Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:15]=[CH:14][C:5]([C:6]([CH:8]([OH:13])[CH2:9][C:10]([OH:12])=[O:11])=[O:7])=[CH:4][CH:3]=1.BrC(C(=O)[C:23]1[CH:28]=[CH:27][C:26](Cl)=[CH:25][CH:24]=1)CC(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>>[C:2]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:15]=[CH:14][C:5]([C:6]([CH:8]([OH:13])[CH2:9][C:10]([OH:12])=[O:11])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(O)CC(O)C(=O)c1ccc(Cl)cc1
Reactant: O=C(O)CC(Br)C(=O)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: O=C(O)CC(O)C(=O)c1ccc(-c2ccccc2)cc1

Procedure:
Groups R1 and R2 are defined above, are either known compounds (U.S. 3,714,218 and U.S. 3,749,750) or are prepared by techniques known to the chemist. For example, 3-(p-chlorobenzoyl)-3-hydroxy-propionic acid is prepared by reacting 3-bromo-3-(p-chlorobenzoyl)propionic acid with aqueous 10 percent sodium carbonate. The same displacement reaction yields 3-(4-biphenylylcarbonyl)-3-hydroxypropionic acid from the 3-bromoprecursor.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:13]([C:14]2[CH:19]=[CH:18][N:17]=[C:16](S(C)(=O)=O)[N:15]=2)=[CH:12][NH:11][N:10]=1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:30]=[C:31]([O:35][CH3:36])[C:32]=1[O:33][CH3:34])[NH2:29]>CC(O)=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:13]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH:29][C:28]3[CH:30]=[C:31]([O:35][CH3:36])[C:32]([O:33][CH3:34])=[C:26]([O:25][CH3:24])[CH:27]=3)[N:15]=2)=[CH:12][NH:11][N:10]=1
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: CS(=O)(=O)c1nccc(-c2c[nH]nc2-c2ccc(Cl)cc2Cl)n1
Solvent: CC(=O)O
Product: COc1cc(Nc2nccc(-c3c[nH]nc3-c3ccc(Cl)cc3Cl)n2)cc(OC)c1OC

Procedure:
{4-[3-(2,4-Dichloro-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-(3,4,5-trimethoxy-phenyl)-amine is synthesized from 4-[3-(2,4-dichloro-phenyl)-1H-pyrazol-4-yl]-2-methanesulfonyl-pyrimidine in analogy to a literature procedure (Klutchko et al., Journal of Medicinal Chemistry, 1998, Vol. 41, No. 17, 3276-3292) using 3,4,5-trimethoxyaniline (Fluka 92129) and glacial HOAc.
Reaction SMILES: [NH:1]=[C:2]1[C:15]([NH:16][C:17]([NH:19][C:20]([O:22][CH3:23])=[O:21])=[S:18])=[CH:14][CH:13]=[C:4]([C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:6])[CH:3]1[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N+:31]([O-:33])=[O:32].[H-].[Na+].S(OC)(O[CH3:39])=O.O>CN(C)C=O>[NH:1]=[C:2]1[C:15]([NH:16][C:17](=[N:19][C:20]([O:22][CH3:23])=[O:21])[S:18][CH3:39])=[CH:14][CH:13]=[C:4]([C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:6])[CH:3]1[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N+:31]([O-:33])=[O:32]
Reactant: COS(=O)OC
Reactant: COC(=O)NC(=S)NC1=CC=C(C(=O)c2ccccc2)C(Cc2ccccc2[N+](=O)[O-])C1=N
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)N=C(NC1=CC=C(C(=O)c2ccccc2)C(Cc2ccccc2[N+](=O)[O-])C1=N)SC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 3-imino-(o-nitrophenyl)methyl-4-(3-carbomethoxythioureido)benzophenone (4.62 g.; 0.01 mol) in dimethyl formamide (40 ml.) there is added 57% sodium hydride (0.42 g.; 0.01 mol) (oil dispersion). The mixture is stirred at room temperature for one hour and to it there is added dimethyl sulfite (1.1 g.; 0.01 mol). The mixture is stirred at room temperature for 11/2 hours and is poured into an excess of water. The suspension formed is vacuum filtered and the filter caked dried to afford 3-imino-(o-nitrophenyl)methyl-4-(3-carbomethoxy-S-methylisothioureido)benzophenone.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][CH2:8][C:9]1[N:10]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:11](=[O:25])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]([NH2:24])=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2].[C:31](Cl)(=[O:33])[CH3:32].O>CN(C)C(=O)C>[C:1]([O:5][C:6](=[O:30])[NH:7][CH2:8][C:9]1[N:10]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:11](=[O:25])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]([NH:24][C:31](=[O:33])[CH3:32])=[CH:14][CH:13]=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(N)cc12
Reactant: CC(=O)Cl
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(NC(C)=O)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.8 %

Procedure:
A solution of tert-butyl(6-amino-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate (synthesized according to the method similar to that in Example 82 (2)) (0.21 g, 0.5 mmol) and acetyl chloride (0.04 ml, 0.6 mmol) in N,N-dimethylacetamide (10 ml) was stirred at room temperature for 2 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-diisopropyl ether to give tert-butyl{6-(acetylamino)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl}methylcarbamate (0.19 g, 80.8%) as crystals.
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:17]([C@@:18]([OH:24])([CH3:23])[C:19]([F:22])([F:21])[F:20])[O:16][C@H:15]2[C@H:11]([N:12]=[C:13]([N:25]([CH2:33][CH3:34])C(=O)OC(C)(C)C)[S:14]2)[C@H:10]1[F:35])C1C=CC=CC=1.B(Cl)(Cl)Cl>>[CH2:33]([NH:25][C:13]1[S:14][C@H:15]2[O:16][C@H:17]([C@@:18]([OH:24])([CH3:23])[C:19]([F:22])([F:21])[F:20])[C@@H:9]([OH:8])[C@H:10]([F:35])[C@H:11]2[N:12]=1)[CH3:34]
Reactant: CCN(C(=O)OC(C)(C)C)C1=N[C@@H]2[C@@H](F)[C@H](OCc3ccccc3)[C@@H]([C@](C)(O)C(F)(F)F)O[C@@H]2S1
Agent: ClB(Cl)Cl
Product: CCNC1=N[C@@H]2[C@@H](F)[C@H](O)[C@@H]([C@](C)(O)C(F)(F)F)O[C@@H]2S1

Procedure:
The above material, tert-butyl ((3aR,5S,6R,7R,7aR)-6-(benzyloxy)-7-fluoro-5-((S)-1,1,1-trifluoro-2-hydroxypropan-2-yl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(ethyl)carbamate (0.057 g, 0.11 mmol), was deprotected with BCl3 using the procedure described for Example 20. After purification on silica gel by flash column chromatography (1.0 M NH3 in MeOH/DCM, 1:17), (3aR,5S,6R,7R,7aR)-2-(ethylamino)-7-fluoro-5-((S)-1,1,1-trifluoro-2-hydroxypropan-2-yl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol was obtained as a white solid (0.031 g, 85%). 1H NMR (400 MHz, CD3OD) δ 6.30 (d, J=6.8 Hz, 1H), 5.03-4.90 (m, 1H), 4.54-4.49 (m, 1H), 4.20-4.13 (m, 1H), 3.61 (d, J=8.5 Hz, 1H), 3.30-3.22 (m, 2H), 1.36 (s, 3H), 1.17 (t, J=7.2 Hz, 3H); 13C NMR (100 MHz, CD3OD) δ 163.48 (d, J=1.7 Hz), 127.48 (q, J=285.5 Hz), 93.70 (d, J=177.4 Hz), 88.94, 75.79 (q, J=27.0 Hz), 74.76 (d, J=1.4 Hz), 73.79 (d, J=26.7 Hz), 68.15 (d, J=25.1 Hz), 40.02, 18.92 (q, J=2.2 Hz), 14.95; MS, (ES, m/z) [M+H]+ 333.1.
Reaction SMILES: C([O:9][C@@H:10]1[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@H:12]([C:22]([O:24][CH3:25])=[O:23])[CH2:11]1)(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>CO.C(OCC)(=O)C>[C:18]([O:17][C:15]([N:13]1[CH2:14][C@@H:10]([OH:9])[CH2:11][C@H:12]1[C:22]([O:24][CH3:25])=[O:23])=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: COC(=O)[C@@H]1C[C@H](OC(=O)c2ccccc2)CN1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H]1C[C@H](O)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.3 %

Procedure:
To a solution of (2S,4S)-4-benzoyloxy-1-t-butoxycarbonyl-2-methoxycarbonylpyrrolidine (30.0 g) in methanol (600 ml) was added potassium carbonate (11.9 g) and the mixture was stirred at room temperature for 1 hour. The solution was diluted with ethyl acetate (1 l) and washed with water. The organic phase was washed with brine. The aqueous phase was saturated with sodium chloride, extracted with chloroform and washed with brine. The combined organic extracts were dried over magnesium sulfate and evaporated in vacuo to give an oil. The oil was chromatographed on a silica gel (500 g) column with a mixture of n-hexane and ethyl acetate (1:1) as an eluent to give (2S,4S)-1-t-butoxycarbonyl-4-hydroxy-2-methoxycarbonylpyrrolidine (20.7 g) as colorless crystal.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:5]2[CH:6]=[C:7]3[N:12]([C:13]=2[N:14]=1)[CH2:11][CH2:10][O:9][C:8]3([CH3:16])[CH3:15].CC1(C)C(C)(C)OB([C:31]2[CH:32]=[N:33][C:34]([NH2:37])=[N:35][CH:36]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[CH3:15][C:8]1([CH3:16])[C:7]2[N:12]([C:13]3[N:14]=[C:2]([C:31]4[CH:32]=[N:33][C:34]([NH2:37])=[N:35][CH:36]=4)[N:3]=[C:4]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)[C:5]=3[CH:6]=2)[CH2:11][CH2:10][O:9]1
Reactant: CC1(C)OCCn2c1cc1c(N3CCOCC3)nc(Cl)nc12
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: CC1(C)OCCn2c1cc1c(N3CCOCC3)nc(-c3cnc(N)nc3)nc12
Temperature: 150 °C
Yield: 14.8 %

Procedure:
A mixture of 3-Chloro-8,8-dimethyl-1-morpholin-4-yl-5,6-dihydro-8H-7-oxa-2,4,4b-triaza-fluorene (75 mg, 0.23 mmol), 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine (115 mg, 0.52 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)-phosphine)dichloropalladium(II) (25 mg, 0.035 mmol) and sodium carbonate (1 mL, 1.0 mmol, 1M aqueous solution) in acetonitrile (3 mL) was degassed and heated at 150° C. for 30 mins in a microwave reactor, then concentrated in vacuo. The resulting residue was purified by column chromatography (SiO2, gradient 0 to 75% ethyl acetate in cyclohexane) followed by reverse phase HPLC (Phenomenex Gemini 5 μm C18, 0.1% HCO2H in water on a gradient acetonitrile 5-98%) affording 177 as a off-white solid (13 mg, 15%). LCMS (method B): RT=3.50 min, [M+H]+=382. 1H NMR (400 MHz, CDCl3): δ 9.27 (2H, s), 6.12 (1H, s), 5.27 (2H, broad s), 4.21 (2H, m), 4.14 m), 3.88 (4H, m), 1.62 (6H, s)
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[C:8]([CH3:24])[C:6]=2[N:7]=1.[NH2:31][C:32]1[N:37]=[CH:36][C:35](B(O)O)=[CH:34][N:33]=1>>[CH3:24][C:8]1[C:6]2[N:7]=[C:2]([C:35]3[CH:34]=[N:33][C:32]([NH2:31])=[N:37][CH:36]=3)[N:3]=[C:4]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[C:5]=2[S:10][C:9]=1[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([S:18]([CH:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])[CH2:14][CH2:13]1
Reactant: Nc1ncc(B(O)O)cn1
Reactant: Cc1c(CN2CCN(S(=O)(=O)C(C)C)CC2)sc2c(N3CCOCC3)nc(Cl)nc12
Product: Cc1c(CN2CCN(S(=O)(=O)C(C)C)CC2)sc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc12

Procedure:
2-Chloro-7-methyl-4-morpholin-4-yl-6-[4-(propane-2-sulfonyl)-piperazin-1-ylmethyl]-thieno[3,2-d]pyrimidine (105 mg) was reacted with 2-aminopyrimidine-5-boronic acid in General Procedure A. Purification on silica and recrystallization from hot DCM/hexane gave 273. NMR (CDCl3): 1.37 (6H, d, J=6.8), 2.44 (3H, s), 2.63-2.66 (4H, m), 3.18-3.25 (1H, m), 3.43-3.46 (4H, m), 3.86 (2H, s), 3.89-3.91 (4H, m), 4.03-4.05 (4H, m), 5.23 (2H, br), 9.35 (2H, s). MS (ESI+): MH+533.31 (40%)
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-])=O)[CH:8]=1)[CH3:5]>CO.[Pd]>[CH3:1][O:2][CH2:3][C@H:4]([O:6][C:7]1[CH:8]=[C:9]([CH:10]=[CH:11][CH:12]=1)[NH2:13])[CH3:5]
Reactant: COC[C@@H](C)Oc1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: COC[C@@H](C)Oc1cccc(N)c1
Reaction time: 24 h
Yield: 102.4 %

Procedure:
1-{[(1R)-2-methoxy-1-methylethyl]oxy}-3-nitrobenzene (1.00 g; 4.74 mmol) was dissolved in MeOH (20 ml) and treated with 10% palladium on carbon then placed under an atmosphere of hydrogen and stirred for 24 h. The reaction mixture was filtered then concentrated by evaporation to give the title compound (Intermediate 81) (0.88 g) as an oil; 1H NMR δ 1.18 (d, 3H), 3.24 (s, 3H), 3.34-3.42 (m, 1H), 3.42-3.52 (m, 1H), 4.37-4.49 (m, 1H), 4.90 (s, 2H), 6.04-6.11 (m, 1H), 6.10-6.18 (m, 2H), 6.83-6.91 (m, 1H); MH+ 182.
Reaction SMILES: C(OC1C(C)=CC(O)=C(C)C=1C)(=O)C.CC(O)(C#N)C=C.P(=O)(O)(O)O.B(F)(F)F.C([O:34][C:35]1[C:36]([CH3:50])=[C:37]2[C:42](=[C:43]([CH3:46])[C:44]=1[CH3:45])[O:41][C:40]([CH3:49])([C:47]#[N:48])[CH2:39][CH2:38]2)(=O)C>>[OH:34][C:35]1[C:36]([CH3:50])=[C:37]2[C:42](=[C:43]([CH3:46])[C:44]=1[CH3:45])[O:41][C:40]([CH3:49])([C:47]#[N:48])[CH2:39][CH2:38]2
Reactant: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(C#N)O2
Agent: C=CC(C)(O)C#N
Agent: CC(=O)Oc1c(C)cc(O)c(C)c1C
Agent: FB(F)F
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C#N)O2
Yield: 15 %

Procedure:
Using the method described in Example 1, last paragraph, 25.0 g (0.129 mole) of 4-acetoxy-2,3,5-trimethylphenol were reacted with 12.3 g (0.129 mole) of methyl vinyl ketone cyanohydrin, stabilized with phosphoric acid, and with 13.3 g (0.129 mole) of BF3. Conventional working up of the reaction mixture gave, according to analysis by gas chromatography, 25% of 6-acetoxy-2,5,7,8-tetramethyl-2-cyanochromane; colorless crystals, melting point 149°-151° C. In addition, 15% of 6-hydroxy-2,5,7,8-tetramethyl-2-cyanochromane were obtained.
Reaction SMILES: [NH2:1][C@H:2]([CH2:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1)[C:3](=[S:5])[NH2:4].[C:17]([O:21][C:22]([N:24]([C@H:26]([CH2:30][C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=1)[C:27](O)=[O:28])[CH3:25])=[O:23])([CH3:20])([CH3:19])[CH3:18].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[C:17]([O:21][C:22](=[O:23])[N:24]([CH3:25])[C@@H:26]([C:27](=[O:28])[NH:1][C@@H:2]([C:3](=[S:5])[NH2:4])[CH2:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1)[CH2:30][C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=1)([CH3:19])([CH3:20])[CH3:18]
Reactant: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccc2ccccc2c1)C(=O)O
Reactant: NC(=S)[C@H](N)Cc1ccc2ccccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccc2ccccc2c1)C(=O)N[C@H](Cc1ccc2ccccc2c1)C(N)=S
Temperature: 25 °C
Reaction time: 12 h
Yield: 81.5 %

Procedure:
(2R)-2-Amino-3-(2-naphthyl)propionthioamide (0.290 g; 1.2 mmol), (2R)-2-(N-tert-butoxycarbonyl-N-methylamino)-3-(2-naphthyl)propionic acid (0.436 g; 1.3 mmol), HOBT (0.176 g; 1.3 mmol) and EDAC (0.267 g; 1.4 mmol) were dissolved in methylene chloride (20 ml) and stirred 12 hours at RT. Methylene chloride (40 ml) was added and the organic phase was washed with aqueous sodium hydrogensulfate (10%; 40 ml), aqueous sodium hydrogencarbonate (satd.; 40 ml) and dried (Magnesium sulfate). The solvent was removed in vacuo to afford 0,53 g of N-methyl-N-((1R)-2-(2-naphthyl)-1-((1R)-2-(2-naphthyl)-1-thiocarbamoylethylcarbamoyl)ethyl)carbamic acid tert-butylester.
Reaction SMILES: [CH:1]([C:3]1[N:34]([S:35]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)(=[O:37])=[O:36])[C:6]2=[N:7][CH:8]=[CH:9][C:10]([C:11]3[C:12]([C:18]4[CH:23]=[CH:22][C:21]([NH:24][C:25]([NH:27][C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)=[O:26])=[CH:20][CH:19]=4)=[N:13][N:14]([CH2:16][CH3:17])[CH:15]=3)=[C:5]2[CH:4]=1)=O.[NH2:44][CH2:45][CH2:46][N:47]1[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C>[CH2:16]([N:14]1[CH:15]=[C:11]([C:10]2[CH:9]=[CH:8][N:7]=[C:6]3[N:34]([S:35]([C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)(=[O:36])=[O:37])[C:3]([CH2:1][NH:44][CH2:45][CH2:46][N:47]4[CH2:52][CH2:51][O:50][CH2:49][CH2:48]4)=[CH:4][C:5]=23)[C:12]([C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25]([NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:26])=[CH:20][CH:19]=2)=[N:13]1)[CH3:17]
Reactant: CCn1cc(-c2ccnc3c2cc(C=O)n3S(=O)(=O)c2ccccc2)c(-c2ccc(NC(=O)Nc3ccccc3)cc2)n1
Reactant: NCCN1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCn1cc(-c2ccnc3c2cc(CNCCN2CCOCC2)n3S(=O)(=O)c2ccccc2)c(-c2ccc(NC(=O)Nc3ccccc3)cc2)n1

Procedure:
A solution of N-(4-{4-[2-formyl-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-1-ethyl-1H-pyrazol-3-yl}phenyl)-N′-phenylurea (0.1 mmol), 4-(2-aminoethyl)-morpholine (0.2 mmol), and sodium triacetoxyborohydride (0.2 mmol) in dichloromethane (1 mL) and acetic acid (0.25 mL) under nitrogen was stirred at room temperature for 30 minutes. The reaction was quenched with 1N sodium hydroxide solution (5 mL) and extracted with ethyl acetate (3×5 mL). The combined organic layers were washed with brine (5 mL), dried over magnesium sulfate, and concentrated in vacuo to give the title compound as the crude product. ESMS [M+H]+: 705.6
Reaction SMILES: C(O[C:4]1[CH2:8][CH2:7][C:6](=[O:9])[CH:5]=1)C.[CH2:10]([Mg]Br)[CH2:11][CH:12]=[CH2:13].Cl>O1CCCC1>[CH2:13]([C:4]1[CH2:8][CH2:7][C:6](=[O:9])[CH:5]=1)[CH2:12][CH:11]=[CH2:10]
Reactant: CCOC1=CC(=O)CC1
Reactant: C=CCC[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: C=CCCC1=CC(=O)CC1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
To a solution of 3-ethoxycyclopent-2-enone (2.37 g) in tetrahydrofuran (30 mL) was added dropwise a 0.5M tetrahydrofuran solution of 3-butenylmagnesium bromide (38.4 mL) under nitrogen atmosphere at −78° C. over 10 minutes, followed by stirring at −78° C. for 3 hours and then at room temperature overnight. Then, after addition of 2N aqueous hydrochloric acid solution, the reaction mixture was stirred for 30 minutes and then extracted with ethyl acetate twice. The organic layer was washed with saturated brine, dried and concentrated. The residue was purified by column chromatography on silica gel to give 3-(3-butenyl)cyclopent-2-enone (1.1 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:18]=[C:17]([CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)[S:16][C:10]=2[NH:11][C:12](=O)[CH2:13][N:14]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:37])=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:18]=[C:17]([CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)[S:16][C:10]=2[NH:11][C:12](=[S:37])[CH2:13][N:14]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cc1ccc(CCc2cc3c(s2)NC(=O)CN=C3c2ccccc2Cl)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(CCc2cc3c(s2)NC(=S)CN=C3c2ccccc2Cl)cc1
Yield: 157.5 %

Procedure:
A suspension of 3.9 g of 5-(2-chlorophenyl)-7-[2-(4-methylphenyl)ethyl]-1,3-dihydro-2H-thieno[2,3-e]-1,4-diazepin-2-one, melting at 195°-197° C. and 2.5 g of Lawesson reagent in 50 ml of toluene is stirred at 40°-43° C. for an hour. The resultant solution is concentrated under reduced pressure, and the residue is subjected to chromatography on silica gel and then eluted with chloroform-methanol (100:1 to 100:2). The objective fraction is concentrated under reduced pressure to give 4 g of 5-(2-chlorophenyl)-7-[2-(4-methylphenyl)ethyl]-1,3-dihydro-2H-thieno[2,3-e]-1,4-diazepine-2-thione, melting at 190°-191° C. with decomposition.
Reaction SMILES: [CH2:1]([C@@H:8]([C:39](=[O:76])[NH:40][C@@H:41]([CH2:72][CH:73]([CH3:75])[CH3:74])[C:42](=[O:71])[C@@:43]([OH:70])([CH3:69])[CH2:44][O:45][S:46]([C:49]1[C:66]([CH3:67])=[CH:65][C:52]([O:53][CH2:54][C:55]([O:57]CC2C=CC=CC=2)=[O:56])=[CH:51][C:50]=1[CH3:68])(=[O:48])=[O:47])[NH:9][C:10](=[O:38])[C@H:11]([CH2:34][CH:35]([CH3:37])[CH3:36])[NH:12][C:13](=[O:33])[C@H:14]([CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[NH:15][C:16](=[O:24])[CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O1CCOCC1.[Pd]>[CH2:1]([C@@H:8]([C:39](=[O:76])[NH:40][C@@H:41]([CH2:72][CH:73]([CH3:75])[CH3:74])[C:42](=[O:71])[C:43]([OH:70])([CH3:69])[CH2:44][O:45][S:46]([C:49]1[C:66]([CH3:67])=[CH:65][C:52]([O:53][CH2:54][C:55]([OH:57])=[O:56])=[CH:51][C:50]=1[CH3:68])(=[O:48])=[O:47])[NH:9][C:10](=[O:38])[C@H:11]([CH2:34][CH:35]([CH3:37])[CH3:36])[NH:12][C:13](=[O:33])[C@H:14]([CH2:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[NH:15][C:16](=[O:24])[CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(OCC(=O)OCc2ccccc2)cc(C)c1S(=O)(=O)OC[C@@](C)(O)C(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCc1ccccc1)NC(=O)CN1CCOCC1
Agent: [Pd]
Solvent: C1COCCO1
Product: Cc1cc(OCC(=O)O)cc(C)c1S(=O)(=O)OCC(C)(O)C(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCc1ccccc1)NC(=O)CN1CCOCC1
Reaction time: 3 h

Procedure:
Referring to FIG. 37, benzyl 2-(4-((((4S,7S,10S,13S,15R)-10-benzyl-15-hydroxy-7,13-diisobutyl-15-methyl-1-morpholino-2,5,8,11,14-pentaoxo-4-phenethyl-3,6,9,12-tetraazahexadecan-16-yl)oxy)sulfonyl)-3,5-dimethylphenoxy)acetate (110 mg, 0.1 mmol) was dissolved in dioxane (10 mL) and Pd/C (50 mg) was added. The mixture was stirred for 3 h under H2 atmosphere (15 psi). The catalyst was filtered off and the filtrate was concentrated under reduced pressure to give compound (100 mg, quantitative); 1H NMR (DMSO-d6, 300 MHz): δ 8.12-8.02 (m, 3H), 7.99-7.89 (m, 1H), 7.32-7.02 (m, 10H), 6.88 (s, 2H), 6.05 (s, 1H), 5.11-5.02 (m, 1H), 5.75 (s, 2H), 4.61-4.22 (m, 4H), 3.65 (m, 4H), 2.95 (m, 2H), 2.78-2.70 (m, 1H), 2.55 (s, 6H), 2.45 (m, 4H), 1.94-1.55 (m, 4H), 0.92-0.74 (m, 12H).
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[Na+].[Br:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([CH2:14]Br)[CH:8]=1.O.CCOCC>CN(C=O)C>[C:1]([O:4][CH2:14][C:9]1[CH:8]=[C:7]([Br:6])[CH:12]=[CH:11][C:10]=1[F:13])(=[O:3])[CH3:2]
Reactant: CC(=O)[O-]
Reactant: Fc1ccc(Br)cc1CBr
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(=O)OCc1cc(Br)ccc1F
Reaction time: 11 h

Procedure:
Anhydrous sodium acetate (1.65 g, 20 mmol) was added to a solution of the compound (1a) (3 g, 14.6 mmol) in DMF (25 mL) and the reaction mixture was stirred under N2 on a steam bath for 11 hours. The reaction mixture was cooled and distributed between H2O (200 mL) and Et2O (100 mL). The organic layer was separated and washed with H2O (3×100 mL), dried, filtered and evaporated, leaving the compound (1b) as a nearly colorless oil; NMR 2.08 (3H, s), 5.08 (2H, s), 6.7-7.9 (3H, m).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:8]=[C:9]([S:13][C:14]2[C:15]([F:25])=[CH:16][C:17]([N+:22]([O-:24])=[O:23])=[C:18]([CH2:20][OH:21])[CH:19]=2)[CH:10]=[CH:11][CH:12]=1>C(Cl)(Cl)Cl.O=[Mn]=O>[O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:8]=[C:9]([S:13][C:14]2[C:15]([F:25])=[CH:16][C:17]([N+:22]([O-:24])=[O:23])=[C:18]([CH:19]=2)[CH:20]=[O:21])[CH:10]=[CH:11][CH:12]=1
Reactant: O=[N+]([O-])c1cc(F)c(Sc2cccc(C3OCCCO3)c2)cc1CO
Agent: O=[Mn]=O
Solvent: ClC(Cl)Cl
Product: O=Cc1cc(Sc2cccc(C3OCCCO3)c2)c(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
[5-(3-[1,3]Dioxan-2-yl-phenylsulfanyl)-4-fluoro-2-nitro-phenyl]-methanol (2.22 g, 6.08 mmol) was placed in chloroform (250 mL), and MnO2 (6.4 g) was added. The resulting mixture was stirred overnight at room temperature. After 18 h of stirring, the mixture was heated at 40° C. for 1 hour. The resulting mixture was worked up by filtration through Celite®. The filtrate was concentrated to yield an oil, which was purified by silica column chromatography (20% EtOAc/heptane) to yield a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=1)=[CH:8][C:7]2=[O:22].[S:23]1[CH:27]=[C:26]([C:28](O)=[O:29])[N:25]=[CH:24]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[O:22]=[C:7]1[C:6]2[C:11](=[C:2]([NH:1][C:28]([C:26]3[N:25]=[CH:24][S:23][CH:27]=3)=[O:29])[CH:3]=[CH:4][CH:5]=2)[O:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:19])[F:20])[CH:13]=2)=[CH:8]1
Reactant: O=C(O)c1cscn1
Reactant: Nc1cccc2c(=O)cc(-c3cccc(C(F)(F)F)c3)oc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cccc2c(=O)cc(-c3cccc(C(F)(F)F)c3)oc12)c1cscn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 29.2 %

Procedure:
8-amino-2-(3-(trifluoromethyl)phenyl)-4H-chromen-4-one (178) (70 mg, 0.23 mmol) was taken up in 2 mL of DMF along with thiazole-4-carboxylic acid 3 (30 mg, 0.23 mmol), HATU (175 mg, 0.46 mmol) and DIEA (80 μL, 0.46 mmol). The reaction mixture was stirred at room temperature for 18 h. It was then diluted with 5 mL of H2O. The resulting solids were collected by filtration, washed successively with a solution of dilute NaHCO3/MeOH (1:1), aqueous MeOH, dilute 1 N HCl/MeOH (1:1), aqueous MeOH, and then pure MeOH. After drying under high vacuum, 28 mg of Compound 204 was obtained as an off-white solid. MS (ESI) calcd for C20H11F3N2O3S: 416.04. found: 417 [M+H].