Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:29](O)=[O:30])[CH2:20][O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1.[NH2:57][CH2:58][CH2:59][CH2:60][CH2:61][N:62]([CH2:75][C:76]1[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=1)[CH2:63][CH2:64][C@H:65]([NH:67][C:68](=[O:74])[O:69][C:70]([CH3:73])([CH3:72])[CH3:71])[CH3:66]>ClCCl.C(OCC)(=O)C>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:20][O:21][CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:29](=[O:30])[NH:57][CH2:58][CH2:59][CH2:60][CH2:61][N:62]([CH2:75][C:76]3[CH:77]=[CH:78][CH:79]=[CH:80][CH:81]=3)[CH2:63][CH2:64][C@@H:65]([CH3:66])[NH:67][C:68]([O:69][C:70]([CH3:73])([CH3:71])[CH3:72])=[O:74])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: C[C@H](CCN(CCCCN)Cc1ccccc1)NC(=O)OC(C)(C)C
Reactant: O=C(N[C@@H](COCc1ccccc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C[C@H](CCN(CCCCNC(=O)[C@H](COCc1ccccc1)NC(=O)OCC1c2ccccc2-c2ccccc21)Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96.9 %

Procedure:
1.71 g (4.1.10-3 mol) of N-[(9H-fluoren-9-yl)methoxycarbonyl]-O-phenylmethyl-(L)-serine are dissolved in 60 ml of dichloromethane. The solution is cooled to 0° C. and a solution of 0.55 g (4.10-3 mol) of HOBT and 1.54 g (7.5.10-3 mol) of DCC in 20 ml of dichloromethane is added. The mixture is stirred for 0.5 hour, 1.30 g (3.72.10-3 mol) of N-[3-[(4-aminobutyl)(phenylmethyl)amino]-1-(R)-methylpropyl]carbamic acid, 1, 1-dimethylethyl ester are then added and the reaction mixture is stirred at room temperature for 16 hours. The solvent is removed under reduced pressure and the residue is purified by chromatography on silica gel using an ethyl acetate/methylcyclohexane mixture (1/1 v/v) and then pure ethyl acetate as the eluent to give 2.7 g of the expected product in the form of a white crystalline solid (yield=96%).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:10](Br)=[C:4]2[C:5]([NH:7][C:8](=[O:9])[C:3]=12)=[O:6].[O:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH:16]=[C:15]1B(O)O.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:1][C:2]1[CH:12]=[CH:11][C:10]([C:15]2[O:14][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[CH:16]=2)=[C:4]2[C:5]([NH:7][C:8](=[O:9])[C:3]=12)=[O:6]
Reactant: Nc1ccc(Br)c2c1C(=O)NC2=O
Reactant: OB(O)c1cc2ccccc2o1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Nc1ccc(-c2cc3ccccc3o2)c2c1C(=O)NC2=O
Yield: 32.6 %

Procedure:
In a similar manner to Step 2 of Example 1, 3-amino-6-bromophthalimide (80.0 mg, 0.332 mmol) was dissolved in acetonitrile (4.0 mL), and, the solution was treated with 2-benzofuraneboronic acid (161 mg, 0.996 mmol), palladium acetate (9.0 mg, 0.040 mmol), tri(o-tolyl)phosphine (24.3 mg, 0.080 mmol) and triethylamine (0.463 mL, 3.32 mmol), followed by purification by preparative thin-layer chromatography (chloroform/acetonitrile=15/1) to obtain Compound 171 (30.1 mg, yield 33%).
Reaction SMILES: C(OCC([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=O)C(=C)C.[CH2:16]([O:20]C1C=CC(N)=CC=1)[C:17](=[CH2:19])[CH3:18]>>[CH2:16]([O:20][C:15]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH2:9])[C:17](=[CH2:18])[CH3:19]
Reactant: C=C(C)COCC(=O)Nc1ccccc1
Reactant: C=C(C)COc1ccc(N)cc1
Product: C=C(C)COc1ccccc1N

Procedure:
The starting material was ortho-methallyloxyacetamidobenzene, which was obtained under the same conditions as those described in Example 4, paragraph (4.1), for paramethallyloxyacetamidobenzene.
Reaction SMILES: N1C=CC=CC=1.[CH3:7][O:8][C:9](=[O:17])[CH2:10][C:11](=[O:16])[CH2:12][CH2:13][O:14][CH3:15].[Cl-].[Mg+2].[Cl-].[C:21](OC(=O)C)(=[O:23])[CH3:22]>ClCCl>[CH3:7][O:8][C:9](=[O:17])[CH:10]([C:21](=[O:23])[CH3:22])[C:11](=[O:16])[CH2:12][CH2:13][O:14][CH3:15]
Reactant: COCCC(=O)CC(=O)OC
Reactant: CC(=O)OC(C)=O
Agent: [Cl-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COCCC(=O)C(C(C)=O)C(=O)OC
Temperature: 25 °C
Yield: 88 %

Procedure:
Pyridine (5.3 ml, 65.92 mmol) was dropped within 3 min to an ice cooled solution of 5-methoxy-3-oxo-pentanoic acid methyl ester (5.28 g, 32.96 mmol) and anhydrous magnesium chloride (3.14 g, 32.96 mmol) in dichloromethane (50 ml). Acetic anhydride (3.27 ml, 34.6 mmol) was added within 3 min. The reaction mixture was stirred over night at RT and after partial removal of the solvent under reduced pressure it was partitioned between ether and 1 N HCl/water. The ether solution was concentrated under reduced pressure to give 5.87 g (29 mmol, 88%) 2-acetyl-5-methoxy-3-oxo-pentanoic acid methyl ester.
Reaction SMILES: [CH2:1](OCC)C.C[Li].O1CCCC1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][N:24]([C:27]3[C:28]([CH3:41])=[C:29]([CH3:40])[C:30]4[O:34][C:33]([CH3:36])([CH3:35])[C:32](=[O:37])[C:31]=4[C:38]=3[CH3:39])[CH2:23][CH2:22]2)=[CH:17][CH:16]=1>C(OCC)(=O)C.O>[CH3:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]2[CH2:22][CH2:23][N:24]([C:27]3[C:28]([CH3:41])=[C:29]([CH3:40])[C:30]4[O:34][C:33]([CH3:36])([CH3:35])[C:32]([CH3:1])([OH:37])[C:31]=4[C:38]=3[CH3:39])[CH2:25][CH2:26]2)=[CH:19][CH:20]=1
Reactant: CCOCC
Reactant: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(=O)C(C)(C)O4)CC2)cc1
Agent: [Li]C
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(C)(O)C(C)(C)O4)CC2)cc1
Reaction time: 0.17 h
Yield: 96.3 %

Procedure:
A diethylether solution (5.60 mL, 6.38 mmol) containing 1.14 M methyl lithium was added dropwise to a solution of tetrahydrofuran (20 mL) containing 5-[4-(4-methoxyphenyl)piperazin-1-yl]-2,2,4,6,7-pentamethyl-1-benzofuran-3(2H)-one (2.00 g, 5.06 mmol) synthesized in Reference Example 42 under ice-cooling condition, and the mixture was stirred for 10 minutes. Water was added to the reaction solution, and extraction was performed using ethyl acetate. The organic layer was washed with water and saturated saline, and then dried using anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the obtained residue was crystallized using hexane to give 2.00 g of the title compound (yield: 96%).
Reaction SMILES: [H-].[Na+].[CH:3]1[C:16]2[NH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[S:8][C:7]=2[CH:6]=[CH:5][C:4]=1[C:17]#[N:18].Cl.C1(C)C=CC(S(O[CH:30]([CH3:37])[CH2:31][N:32]([CH2:35][CH3:36])[CH2:33][CH3:34])(=O)=O)=CC=1.C(OCC)(=O)C>CN(C)C=O>[CH2:33]([N:32]([CH2:35][CH3:36])[CH2:31][CH:30]([N:15]1[C:16]2[CH:3]=[C:4]([C:17]#[N:18])[CH:5]=[CH:6][C:7]=2[S:8][C:9]2[C:14]1=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH3:37])[CH3:34]
Reactant: CCN(CC)CC(C)OS(=O)(=O)c1ccc(C)cc1
Reactant: N#Cc1ccc2c(c1)Nc1ccccc1S2
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCN(CC)CC(C)N1c2ccccc2Sc2ccc(C#N)cc21
Temperature: 110 °C
Reaction time: 7 h

Procedure:
Sodium hydride (19.2 g; in 50% strength dispersion in vaseline) is added in the course of 20 minutes to a solution of 2-phenothiazinecarbonitrile (44.86 g) in N,N-dimethylformamide (600 cc). The mixture obtained is then heated to 110° C., after which the solution of 1-diethylamino-2-propyl p-toluenesulphonate hydrochloride prepared above is added in the course of 35 minutes. The reaction mixture is stirred at 110° C. for 7 hours and then diluted, after cooling, with ethyl acetate (2 liters). The mixture is washed with distilled water (5×1 liter). The organic phase is extracted with 4N hydrochloric acid (240 cc) and the acid aqueous phase is washed with ethyl acetate (750 cc) and then alkalinized with 5N caustic soda (250 cc). The alkaline medium is then extracted with ethyl acetate (1250 cc). The organic phase is washed with distilled water (3×300 cc), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residue is stirred in the presence of ethyl ether (100 cc); a precipitate forms and this is filtered off, and the filtrate is purified by chromatography on a column of silica gel (0.2-0.063 mm) (height: 82 cm; diameter: 4.5 cm), eluting with an 80:20 (by volume) mixture (7 liters) of cyclohexane and ethyl acetate and collecting 100-cc fractions. After concentration to dryness under reduced pressure (30 mm Hg; 4 kPa) at 50° C., 10-[(2RS)-1-diethylamino-2-propyl]-2-phenothiazinecarbonitrile (6.76 g) is obtained from fractions 4 to 9, and a mixture (8.5 g) of 10-[(2RS)-1-diethylamino-2-propyl]-2-phenothiazinecarbonitrile and 10-[(1RS)-2-diethylamino-1-propyl]-2-phenothiazinecarbonitrile is obtained from fractions 10 to 22. The mixture is purified by chromatography on column of silica gel (0.2-0.063 mm) (height: 67 cm; diameter: 3.0 cm), eluting with an 85:15 (by volume) mixture (3 liters) of cyclohexane and ethyl acetate and collecting 50-cc fractions. Fractions 22 to 29 are combined and concentrated to dryness at 50° C. under reduced pressure (30 mm Hg; 4 kPa) to give 10 -[(2RS)-1-diethylamino-2-propyl]-2-phenothiazinecarbonitrile (2.76 g).
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][C:15]=2[C:16]([NH2:18])=[O:17])[N:12]([CH2:19][CH:20]([CH3:22])[CH3:21])[N:11]=[CH:10]3)=[CH:4][CH:3]=1.[C:25]([N:32]1[CH:36]=[CH:35]N=[CH:33]1)(N1C=CN=C1)=O.[CH2:37]1COCC1>>[CH3:33][N:32]([CH3:25])[CH2:36][CH2:35][CH2:37][NH:18][C:16]([C:15]1[CH:14]=[C:13]2[C:9]([CH:10]=[N:11][N:12]2[CH2:19][CH:20]([CH3:22])[CH3:21])=[CH:8][C:7]=1[O:6][C:5]1[CH:23]=[CH:24][C:2]([F:1])=[CH:3][CH:4]=1)=[O:17]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: C1CCOC1
Reactant: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3)c(C(N)=O)cc21
Product: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3)c(C(=O)NCCCN(C)C)cc21
Reaction time: 18 h
Yield: 44 %

Procedure:
A solution of 5-(4-fluorophenoxy)-1-isobutyl-1H-indazole-6-carboxylic acid (compound 10g, prepared as described in Example 46) in THF was treated with carbonyldiimidazole (1.2 equivalents) at room temperature under nitrogen atmosphere. After stirring for 18 hours, the reaction was treated with N-1-dimethyl-propane-1,3-diamine (1 equivalent). After 18 additional hours, the solvent was allowed to slowly evaporate and the residue was purified in a Sep Pak cartridge eluting with a gradient of 100% CH2Cl2 to 5% MeOH/CH2Cl2 to provide compound 11g-9 as an oil in 44% yield.
Reaction SMILES: S(Cl)([Cl:3])=O.CN(C)C=O.O[CH2:11][N:12]1[CH:17]=[C:16]([Cl:18])[CH:15]([Cl:19])[C:14](=O)[NH:13]1.C([O-])(O)=O.[Na+]>O.C(Cl)Cl>[Cl:18][C:16]1[C:15]([Cl:19])=[CH:14][NH:13][N:12]([CH2:11][Cl:3])[CH:17]=1
Reactant: O=S(Cl)Cl
Reactant: O=C1NN(CO)C=C(Cl)C1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: ClCN1C=C(Cl)C(Cl)=CN1
Temperature: 0 °C

Procedure:
4,5-dichloripyridazine-3(2H)-one (60 g, 364 mmol) and distilled water 350 mL) were stirred at room temperature for 10 minutes. A formaldehyde solution (36%, 70 mL) were added and refluxed for 1.5 hours. The resulting material was cooled down to 5-10° C., and the produced precipitate was filtered, washed with cold water (0-5° C., 200 mL), and dried in the air to obtain N-hydroxymethyl-4,5-dichloropyridazine-3(2H)-one. A methylene chloride solution (50 mL) of thionyl chloride (357 mmol) and dimethyl formamide (360 mmol) was slowly added to a mixture of the N-hydroxymethyl-4,5-dichloropyridazine-3(2H)-one and methylene chloride (550 mL) and methylene chloride (550 mL) at room temperature for 30 minutes with stirring. The mixture was stirred at room temperature for 2 hours. After the mixture was cooled down to 0° C., water (200 mL) was slowly added. The solution was neutralized to pH 6.7-7.4 by using NaHCO3 saturated solution. An organic layer was separated and dried on anhydrous magnesium sulfate. The organic solution was evaporated to concentrated under reduced pressure. The residue was washed with n-hexane (100 mL) to obtain 4,5-dichloro-2-chloromethylpyridazine)-3(2H)-one (71.2 g, 92%). White crystal (diethyl ether/n-hexane=1:5, v/v). mp 69-70° C. TLC (CH2Cl2) Rf=0.65. IR (KBr) 3046, 2984, 1670, 1292, 1122, 964 cm-1; 1H NMR (CDCl3): δ 5.83 (s, 2H), 7.88 ppm (s, 1H); 13C NMR (CDCl3) δ 58.40, 134.87, 137.23, 137.34, 155.58 ppm. Elemental analysis calcd. for C5H3Cl3N2O: C, 28.13; H, 1.42; N, 13.12. Found: C, 28.10; H, 1.41; N, 13.09.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[C:7]3[CH:13]=[C:12]([CH3:14])[N:11]([CH2:15][C:16]4[CH:17]=[C:18]([CH2:22]O)[CH:19]=[CH:20][CH:21]=4)[C:8]=3[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[CH:24]([N:27]([CH:30]([CH3:32])C)CC)([CH3:26])C.CS(OS(C)(=O)=O)(=O)=O.S([O-])(=O)(=O)C.N1CCCC1>C(Cl)Cl>[CH3:1][C:2]1[N:6]2[C:7]3[CH:13]=[C:12]([CH3:14])[N:11]([CH2:15][C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][N:27]5[CH2:24][CH2:26][CH2:32][CH2:30]5)[CH:17]=4)[C:8]=3[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1
Reactant: Cc1cc2c(ccc3nnc(C)n32)n1Cc1cccc(CO)c1
Reactant: CCN(C(C)C)C(C)C
Agent: CS(=O)(=O)OS(C)(=O)=O
Agent: CS(=O)(=O)[O-]
Solvent: C1CCNC1
Solvent: ClCCl
Product: Cc1cc2c(ccc3nnc(C)n32)n1Cc1cccc(CN2CCCC2)c1
Reaction time: 2.5 h

Procedure:
To {3-[(1,7-dimethyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridin-6-yl)methyl]phenyl}methanol (15 mg, 0.049 mmol, from Example 36, Step 1) in DCM (1.0 mL) was added diisopropylethylamine (26 μL, 0.15 mmol) followed by methanesulphonic anhydride (17 mg, 0.098 mmol). After mesylate formation was determined to be complete as judged by LCMS, solvent was removed in vacuo and the residue was re-dissolved in a mixture of THF (0.50 mL) and methanol (0.50 mL). Pyrrolidine (0.016 mL, 0.20 mmol, Aldrich) was added and the reaction was stirred for 2.5 hours. The product was purified using preparative HPLC-MS (Waters XBridge C18, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) (11.4 mg, 65%).
Reaction SMILES: C([O:5][C:6](=[O:48])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)[C:10]([C:18]2[N:19]=[C:20]3[C:26]([C:27](=[O:39])[NH:28][C@H:29]([CH3:38])[C:30]([N:32]4[CH2:35][CH:34]([C:36]#[N:37])[CH2:33]4)=[O:31])=[CH:25][N:24](COCC[Si](C)(C)C)[C:21]3=[N:22][CH:23]=2)=[N:9]1)(C)(C)C.C(O)(C(F)(F)F)=O.C(N)CN>C(Cl)Cl>[Cl:17][C:14]1[CH:15]=[C:16]2[C:11]([C:10]([C:18]3[N:19]=[C:20]4[C:26]([C:27](=[O:39])[NH:28][C@H:29]([CH3:38])[C:30]([N:32]5[CH2:35][CH:34]([C:36]#[N:37])[CH2:33]5)=[O:31])=[CH:25][NH:24][C:21]4=[N:22][CH:23]=3)=[N:9][N:8]2[CH2:7][C:6]([OH:48])=[O:5])=[CH:12][CH:13]=1
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CC(=O)OC(C)(C)C)c4cc(Cl)ccc34)nc12)C(=O)N1CC(C#N)C1
Solvent: O=C(O)C(F)(F)F
Solvent: NCCN
Solvent: ClCCl
Product: C[C@@H](NC(=O)c1c[nH]c2ncc(-c3nn(CC(=O)O)c4cc(Cl)ccc34)nc12)C(=O)N1CC(C#N)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.7 %

Procedure:
In a 5 mL pear-shaped flask, {6-chloro-3-[7-[(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethylcarbamoyl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-indazol-1-yl}-acetic acid tert-butyl ester (30 mg, 0.043 mmol) was combined with CH2Cl2 (1 ml) to give a light yellow solution. TFA (0.10 ml, 1.3 mmol) was added and the reaction was stirred at room temperature for 2 h. The crude reaction mixture was concentrated in vacuo and redissolved in CH2Cl2. Ethylenediamine (88 μl, 1.3 mmol) was added dropwise and the reaction was stirred at room temperature for 30 min. The crude reaction mixture was concentrated in vacuo. The residue was dissolved in water and it was lyophilized overnight. The yellow waxy solid was suspended in water and filtered, washing with water then dried on high vacuum to give 8 mg (32%) of (6-Chloro-3-{7-[(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethylcarbamoyl]-5H-pyrrolo[2,3-b]pyrazin-2-yl}-indazol-1-yl)-acetic acid as a yellow solid. MS: (M+H)+=507.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Si:11]([O:28][CH2:29][C@@H:30]([N:33]1[C@H:38]([C:39]2[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=2)[C@@H:37]([C:46]2[CH:51]=[CH:50][CH:49]=[C:48]([Cl:52])[CH:47]=2)[CH2:36][CH2:35][C:34]1=[O:53])[CH2:31][CH3:32])([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Br[CH2:55][CH:56]=[CH2:57].[Li+].CC([N-]C(C)C)C.Cl[CH2:67][O:68][CH2:69][CH2:70][Si:71]([CH3:74])([CH3:73])[CH3:72]>C1(C)C=CC=CC=1.C1COCC1.CCOC(C)=O>[CH2:55]([C@@:35]1([CH2:67][O:68][CH2:69][CH2:70][Si:71]([CH3:74])([CH3:73])[CH3:72])[CH2:36][C@H:37]([C:46]2[CH:51]=[CH:50][CH:49]=[C:48]([Cl:52])[CH:47]=2)[C@@H:38]([C:39]2[CH:40]=[CH:41][C:42]([Cl:45])=[CH:43][CH:44]=2)[N:33]([C@@H:30]([CH2:31][CH3:32])[CH2:29][O:28][Si:11]([C:24]([CH3:27])([CH3:26])[CH3:25])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:34]1=[O:53])[CH:56]=[CH2:57]
Reactant: C[Si](C)(C)CCOCCl
Reactant: C=CCBr
Reactant: CC[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)N1C(=O)CC[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: CC(C)[N-]C(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C=CC[C@@]1(COCC[Si](C)(C)C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Lithium bis(trimethylsilyl)amide, (1M solution in toluene, 4.76 mL, 4.76 mmol) was added to a solution of (5R,6S)-1-((S)-1-(tert-butyldiphenylsilyloxy)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one (Example 185, Step C, 2.0 g, 3.17 mmol) and 3-bromopropene (0.274 mL, 3.17 mmol) in THF at −78° C. The reaction was warmed to 0° C. and stirred for 2 hours. After recooling to −78° C., a solution of LDA (7.93 mmol in THF) followed by 2-(chloromethoxy)ethyltrimethylsilane (0.842 mL, 4.76 mmol) was added. The reaction was warmed to 50° C. and stirred for 1.5 hours. The reaction mixture was diluted with EtOAc and washed with HCl (1N). The organic extract was washed with satd NaCl and dried over Na2SO4. The solution was filtered and concentrated in vacuo. The crude material was purified by chromatography on silica gel, eluting with a gradient of 0% to 20% EtOAc in hexane, to provide (3S,5R,6S)-3-allyl-1-((S)-1-(tert-butyldiphenylsilyloxy)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-((2-(trimethylsilyl)ethoxy)methyl)piperidin-2-one as the first eluting diastereomer and the title compound as the second diastereomer as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:31]C)=[C:6]([C:8]2([CH2:11][C:12]([OH:30])([C:26]([F:29])([F:28])[F:27])[C:13]([NH:15][C:16]3[CH:17]=[C:18]4[C:23](=[CH:24][CH:25]=3)[C:21](=[O:22])[O:20][CH2:19]4)=[O:14])[CH2:10][CH2:9]2)[CH:7]=1.B(Br)(Br)Br.O>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:31])=[C:6]([C:8]2([CH2:11][C:12]([OH:30])([C:26]([F:28])([F:27])[F:29])[C:13]([NH:15][C:16]3[CH:17]=[C:18]4[C:23](=[CH:24][CH:25]=3)[C:21](=[O:22])[O:20][CH2:19]4)=[O:14])[CH2:9][CH2:10]2)[CH:7]=1
Reactant: COc1ccc(F)cc1C1(CC(O)(C(=O)Nc2ccc3c(c2)COC3=O)C(F)(F)F)CC1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: O=C1OCc2cc(NC(=O)C(O)(CC3(c4cc(F)ccc4O)CC3)C(F)(F)F)ccc21
Temperature: 0 °C
Reaction time: 3 h

Procedure:
225 mg of 5-{3-[1-(5-fluoro-2-methoxyphenyl)-cyclopropyl]-2-hydroxy-2-trifluoromethyl-propionylamino}-phthalide is mixed in 4.5 ml of dichloromethane at 0° C. with 2.48 ml of a 1 molar solution of boron tribromide in dichloromethane. After 3 hours of stirring at 0° C., the mixture is added to water, extracted with ethyl acetate, the organic phase is dried (Na2SO4) and concentrated by evaporation. After the residue is triturated with hexane, the title compound is obtained in crystalline form, flash point 196-199° C.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9]O)=[CH:5][N:4]=1)=[O:2].S(Cl)([Cl:13])=O>O1CCCC1>[ClH:13].[CH:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][Cl:13])=[CH:5][N:4]=1)=[O:2]
Reactant: O=Cc1ccc(CO)cn1
Reactant: O=S(Cl)Cl
Solvent: C1CCOC1
Product: Cl
Product: O=Cc1ccc(CCl)cn1

Procedure:
2-Formyl-5-hydroxymethylpyridine (0.1 mole) in 100 ml. of tetrahydrofuran is treated with 0.11 mole of thionyl chloride, and the mixture is refluxed 3 hours. The product, 2-formyl-5-chloromethylpyridine hydrochloride is collected by filtration from the cooled reaction mixture.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([N:13]3[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]3)[CH:6]=[CH:7][C:8]=2[OH:12])[CH2:3]1.C(N(CC)CC)C.[CH2:27]([O:31][C:32]1[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][CH:33]=1)[CH2:28][CH2:29][CH3:30]>CN(C)C=O>[OH:12][C:8]1[CH:7]=[CH:6][C:5]([N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)=[C:4]2[C:9]=1[CH2:10][CH2:11][C@@H:2]([NH:1][C:36](=[O:37])[C:35]1[CH:34]=[CH:33][C:32]([O:31][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:40][CH:39]=1)[CH2:3]2
Reactant: CN1CCN(c2ccc(O)c3c2C[C@H](N)CC3)CC1
Reactant: CCCCOc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCOc1ccc(C(=O)N[C@@H]2CCc3c(O)ccc(N4CCN(C)CC4)c3C2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To an ice-cooled solution of (R)-2-amino-5-hydroxy-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (100 mg, 0.38 mmol) and triethylamine (79 μL, 0.57 mmol) in N,N-dimethylformamide (30 mL) was 4-butoxybenzoyl chloride in N,N-dimethylformamide (5 mL) added dropwise. After the addition the reaction was stirred at ambient temperature for 15 min. The solvent was evaporated in vacuo and the residue was purified on a silica gel column using chloroform/methanol/concentrated ammonium hydroxide (95:5:0.5) as the eluent. Yield: 73 mg (44%) as an amorphous solid: mp 125° C. (decomp.); [α]21D−20° (c=0.25, chloroform); EIMS (70 eV) m/z (relative intensity) 437 (16, M+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:17]2[O:16][CH:15]([CH2:18][NH2:19])[CH2:14][C:13]=2[CH:12]=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.Cl[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31]>>[CH2:33]([O:32][C:30](=[O:31])[NH:19][CH2:18][CH:15]1[CH2:14][C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[C:17]=2[O:16]1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCC1Cc2cccc(-c3ccc(Cl)cc3Cl)c2O1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1Cc2cccc(-c3ccc(Cl)cc3Cl)c2O1)OCc1ccccc1
Yield: 86.9 %

Procedure:
Treatment of (±)-1-[7-(2,4-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine (1.9 g, 5.75 mmol) with diisopropylethylamine (1.11 g, 8.62) and benzyl chloroformate (1.18 g, 6.89 mmol) generally according to the procedure described for Intermediate 12 afforded 2.14 g (87%) of (±)-benzyl[7-(2,4-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate as a white solid. mp 87-89° C.; Anal. calcd. for C23H19Cl2NO3: C, 64.5; H, 4.47; N, 3.27. Found: C, 64.65; H, 4.78; N, 3.08.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.[C:13](OC)(=[O:21])[C:14]1[C:15](=[CH:17][CH:18]=[CH:19][CH:20]=1)[SH:16].C(N(CC)CC)C>C1(C)C=CC=CC=1>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:10]=[CH:9][C:6]([C:7]2[S:16][C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[C:13](=[O:21])[N:8]=2)=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccccc1S
Reactant: N#Cc1ccc(C(F)(F)F)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=c1nc(-c2ccc(C(F)(F)F)cc2)sc2ccccc12
Yield: 15.7 %

Procedure:
A mixture of 4-trifluoromethylbenzonitrile (2.00 g, 12 mmol), methyl thiosalicylate (3.93 g, 23 mmol), triethylamine (2.40 g, 24 mmol) and toluene (10 ml) was heated and refluxed for 25 hours under a nitrogen flow. The reaction solution was concentrated under reduced pressure and the residue was applied to column chromatography using silica gel (100 g). Fractions eluted with hexane-ethyl acetate (5:1, v/v) were concentrated under reduced pressure. The residue was recrystallized from isopropyl ether to give the title compound (0.58 g, 16%) as crystals.