Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:13]([F:14])=[CH:12][C:11]([C:15]2[CH:16]=[N:17][CH:18]=[N:19][CH:20]=2)=[CH:10][C:7]=1[CH:8]=O)[CH2:2][CH:3]=[CH2:4].[NH2:21][C:22]([NH2:24])=[S:23].Cl[Si](C)(C)C>C(#N)C.CN(C=O)C.CCOC(C)=O>[F:14][C:13]1[C:6]2[O:5][CH2:1][CH2:2][C@@H:3]3[CH2:4][S:23][C:22]([NH2:24])=[N:21][C@@H:8]3[C:7]=2[CH:10]=[C:11]([C:15]2[CH:16]=[N:17][CH:18]=[N:19][CH:20]=2)[CH:12]=1
Reactant: C=CCCOc1c(F)cc(-c2cncnc2)cc1C=O
Reactant: NC(N)=S
Agent: C[Si](C)(C)Cl
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: NC1=N[C@@H]2c3cc(-c4cncnc4)cc(F)c3OCC[C@@H]2CS1
Reaction time: 1 h
Yield: 0.3 %

Procedure:
To a solution of 2-(but-3-enyloxy)-3-fluoro-5-(pyrimidin-5-yl)benzaldehyde from step 4C (662 mg, 2.43 mmol) in acetonitrile (1.62 ml) and DMF (0.810 ml) was added thiourea (185 mg, 2.43 mmol) and chlorotrimethylsilane (0.311 ml, 2.43 mmol). The resulting mixture was brought to reflux and stirred for 1 h. The reaction mixture was then diluted with EtOAc (10 mL), washed with water (3×2 mL), brine (5 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by silica gel column chromatography (0-80% EtOAc/hexanes) gave the desired product (3.1 mg, 8.44 μmol, 0.35% yield). 1H NMR (500 MHz, methanol-d4) δ 7.63 (d, J=2.1 Hz, 1H), 7.57 (d, J=2.1 Hz, 2H), 6.03 (s, 1H), 5.99 (d, J=10.4 Hz, 1H), 3.12-3.01 (m, J=6.1, 6.1 Hz, 1H), 2.29-2.16 (m, J=4.6 Hz, 1H), 1.82 (d, J=1.2 Hz, 2H), 1.58 (t, J=12.1 Hz, 1H), 1.35 (dd, J=12.5, 3.1 Hz, 1H), 0.62-0.47 (m, 2H), 0.35-0.18 (m, 1H), −0.07-−0.31 (m, 1H). MS (ESI, M+H)+=331.16
Reaction SMILES: C(=O)([O-])O.[Na+].[CH2:6](Br)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:14]([O:18][C:19]([CH2:21][C@@H:22]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:23]([OH:25])=[O:24])=[O:20])([CH3:17])([CH3:16])[CH3:15].O>CN(C)C=O>[CH2:6]([O:25][C:23]([C@H:22]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:21][C:19]([O:18][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:20])=[O:24])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCCCC[C@H](CC(=O)OC(C)(C)C)C(=O)O
Reactant: BrCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCC[C@H](CC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium hydrogencarbonate (305 mg) and benzyl bromide (1.0 ml) were added Successively to a solution of 2-(R)-(tert-butoxycarbonylmethyl)heptanoic acid (440 mg), prepared in Referential Example 5, in 18 ml of dimethylformamide (DMF), and the resulting mixture was stirred overnight at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The organic extract was successively washed with water and a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. After the solvent had been distilled off under reduced pressure, the residue was purified by column chromatography through silica gel, using a 20:1 mixture of hexane and ethyl acetate as an eluent, to give 476 mg of the desired compound as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]([C:17]2[C:18]3[CH:32]=[CH:31][C:30]([O:33]CC4C=CC=CC=4)=[CH:29][C:19]=3[S:20][C:21]=2[C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=2)=O)[CH:6]=[CH:7][C:8]=1[CH2:9][N:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:47]([SiH](CC)CC)C.F[C:55](F)(F)[C:56]([OH:58])=[O:57]>C1COCC1.ClCCl>[OH:33][C:30]1[CH:31]=[CH:32][C:18]2[C:17]([CH2:15][C:5]3[CH:6]=[CH:7][C:8]([CH2:9][N:10]4[CH2:14][CH2:13][CH2:12][CH2:11]4)=[C:3]([O:2][CH3:1])[CH:4]=3)=[C:21]([C:22]3[CH:23]=[CH:24][C:25]([O:28][CH2:55][C:56]([O:58][CH3:47])=[O:57])=[CH:26][CH:27]=3)[S:20][C:19]=2[CH:29]=1
Reactant: CC[SiH](CC)CC
Reactant: O=C(O)C(F)(F)F
Reactant: COc1cc(C(=O)c2c(-c3ccc(O)cc3)sc3cc(OCc4ccccc4)ccc23)ccc1CN1CCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)COc1ccc(-c2sc3cc(O)ccc3c2Cc2ccc(CN3CCCC3)c(OC)c2)cc1
Reaction time: 0.75 h
Yield: 78 %

Procedure:
6-Benzyloxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl 3-methoxy-4-(1-pyrrolidinylmethyl)phenyl ketone (2.75 g, 5.0 mmol) in THF (25 mL) was treated with lithium aluminum hydride (420 mg) at 0° C. for 2 h, then quenched with water (1 mL) and sodium hydroxide (1.0 M, 3 mL). Stirring was continued for 45 min. The reaction mixture was diluted with brine (100 mL) and extracted with dichloromethane (100 mL×3). The combined organic layers were dried with sodium sulfate and concentrated in vacuo to give a white foam-like material. This material was dissolved in dichloromethane (50 mL), treated with triethylsilane (6.0 mL) and trifluroacetic acid (5.0 mL) at 0° C. for 2 h, and concentrated under reduced pressure. The residue was extracted with dichloromethane (100 mL×3) which was washed with saturated aqueous sodium bicarbonate (100 mL). The combined organic layers were dried with sodium sulfate and concentrated. Chromatography with Et3N:MeOH:EtOAc (5:5:90) afforded the product as a white solid (2.1 g, 78%).
Reaction SMILES: [CH2:1]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]([CH:15]=[O:16])=[CH:9]2)[CH2:2][CH:3]([CH3:5])[CH3:4].CI.[C:19](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH3:19])[C:10]([CH:15]=[O:16])=[CH:9]2)[CH2:2][CH:3]([CH3:5])[CH3:4]
Reactant: O=C([O-])[O-]
Reactant: CC(C)CCc1ccc2[nH]c(C=O)cc2c1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CC(C)CCc1ccc2c(c1)cc(C=O)n2C
Temperature: 150 °C
Reaction time: 1 h
Yield: 15.2 %

Procedure:
To a solution of 5-isopentyl-1H-indole-2-carbaldehyde (100 mg, 0.46 mmol) and methyl iodide (71 mg, 0.50 mmol) in 0.93 mL dimethylformamide was added potassium carbonate (71 mg, 0.51 mmol). The resulting suspension was stirred vigorously at 150° C. in a sealed vial under argon for 1 h. Solids were filtered and the liquor concentrated before being subjected to chromatography on silica gel (40% ethyl acetate in hexanes) to give 5-isopentyl-1-methyl-1H-indole-2-carbaldehyde (16 mg, 15%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[C:13]([C:15](=[CH:25][N:26](C)C)[C:16]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=O)[CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC([NH:36]C1C=C(C(=CN(C)C)C(C2C=CC(F)=CC=2)=O)C=CN=1)=O)(C)(C)C>>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[C:13]([C:15]2[C:16]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)=[N:36][NH:26][CH:25]=2)[CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C=C(C(=O)c1ccc(F)cc1)c1ccnc(NC(=O)OC(C)(C)C)c1
Reactant: CN(C)C=C(C(=O)c1ccc(Cl)cc1)c1ccnc(NC(=O)OC(C)(C)C)c1
Product: CC(C)(C)OC(=O)Nc1cc(-c2c[nH]nc2-c2ccc(Cl)cc2)ccn1
Yield: 97 %

Procedure:
The reaction was carried out in the same manner as in Example 2-2) except for using 10.1 g (25.0 mmol) of 2-(2-t-butoxycarbonylaminopyridin-4-yl)-1-(4-chlorophenyl)-3-dimethylamino-2-propen-1-one obtained in Example 23-1) in place of 2-(2-t-butoxycarbonylaminopyridin-4-yl)-3-dimethylamino-1-(4-fluorophenyl)-2-propen-1-one to obtain 9.01 g of the title compound as a pale yellowish white powder. (Yield: 97%)
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([NH:7][C:8]1[N:12]2[N:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]2=[N:10][CH:9]=1)=[O:6].[H-].[Na+]>CN(C=O)C.CCOC(C)=O>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]2[N:12]([C:8]([N:7]3[CH2:2][CH2:3][CH2:4][C:5]3=[O:6])=[CH:9][N:10]=2)[N:13]=1
Reactant: O=C(CCCBr)Nc1cnc2ccc(Cl)nn12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1CCCN1c1cnc2ccc(Cl)nn12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.7 %

Procedure:
To 1.0 g of 4-bromo-N-(6-chloroimidazo[1,2-b]pyridazin-3-yl)butanamide (3.15 mmol) dissolved in 39 mL DMF was added NaH (189 mg, 4.72 mmol), and stirred at rt for 0.5 hr. Dilute with 50 mL EtOAc and separate the organic layer. Wash twice with water, once with brine and dry over MgSO4. Concentrate to obtain the product 0.49 g (66%). No purification was needed.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[CH:3]=1.[Cl:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:17][NH2:18]>>[Cl:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:17][NH:18][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[CH:3]=1
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: Cc1cc(Cl)c2ccccc2n1
Product: Cc1cc(NCc2ccc(Cl)c(Cl)c2)c2ccccc2n1

Procedure:
Preparation was made using a similar procedure as described in example 1, method 1.3. Starting materials were 4-chloro-2-methylquinoline and 3,4-dichlorobenzylamine.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][O:13][CH3:14])=[CH:7][C:6]=1[N+:15]([O-])=O)(=[O:3])[CH3:2].CO>[Fe].O>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][O:13][CH3:14])=[CH:7][C:6]=1[NH2:15])(=[O:3])[CH3:2]
Reactant: COCSc1ccc(NC(C)=O)c([N+](=O)[O-])c1
Agent: [Fe]
Solvent: CO
Solvent: O
Product: COCSc1ccc(NC(C)=O)c(N)c1

Procedure:
1.5 G. of 1-acetamido-2-nitro-4-methoxymethylthiobenzene, also prepared according to Example VIII, is treated for 4 hours in a refluxing mixture of 160 ml. methanol and 40 ml. water with 4 g. of iron powder (added in two portions) and 1 g. ferrous sulfate. The mixture is filtered, and the filtrate concentrated. The residue is dissolved in chloroform and washed with water, then the solvent evaporated to afford 1-acetamido-2-amino-4-methoxymethylthiobenzene.
Reaction SMILES: O1CCOCC1.[F:7][C:8]([F:56])([F:55])[C:9]1[CH:10]=[C:11]([CH:48]=[C:49]([C:51]([F:54])([F:53])[F:52])[CH:50]=1)[CH2:12][N:13]1[C@H:17]([CH3:18])[C@@H:16]([C:19]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:20]=2[C:29]2[CH:30]=[C:31]([C:36]3[CH:41]=[CH:40][C:39]([C:42]([O:44]C)=[O:43])=[CH:38][C:37]=3[CH3:46])[CH:32]=[CH:33][C:34]=2[Cl:35])[O:15][C:14]1=[O:47].O.[OH-].[Li+].Cl>O>[F:56][C:8]([F:7])([F:55])[C:9]1[CH:10]=[C:11]([CH:48]=[C:49]([C:51]([F:53])([F:54])[F:52])[CH:50]=1)[CH2:12][N:13]1[C@H:17]([CH3:18])[C@@H:16]([C:19]2[CH:24]=[C:23]([C:25]([F:27])([F:26])[F:28])[CH:22]=[CH:21][C:20]=2[C:29]2[CH:30]=[C:31]([C:36]3[CH:41]=[CH:40][C:39]([C:42]([OH:44])=[O:43])=[CH:38][C:37]=3[CH3:46])[CH:32]=[CH:33][C:34]=2[Cl:35])[O:15][C:14]1=[O:47]
Reactant: COC(=O)c1ccc(-c2ccc(Cl)c(-c3ccc(C(F)(F)F)cc3[C@H]3OC(=O)N(Cc4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H]3C)c2)c(C)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(C(=O)O)ccc1-c1ccc(Cl)c(-c2ccc(C(F)(F)F)cc2[C@H]2OC(=O)N(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)c1

Procedure:
To a 1,4-dioxane solution (3 mL) of methyl 2″-{(4R,5R)-3-[3,5-bis(trifluoromethyl)benzyl]-4-methyl-2-oxo-1,3-oxazolidin-5-yl}-4′-chloro-2-methyl-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylate (65 mg, 0.089 mmol) was added a solution of lithium hydroxide monohydrate (26 mg, 0.623 mmol) in water (1.2 mL). Aliquot at reaction time 2 hours indicated completion of reaction (atropisomers present). Crude mixture was acidified by HCl (aq, 1N, 1 mL). The cloudy precipitation was dissolved by MeCN (2 mL). The resulting solution was purified by reverse-phase prep-HPLC (Kromasil 100-5C18, 100×21.1 mm) eluting w/ a MeCN (0.1% TFA, v/v)/H2O (0.1% TFA, v/v) gradient mixtureaffording 2″-{(4R,5R)-3-[3,5-bis(trifluoromethyl)benzyl]-4-methyl-2-oxo-1,3-oxazolidin-5-yl}-4′-chloro-2-methyl-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylic acid. LCMS calc.=715.12; found=716.20 (M+1)+. 1H NMR signals are doubled because of atropoisomerism. 1H NMR
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15]([C:19](Cl)=[O:20])=[N:14][CH:13]=[CH:12]3)[CH:3]=1.N1C=CC=CC=1.[C:28]([C:32]1[CH:33]=[C:34]([NH2:45])[N:35]([C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=2)[N:36]=1)([CH3:31])([CH3:30])[CH3:29].O>C(Cl)Cl>[C:28]([C:32]1[CH:33]=[C:34]([NH:45][C:19]([C:15]2[C:16]3[C:11](=[CH:10][C:9]([O:8][C:4]4[CH:3]=[C:2]([Cl:1])[N:7]=[CH:6][N:5]=4)=[CH:18][CH:17]=3)[CH:12]=[CH:13][N:14]=2)=[O:20])[N:35]([C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=2)[N:36]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: O=C(Cl)c1nccc2cc(Oc3cc(Cl)ncn3)ccc12
Reactant: COc1ccc(-n2nc(C(C)(C)C)cc2N)cc1
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)c2nccc3cc(Oc4cc(Cl)ncn4)ccc23)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
454.6 mg (1.42 mMol) 6-(6-Chloropyrimidin-4-yloxy)-isoquinoline-1-carbonyl chloride is dissolved in 10 ml CH2Cl2 and cooled to 0° C. At this temperature 0.46 ml (5.9 mMol) pyridine are added followed by 418.0 mg (1.7 mMol) 5-tert-butyl-2-(4-methoxy-phenyl)-2H-pyrazol-3-ylamine (Step 19.1). The reaction mixture is then allowed to warm to rt and stirred at ambient temperature for 1 h. It is worked up by addition of H2O and CH2Cl2. The organic layer is separated washed with brine and dried. After evaporation of the solvents the crude product is purified by chromatography (combi-flash: 40 g column, hexanes/EtOAc, gradient 0-50% EtOAc) to give the title compound as a yellow solid: m.p.: 156° C.; MS.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=[O:3].C(Cl)Cl.[CH2:10]([C:12]1[CH:20]=[C:19]2[C:15]([CH:16]=[CH:17][NH:18]2)=[CH:14][CH:13]=1)[CH3:11].[CH3:21][O-:22].[Na+].CO>CCOCC>[CH2:10]([C:12]1[CH:20]=[C:19]2[C:15]([C:16]([C:1](=[O:5])[C:2]([O:22][CH3:21])=[O:3])=[CH:17][NH:18]2)=[CH:14][CH:13]=1)[CH3:11]
Reactant: CCc1ccc2cc[nH]c2c1
Reactant: O=C(Cl)C(=O)Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Solvent: ClCCl
Product: CCc1ccc2c(C(=O)C(=O)OC)c[nH]c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
A 2.0 M solution of oxalyl chloride in methylene chloride (4.75 mL, 9.6 mmol) was added to a solution of 6-ethylindole (1.39 g, 9.6 mmol) in ether (20 mL) dropwise over 10 min at 4° C. under N2. The ice bath was removed and the resulting mixture was stirred for 2 h. A 25% sodium methoxide in methanol solution (4.3 mL, 18.8 mmol) was added at −78° C. over 5 min. The mixture was allowed to warm up to room temperature and stirred for 1 h. The reaction was quenched with water (10 mL), filtered and rinsed with cold ether to afford the title compound (1.34, 72%) as a yellow solid. 1H NMR (CDCl3) δ 9.07 (bs, 1H), 8.43 (m, 1H), 8.32 (m, 1H), 7.29–7.21 (m, 2H), 3.95 (m, 3H), 2.78 (m, 2H), 1.29 (m, 3H).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:12][CH2:11][N:10]([CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:9]1)(C)(C)C.[ClH:19]>CO.C(O)(C)C>[Cl-:19].[Cl-:19].[NH2:7][CH:8]1[CH2:12][CH2:11][NH+:10]([CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:9]1.[NH2:7][CH:8]1[CH2:12][CH2:11][NH+:10]([CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1CCN(C2CCCC2)C1
Reactant: Cl
Solvent: CC(C)O
Solvent: CO
Product: NC1CC[NH+](C2CCCC2)C1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Pyrrolidin-3-yl-carbamic acid tert-butyl ester (9) (0.25 g, 1.00 mmol, 1 equiv) was dissolved in methanol (50 mL), followed by the addition of 5-6 N HCl in isopropanol (10 mL). The solution was stirred at room temperature for 24 h. The solution was evaporated under reduced pressure to give the title compound (0.22 g, 1.00 mmol, quantitative).
Reaction SMILES: [C:1]([C:3]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C:5](=[CH:6][CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:22](=[O:30])SC2C=CC=CN=2)[CH:4]=1)#[N:2].[F:31][C:32]1[CH:46]=[CH:45][C:35]([CH:36]([NH2:44])[C:37]2[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=2)=[CH:34][CH:33]=1>>[F:31][C:32]1[CH:33]=[CH:34][C:35]([CH:36]([NH:44][C:22]([C@H:12]2[CH2:11][CH2:10][C@H:9]3[C@H:8]4[C@H:17]([CH2:16][CH2:15][C@:13]23[CH3:14])[C@:18]2([CH3:21])[C:5]([CH:4]=[C:3]([C:1]#[N:2])[CH2:20][CH2:19]2)=[CH:6][CH2:7]4)=[O:30])[C:37]2[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=2)=[CH:45][CH:46]=1
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4C=C(C#N)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)Sc1ccccn1
Reactant: NC(c1ccc(F)cc1)c1ccc(F)cc1
Product: C[C@]12CC[C@H]3[C@@H](CC=C4C=C(C#N)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)NC(c1ccc(F)cc1)c1ccc(F)cc1
Yield: 91 %

Procedure:
Following a procedure similar to that described in Example 3(b), but using S-2-pyridyl 3-cyanoandrosta-3,5-diene-17β-thiocarboxylate [prepared as described in Example 3(a)] and 4,4'-difluorobenzhydrylamine (prepared as described in Preparation 12) as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained in a yield of 91%.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][OH:22])=[CH:15][C:14]=2[F:23])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=[O:6].[NH2:24][O:25][CH2:26][CH2:27][O:28][CH:29]=[CH2:30].C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-]>>[F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[C:20][CH2:21][OH:22])=[CH:15][C:14]=2[F:23])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([O:7][CH3:26])=[O:6].[F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][OH:22])=[CH:15][C:14]=2[F:23])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([NH:24][O:25][CH2:26][CH2:27][O:28][CH:29]=[CH2:30])=[O:7]
Reactant: C=COCCON
Reactant: O=C(O)c1ccc(F)c(F)c1Nc1ccc(CCCO)cc1F
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Product: C=COCCONC(=O)c1ccc(F)c(F)c1Nc1ccc(CCCO)cc1F
Product: COC(=O)c1ccc(F)c(F)c1Nc1ccc(C#CCO)cc1F
Yield: 46 %

Procedure:
The title compound was prepared from reaction of 3,4-difluoro-2-[2-fluoro-4-(3-hydroxypropyl)anilino]benzoic acid with 1-[2-(aminooxy)ethoxy]ethylene and DMT-MM by the general procedure of Example 6, Step B, then purified by column chromatography on silica gel (20% EtOAc/PE as eluant) to give 3,4-difluoro-2-[2-fluoro-4-(3-hydroxypropyl)anilino]-N-[2-(vinyloxy)ethoxy]benzamide as a white solid (46%), which was employed directly in the next step. 1H NMR [400 MHz, (CD3)2SO] δ 11.93 (br s, 1 H), 8.79 (br s, 1 H), 7.44-7.38 (m, 1 H), 7.14-7.05 (m, 1 H), 7.04 (dd, J=12.6, 1.6 Hz, 1 H), 6.89 (dd, J=8.2, 1.6 Hz, 1 H), 6.82 (ddd, J=8.7, 8.7, 4.4 Hz, 1 H), 6.50 (dd, J=14.3, 6.7 Hz, 1 H), 4.45 (t, J=5.1 Hz, 1 H), 4.18 (dd, J=14.3, 1.9 Hz, 1 H), 4.06-4.01 (m, 2 H), 3.98 (dd, J=6.6, 1.9 Hz, 1 H), 3.89-3.82 (m, 2 H), 3.42-3.35 (m, 2 H), 2.56 (t, J=7.7 Hz, 2 H), 1.72-1.64 (m, 2 H). LCMS (APCI−) 409 (M−H).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[S:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[C:9](=O)[NH:10][C:4]=2[CH:3]=1.P(Cl)(Cl)(Cl)=O.CN(C)C1C=CC=CC=1.[CH2:32]([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)[CH3:33]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[S:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[C:9]([N:37]3[CH2:38][CH2:39][N:34]([CH2:32][CH3:33])[CH2:35][CH2:36]3)=[N:10][C:4]=2[CH:3]=1
Reactant: CCN1CCNCC1
Reactant: O=C1Nc2cc(Cl)ccc2Sc2ccccc21
Solvent: Cc1ccccc1
Solvent: CN(C)c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: CCN1CCN(C2=Nc3cc(Cl)ccc3Sc3ccccc32)CC1

Procedure:
8-Chloro-10H-dibenzo[b,f][1,4]thiazepin-11-one 2 (X=S and R1=Cl) (0.5 g, 1.91 mol), phosphorus oxychloride (5 ml, 53 mmol), toluene (25 ml) and N,N-dimethylaniline (1.0 ml) were heated at reflux for 3 hours. After evaporation of the volatiles, 25 ml of toluene and 5 ml (45 mmol) of 1-ethylpiperazine were added. Work-up and purification as described in Example 1 gave 150 mg (22%) of light yellow crystals, mp 100-101° C., 1H NMR (300 MHz, CDCl3), 1.11 (t, 3H, J=6.0 Hz, CH3), 2.55 (q, 2H, J=6.0 Hz, —CH2—), 2.55-2.65 (broad s, 4H, piperazinyl CH2), 3.55-3.65 (broad s, 4H, piperazinyl CH2), 6.83 (dd, 1H, J=1.5 and 6.0 Hz), 7.07 (d, 1H, J=1.5 Hz), 7.25-7.40 (mult., 4H), 7.50 (dd, 1H, J=7.5 Hz), MS (EI) m/z 357 (M+, 16.1%), 244(34.2), 209(30.1), 97(93.7), 84(100), HRMS calcd for C19H20N3SCl 357.1066, found 357.1067.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=[O:9])([CH3:3])[CH3:2].[Br:13]Br>ClCCl>[Br:13][C:10]1[CH:11]=[CH:12][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[CH:6][C:7]=1[CH:8]=[O:9]
Reactant: CC(C)Oc1cccc(C=O)c1
Reactant: BrBr
Solvent: ClCCl
Product: CC(C)Oc1ccc(Br)c(C=O)c1
Reaction time: 8 h
Yield: 61.8 %

Procedure:
To a suspension of 50.0 g (110 mmol) 3-hydroxybenzaldehyde and 100 g (725 mmol) dry K2CO3 in 100 mL dry DMF, 61.5 g (500 mmol) isopropylbromide was added at room temperature. The reaction mixture was heated for 17 h at 90° C. The solvent was removed under reduced pressure and the residue was partitioned between 2N NaOH and toluene. The collected organic layers were dried (MgSO4), filtered and the solvent removed under pressure. The residue was distilled in vacuo to give 58.8 g (88%) colorless liquid. To a solution of 57.0 g (347 mmol) 3-isopropoxybenzaldehyde in 200 mL dichloromethane 30.5 g (372 mmol) NaOAc was added. After that a solution of 55.5 g (347 mmol) bromine in 50 mL dichloromethane was added dropwise and the reaction mixture was stirred overnight. The reaction mixture was extracted with saturated aqueous Na2SO3 and the combined organic phases were dried (MgSO4), filtered and concentrated under reduced pressure. The residue was distilled in vacuo to give 1 (52.1 g, 62%) as a yellow oil.
Reaction SMILES: [CH2:1]([CH:8]1[C:13](=O)[N:12]([CH3:15])[CH2:11][C:10](=O)[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[C:23](=O)([O:29]C(C)(C)C)[O:24][C:25]([CH3:28])([CH3:27])[CH3:26]>C1COCC1>[CH2:1]([CH:8]1[CH2:13][N:12]([CH3:15])[CH2:11][CH2:10][N:9]1[C:23]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: CN1CC(=O)NC(Cc2ccccc2)C1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCN(C(=O)OC(C)(C)C)C(Cc2ccccc2)C1

Procedure:
The compound obtained in Step (ii) was subjected to reduction with lithium aluminum hydride in THF. Then, the resultant was subjected to Boc-introducing reaction with di-tert-butyl carbonate to give the subtitle compound.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[C:15]2[C:10]([CH:11]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=3)[CH2:12][NH:13][CH2:14]2)=[CH:9][CH:8]=1)(=O)=O.[C:27]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)(=[O:29])[NH2:28].C(=O)([O-])[O-].[Cs+].[Cs+]>O.CN(C)C=O>[Cl:24][C:19]1[CH:18]=[C:17]([CH:11]2[C:10]3[C:15](=[CH:16][C:7]([C:33]4[CH:34]=[CH:35][C:30]([C:27]([NH2:28])=[O:29])=[CH:31][CH:32]=4)=[CH:8][CH:9]=3)[CH2:14][NH:13][CH2:12]2)[CH:22]=[CH:21][C:20]=1[Cl:23]
Reactant: O=S(=O)(Oc1ccc2c(c1)CNCC2c1ccc(Cl)c(Cl)c1)C(F)(F)F
Reactant: NC(=O)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(-c2ccc3c(c2)CNCC3c2ccc(Cl)c(Cl)c2)cc1
Temperature: 90 °C
Yield: 9 %

Procedure:
A mixture of 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinolin-7-yl trifluoromethanesulfonate (225 mg, 0.53 mmol), 4-carbamoylphenylboronic acid (132 mg, 0.8 mmol) and cesium carbonate (521 mg, 1.6 mmol) in water (2 mL) and N,N-dimethylformamide (4 mL) was degassed with argon and then [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) (22 mg, 0.03 mmol) was added. The mixture was degassed again and then heated to 90° C. for 2 hours. The mixture was partitioned between water and ethyl acetate (3×) and the combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by semi-preparative HPLC followed by lyophilization to give 4-(4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)benzamide (19 mg, 7%) as a yellow oil: 1H NMR (CD3OD, 500 MHz) δ 7.96 (d, J=8.3 Hz, 2H), 7.74 (d, J=8.3 Hz, 2H), 7.64 (s, 1H), 7.62-7.59 (m, 1H), 7.56 (d, J=8.3 Hz, 1H), 7.49 (d, J=2.0 Hz, 1H), 7.23 (dd, J=8.3, 2.0 Hz, 1H), 7.02 (d, J=8.2 Hz, 1H), 4.67-4.53 (m, 3H), 3.82 (dd, J=12.6, 6.1 Hz, 1H), 3.51 (dd, J=12.5, 10.9 Hz, 1H); ESI MS m/z 397 [M+H]+.