Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:28][CH:29]1[CH2:31][CH2:30]1.[Cl-].[NH4+]>CN(C)C=O>[CH:29]1([CH2:28][N:22]2[CH2:21][CH2:20][N:16]3[C:17]4[CH:18]=[CH:19][C:11]([O:10][CH:7]5[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]5)=[CH:12][C:13]=4[CH:14]=[C:15]3[C:23]2=[O:24])[CH2:31][CH2:30]1
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCNC2=O)CC1
Reactant: BrCC1CC1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCN(CC3CC3)C2=O)CC1
Reaction time: 0.5 h
Yield: 38 %

Procedure:
To the solution of 0.15 g (0.46 mmol) 8-(1-isopropyl-piperidin-4-yloxy)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 1) in 3 mL N,N-dimethylformamide, 24 mg (0.55 mmol, 55% dispersion in mineral oil) sodium hydride was added. After 30 min., 1-(bromomethyl)cyclopropane was added and the mixture was stirred until completion of the reaction as indicated by TLC (2 h). The reaction mixture was poured on 10% aqueous ammonium chloride solution and was extracted three times with ethyl acetate. The organic layers were washed with water and brine, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography on silica gel with dichloromethane:methanol:ammonia (9:1:0.1 v/v) to give the desired compound as a white solid (38%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][NH:5][S:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:8])=[O:7].C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[S:6]1(=[O:8])(=[O:7])[NH:5][CH2:4][CH2:3][CH2:2][N:9]1[C:10]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:16]
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)NCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCCNS1(=O)=O
Reaction time: 4 h
Yield: 39.8 %

Procedure:
To a solution of tert-butyl N-(3-chloropropyl)sulfamoylcarbamate (2 g, 7.333 mmol) in DMSO (10 mL), was added K2CO3 (5.068 g, 36.665 mmol) at room temperature. The reaction mixture was agitated for 4 hr and extracted using ethyl acetate and NH4Cl solution. The organic layer was dried over MgSO4. The residue was purified by silica gel column chromatography to give tert-butyl 1,2,6-thiadiazinan-2-carboxylate 1,1-dioxide (689 mg, 2.92 mmol, 40%, white solid). 1H NMR (300 MHz, CDCl3): δ 4.47 (br, 1H), 3.95-3.91 (m, 2H), 3.55-3.49 (m, 2H), 1.89-1.82 (m, 2H), 1.54 (m, 9H).
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[C@H:10]([NH:19][C:20]2[C:21](=[O:33])[N:22]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:23]([Cl:26])=[CH:24][N:25]=2)[CH2:9]1)=O)(C)(C)C.CCN(C(C)C)C(C)C.[CH3:43][S:44](Cl)(=[O:46])=[O:45]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[CH3:43][S:44]([N:8]1[CH2:12][C@@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[C@H:10]([NH:19][C:20]2[C:21](=[O:33])[N:22]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:23]([Cl:26])=[CH:24][N:25]=2)[CH2:9]1)(=[O:46])=[O:45]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)Cn1c(Cl)cnc(N[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2c2ccccn2)c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)Cn1c(Cl)cnc(N[C@@H]2CN(S(C)(=O)=O)C[C@H]2c2ccccn2)c1=O
Temperature: 0 °C
Reaction time: 6 h

Procedure:
To a stirred solution of the hydrochloride salt of 3-(trans-4-(2-pyridyl)-pyrrolidin-3-ylamino)-6-chloro-1-ethoxycarbonylmethylpyrazinone from step 9 above (0.2 g, 0.48 mmol) in CH2Cl2 (20 mL) at 0° C. was added DIEA (0.30 mL, 1.7 mmol) and methanesulfonyl chloride (63 mg, 0.55 mmol). The resulting solution was stirred at 0° C. for 6 h and then at ambient temperature for 12 h. The mixture was diluted with CH2Cl2 and aqueous NaHCO3. The organic phase was separated, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography using a gradient elution of 2-4% MeOH:CH2Cl2 (0.20 g, TLC Rf=0.5, 95:5 CH2Cl2:MeOH; HPLC RT=5.47 min, method A).
Reaction SMILES: O1C=CC=C1.[C:6]([O:10][CH2:11][CH3:12])(=O)[CH:7]=[CH2:8].[C:13]([O:16][CH2:17][CH3:18])(=[O:15])[CH3:14]>[I-].[Zn+2].[I-]>[C@@H:6]12[O:10][C@@H:11]([CH:8]=[CH:7]1)[CH2:12][C@H:14]2[C:13]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: C=CC(=O)OCC
Reactant: CCOC(C)=O
Agent: [I-]
Agent: [Zn+2]
Solvent: c1ccoc1
Product: CCOC(=O)[C@@H]1C[C@@H]2C=C[C@H]1O2
Temperature: 40 °C
Yield: 46.5 %

Procedure:
A flask was charged with zinc iodide (1.010 ml, 14.98 mmol), then heated with a heat gun under high vacuum for 5 minutes. The flask was charged with furan (5.09 ml, 69.9 mmol) and ethyl acrylate (5.43 ml, 49.9 mmol), then covered in foil and heated at 40° C. for 48 hours. The solution was then diluted with ethyl acetate and washed with 10% aqueous Na2SO3. After drying with Na2SO4 and filtration, the solvents were removed under reduced pressure then purified by silica gel chromatography (RediSep Gold 80 g, gradient elution 0-50% EtOAc:Heptane) to afford (1R,2R,4R)-ethyl 7-oxabicyclo[2.2.1]hept-5-ene-2-carboxylate (3.91 g, 23.25 mmol, 46.5% yield) as a clear colorless oil (2.5:1 mixture of endo and exo isomers). 1H NMR (400 MHz, CHLOROFORM-d) δ=6.44 (dd, J=1.7, 5.8 Hz, 1H), 6.41-6.38 (m, 1H), 6.38-6.34 (m, 1H), 6.24 (dd, J=1.6, 5.8 Hz, 1H), 5.19 (dd, J=0.7, 1.6 Hz, 1H), 5.18-5.16 (m, 1H), 5.08 (dd, J=0.7, 4.6 Hz, 1H), 5.02 (ddd, J=0.7, 1.7, 4.7 Hz, 1H), 4.19 (q, J=7.1 Hz, 2H), 4.10 (ttd, J=3.6, 7.1, 10.7 Hz, 1H), 3.11 (ddd, J=3.8, 4.9, 9.1 Hz, 1H), 2.42 (dd, J=3.9, 8.5 Hz, 1H), 2.17 (td, J=4.4, 11.2 Hz, 1H), 2.11 (ddd, J=4.7, 9.3, 11.4 Hz, 1H), 1.60 (dd, J=3.8, 11.5 Hz, 1H), 1.56 (dd, J=8.6, 11.6 Hz, 1H), 1.29 (t, J=7.2 Hz, 3H), 1.25 (t, J=7.2 Hz, 1H)
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH3:33])[CH:25]=2)[C:7]([C:22]#[N:23])=[C:8]([CH3:21])[N:9]([CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:10]=1[CH3:11])=O.[H-].[H-].[H-].[H-].[Li+].[Al+3].C(OCC)C>O1CCCC1>[CH3:33][O:32][C:26]1[CH:25]=[C:24]([C:6]2[C:5]([CH2:3][OH:2])=[C:10]([CH3:11])[N:9]([CH2:12][CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:8]([CH3:21])[C:7]=2[C:22]#[N:23])[CH:29]=[CH:28][C:27]=1[O:30][CH3:31]
Reactant: COC(=O)C1=C(C)N(CCCc2ccccc2)C(C)=C(C#N)C1c1ccc(OC)c(OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(C2=C(C#N)C(C)N(CCCc3ccccc3)C(C)=C2CO)cc1OC
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 78 %

Procedure:
To a solution of 1.48 g (3.32 mmol) of 1.4-dihydro-4-(3,4-dimethoxyphenyl)-2,6-dimethyl -1-(3-phenylpropyl)-3-cyano-5-pyridine carboxylic acid-5-methylester in 42 ml of dry tetrahydrofuran (THF) was added with stirring 1.8 ml of 1N LiAlH4 /diethyl ether solution at room temperature (about 20°-30° C.). The mixture was stirred for 20 min. and was poured into ice-water. The mixture was filtered and extracted with CH2Cl2. This oil was purified by column chromatography (AcOEt:Hexane 1:1) to give 1.08 g (2.58 mmol) of 1,4-dihydro-4-(3,4-dimethoxyphenyl-2,6-dimethyl -1-(3-phenylpropyl)-3-cyano-5-hydroxymethylpyridine (78% yield: oil).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][NH:9][C:10]2[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][N:13]=[C:12]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][C:28]([F:31])([F:30])[F:29])[N:11]=2)[CH2:4][CH2:3]1.[CH3:32][N:33]1[C:37]([CH3:38])=[C:36]([CH:39]=O)[CH:35]=[N:34]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>[CH3:32][N:33]1[C:37]([CH3:38])=[C:36]([CH2:39][NH:1][C@H:2]2[CH2:3][CH2:4][C@H:5]([CH2:8][NH:9][C:10]3[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][N:13]=[C:12]([NH:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:27][C:28]([F:30])([F:31])[F:29])[N:11]=3)[CH2:6][CH2:7]2)[CH:35]=[N:34]1
Reactant: N[C@H]1CC[C@H](CNc2nc(NCc3ccccc3OC(F)(F)F)ncc2[N+](=O)[O-])CC1
Reactant: Cc1c(C=O)cnn1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1c(CN[C@H]2CC[C@H](CNc3nc(NCc4ccccc4OC(F)(F)F)ncc3[N+](=O)[O-])CC2)cnn1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of N4-[(trans-4-aminocyclohexyl)methyl]-5-nitro-N2-[2-(trifluoromethoxy)benzyl]-pyrimidine-2,4-diamine (100 mg, 0.23 mmol) and 1,5-dimethyl-1H-pyrazole-4-carbaldehyde (23 mg, 0.19 mmol) in CH2Cl2 (15 mL) was stirred at room temperature for 1 h. NaBH(OAc)3 (200 mg, 0.95 mmol) was then added to the reaction mixture and stirred for another 16 h. The reaction mixture was diluted with 1M Na2CO3 to pH 9-10 and the organic phase was separated. The aqueous phase was extracted with CH2Cl2. The combined organic phase was dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel prep TLC using 98:2 CH2Cl2:MeOH as an eluent to afford 54 mg (52%) of the title compound as a pale yellow foam, m/z 549.7 [M+1]+
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=2)[O:3]1.C([O-])([O-])=O.[Cs+].[Cs+].[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][CH:33](OS(C)(=O)=O)[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>CN1C(=O)CCC1.O>[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][CH:33]([O:15][C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([B:4]3[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]3)[CH:10]=2)[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: CC1(C)OB(c2cccc(O)c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Oc2cccc(B3OC(C)(C)C(C)(C)O3)c2)CC1
Temperature: 80 °C
Yield: 51.9 %

Procedure:
To a solution of 3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol (10.0 g, 45.4 mmol, 1.0 equiv) in NMP (100 ml) was added Cs2CO3 (44.4 g), 136.3 mmol, 3.0 equiv) and 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (19.0 g, 68.2 mmol, 1.5 equiv). The reaction mixture was heated to 80° C. and monitored until complete. The reaction mixture was cooled to room temperature, diluted with water and extracted with EtOAc. The organic layer was washed successively with 2N KOH, water, brine, dried (MgSO4), filtered and concentrated under reduced pressure. The target molecule was purified by column chromatography (SiO2), eluted with 5→30% EtOAc-petrol to afford a colourless liquid (9.5 g) that crystallised on standing. 1H NMR (400 MHz, CDCl3): 7.42 (1H, d), 7.37 (1H, d), 7.31 (1H, t), 7.03 (1H, dd), 4.61-4.49 (1H, m), 3.76-3.62 (2H, m), 3.47-3.32 (2H, m), 1.99-1.86 (2H, m), 1.86-1.70 (2H, m), 1.49 (9H, s).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[N:15]3[CH2:16][C:17]4[C:22]([C:14]3=[CH:13][C:12]=2[N:23]=1)=[CH:21][CH:20]=[CH:19][CH:18]=4.CN(C)[CH:26]=[O:27]>>[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[N:15]3[CH2:16][C:17]4[C:22]([C:14]3=[C:13]([CH:26]=[O:27])[C:12]=2[N:23]=1)=[CH:21][CH:20]=[CH:19][CH:18]=4
Reactant: CN(C)C=O
Reactant: COc1ccc2c(cc3n2Cc2ccccc2-3)n1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(n1)c(C=O)c1n2Cc2ccccc2-1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Under argon and in an anhydrous medium, 291 μl (3.17 mmol) of phosphorus oxychloride are added dropwise to 6 ml of N,N-dimethylformamide maintained at 0° C.; after 15 minutes' stirring, 500 mg (2.11 mmol) of the compound obtained in Step D dissolved in 10 ml of N,N-dimethylformamide are added by transfer. The reaction mixture is stirred for 30 minutes at 0° C. and then for 2 hours at room temperature. The reaction mixture is evaporated to dryness and then taken up in water; the aqueous phase is rendered alkaline with a 6N sodium hydroxide solution and extracted several times with ethyl acetate. The combined organic phases are dried over magnesium sulphate, filtered and evaporated. After washing with a petroleum ether/diethyl ether mixture, the title compound is obtained in the form of a brown solid.
Reaction SMILES: CN(C)C=O.P(Cl)(Cl)([Cl:8])=O.[NH2:11][C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:30][CH3:31])=[C:19]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:20]=2)[N:15]=[C:14](O)[N:13]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(C)C.C(OCC)(=O)C>[NH2:11][C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:30][CH3:31])=[C:19]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:20]=2)[N:15]=[C:14]([Cl:8])[N:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc2nc(O)nc(N)c2cc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: COc1cc2nc(Cl)nc(N)c2cc1OCc1ccccc1
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 26.7 %

Procedure:
N,N-Dimethyl formamide (7.9 ml, 0.10 mol) was added dropwise to phosphorus oxychloride (47.9 ml, 0.52 mol) with stirring. After 10 minutes, 4-amino-6-benzyloxy-2-hydroxy-7-methoxyquinazoline (16.4 g, 0.055 mol) was added portionwise and the resulting mixture heated at 90° C. for 1.5 hours, then cooled and poured into ethyl acetate (750 ml). The mixture was neutralised by the portionwise addition of aqueous sodium carbonate and the phases were separated. The organic layer was evaporated to dryness and the residue combined with the organic phase which was then treated with aqueous sodium hydroxide to basify (pH10) and the mixture was heated at 90° C. for 2 hours. After cooling, the mixture was partitioned between dichloromethane (11) and water (11), the organic phase washed with water, dried over MgSO4 and evaporated to give a pale yellow solid. Trituration with isopropanol afforded the subtitle compound as a colourless solid (4.64 g, 27%). Rf 0.64 (ethyl acetate:methanol 95:5, v/v). MS m/z 316, 318 (MH+).
Reaction SMILES: C[Si](C)(C)[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][Si](C)(C)C)[N:5]=1.[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(#N)C>[C:17]([O:3][C:4]1[NH:5][C:6](=[O:10])[CH:7]=[CH:8][CH:9]=1)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: C[Si](C)(C)Oc1cccc(O[Si](C)(C)C)n1
Reactant: O=C(Cl)c1ccccc1
Solvent: CC#N
Product: O=C(Oc1cccc(=O)[nH]1)c1ccccc1
Yield: 33 %

Procedure:
A 1.60 g quantity of 2,6-bis(trimethylsilyloxy)pyridine was dissolved in 10 ml of acetonitrile and 5 ml of acetonitrile solution containing 1.30 g of benzoyl chloride was added dropwise to the solution. After the mixture was reacted at room temperature for one day, the reaction mixture was concentrated and subjected to silica gel chromatography using chloroform as an eluent to produce 0.50 g of the title compound in a yield of 33%.
Reaction SMILES: Cl[C:2]1[C:11]([Cl:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20]([NH2:23])(=[O:22])=[O:21].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20]([NH:23][C:2]1[C:11]([Cl:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)(=[O:22])=[O:21]
Reactant: NS(=O)(=O)c1ccccc1Cl
Reactant: Clc1nc2ccccc2nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=S(=O)(Nc1nc2ccccc2nc1Cl)c1ccccc1Cl
Yield: 93.4 %

Procedure:
According to the step of Example 6-1, by use of 2,3-dichloroquinoxaline (5.00 g, 25.1 mmol) dissolved in dimethyl sulfoxide (100 mL), 2-chlorobenzene-1-sulfonamide (4.81 g, 25.1 mmol) and potassium carbonate (3.47 g, 25.1 mmol), the mixture was stirred and reacted at 150° C. for 3 hours. Then, slurry purification was performed using diisopropyl ether, to give 2-chloro-N-(3-chloroquinoxalin-2-yl)benzenesulfonamide (Compound AD) (8.30 g, yield: 93%).
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[CH:8]=[C:7](Cl)[S:6]1(=[O:13])=[O:12])([CH3:4])([CH3:3])[CH3:2].[F:14][C:15]([F:20])([F:19])[C:16]([OH:18])=[O:17].[C:21]([O:25][C:26]([NH:28][CH2:29][CH:30]1[C:35]2[S:36][C:37](B(O)O)=[CH:38][C:34]=2[CH2:33][CH2:32][N:31]1[CH2:42][C:43]1[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=1)=[O:27])([CH3:24])([CH3:23])[CH3:22]>>[F:14][C:15]([F:20])([F:19])[C:16]([OH:18])=[O:17].[C:21]([O:25][C:26](=[O:27])[NH:28][CH2:29][CH:30]1[C:35]2[S:36][C:37]([C:7]3[S:6](=[O:13])(=[O:12])[N:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:9](=[O:10])[CH:8]=3)=[CH:38][C:34]=2[CH2:33][CH2:32][N:31]1[CH2:42][C:43]1[CH:44]=[CH:45][C:46]([O:49][CH3:50])=[CH:47][CH:48]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)N1C(=O)C=C(Cl)S1(=O)=O
Reactant: COc1ccc(CN2CCc3cc(B(O)O)sc3C2CNC(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CN2CCc3cc(C4=CC(=O)N(C(C)(C)C)S4(=O)=O)sc3C2CNC(=O)OC(C)(C)C)cc1

Procedure:
This compound was prepared according to the procedure of Example 1.1, Step 4, using 9-A and 4.11-C as the starting materials. 1H NMR (500 MHz, CDCl3): δ 7.56 (s, 1H), 7.36 (d, J=8.4 Hz, 2H), 6.96 (d, J=8.4 Hz, 2H), 6.46 (s, 1H), 4.75–4.65 (m, 1H), 4.58–4.50 (m, 1H), (m, 1H), 4.08–4.00 (m, 1H), 3.83 (s, 3H), 3.80–3.65 (m, 3H), 3.55–3.48 (m, 1H), 3.18–3.10 (m, 2H), 1.75 (s, 9H), 1.36 (s, 9H); LCMS found for C28H38N3O6S2 (M+H)+: m/z=576.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[NH2:27][CH2:28][C:29]1[CH:45]=[CH:44][C:32]([C:33]([NH:35][CH2:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=2)=[O:34])=[CH:31][CH:30]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:27][CH2:28][C:29]1[CH:45]=[CH:44][C:32]([C:33](=[O:34])[NH:35][CH2:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=2)=[CH:31][CH:30]=1
Reactant: NCc1ccc(C(=O)NCCc2ccccn2)cc1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: O=C(NCCc1ccccn1)c1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1
Yield: 42.8 %

Procedure:
Use a method similar to the General Procedure 5-3 to react 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (200 mg, 0.471 mmol) and 4-aminomethyl-N-(2-pyridin-2-yl-ethyl)-benzamide (241 mg, 0.942 mmol) using palladium(II) acetate (21 mg, 0.094 mmol), tris(dibenzylideneacetone)dipalladium(0) (43 mg, 0.047 mmol), BINAP (176 mg, 0.283 mmol) and cesium carbonate (307 mg, 0.942 mmol) in dioxane (5 mL). Purify by chromatography on silica gel eluting with hexane and hexane/EtOAc/DCM/methanol (7:1:1:1) to give 7-chloro-6-[4-(2-pyridin-2-yl-ethylcarbamoyl)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as an oil (107 mg, 43%). MS (ES+) m/z: 531 (+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:12][C@@H:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH3:14])[CH2:10][OH:11])=[CH:5][CH:4]=1)#[N:2].N1C=CN=C1.[Si:27](Cl)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28].O>C(Cl)Cl>[Si:27]([O:11][CH2:10][CH:9]([NH:12][C@@H:13]([C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])[CH3:14])[C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]
Reactant: C[C@@H](NC(CO)c1ccc(C#N)cc1)C(=O)OC(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: C[C@@H](NC(CO[Si](C)(C)C(C)(C)C)c1ccc(C#N)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 72.7 %

Procedure:
To a solution of tert-butyl N-[1-(4-cyanophenyl)-2-hydroxyethyl]-D-alaninate (2 g, 0.0068 mol) in DCM (30 ml) were added imidazole (0.92 g, 0.0136 mol) and tert-Butyldimethylsilylchloride (1.25 g, 0.0082 mol) at RT. The reaction mixture was stirred at RT for 6 h and portioned between DCM and water, separated the layer and concentrated under reduced pressure. The crude material was purified by column chromatography using petroleum ether and ethyl acetate (80:20) as an eluent to afford (2 g, 74%) of the title compound as brown oil. 1H NMR: (DMSO-d6, 400 MHz) δ 7.80-7.77 (m, 2H), 7.53-7.50 (m, 2H), 4.86-4.85 (t, J=3.9 Hz, 1H), 3.17-3.13 (m, 1H), 2.61-2.55 (m, 1H), 1.95-1.89 (m, 1H), 1.39 (s, 9H), 1.09-1.07 (d, J=7.1 Hz, 3H), 0.80 (s, 9H), 0.04 (s, 3H), −0.12 (s, 3H). LC/MS (Method A): 405.3 (M+H)+. HPLC (Method A) Rt 5.13 min. (Purity: 73.7%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:26])[CH2:8][CH2:9][CH:10]2[CH2:13][CH2:14][N:15]2[C:23](=[O:24])[C:22]3C(=CC=CC=3)C2=O)=[CH:5][CH:4]=1.[BH4-].[Na+].[OH-].[Na+].CN(C1C=CC=CN=1)C.[C:40](OC(=O)C)(=[O:42])[CH3:41].C(=O)([O-])O.[Na+]>C(O)(C)C.O.ClCCl.CC(C)=O>[C:40]([O:26][CH:7]1[C:6]2[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:10]([CH2:13][CH2:14][NH:15][C:23](=[O:24])[CH3:22])[CH2:9][CH2:8]1)(=[O:42])[CH3:41]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc2c(c1)C(CCN1C(=O)c3ccccc3C1=O)CCC2=O
Agent: CN(C)c1ccccn1
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CC(C)O
Solvent: ClCCl
Solvent: O
Product: COc1ccc2c(c1)C(CCNC(C)=O)CCC2OC(C)=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 79 %

Procedure:
To a solution of the tetralone obtained in Step C (350 mg, 1.0 mmol) in isopropanol (10 mL) at ambient temperature there is added sodium borohydride (190 mg, 5.0 mmol). The mixture is stirred at reflux overnight and then a solution of sodium hydroxide (80 mg, 2.0 mmol) in water (2.0 mL) is added dropwise. The mixture is maintained under reflux for 30 minutes, and then acetone (1.5 mL) is added. After 10 minutes, the mixture is cooled to ambient temperature before being concentrated under reduced pressure. The oil thereby obtained is dissolved in dichloromethane (10 mL). Dimethylaminopyridine (270 mg, 2.2 mmol) is then added, followed by acetic anhydride (210 μL, 2.2 mmol) dropwise. The solution is stirred at ambient temperature for 1 hour and then water is added. The pH of the solution is adjusted to from 8 to 9 by adding saturated sodium hydrogen carbonate solution. The aqueous phase is extracted with dichloromethane and the organic phases are washed with saturated NaCl solution, dried over magnesium sulphate, filtered and evaporated. The title compound is obtained after purification by flash column chromatography (ethyl acetate-petroleum ether: 90-10, then ethyl acetate-methanol: 90-10) in the form of an oil in a yield of 79%.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[Cl:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH2:18]Br>O1CCCC1>[Cl:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH2:18][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: Clc1ccc(CBr)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a suspension of methyl 4-hydroxybenzoate (366 mg, 2.41 mmol) and sodium hydride (116 mg, 60% w/w dispersion in oil, 2.65 mmol) in tetrahydrofuran (12 mL) was added 3,4-dichlorobenzyl bromide (578 mg, 2.41 mmol) and the reaction mixture was stirred at room temperature for 48 hours. The reaction was quenched by addition of methanol (15 mL) and was then evaporated to dryness. The resulting residue was purified by flash column chromatography using ethyl acetate/heptane as eluant. The title compound was isolated as a white solid (750 mg, 100%).