H), 1.35(s, 12H), 1.57 (s, 6H), 1.62 (m, 1H), 2.97 (t, 2H), 5.15 (br-s, 1H), 7.38-7.40 (d, 2H), 7.79-7.81 (d, 2H). MS (M+H, 346).
Reaction SMILES: [Cl:1][C:2]1[CH:43]=[C:42]([S:44](=[O:63])(=[O:62])[N:45](CC2C=CC(OC)=CC=2OC)[C:46]2[S:47][CH:48]=[N:49][N:50]=2)[C:41]([F:64])=[CH:40][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[CH:7][C:6]=1[C:21]1[CH:26]=[CH:25][N:24]=[C:23]([N:27]2[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]2)[CH:22]=1.Cl>CO.O1CCOCC1>[ClH:1].[Cl:1][C:2]1[C:3]([O:4][C:5]2[CH:10]=[CH:9][C:8]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:13][CH:12]=3)=[CH:7][C:6]=2[C:21]2[CH:26]=[CH:25][N:24]=[C:23]([N:27]3[CH2:28][CH2:29][NH:30][CH2:31][CH2:32]3)[CH:22]=2)=[CH:40][C:41]([F:64])=[C:42]([S:44]([NH:45][C:46]2[S:47][CH:48]=[N:49][N:50]=2)(=[O:63])=[O:62])[CH:43]=1
Reactant: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(Oc3ccc(-c4ccc(C(F)(F)F)cc4)cc3-c3ccnc(N4CCN(C(=O)OC(C)(C)C)CC4)c3)cc2F)c(OC)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: O=S(=O)(Nc1nncs1)c1cc(Cl)c(Oc2ccc(-c3ccc(C(F)(F)F)cc3)cc2-c2ccnc(N3CCNCC3)c2)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.5 %

Procedure:
tert-Butyl 4-(4-(4-(2-chloro-4-(N-(2,4-dimethoxybenzyl)-N-(1,3,4-thiadiazol-2-yl)sulfamoyl)-5-fluorophenoxy)-4′-(trifluoromethyl)biphenyl-3-yl)pyridin-2-yl)piperazine-1-carboxylate (Preparation 113, 340 mg, 0.361 mmol) was dissolved in methanol (1 mL) and a 4M solution of hydrogen chloride in 1,4-dioxane (3 mL) was added. The reaction mixture was stirred at room temperature for 3 hours and then concentrated in vacuo. The resulting residue was purified by reverse phase chromatography using the ISCO™ system and acetonitrile/water 5/95-95/5 with 0.1% formic acid as eluent to afford the title compound (90 mg, 34%) as a white solid.
Reaction SMILES: C([SiH](CC)CC)C.[Br:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)=O>CCOCC>[Br:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:18]1[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=1
Reactant: O=C(CCCCCCCBr)c1ccc(F)cc1
Agent: CC[SiH](CC)CC
Solvent: CCOCC
Product: Fc1ccc(CCCCCCCCBr)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Triethylsilane (30.5 g, 260 mmol) was added dropwise to 8-bromo-1-(4-fluorophenyl)octan-1-one (230 ml, 105 mmol) over 20 min, with cooling to keep the temperature at ca 30° C. After 2 hours stirring, a further 3.1 g (27 mmol) triethylsilane was added, and reaction continued for an additional 2 hours. The mixture was poured into ice-water (200 ml) and ether (300 ml), then the organic layer was washed with aqueous sodium hydroxide. dried and evaporated, finally at 65° C./0.01 mm. The residue was filtered through silica gel, eluting with petroleum ether, then distilled, collecting the fraction at 122-140° C./0.5 mm (24.2 g). 1H-NMR (CDCl3) δ 1.2-1.7 (10H, m), 1.85 (2H, m), 2.57 (2H, t), 3.40 (2H, t), 6.9-7.05 (2H, m) and 7.05-7.2 (2H, m).
Reaction SMILES: C(OP([CH:9]([F:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.[Br-].[Mg+2].[Br-].CCN(CC)CC.[Cl:26][C:27]1[C:28]([NH:35][C@@H:36]2[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37]2)=[N:29][CH:30]=[C:31]([CH:33]=O)[CH:32]=1>C1COCC1.C(OCC)(C)=O.O>[Cl:26][C:27]1[C:28]([NH:35][C@@H:36]2[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37]2)=[N:29][CH:30]=[C:31](/[CH:33]=[C:9](\[F:15])/[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:32]=1
Reactant: CCOC(=O)C(F)P(=O)(OCC)OCC
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Nc2ncc(C=O)cc2Cl)C1
Agent: [Br-]
Agent: [Mg+2]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)/C(F)=C/c1cnc(N[C@@H]2CCN(C(=O)OC(C)(C)C)C2)c(Cl)c1
Temperature: 7.5 °C
Yield: 92.1 %

Procedure:
To a mixture of ethyl (diethoxyphosphoryl)(fluoro)acetate (2.08 g) and magnesium bromide (1.9 g) in THF (20 ml) was added dropwise to a Et3N (1.32 ml) with stirring at 0-15° C. under atmospheric pressure of nitrogen, and the reaction mixture was stirred at same condition for an hour. A solution of tert-butyl (3R)-3-[(3-chloro-5-formyl-2-pyridinyl)amino]-1-pyrrolidinecarboxylate (2.0 g) in THF (10 ml) solution was added the above mixture and resultant mixture was stirred at 0-15° C. for 4 hours. The reaction mixture was poured into a mixture of AcOEt-H2O and the organic layer was washed with brine and dried over MgSO4. The solvent was evaporated in vacuo and the residue was chromatographed on silicagel eluting with AcOEt-n-hexane (3:7). The eluted fractions containing the desired product were collected and evaporated in vacuo to give tert-butyl (3R)-3-({3-chloro-5-[(1Z)-3-ethoxy-2-fluoro-3-oxo-1-propen-1-yl]-2-pyridinyl}amino)-1-pyrrolidinecarboxylate (2.34 g)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[Cl:9][C:10](Cl)=[CH:11][C:12]([CH3:15])([CH3:14])[CH3:13]>>[Cl:9][CH:10]=[C:11]([O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=1)[C:12]([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)C=C(Cl)Cl
Reactant: Cc1cccc(O)c1
Product: Cc1cccc(OC(=CCl)C(C)(C)C)c1
Yield: 87.2 %

Procedure:
Analogously to Example A6(a), 0.2 mol of 3-methylphenol and 0.1 mol of 1,1-dichloro-3,3-dimethyl-1-butene are reacted to give 19.6 g of 1-chloro-3,3-dimethyl-2-(3'-methylphenoxy)-1-butene of boiling point 95°-100° C./0.7 mm Hg. The yield is 87% of theory.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:31](Cl)=[O:32])[CH:13]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[C:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:34][CH2:35][CH3:36])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:37]1([C:43]([CH:45]2[CH2:49][CH2:48][CH2:47][O:46]2)=[O:44])[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:31]([N:40]3[CH2:41][CH2:42][N:37]([C:43]([CH:45]4[CH2:49][CH2:48][CH2:47][O:46]4)=[O:44])[CH2:38][CH2:39]3)=[O:32])[C@H:13]([C:24]3[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=3)[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:34][CH2:35][CH3:36])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(C1CCCO1)N1CCNCC1
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(C(=O)C2CCCO2)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4-methyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with piperazin-1-yl-(tetrahydro-furan-2-yl)-methanone (Aldrich) to give the title compound. LC-MS: 691.3 [(M+H)+]