Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([CH2:6][CH:7]1[CH2:9][CH2:8]1)[C:3]([OH:5])=[O:4].[OH-].[Na+].[C:12](=O)([O:18]C(C)(C)C)[O:13][C:14]([CH3:17])([CH3:16])[CH3:15]>C(O)C.O.C1COCC1>[C:14]([O:13][C:12]([NH:1][C@H:2]([CH2:6][CH:7]1[CH2:9][CH2:8]1)[C:3]([OH:5])=[O:4])=[O:18])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: N[C@H](CC1CC1)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](CC1CC1)C(=O)O
Temperature: 25 °C
Reaction time: 15 h
Yield: 56.3 %

Procedure:
To a solution of (R)-2-amino-3-cyclopropylpropanoic acid (1.0 g, 7.7.4 mmol) in Ethanol (15 mL) and water (8 mL) was added 1N NaOH (10 mL) and Di-tert-butyl carbonate (1.86 g, 8.52 mmol) in THF (8 mL). After stirring at room temperature for 15 h, the solution was diluted with water, extracted with ether, the aqueous layer was separated and was acidified to pH 2 with conc. HCl, the aqueous layer was extracted with EtOAc, organic layer was separated, washed with brine, dried and concentrated to give (R)-2-(tert-butoxycarbonylamino)-3-cyclopropylpropanoic acid (1.0 g).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:14][C:15]([F:24])([F:23])[C:16]1[N:21]=[CH:20][N:19]=[C:18](O)[CH:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:18]1[CH:17]=[C:16]([C:15]([F:24])([F:23])[F:14])[N:21]=[CH:20][N:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1cc(C(F)(F)F)ncn1
Reactant: OCCCCOCc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: FC(F)(F)c1cc(OCCCCOCc2ccccc2)ncn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.1 %

Procedure:
To a solution of 4-(benzyloxy)butan-1-ol (3.00 g), 6-(trifluoromethyl)pyrimidin-4-ol (3.00 g), and triphenylphosphine (5.25 g) in THF (30 mL) was added diisopropyl azodicarboxylate (4.05 g), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and then the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=9/1) to obtain 4-[4-(benzyloxy)butoxy]-6-(trifluoromethyl)pyrimidine (2.83 g).
Reaction SMILES: CC1C(C)=CC=CC=1OCCCC(N1C2C(=C(C3C=CN=C(C(OC)=O)C=3)C=CC=2)CCC1)=O.CC1C(C)=CC=CC=1OCCCC(N1C2C(=C(B3OC(C)(C)C(C)(C)O3)C=CC=2)CCC1)=O.CC1(C)C(C)(C)OB([C:76]2[CH:77]=[C:78]([CH:93]=[CH:94][CH:95]=2)[CH2:79][O:80][C:81]([NH:83][CH2:84][CH2:85][C:86]([O:88][C:89]([CH3:92])([CH3:91])[CH3:90])=[O:87])=[O:82])O1.BrC1C=CN=C(C(OC)=O)C=1.Br[C:109]1[CH:118]=[CH:117][CH:116]=[C:115]2[C:110]=1[CH2:111][CH2:112][CH2:113][N:114]2[C:119]([O:121][CH2:122][CH2:123][O:124][C:125]1[CH:130]=[CH:129][CH:128]=[C:127]([CH3:131])[C:126]=1[CH3:132])=[O:120]>>[C:89]([O:88][C:86](=[O:87])[CH2:85][CH2:84][NH:83][C:81]([O:80][CH2:79][C:78]1[CH:77]=[C:76]([C:109]2[CH:118]=[CH:117][CH:116]=[C:115]3[C:110]=2[CH2:111][CH2:112][CH2:113][N:114]3[C:119]([O:121][CH2:122][CH2:123][O:124][C:125]2[CH:130]=[CH:129][CH:128]=[C:127]([CH3:131])[C:126]=2[CH3:132])=[O:120])[CH:95]=[CH:94][CH:93]=1)=[O:82])([CH3:90])([CH3:91])[CH3:92]
Reactant: CC(C)(C)OC(=O)CCNC(=O)OCc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Cc1cccc(OCCOC(=O)N2CCCc3c(Br)cccc32)c1C
Agent: COC(=O)c1cc(-c2cccc3c2CCCN3C(=O)CCCOc2cccc(C)c2C)ccn1
Agent: COC(=O)c1cc(Br)ccn1
Agent: Cc1cccc(OCCCC(=O)N2CCCc3c(B4OC(C)(C)C(C)(C)O4)cccc32)c1C
Product: Cc1cccc(OCCOC(=O)N2CCCc3c(-c4cccc(COC(=O)NCCC(=O)OC(C)(C)C)c4)cccc32)c1C

Procedure:
The title compound was prepared using a procedure analogous to methyl 4-(1-(4-(2,3-dimethylphenoxy)butanoyl)-1,2,3,4-tetrahydroquinolin-5-yl)picolinate except that 4-(2,3-dimethylphenoxy)-1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-1(2H)-yl)butan-1-one was replaced by tert-butyl 3-((3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyloxy)carbonylamino)propanoate, and methyl 4-bromopicolinate was replaced by 2-(2,3-dimethylphenoxy)ethyl 5-bromo-3,4-dihydroquinoline-1(2H)-carboxylate. LCMS, [M-tBu+2H]+=547.2. 1H NMR (400 MHz, CDCl3) δ 7.64 (d, J=8.1 Hz, 1H), 7.46-7.35 (m, 2H), 7.34-7.27 (m, 1H), 7.27-7.20 (m, 1H), 7.16 (t, J=7.9 Hz, 1H), 7.03 (t, J=7.9 Hz, 1H), 6.97 (d, J=7.5 Hz, 1H), 6.79 (d, J=7.7 Hz, 1H), 6.70 (d, J=8.1 Hz, 1H), 5.12 (s, 2H), 4.60-4.52 (m, 2H), 4.24-4.19 (m, 2H), 3.73 (t, J=6.4 Hz, 2H), 3.41 (dd, J=12.0, 6.0 Hz, 2H), 2.57 (t, J=6.3 Hz, 2H), 2.44 (t, J=5.9 Hz, 2H), 2.26 (s, 3H), 2.17 (s, 3H), 1.86-1.75 (m, 2H), 1.42 (s, 9H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[CH:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[I:43][CH2:44][C:45]1[CH:46]=C(C=C[CH:51]=1)N.CC[N:54]([CH:58]([CH3:60])[CH3:59])C(C)C>CN(C=O)C>[I:43][C:44]1[CH:60]=[C:58]([NH:54][C:6]([C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)=[O:8])[CH:59]=[CH:51][C:45]=1[CH3:46]
Reactant: Nc1cccc(CI)c1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)c1ccsc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2ccsc2)cc1I
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Thiophene-3-carboxylic acid (2.75 g) and HATU (8.15 g) in DMF (25 ml) were stirred at room temp for 15 min. HOBT (2.9 g), 3-iodomethylaniline (5.0 g) and DIPEA (11.2 ml, 64.35 mmol) were added and the reaction was stirred at room temp for 16 h. The solvent was evaporated under vacuum and the residue was partitioned between ethyl acetate (100 ml) and aqueous sodium carbonate (10%, 100 ml). The aqueous layer was extracted with ethyl acetate (50 ml) and the combined organic phases washed with hydrochloric acid (2N, 75 ml), water (75 ml) and brine (75 ml). The organic phase was dried (magnesium sulphate) and absorbed onto silica. The silica was applied to a silica column and eluted with cyclohexane/ethyl acetate (4:1). The solvent was evaporated from the product fractions under vacuum to the tide compound.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3](=O)/[CH:4]=[C:5](\[CH3:13])/[C:6]1[CH:11]=[CH:10][C:9](C)=[CH:8][CH:7]=1.[NH2:17][S:18]([C:21]1[CH:26]=[CH:25][C:24]([NH:27][NH2:28])=[CH:23][CH:22]=1)(=[O:20])=[O:19].N1CCCCC1.O>C(O)C>[NH2:17][S:18]([C:21]1[CH:22]=[CH:23][C:24]([N:27]2[C:5]([C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=3)([CH3:13])[CH2:4][C:3]([C:2]([F:1])([F:15])[F:16])=[N:28]2)=[CH:25][CH:26]=1)(=[O:20])=[O:19]
Reactant: C/C(=C\C(=O)C(F)(F)F)c1ccc(C)cc1
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Solvent: C1CCNCC1
Solvent: O
Solvent: CCO
Product: CC1(c2ccccc2)CC(C(F)(F)F)=NN1c1ccc(S(N)(=O)=O)cc1

Procedure:
In a flask with an inert atmosphere (E)-1,1,1-trifluoro-4-methyl-4-(4-methylphenyl)-3-butene-2-one (1.75 g, 8.2 mmoles), 4-(aminosulphonyl)phenylhydrazine chlorohydrate (2 g, 9 mmoles) and piperidine (0.85 g, 10 mmoles) are added, dissolved in 100 ml of ethanol, and heated under reflux for 5.5 hours. The mixture is cooled, the solvent eliminated with a rotavapor, water added to the residue and the solution extracted with AcOEt. The organic phase is washed with water, dried over anhydrous sodium sulphate and evaporated to dryness. The crude product is purified using column chromatography through silica gel under pressure, eluting with AcOEt-petrol ether (4:6) obtaining 1-(4-aminosulphonylphenyl)-4,5-dihydro-5-phenyl-5-methyl-3-trifluoromethyl-1H-pyrazole in the form of a white solid (1.46 g, yield: 47%) with a
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH:10]=[CH2:11])=[CH:8][CH:7]=[C:6]([F:12])[C:3]=1[C:4]#[N:5].C1C=C(Cl)C=C(C(OO)=[O:21])C=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:9]([CH:10]2[CH2:11][O:21]2)=[CH:8][CH:7]=[C:6]([F:12])[C:3]=1[C:4]#[N:5]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=Cc1ccc(F)c(C#N)c1Cl
Solvent: ClC(Cl)Cl
Product: N#Cc1c(F)ccc(C2CO2)c1Cl

Procedure:
2-chloro-6-fluoro-3-vinylbenzonitrile dissolved in CHCl3 (300 mL) then added mCPBA (29.4 g, 171 mmol) and stirred at RT for 16 h. When TLC showed starting materials were consumed, the mixture was washed with Na2S2O3 (1×), 1N NaOH (1×), brine (2×), then dried over Na2SO4. Filtered and concentrated then purified by MPLC chromatography using 330 g ISCO Redi-sep column and eluted with 20% ethyl acetate/hexane solvent system to yield 2-chloro-6-fluoro-3-(oxiran-2-yl)benzonitrile.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][C:9]1[N:14]=[C:13]([CH3:15])[CH:12]=[C:11]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC=CC=1>[C:1]([NH:8][C:9]1[N:14]=[C:13]([CH3:15])[CH:12]=[C:11]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:10]=1)(=[O:3])[CH3:2]
Reactant: Cc1cc(OCc2ccccc2)nc(N)n1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CC(=O)Nc1nc(C)cc(OCc2ccccc2)n1

Procedure:
Acetic anhydride (15.3 g, 0.15 mole) is added to a stirred suspension of 2-amino-4-methyl-6-benzyloxypyrimidine (23.6 g, 0.11 mole) in 150 ml of benzene. The mixture is heated at reflux for 4 hours. It is cooled, neutralized with aqueous sodium carbonate and the benzene layer separated. The benzene solution is concentrated under vacuum to an oil from which 2-acetamido-4-methyl-6-benzyloxy-pyrimidine melting at 121°-122° C. is isolated by crystallization from hexane n-butyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][NH:7][C:8]2[CH:9]=[C:10]([CH:17]=[CH:18][CH:19]=2)[C:11]([NH:13][CH:14]([CH3:16])[CH3:15])=[O:12])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[CH3:31][N:32]1[C:36]([S:37](Cl)(=[O:39])=[O:38])=[CH:35][CH:34]=[N:33]1>ClCCl.O>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]([S:37]([C:36]2[N:32]([CH3:31])[N:33]=[CH:34][CH:35]=2)(=[O:39])=[O:38])[C:8]2[CH:9]=[C:10]([CH:17]=[CH:18][CH:19]=2)[C:11]([NH:13][CH:14]([CH3:16])[CH3:15])=[O:12])=[CH:4][CH:3]=1
Reactant: CC(C)NC(=O)c1cccc(NCc2ccc(Cl)cc2)c1
Reactant: Cn1nccc1S(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)NC(=O)c1cccc(N(Cc2ccc(Cl)cc2)S(=O)(=O)c2ccnn2C)c1
Yield: 26.6 %

Procedure:
3-(4-Chloro-benzylamino)-N-isopropyl-benzamide (30 mg, 0.1 mmol), diisopropylethylamine (35 μL, 0.2 mmol) and 1-methyl-1H-pyrazole-5-sulfonyl chloride (36 mg, 0.2 mmol) were stirred in dry dichloromethane (2 ml) at room temperature for 72 hrs. The reaction was diluted with dichloromethane (5 ml) and water (5 ml) with stirring. The organics were collected, dried (PTFE frit) and concentrated in vacuo. The residue was purified by preparative TLC (10% ethyl acetate/dichloromethane) to yield the product as an off-white solid (11.9 mg). HPLC retention time 8.04 min. Mass spectrum (ES+) m/z 447 (M+H).
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[C:10](I)[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([C:18]1[CH:32]=[CH:31][C:21]([CH2:22][N:23]2[CH2:26][CH:25]([C:27]([O:29][CH3:30])=[O:28])[CH2:24]2)=[CH:20][C:19]=1[F:33])#[CH:17].C(N(C(C)C)C(C)C)C>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH2:1]([C:8]1[CH:9]=[C:10]2[C:11](=[CH:12][CH:13]=1)[NH:14][C:16]([C:18]1[CH:32]=[CH:31][C:21]([CH2:22][N:23]3[CH2:26][CH:25]([C:27]([O:29][CH3:30])=[O:28])[CH2:24]3)=[CH:20][C:19]=1[F:33])=[CH:17]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cc2ccccc2)cc1I
Reactant: C#Cc1ccc(CN2CC(C(=O)OC)C2)cc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CN(Cc2ccc(-c3cc4cc(Cc5ccccc5)ccc4[nH]3)c(F)c2)C1
Reaction time: 3 h

Procedure:
To a sealed flask was added 4-benzyl-2-iodobenzenamine (0.20 g, 0.65 mmol) and methyl 1-(4-ethynyl-3-fluorobenzyl)azetidine-3-carboxylate (0.32 g, 1.3 mmol) in THF (15 mL). To this solution was added PdCl2(PPh3)2 (0.045 g, 0.065 mmol), CuI (0.025 g, 0.13 mmol), and ethyldiisopropylamine (0.90 mL, 5.2 mmol). The flask was flushed with Ar, sealed and placed in a preheated oil bath at 100° C. for 3 h. The mixture was concentrated under reduced pressure to afford a dark oil which was adsorbed onto silica and purified (30% EtOAc/hexanes to 100% EtOAc) to afford title compound as a yellow oil. MS (ESI) m/z: Calculated: 428.1; Observed: 429.1 (M++1).
Reaction SMILES: I.[C:2]([O:6][CH2:7][CH2:8][N:9]([CH3:14])[CH:10](SC)[CH3:11])([CH3:5])([CH3:4])[CH3:3].Cl.C(OCCN)(C)(C)C.[NH2:24][C:25]1[CH:33]=[C:32]2[C:28]([CH2:29][C@@H:30]([OH:49])[C@@H:31]2[NH:34][C:35]([C:37]2[CH:42]=[CH:41][C:40]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[CH:39][CH:38]=2)=[O:36])=[CH:27][CH:26]=1>N1C=CC=CC=1>[C:2]([O:6][CH2:7][CH2:8][N:9]([CH3:14])[C:10](=[N:24][C:25]1[CH:33]=[C:32]2[C:28]([CH2:29][C@@H:30]([OH:49])[C@@H:31]2[NH:34][C:35]([C:37]2[CH:42]=[CH:41][C:40]([C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)=[CH:39][CH:38]=2)=[O:36])=[CH:27][CH:26]=1)[CH3:11])([CH3:5])([CH3:4])[CH3:3]
Reactant: Nc1ccc2c(c1)[C@@H](NC(=O)c1ccc(-c3ccccc3)cc1)[C@H](O)C2
Reactant: CSC(C)N(C)CCOC(C)(C)C
Agent: CC(C)(C)OCCN
Agent: Cl
Agent: I
Solvent: c1ccncc1
Product: CC(=Nc1ccc2c(c1)[C@@H](NC(=O)c1ccc(-c3ccccc3)cc1)[C@H](O)C2)N(C)CCOC(C)(C)C
Reaction time: 18 h
Yield: 22 %

Procedure:
Dissolve the crude HI salt of (2-tert-butoxyethyl)methyl-(1-methylsulfanylethyl)amine (obtained using the crude HCl salt of 2-tert-butoxyethylamine, referenced in Example 9-1, using the methodology detailed in Example 6-1) (297.1 mg, 0.897 mmol) in 20 mL pyridine and add biphenyl-4-carboxylic acid (R)-(6-amino-2(R)-hydroxyindan-1-yl)amide (290.7 mg, 0.844 mmol). Allow the reaction to stir for 18 hours. Remove the solvent in vacuo and dissolve the residue in methylene chloride and wash with saturated aqueous sodium hydrogen carbonate. Dry the organic layer with magnesium sulfate. Filter and remove the solvent in vacuo to afford 248.7 mg of crude product. Purify the residue by Biotage chromatography (10% MeOH/EtOAc to 25% MeOH/EtOAc) to afford 91.7 mg of the titled product (22% yield). MS (ES): m/z 500.5 (M+H).
Reaction SMILES: [CH3:1]/[CH:2]=[C:3](/[C:5]([O:7][C@@H:8]1[C@:16]23[C@H:20]([C@@:21]([C@:25]45[O:30][C@@:29]4([CH3:31])[C@H:28]4[C@:32]6([OH:38])[C@H:36]([O:37][C@@H:26]5[CH2:27]4)[O:35][CH:34]=[CH:33]6)([CH3:24])[C@H:22]([OH:23])[C@H:14]4[C@H:15]2[C@:11]([C:44]([O:46][CH3:47])=[O:45])([CH2:12][O:13]4)[C@H:10]([O:48][C:49]([CH3:51])=[O:50])[CH2:9]1)[C@@:19]([OH:43])([C:39]([O:41][CH3:42])=[O:40])[O:18][CH2:17]3)=[O:6])\[CH3:4].[H][H]>O.O.[Pt](=O)=O.C(OCC)(=O)C>[CH3:1]/[CH:2]=[C:3](/[C:5]([O:7][C@@H:8]1[C@:16]23[C@H:20]([C@@:21]([C@:25]45[O:30][C@@:29]4([CH3:31])[C@@H:28]4[C@:32]6([OH:38])[C@@H:36]([O:37][C@H:26]5[CH2:27]4)[O:35][CH2:34][CH2:33]6)([CH3:24])[C@H:22]([OH:23])[C@H:14]4[C@H:15]2[C@:11]([C:44]([O:46][CH3:47])=[O:45])([CH2:12][O:13]4)[C@H:10]([O:48][C:49]([CH3:51])=[O:50])[CH2:9]1)[C@@:19]([OH:43])([C:39]([O:41][CH3:42])=[O:40])[O:18][CH2:17]3)=[O:6])\[CH3:4]
Reactant: C/C=C(\C)C(=O)O[C@H]1C[C@@H](OC(C)=O)[C@@]2(C(=O)OC)CO[C@H]3[C@@H](O)[C@@](C)([C@]45O[C@@]4(C)[C@@H]4C[C@H]5O[C@@H]5OC=C[C@@]54O)[C@H]4[C@]1(CO[C@]4(O)C(=O)OC)[C@@H]32
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Solvent: O
Product: C/C=C(\C)C(=O)O[C@H]1C[C@@H](OC(C)=O)[C@@]2(C(=O)OC)CO[C@H]3[C@@H](O)[C@@](C)([C@]45O[C@@]4(C)[C@H]4C[C@@H]5O[C@H]5OCC[C@@]54O)[C@H]4[C@]1(CO[C@]4(O)C(=O)OC)[C@@H]32
Reaction time: 1.25 h

Procedure:
40.8 mg. azadirachtin A (5.67×1031 5 mole) were dissolved in 4 ml. ethyl acetate and 20 mg. platinum dioxide dihydrate were added thereto. The mixture was stirred and hydrogen passed therethrough for 75 minutes, the course of the reaction being monitored by HPLC. After the disappearance of the azadirachtin A peak, the reaction was discontinued and the reaction mixture centrifuged. The supernatant solution was evaporated and purified on silicon dioxide thin layer chromatography plates using the elution agent chloroform/acetone (7:3 v/v); Rf 0.33. Yield: 28.2 mg. (69% of theory).
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].OS(O)(=O)=O.[CH3:18]O>>[C:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([O:10][CH3:18])=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CO
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(C(C)=O)cc1

Procedure:
4-Acetylbenzoic acid (12.7 g., 0.077 mol) was dissolved in 750 ml. methanol. Concentrated H2SO4 (1.6 ml.) was added and the mixture heated at 70° for 8 hours, cooled, stripped solids, taken up in 400 ml. ether, washed 3×150 ml. saturated NaHCO3 and 1×150 ml. brine, dried over MgSO4 and stripped to yield title product, 12.9 g.; tlc Rf 0.46 (2:1 hexane:ethyl acetate).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[CH:8]=[C:9]([F:25])[CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[S:17][CH2:18][C@@H:19]([CH2:21][C:22]([OH:24])=[O:23])[N:20]=2)=[CH:12]3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:26](Cl)(=O)[CH3:27]>C(O)C.C(OCC)(=O)C>[CH2:26]([O:23][C:22](=[O:24])[CH2:21][C@@H:19]1[CH2:18][S:17][C:16]([C:13]2[NH:14][C:15]3[C:11]([CH:12]=2)=[CH:10][C:9]([F:25])=[CH:8][C:7]=3[NH:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[N:20]1)[CH3:27]
Reactant: O=C(O)C[C@@H]1CSC(c2cc3cc(F)cc(NC4CCCC4)c3[nH]2)=N1
Reactant: CC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)C[C@@H]1CSC(c2cc3cc(F)cc(NC4CCCC4)c3[nH]2)=N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
The compound (80 mg, 0.22 mmol) prepared in Example 37 was dissolved in ethanol (2 ml). Acetyl chloride (0.1 ml) was added thereto, and the mixture was stirred for 8 h at room temperature. After completion of the reaction, the reaction solution was diluted with ethyl acetate, washed with saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure, and purified by column chromatography to give the title compound (50 mg, Yield 58%).
Reaction SMILES: [OH:1][CH:2]([C:5]1[N:6]([CH3:10])[CH:7]=[CH:8][CH:9]=1)[C:3]#[CH:4].Br[C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1/[C:14](=[CH:22]/[C:23]1[NH:24][CH:25]=[CH:26][C:27]=1[O:28][CH3:29])/[C:15](=[O:21])[NH:16]2>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CN(C=O)C.CCN(CC)CC>[OH:1][CH:2]([C:5]1[N:6]([CH3:10])[CH:7]=[CH:8][CH:9]=1)[C:3]#[C:4][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1/[C:14](=[CH:22]/[C:23]1[NH:24][CH:25]=[CH:26][C:27]=1[O:28][CH3:29])/[C:15](=[O:21])[NH:16]2
Reactant: C#CC(O)c1cccn1C
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(Br)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CC(O)c3cccn3C)c21

Procedure:
Using Method D above, 3-hydroxy-3-(1-methyl-pyrrol-2-yl)-1-propyne (132 mg, 0.98 mmol) (from Example 27 above) was coupled to (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (112 mg, 0.35 mmol) (Starting Material 2) using (Ph3P)2PdCl2 (31 mg)(Aldrich) and CuI (17 mg)(Aldrich) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 70° C. for 28 h, yielding rac-(Z)-1,3-dihydro-4-[3-hydroxy-3-(1-methyl-pyrrol-2-yl)-1-propynyl]-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 114 mg, 87%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][C:7]1=[O:16].BrCCCCN1C2C(=CC=CC=2)CCC1=O.[C:33]([C:37]1[N:42]=[C:41]([N:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)[CH:40]=[C:39]([C:49]([F:52])([F:51])[F:50])[N:38]=1)([CH3:36])([CH3:35])[CH3:34].CCN(CC)CC>CN(C)C=O.C(OCC)(=O)C>[C:33]([C:37]1[N:42]=[C:41]([N:43]2[CH2:44][CH2:45][N:46]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[CH2:9][CH2:8][C:7]3=[O:16])[CH2:47][CH2:48]2)[CH:40]=[C:39]([C:49]([F:50])([F:51])[F:52])[N:38]=1)([CH3:36])([CH3:34])[CH3:35]
Reactant: O=C1CCc2ccccc2N1CCCCCl
Reactant: CC(C)(C)c1nc(N2CCNCC2)cc(C(F)(F)F)n1
Agent: O=C1CCc2ccccc2N1CCCCBr
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)c1nc(N2CCN(CCCCN3C(=O)CCc4ccccc43)CC2)cc(C(F)(F)F)n1
Temperature: 100 °C
Reaction time: 20 h

Procedure:
A mixture of 1-(4-chlorobutyl)-3,4-dihydroquinolin-2(1H)-one and 1-(4-bromobutyl)-3,4-dihydroquinolin-2(1H)-one (0.30 g), 2-tert-butyl-4-piperazin-1-yl-6-(trifluoromethyl)-pyrimidine (1.08 mmol, 0.31 g; prepared as in DE 19735410) and NEt3 (4.54 mmol, 0.46 g) in N,N-dimethylformamide (10 ml) was heated at 100° C. while stirring for 20 hours. The reaction mixture was allowed to cool, ethyl acetate was added, and the reaction mixture was washed twice with water. The combined organic phases were dried over Na2SO4, the desiccant was filtered off, and the organic phase was concentrated in vacuo. The resulting oily residue was purified by chromatography on silica gel (eluent: methyl tert-butyl ether:methanol 0-100%), resulting in 0.17 g of the title compound.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([Cl:17])=[CH:10][C:9]=1[NH:18][C:19](=[O:43])[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[N:30]([CH3:42])[N:31]=[C:32]([CH2:34][O:35]C3CCCCO3)[CH:33]=2)[CH:24]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:17][C:11]1[C:12]([N:14]([CH3:16])[CH3:15])=[CH:13][C:8]2[N:7]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]4[N:30]([CH3:42])[N:31]=[C:32]([CH2:34][OH:35])[CH:33]=4)[CH:24]=3)[CH2:20][C:19](=[O:43])[NH:18][C:9]=2[CH:10]=1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cc(COC4CCCCO4)nn3C)c2)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-c3cc(CO)nn3C)c1)=N2

Procedure:
The title compound was prepared from (RS)-[4-chloro-5-dimethylamino-2-(3-{3-[2-methyl-5-(tetrahydro-pyran-2-yloxymethyl)-2H-pyrazol-3-yl]-phenyl}-3-oxo-propionylamino)-phenyl]-carbamic acid tert.-butyl ester (Example M35) (278 mg, 0.44 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (129 mg).
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]([CH3:25])=[C:6]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[C:14]([O:18][C@H:19]([CH3:24])[C:20]([F:23])([F:22])[F:21])=[N:13][N:12]=[CH:11]3)[CH:7]=1.[Cu](C#N)[C:27]#[N:28]>CN(C=O)C.C(Cl)Cl>[CH3:25][C:5]1[CH:4]=[CH:3][C:2]([C:27]#[N:28])=[CH:7][C:6]=1[C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[C:14]([O:18][C@H:19]([CH3:24])[C:20]([F:21])([F:22])[F:23])=[N:13][N:12]=[CH:11]2
Reactant: N#C[Cu]C#N
Reactant: Cc1ccc(I)cc1-c1ccc2c(O[C@H](C)C(F)(F)F)nncc2c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccc(C#N)cc1-c1ccc2c(O[C@H](C)C(F)(F)F)nncc2c1
Temperature: 120 °C

Procedure:
A mixture of 6-(5-iodo-2-methylphenyl)-1-((R)-1,1,1-trifluoropropan-2-yloxy)phthalazine (100 mg, 0.22 mmol) and copper cyanide (98 mg, 1.09 mmol) in 1.0 mL of DMF in a sealed glass tube was heated at 120° C. in a microwave synthesizer for 20 min. The cooled reaction was diluted with CH2Cl2 and washed with water and brine. The organic layer was dried (MgSO4), filtered, and concentrated. Purification on a silica gel column (20-50% of EtOAc in Hexanes) afforded 4-methyl-3-(1-((R)-1,1,1-trifluoropropan-2-yloxy)phthalazin-6-yl)benzonitrile as a white solid. MS (ESI, pos. ion) m/z: 358.4 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5](Br)=[CH:4][N:3]=1.[C:9]([C:11]1[S:15][C:14](B(O)O)=[CH:13][CH:12]=1)#[N:10].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(O)C.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:14]2[S:15][C:11]([C:9]#[N:10])=[CH:12][CH:13]=2)=[N:6][CH:7]=1
Reactant: Nc1cnc(Br)cn1
Reactant: N#Cc1ccc(B(O)O)s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: CCO
Product: N#Cc1ccc(-c2cnc(N)cn2)s1
Yield: 14.1 %

Procedure:
A mixture of 2-amino-5-bromopyrazine (300 mg, 1.724 mmol), dichlorobis(triphenylphosphine)palladium(II) (175 mg, 0.249 mmol), 5-cyanothiophene-2-boronic acid acid (540 mg, 3.53 mmol) and a saturated aqueous sodium carbonate solution (2 mL) in ethylene glycol dimethyl ether (5 mL) and ethanol (5 mL) was heated under reflux overnight. The reaction mixture was cooled, diluted with ethyl acetate, and washed with water and a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 2/3 to 1/9 hexanes/ethyl acetate) afforded 5-(5-amino-pyrazin-2-yl)-thiophene-2-carbonitrile (49.1 mg, 14.1%) as a yellow solid: LRMS for C9H6N4S (M+H)+ at m/z=203.