Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH2:4][CH3:5].[Mg].Cl[SiH:9]1[CH2:14][CH2:13][CH:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH:28]([F:30])[F:29])=[C:23]([F:31])[CH:22]=3)=[CH:17][CH:16]=2)[CH2:11][CH2:10]1>C1COCC1>[CH2:1]([Si@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH:28]([F:29])[F:30])=[C:23]([F:31])[CH:22]=3)=[CH:19][CH:20]=2)[CH2:11][CH2:10]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: Fc1cc(-c2ccc(C3CC[SiH](Cl)CC3)cc2)ccc1OC(F)F
Reactant: CCCCCBr
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCC[Si@H]1CC[C@H](c2ccc(-c3ccc(OC(F)F)c(F)c3)cc2)CC1

Procedure:
3.0 g (20 mmol) of n-pentyl bromide was dripped into a mixture of 0.5 g of magnesium (21 mmol) and 50 ml of THF to obtain a Grignard's reagent. This solution was then dripped into a 50 ml THF solution of 7.4 g (20 mmol) of 4'-(4-chloro-4-silacyclohexyl)-3-fluoro-4-difluoromethoxybiphenyl to obtain 4'-(trans-4-n-pentyl-4-silacyclohexyl)-3-fluoro-4-difluoromethoxybiphenyl. The silacyclohexane rings of this product were a mixture of trans and cis isomers. They were separated by means of chromatography to obtain 6.6 g of the trans isomer (yield 81%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@@H:13]2[O:18][C:17]3[CH:19]=[CH:20][C:21]([O:23][CH3:24])=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[N+:25]([O-])([OH:27])=[O:26]>ClCCCl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[O:18][C:17]3[CH:19]=[C:20]([N+:25]([O-:27])=[O:26])[C:21]([O:23][CH3:24])=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: COc1ccc2c(c1)OC[C@H](COS(=O)(=O)c1ccc(C)cc1)O2
Reactant: O=[N+]([O-])O
Solvent: ClCCCl
Product: COc1cc2c(cc1[N+](=O)[O-])OC(COS(=O)(=O)c1ccc(C)cc1)CO2
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 5.91 g (16.9 mmole) of {(2R)-6-methoxy-2,3-dihydro-1,4-benzodioxin-2-ylmethyl 4-methylbenzenesulfonate in 200 mL of 1,2-dichloro-ethane in an ice/water bath was added dropwise a solution of 2.50 mL (59.1 mmole) of fuming nitric acid (d 1.49) in 75 mL of 1,2-dichloroethane and the mixture was stirred for 2 hours at 0° C. After the reaction was complete, it was quenched with ice and diluted with 500 mL of methylene chloride. After the ice had melted, the organic layer was separated and washed with equal volumes of saturated aqueous sodium bicarbonate and saturated brine, dried over magnesium sulfate, filtered and concentrated in vacuum to give 6.19 g of the (R)-enantiomer of the title compound as a light yellow solid. 1H-NMR (CDCl3): doublet 7.8 δ (2 H); multiplet 7.4 δ (3 H); singlet 6.5 δ (1 H); multiplet 4.10-4.5 δ (5 H); singlet 3.85 δ (3 H); singlet 2.5 δ (3 H).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH:12](OCC)(OCC)OCC>>[F:11][C:9]1[CH:8]=[CH:7][C:3]2[C:4](=[O:5])[NH:6][CH:12]=[N:1][C:2]=2[N:10]=1
Reactant: NC(=O)c1ccc(F)nc1N
Reactant: CCOC(OCC)OCC
Product: O=c1[nH]cnc2nc(F)ccc12
Temperature: 25 °C
Yield: 96 %

Procedure:
A suspension of 2-amino-6-fluoronicotinamide (0.74 g, 4.77 mmol) in triethyl orthoformate (25 mL) is heated at reflux for 8 h. After cooling to room temperature the precipitate is filtered off and washed well with petroleum ether to give 7-fluoropyrido[2,3-d]pyrimid-4(3H)-one (0.76 g, 96%), 1H NMR (DMSO) δ 12.75 (1H, brs), 8.66 (1H, dd, J=10.4, 8.4 Hz), 8.38 (1H, s), 7.33 (1H, dd, J=8.4, 2.6 Hz).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:13][CH3:14])[CH2:4][C:5]1[N:12]=[CH:11][CH:10]=[CH:9][C:6]=1[C:7]#[N:8].C(=O)([O-])[O-:16].[Na+].[Na+].OO>CO>[CH3:14][O:13][CH:3]([O:2][CH3:1])[CH2:4][C:5]1[N:12]=[CH:11][CH:10]=[CH:9][C:6]=1[C:7]([NH2:8])=[O:16]
Reactant: COC(Cc1ncccc1C#N)OC
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: CO
Product: COC(Cc1ncccc1C(N)=O)OC
Reaction time: 4.5 h
Yield: 85 %

Procedure:
The product from Example 36b (1.46 g, 7.6 mmol) was dissolved in methanol (20 mL) to which was added at room temperature sodium carbonate as a 3N solution (35 mL) followed by hydrogen peroxide as a 15% solution (35 mL). The reaction was allowed to stir for 4.5 hours then partitioned by the addition of ethyl acetate and solid sodium chloride. The aqueous phase was extracted several times with ethyl acetate and the combined organics stirred with solid sodium bisulfite followed by drying over MgSO4, filtered and concentration under vacuum to give the title compound (1.36 g, 85%) sufficiently pure for use as isolated.
Reaction SMILES: [CH:1](=[N:9][OH:10])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].ClN1C(=O)CCC1=O.[CH:19]([P:21](=[O:26])([O:24][CH3:25])[O:22][CH3:23])=[CH2:20].C(N(CC)CC)C>ClCCl.N1C=CC=CC=1>[OH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]1[CH2:20][CH:19]([P:21](=[O:26])([O:24][CH3:25])[O:22][CH3:23])[O:10][N:9]=1
Reactant: ON=Cc1ccccc1O
Reactant: C=CP(=O)(OC)OC
Agent: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: COP(=O)(OC)C1CC(c2ccccc2O)=NO1
Temperature: 0 °C
Yield: 63.4 %

Procedure:
41.1 g (0.3 mol) of salicylaldoxime in dichloromethane are refluxed with 40.1 g (0.3 mol) of N-chlorosuccinimide and 1.5 ml of pyridine for 3 hours. Ice-water is added and the mixture is extracted, and the hydroxamoyl chloride is recrystallized from dichloromethane/petroleum ether. 25.5 g (0.15 mol) of this are reacted with 20.4 g (0.15 mol) of dimethyl vinylphosphonate and 22.9 ml (0.165 mol) of triethylamine in dichloromethane in analogy to Example 5 to give 25.8 g of oily product.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([CH2:13][CH:14]([NH:23][C:24](=[O:45])[CH2:25]NS(C3C(C)=C(C)C4OC(C)(C)CCC=4C=3C)(=O)=O)[C:15](=[O:22])[N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:10][CH:11]=2)[CH:6]=[CH:5][N:4]=1.[NH2:46]C1C2C(=CC(CC(NC(=O)OC(C)(C)C)C(=O)N3CCCCC3)=CC=2)C=CN=1.NC(=O)C[C@H:78]([NH:82][S:83]([C:86]1[C:91]([CH3:92])=[CH:90][C:89]([O:93][CH3:94])=[C:88]([CH3:95])[C:87]=1[CH3:96])(=[O:85])=[O:84])[C:79](O)=[O:80].N[C@H](C(O)=O)CC(=O)N.[Cl-]>>[ClH:1].[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([CH2:13][CH:14]([NH:23][C:24](=[O:45])[CH2:25][C@H:78]([NH:82][S:83]([C:86]3[C:91]([CH3:92])=[CH:90][C:89]([O:93][CH3:94])=[C:88]([CH3:95])[C:87]=3[CH3:96])(=[O:85])=[O:84])[C:79]([NH2:46])=[O:80])[C:15](=[O:22])[N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:10][CH:11]=2)[CH:6]=[CH:5][N:4]=1
Reactant: Cc1c(C)c(S(=O)(=O)NCC(=O)NC(Cc2ccc3c(N)nccc3c2)C(=O)N2CCCCC2)c(C)c2c1OC(C)(C)CC2
Reactant: COc1cc(C)c(S(=O)(=O)N[C@@H](CC(N)=O)C(=O)O)c(C)c1C
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc2c(N)nccc2c1)C(=O)N1CCCCC1
Agent: Cl
Agent: NC(=O)C[C@H](N)C(=O)O
Agent: [Cl-]
Product: COc1cc(C)c(S(=O)(=O)N[C@@H](CC(=O)NC(Cc2ccc3c(N)nccc3c2)C(=O)N2CCCCC2)C(N)=O)c(C)c1C

Procedure:
The procedure described for 5c was used. Deprotection of 100 mg of 5a and coupling with 105 mg of (2S)-4-amino-2-[[(4-methoxy-2,3,6-trimethylphenyl)sulfonyl]amino]-4-oxobutanoic acid (prepared from Asn-OH and 4-methoxy-2,3,6-trimethylsulfonylchloride (Mtr-chloride)using the procedure described for 5b) yielded the title compound (66 mg) as a mixture of diastereomers (1:1). 1H-NMR 400 MHz (CD3OD) δ: 1.20-1.68 (6H, m), 2.15 and 2.16 (3H, 2×s), 2.27-2.58 (2H, m), 2,57 (3H,s), 2.64 (3H, s), 2.93-3.57 (6H, m), 3.83 and 3.87 (3H, 2×s), 3.98-4.09 (1H, m), 5.07-5.19 (1H, m), 6.75 and 6.76 (1H, 2×s), 7.22-7.27 (1H, m), 7.55-7.79 (3H, m), 8.33-8.38 (1H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH:11](=O)[CH2:12][CH3:13].N1CCCCC1>C(O)C>[Cl:10][C:8]1[CH:9]=[C:2]2[C:3]([CH:4]=[C:12]([CH3:13])[CH:11]=[N:1]2)=[CH:6][CH:7]=1
Reactant: Nc1cc(Cl)ccc1C=O
Reactant: CCC=O
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cnc2cc(Cl)ccc2c1
Yield: 75 %

Procedure:
Under nitrogen atmosphere, to a solution of 2-amino-4-chloro-benzaldehyde (467 mg) in ethanol (10 mL) were added propanal (250 μL) and piperidine (50 μl), and the mixture was heated under reflux. Further, to the mixture were added propanal (800 μL) and piperidine (250 μL) in several portions, and the mixture was heated under reflux for total 9 hours. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column (hexane/ethyl acetate=6/1) to give 7-chloro-3-methylquinoline (401 mg, 75%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:55])[NH:11][C:12]1[CH:53]=[CH:52][C:15]([O:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]3[CH:23]=[C:24]([C:26]4[N:27]([CH3:51])[C:28]([CH2:31][N:32]([CH2:47][CH2:48][O:49][CH3:50])[C:33](=[O:46])[C@@H:34]([NH:38]C(=O)OC(C)(C)C)[CH:35]([CH3:37])[CH3:36])=[CH:29][N:30]=4)[S:25][C:18]=23)=[C:14]([F:54])[CH:13]=1.Cl.O1CCOCC1>C(Cl)Cl.O.C([O-])(O)=O.[Na+]>[NH2:38][C@@H:34]([CH:35]([CH3:37])[CH3:36])[C:33]([N:32]([CH2:31][C:28]1[N:27]([CH3:51])[C:26]([C:24]2[S:25][C:18]3[C:19](=[N:20][CH:21]=[CH:22][C:17]=3[O:16][C:15]3[CH:52]=[CH:53][C:12]([NH:11][C:10]([NH:9][C:3]4[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=4[F:1])=[O:55])=[CH:13][C:14]=3[F:54])[CH:23]=2)=[N:30][CH:29]=1)[CH2:47][CH2:48][O:49][CH3:50])=[O:46]
Reactant: COCCN(Cc1cnc(-c2cc3nccc(Oc4ccc(NC(=O)Nc5ccc(F)cc5F)cc4F)c3s2)n1C)C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: COCCN(Cc1cnc(-c2cc3nccc(Oc4ccc(NC(=O)Nc5ccc(F)cc5F)cc4F)c3s2)n1C)C(=O)[C@@H](N)C(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.8 %

Procedure:
To a suspension of the compound 352 (200 mg, 0.256 mmol) in DCM (10 ml) was added HCl in dioxane (0.7 ml, 10.95 eq, 2.80 mmol, 4M in dioxane) and the reaction mixture was stirred at RT for 3 hours. The mixture wad diluted with water and solid NaHCO3 was added. The reaction mixture was extracted with EtOAc then the organic phase was collected, dried over Na2SO4, filtered and concentrated. Purification of the residue by column chromatography (eluent 30% MeOH in EtOAc) afforded the desired compound 353 as pale yellow powder (155 mg, 89% yield). 1H NMR (d6-DMSO) 9.36 (s, 1H), 8.60 (s, 1H), 8.49 (m, 1H), 8.01 (m, 1H), 7.87 (s, 1H), 7.71 (m, 1H), 7.41 (t, J=8.99 Hz, 1H), 7.31 (m, 1H), 7.20 (m, 1H), 7.02 (m, 1H), 6.98 (s, 1H), 6.65 (d, J=5.09 Hz, 1H), 4.83 (d, J=15.65 Hz, 1H), 4.48 (d, J=15.65 Hz, 1H), 3.81 (s, 1H), 3.80 (s, 2H), 3.40 (m, 1H), 3.39-3.295 (m, 6H), 1.71 (m, 2H), 0.81 (m, 6H).
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:37][NH:38][CH2:39][CH2:40]O.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:37][NH:38][CH2:39][CH2:40][O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][CH2:9][NH:8][C:1](=[O:2])[O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(O)cc1
Reactant: CNCCO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CNCCOc1ccc(CCNC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 43.8 %

Procedure:
To a solution of N-Boc-tyramine (750 mg, 3.16 mmol) and triphenylphosphine (1.655 g, 6.308 mmol) in THF (30 mL) was added 2-(methylamino)ethanol (0.38 mL, 4.75 mmol) followed by DIAD (1.25 mL, 6.31 mmol). After stirring at room temperature for 72 h, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (gradient elution 1:20 to 1:3 MeOH/DCM) to afford the title compound (407 mg, 44%) as an oily white solid. ES/MS calcd. for C16H27N2O3+ 295.2. Found m/z=295.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH:9]=O)=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.[NH2:11][C:12](N)=[O:13]>O>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]2[C:3]([N:4]=1)=[CH:9][NH:11][C:12](=[O:13])[N:1]=2
Reactant: Nc1ccc(Cl)nc1C=O
Reactant: NC(N)=O
Solvent: O
Product: O=c1nc2ccc(Cl)nc2c[nH]1
Temperature: 180 °C

Procedure:
3-amino-6-chloro-pyridine-2-carbaldehyde (3.2 g, 13.0 mmol) is mixed thoroughly with urea (7.8 g, 130 mmol) and heated to 180° C. in the preheated oil bath for 3 h. Then the reaction mixture is suspended in H2O, the precipitate is filtered off and 6-chloro-3H-pyrido[3,2-d]pyrimidin-2-one is obtained.
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[C:6](OCC)(OCC)([O:8][CH2:9][CH3:10])[CH3:7]>>[CH2:6]([O:8][C:9](=[C:2]([C:1]#[N:5])[C:3]#[N:4])[CH3:10])[CH3:7]
Reactant: CCOC(C)(OCC)OCC
Reactant: N#CCC#N
Product: CCOC(C)=C(C#N)C#N

Procedure:
8.26 g (125 mmol) of malononitrile and 20.25 g (125 mmol) of triethyl orthoacetate are refluxed for hours. After cooling, the mixture is dried in vacuo.
Reaction SMILES: O1CCCC1.C([O:8][C:9](=[O:40])[CH:10]([NH:33][C:34]([O:36][CH2:37][CH:38]=[CH2:39])=[O:35])[CH2:11][C:12]1[O:16][N:15]=[C:14]([CH:17]2[CH2:21][CH2:20][CH2:19][N:18]2[S:22]([C:25]2[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:32])[CH:26]=2)(=[O:24])=[O:23])[CH:13]=1)C.[OH-].[Li+].Cl>CO>[CH2:37]([O:36][C:34]([NH:33][CH:10]([CH2:11][C:12]1[O:16][N:15]=[C:14]([CH:17]2[CH2:21][CH2:20][CH2:19][N:18]2[S:22]([C:25]2[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:32])[CH:26]=2)(=[O:23])=[O:24])[CH:13]=1)[C:9]([OH:40])=[O:8])=[O:35])[CH:38]=[CH2:39]
Reactant: C=CCOC(=O)NC(Cc1cc(C2CCCN2S(=O)(=O)c2cc(Cl)cc(Cl)c2)no1)C(=O)OCC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C=CCOC(=O)NC(Cc1cc(C2CCCN2S(=O)(=O)c2cc(Cl)cc(Cl)c2)no1)C(=O)O
Yield: 91.1 %

Procedure:
A tetrahydrofuran (1.0 mL) and methanol (0.5 mL) solution of 2-allyloxycarbonylamino-3-{3-[1-(3,5-dichloro-benzenesulfonyl)-pyrrolidin-2-yl]-isoxazol-5-yl}-propionic acid ethyl ester (59 mg, 0.108 mmol) was stirred with 2M aqueous lithium hydroxide (0.5 mL) at room temperature for 40 minutes. The reaction was acidified to pH 1 with 1 M hydrochloric acid and extracted twice with ethyl acetate. The combined extracts were dried over magnesium sulfate and concentrated in vacuo to give the title compound as a white solid (51 mg, 91%). MS (CI) m/z 518 (M+1).
Reaction SMILES: [CH:1]1([C:4]2[C:9]([CH2:10]O)=[CH:8][CH:7]=[C:6]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)[N:5]=2)[CH2:3][CH2:2]1.O=S(Cl)[Cl:24]>C(Cl)Cl>[Cl:24][CH2:10][C:9]1[C:4]([CH:1]2[CH2:3][CH2:2]2)=[N:5][C:6]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:7][CH:8]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc(-c2ccc(C(F)(F)F)cc2)nc1C1CC1
Solvent: ClCCl
Product: FC(F)(F)c1ccc(-c2ccc(CCl)c(C3CC3)n2)cc1

Procedure:
0.127 g (0.433 mmol) of the above prepared [2-cyclopropyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-methanol was dissolved in 2.0 ml of CH2Cl2 and treated at 0° C. with 0.063 ml (2 eq.) of SOCl2. The reaction mixture was kept at 0° C. for 5 Min. and at RT for 60 Min. Pouring onto crashed ice/NaHCO3, twofold extraction with AcOEt, washing with water and brine, drying over magnesium sulfate, and evaporation of the solvents afforded 0.137 g of pure title compound as off-white solid.
Reaction SMILES: C1C2C(COC([N:18]3[CH2:23][CH2:22][N:21]([C:24](=[O:60])[C@@H:25]([N:33]([CH2:48][C:49]4[CH:54]=[CH:53][C:52]([CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])=[CH:51][CH:50]=4)[C:34](=[O:47])[CH:35]=[CH:36][C:37]4[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][CH:38]=4)[CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:20][CH2:19]3)=O)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1.CCOC(C)=O>CN(C=O)C>[CH2:26]([C@H:25]([N:33]([CH2:48][C:49]1[CH:50]=[CH:51][C:52]([CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])=[CH:53][CH:54]=1)[C:34](=[O:47])[CH:35]=[CH:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][CH:38]=1)[C:24](=[O:60])[N:21]1[CH2:20][CH2:19][NH:18][CH2:23][CH2:22]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCCCCc1ccc(CN(C(=O)C=Cc2ccc(C(F)(F)F)cc2)[C@@H](Cc2ccccc2)C(=O)N2CCN(C(=O)OCC3c4ccccc4-c4ccccc43)CC2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: CCCCCc1ccc(CN(C(=O)C=Cc2ccc(C(F)(F)F)cc2)[C@@H](Cc2ccccc2)C(=O)N2CCNCC2)cc1
Reaction time: 0.5 h
Yield: 82.5 %

Procedure:
4-(2-{(4-pentyl-benzyl)-[3-(4-trifluoromethyl-phenyl)-acryloyl]-amino}-(S)-3-phenyl-propionyl)-piperazine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester (1.75 g, 2.15 mmol) was dissolved in DMF (47.5 mL) and piperidine (2.5 mL) was added. Stirring was continued at rt for 30 min. EtOAc (150 mL) was added and the mixture was washed with water (2×150 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (silicagel, MeOH/DCM=1/99) to give 1.05 g (82.5%) of N—((S)-1-Benzyl-2-oxo-2-piperazin-1-yl-ethyl)-N-(4-pentyl-benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide. LC-MS: tR=0.97 min; [M+H]+=592.19.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C@@H:4]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9](OS(C(F)(F)F)(=O)=O)=[CH:8][CH:7]=1.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.O>[CH3:1][O:2][C:3](=[O:28])[C@@H:4]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[O:30][CH3:29])=[CH:8][CH:7]=1
Reactant: COc1ccccc1B(O)O
Reactant: COC(=O)[C@H](Cc1ccc(OS(=O)(=O)C(F)(F)F)cc1)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)[C@H](Cc1ccc(-c2ccccc2OC)cc1)NC(=O)OC(C)(C)C
Temperature: 80 °C
Yield: 65 %

Procedure:
(S)-2-tert-Butoxycarbonylamino-3-(4-trifluoromethanesulfonyloxyphenyl) propionic acid methyl ester (1.88 g, 4.39 mmol, prepared as described in Preparation 23, was dissolved in glyme (58 ml) and water (4 ml). To this solution 2-methoxyphenylboronic acid (2.0 g, 13.16 mmol), tetrakistriphenylphosphine palladium (0) (2.79 g, 2.41 mmol) and potassium carbonate (2.12 g, 15.37 mmol) were added. The reaction mixture was degassed and then heated at 80° C. for 6 h. The mixture was diluted with EtOAc (100 ml), washed with saturated aqueous NaHCO3 (100 ml) and brine (100 ml) and dried over MgSO4. The mixture was filtered and concentrated in vacuo. The residue was purified by flash chromatography over silica gel (9:1 to 4:1 hexanes/EtOAc) to give (S)-2-tert-butoxycarbonylamino-3-(2′-methoxy-biphenyl-4-yl)-propionic acid methyl ester (1.1 g, 65%) as a white solid.
Reaction SMILES: Br[CH:2]([CH:6]([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4].[CH2:9]1[O:18][C:17]2[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][C:11]=2[O:10]1>>[CH2:9]1[O:18][C:17]2[CH:16]=[CH:15][C:13]([NH:14][C@H:2]([C:3]([OH:5])=[O:4])[CH:6]([CH3:8])[CH3:7])=[CH:12][C:11]=2[O:10]1
Reactant: CC(C)C(Br)C(=O)O
Reactant: Nc1ccc2c(c1)OCO2
Product: CC(C)[C@H](Nc1ccc2c(c1)OCO2)C(=O)O

Procedure:
Following the procedure of Example 1, the m-phenoxybenzyl ester of α-bromoisovaleric acid is reacted with 3,4-methylenedioxyaniline (3equivalents) at about 75° for about 14 hours to yield the m-phenoxybenzyl ester of N-(3,4-methylenedioxyphenyl)valine, MS m/e 419 (M+, 13.2), 192 (100).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23].C([O-])([O-])=O.[K+].[K+]>C(#N)C.Cl>[S:8]([C:5]1[CH:6]=[CH:7][C:2]([O:1][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:3][CH:4]=1)(=[O:9])(=[O:10])[NH2:11]
Reactant: CC(C)(C)OC(=O)NCCCCCCBr
Reactant: NS(=O)(=O)c1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCCCCCCOc1ccc(S(N)(=O)=O)cc1
Temperature: 75 °C
Reaction time: 8 h
Yield: 42.7 %

Procedure:
To a solution of 4-hydroxybenzenesulfonamide (1.73 g, 10.0 mmol) and tert-butyl (6-bromohexyl)carbamate (2.1 g, 7.5 mmol) in acetonitrile (50 mL) was added anhydrous K2CO3 (2.07 g, 15 mmol). The reaction mixtures were stirred at 75° C. for overnight. Solvent was evaporated under reduced pressure to give a residue. The residue was diluted with 1 N HCl (40 mL), extracted with DCM, and dried over Na2SO4. Solvent was evaporated under reduce pressure to afford a residue, which was purified by biotage eluting with DCM to 10% MeOH in DCM to afford tert-butyl (6-(4-sulfamoylphenoxy)hexyl)carbamate (1.192 g, 43%).
Reaction SMILES: [CH2:1]([N:3]([CH2:29][CH3:30])[CH2:4][CH2:5][S:6][C:7]1[CH:8]=[CH:9][C:10]2[C:22](=[O:23])[C:21]3[C:20]4[C:15](=[CH:16][C:17]([C:24]#[N:25])=[CH:18][CH:19]=4)[NH:14][C:13]=3[C:12]([CH3:27])([CH3:26])[C:11]=2[CH:28]=1)[CH3:2].[OH:31]OS([O-])=O.[K+].[OH2:37]>CO>[CH2:29]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][S:6]([C:7]1[CH:8]=[CH:9][C:10]2[C:22](=[O:23])[C:21]3[C:20]4[C:15](=[CH:16][C:17]([C:24]#[N:25])=[CH:18][CH:19]=4)[NH:14][C:13]=3[C:12]([CH3:26])([CH3:27])[C:11]=2[CH:28]=1)(=[O:31])=[O:37])[CH3:30]
Reactant: O
Reactant: O=S([O-])OO
Reactant: CCN(CC)CCSc1ccc2c(c1)C(C)(C)c1[nH]c3cc(C#N)ccc3c1C2=O
Agent: [K+]
Solvent: CO
Product: CCN(CC)CCS(=O)(=O)c1ccc2c(c1)C(C)(C)c1[nH]c3cc(C#N)ccc3c1C2=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
8-(2-Diethylamino-ethylsulfanyl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Compound B2-17, 16.8 mg, 0.0402 mmol) was dissolved in methanol (1.5 mL), added with oxone (54.3 mg, 2.2 eq.) which had been dissolved in water (0.5 mL), and then stirred at room temperature for 2 hr. The reaction solution was concentrated, extracted with ethyl acetate, washed with saturated sodium hydrogen carbonate, and dried over magnesium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (dichloromethane/methanol) to obtain the target compound (white solid, 5.8 mg, 32%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:11]([O:18][C:19]1[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=1[NH2:21])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.O>CN(C=O)C>[CH2:11]([O:18][C:19]1[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=1[NH:21][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][N:9]=[CH:10][C:2]=1[F:1])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Nc1ccccc1OCc1ccccc1
Reactant: O=C(O)c1ccncc1F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1ccccc1OCc1ccccc1)c1ccncc1F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 97.2 %

Procedure:
To a mixture of 3-fluoroisonicotinic acid (2.20 g, 15.6 mmol), 2-(benzyloxy)aniline (2.84 g, 14.2 mmol) and BOP (6.94 g, 15.6 mmol) in DMF (20.0 mL) was added TEA (4.4 mL, 31.2 mmol). The reaction mixture was stirred at room temperature for 20 min and poured into water. The aqueous layer was extracted with ethyl acetate (2×). The combined organic extracts were washed with water and brine, dried over sodium sulfate and concentrated in vacuo to a quarter volume. The resulting solid was found to be the desired compound. The filtrate was concentrated in vacuo to dryness. The residue was triturated in 30% ethyl acetate in hexanes and the 2 solids were combined to afford compound 24 (4.45 g, 97%) as a white solid. LRMS (ESI): (calc) 322.11. (found) 323.2 (MH)+.
Reaction SMILES: [C:1]1([CH:11]=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.CCCCCC.[C:19]([O:22][CH2:23][CH3:24])(=[O:21])[CH3:20]>C(#N)C.O1CCCC1>[CH2:23]([O:22][C:19](=[O:21])[CH:20]=[CH:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)[CH3:24]
Reactant: CCOC(C)=O
Reactant: O=Cc1cccc2ccccc12
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC#N
Product: CCOC(=O)C=Cc1cccc2ccccc12
Reaction time: 8 h
Yield: 90 %

Procedure:
22.4 g (0.10 mol) of triethylphosphonoacetate was dissolved in 500 M of acetonitrile and 30.4 g (0.2 mol) of 1,8-diazabicyclo[5.4.0]undec-7-ene(1,5-5)(DBU) was slowly added thereto. To this solution was slowly added 15.6 g (0.10 mol) of 1-naphthaldehyde dissolved in 20 ml of tetrahydrofuran and the mixture was stirred for 8 hours. The organic solvent was removed by distillation under reduced pressure. The resulting residue was dissolved in ethyl acetate, washed twice with water, dried over magnesium sulfate, concentrated and then subjected to silica gel column chromatography (eluent: n-hexane/ethyl acetate=95/5, v/v) to obtain 20.3 g (0.090 mol, Yield 90%) of the title compound.