Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:12]=[CH:11][NH:10][N:9]=2)=[C:4]2[NH:13][CH:14]=[C:15]([C:16](=[O:36])[C:17]([N:19]3[CH2:24][CH2:23][N:22]([C:25]4[N:29]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)[N:28]=[N:27][N:26]=4)[CH2:21][CH2:20]3)=[O:18])[C:3]=12.[H-].[Na+].[CH3:39]I>CN(C=O)C>[F:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:12]=[CH:11][N:10]([CH3:39])[N:9]=2)=[C:4]2[NH:13][CH:14]=[C:15]([C:16](=[O:36])[C:17]([N:19]3[CH2:24][CH2:23][N:22]([C:25]4[N:29]([C:30]5[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=5)[N:28]=[N:27][N:26]=4)[CH2:21][CH2:20]3)=[O:18])[C:3]=12
Reactant: O=C(C(=O)N1CCN(c2nnnn2-c2ccccc2)CC1)c1c[nH]c2c(-c3cc[nH]n3)ncc(F)c12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ccc(-c2ncc(F)c3c(C(=O)C(=O)N4CCN(c5nnnn5-c5ccccc5)CC4)c[nH]c23)n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 66.6 %

Procedure:
1-(4-fluoro-7-(1H-pyrazol-3-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione (30 mg, 0.06 mmol) in DMF (1 mL) was treated with sodium hydride (60% in oil, 31.2 mg, 0.78 mmol) and stirred at room temperature for 5 min. Methyl iodide (56 uL, 0.9 mmol)was added and the mixture was stirred at rt for 1 h. Reaction was quenched with H2O and concentrated under reduced pressure. The residue was dissolved in DMF and purified using reverse phase prep HPLC to afford the title compound as a white solid (20 mg, 67%). 1H NMR (500 MHz, DMSO-D6) δ ppm 3.15 (s, 2 H) 3.32 (s, 2 H) 3.47 (s, 2 H) 3.71 (s, 2 H) 4.05 (s, 3 H) 6.92 (s, 1 H) 7.58-7.65 (m, 3 H) 7.69 (s, 2 H) 7.91 (s, 1 H) 8.30 (d, J=12.83 Hz, 2 H) 12.30 (s, 1 H). LCMS: m/e 501 (M+H)+, ret time 1.37 min (method 3).
Reaction SMILES: C(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:9]([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])OCC.Cl.C(OCC)C>C(O)C>[CH2:17]([O:16][CH:9]([O:13][CH2:14][CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:18]
Reactant: CCOC(OCC)OCC
Reactant: O=Cc1ccccc1
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: CCOC(OCC)c1ccccc1
Yield: 82 %

Procedure:
A solution of benzaldehyde (6.82 mmol), triethyl orthoformate (3.3 g, 22.5 mmol), and conc. HCl (10 μL, 90 μmol) was refluxed in 3.7 mL of ethanol for 24 hrs. Diethyl ether was added and the organic layer was extracted with 3×2 M NaOH. The organic layer was dried over anhydrous Na2SO4. After removal of diethyl ether under reduced pressure, the crude mixture was distilled under vacuum (55-65° C./0.5 mmHg) to give pure benzaldehyde diethylacetal (82-91% yield). All acetals were characterized by 1H-NMR and used without further purification.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[C:11]([O:15][C:16]([NH:18][C@H:19]1[CH2:23][C@@H:22]([C:24]([O:26][CH3:27])=[O:25])[CH:21]=[CH:20]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].[CH:28](I)([CH3:30])[CH3:29]>C1COCC1>[C:11]([O:15][C:16]([NH:18][C@H:19]1[CH2:23][C@@:22]([CH:28]([CH3:30])[CH3:29])([C:24]([O:26][CH3:27])=[O:25])[CH:21]=[CH:20]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: COC(=O)[C@H]1C=C[C@@H](NC(=O)OC(C)(C)C)C1
Reactant: CC(C)I
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)[C@@]1(C(C)C)C=C[C@@H](NC(=O)OC(C)(C)C)C1
Reaction time: 8 h
Yield: 77.8 %

Procedure:
To a 1.00 M solution of lithium hexamethyldisilazide in THF (202 mL) at −78° C. was added a solution of methyl (1R,4S)-4-[(tert-butoxycarbonyl)amino]cyclopent-2-ene-1-carboxylate (22.10 g, 91.59 mmol) in THF (36.2 mL) over 10 min. The solution was stirred at −78° C. for 30 min before isopropyl iodide (10.0 mL, 100 mmol) was added in one portion. The mixture was then moved to a freezer reading at −24° C. and kept overnight. The reaction was quenched with aqueous ammonium chloride and the resulting solution was extracted with ether three times. The ether layers were dried over sodium sulfate and evaporated in vacuo. The residue was purified by flash chromatography on silica eluting with 10% ethyl acetate/hexane to give the title compound (20.2 g). MS calculated for C15H25NO4: (M+H)+284; found 184.2 (M−Boc+H)+.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[Cl:24][CH2:25][C:26](Cl)=[O:27]>ClCCl>[Cl:24][CH2:25][C:26]([N:12]1[CH2:13][CH2:14][N:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:15])[F:16])=[CH:8][CH:7]=2)[CH2:10][CH2:11]1)=[O:27]
Reactant: O=C(Cl)CCl
Reactant: FC(F)(F)c1ccc(N2CCNCC2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCl)N1CCN(c2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.8 %

Procedure:
To a mixture of 1-[4-(trifluoromethyl)phenyl]piperazine (600 mg, 2.61 mmol) and triethylamine (660 mg, 6.52 mmol) in dichloromethane (20 ml) was added 2-chloroacetyl chloride (380 mg, 3.36 mmol) dropwise at 0° C. The resulting solution was stirred for 1 hour at room temperature. The reaction mixture was then quenched by water (80 ml) and extracted with dichloromethane (3×30 ml). The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography using 1%-10% ethyl acetate in petroleum ether to afford 2-chloro-1-[4-[4-(trifluoromethyl)phenyl]piperazin-1-yl]ethan-1-one as a white solid (479 mg, 60%). (ES, m/z): [M+H]+ 307.1; 1H NMR (300 MHz, CDCl3): δ 7.52 (d, J=8.4 Hz, 2H), 6.97 (d, J=8.7 Hz, 2H), 4.12 (s, 1H), 3.81 (t, J=5.1 Hz, 2H), 3.72 (t, J=5.1 Hz, 2H), 3.36 (t, J=5.1 Hz, 2H), 3.30 (t, J=5.1 Hz, 2H).
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8](=[O:16])[C:7]2=[CH:17][CH:18]=[CH:19][N:6]2[N:5]=1)[CH3:3].Cl[C:21]1[C:26]([I:27])=[CH:25][N:24]=[CH:23][N:22]=1.[F-].[Cs+].C(N(CC)C(C)C)(C)C>>[I:27][C:26]1[C:21]([NH:1][C@H:2]([C:4]2[N:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:8](=[O:16])[C:7]3=[CH:17][CH:18]=[CH:19][N:6]3[N:5]=2)[CH3:3])=[N:22][CH:23]=[N:24][CH:25]=1
Reactant: Clc1ncncc1I
Reactant: C[C@H](N)c1nn2cccc2c(=O)n1-c1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncncc1I)c1nn2cccc2c(=O)n1-c1ccccc1
Yield: 15.2 %

Procedure:
(S)-2-(1-Aminoethyl)-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (110 mg, 0.43 mmol) was treated with 4-chloro-5-iodopyrimidine (166 mg, 0.69 mmol), cesium fluoride (131 mg, 0.86 mmol) and N,N-diisopropylethylamine (377 μL, 2.16 mmol) according to Preparation 13. The residue was purified by reverse phase using SP1® Purification System to give 30 mg (13% yield) of the title compound as a solid. Purity 86%.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:8])([CH3:7])[CH:5]([CH2:9][CH:10]=O)[CH2:4][CH:3]=1.[CH:12](=[O:15])[CH2:13][CH3:14]>N1CCCCC1.C(O)(=O)C>[CH3:14][C:13](=[CH:10][CH2:9][CH:5]1[CH2:4][CH:3]=[C:2]([CH3:1])[C:6]1([CH3:7])[CH3:8])[CH:12]=[O:15]
Reactant: CCC=O
Reactant: CC1=CCC(CC=O)C1(C)C
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: CC(C=O)=CCC1CC=C(C)C1(C)C
Temperature: 100 °C
Yield: 80.6 %

Procedure:
A 500 mL four-necked flask equipped with a stirrer, a thermometer, a reflux condenser and a dropping funnel was charged with 171 g (0.98 mol) of campholenic aldehyde (purity: 88%), 3.8 g (0.045 mol) of piperidine and 2.8 g (0.046 mol) of acetic acid, and the contents in the flask were stirred while heating at 100° C. Then, 92 g (1.6 mol) of propionaldehyde was gradually dropped into the flask for 6 h, and the resultant mixture was aged for 1 h and then cooled. Thereafter, 3.2 g (0.053 mol) of acetic acid was added to the mixture to remove amines therefrom, thereby separating the mixture into two layers. The thus separated organic layer was washed with water and separated into two layers, thereby obtaining 279 g (0.79 mol) of 2-methyl-4-(2,2,3-trimethylcyclopent-3-en-1-yl)-but-2-en-1-al (purity as measured by gas chromatography: 54.7%) (yield based on theoretical amount: 81%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:17]([C:18]([OH:20])=O)[CH2:16][C:15]2[CH:14]=[C:13]3[O:21][CH2:22][C@H:23]([C:25]4[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]5[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([Cl:40])[CH:34]=5)=[CH:27][CH:26]=4)[O:24][C:12]3=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:74][O:75][C:76](=[O:94])[C@@H:77]([NH2:93])[CH2:78][C:79]1[CH:84]=[CH:83][C:82]([C:85]2[CH:90]=[CH:89][C:88]([C:91]#[N:92])=[CH:87][CH:86]=2)=[CH:81][CH:80]=1.Cl>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH:17]([C:18](=[O:20])[NH:93][C@H:77]([C:76]([O:75][CH3:74])=[O:94])[CH2:78][C:79]2[CH:80]=[CH:81][C:82]([C:85]3[CH:90]=[CH:89][C:88]([C:91]#[N:92])=[CH:87][CH:86]=3)=[CH:83][CH:84]=2)[CH2:16][C:15]2[CH:14]=[C:13]3[O:21][CH2:22][C@H:23]([C:25]4[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]5[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([Cl:40])[CH:34]=5)=[CH:27][CH:26]=4)[O:24][C:12]3=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccc(C#N)cc2)cc1
Reactant: CC(C)(C)OC(=O)N1Cc2cc3c(cc2CC1C(=O)O)OC[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7,8-dicarboxylic acid 7-tert-butyl ester, HBTU and DIEA were dissolved in DMF (20 mL). (S)-2-Amino-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester was added and the mixture stirred at r.t. for 16 h. The reaction mixture was poured into 1 N HCl and extracted with ethyl acetate. The organic extracts were combined and washed with 1 N HCl and 10% sodium carbonate, concentrated and purified by column chromatography on silica gel (hexanes-ethyl acetate) to afford the product (4.9 g). LCMS (m/z) 851.
Reaction SMILES: C[Al](C)C.C(N(C(C)C)CC)(C)C.[C:14](Br)(=[O:16])[CH3:15].[CH3:18][O:19][CH:20]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:21][CH:22]=[O:23].Cl>C(Cl)Cl>[CH3:18][O:19][CH:20]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:21][C@H:22]1[O:23][C:14](=[O:16])[CH2:15]1
Reactant: CC(=O)Br
Reactant: CCCCCCCCCC(CC=O)OC
Agent: C[Al](C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCCCCCCC(C[C@@H]1CC(=O)O1)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.3 %

Procedure:
A solution of N,N′-(1R,1′R)-1,1′-(benzylazanediyl)bis(2-methylpropane-1,1-diyl)bis(1,1,1-trifluoromethanesulfonamide) (81.2 mg, 0.15 mmol, 30 mol %) in CH2Cl2 (1 mL) was treated at rt under N2 slowly with a solution of AlMe3 (10.8 mg, 0.15 mmol) in CH2Cl2 (0.5 mL). The mixture was stirred at room temperature (rt) for 2 h, cooled to −45° C. and treated sequentially with diisopropylethylamine (11 mg, 1.7 equiv), acetyl bromide (117 mg, 1.9 equiv) and 5 (107 mg, 0.500 mmol, 1.0 equiv). The resulting pale yellow solution was stirred for 14 h at −45° C., warmed to rt, and poured into a separatory funnel containing 0.1 N HCl (10) mL). The organic layer was washed with saturated NaHCO3, brine, and dried (Na2SO4). The solvent was removed in vacuo and the yellow oily product was purified by chromatography on SiO2 (4% EtOAc/hexanes to 6% EtOAc/hexanes) to give 6 (99.1 mg, 77%) as a colorless oil: 1H NMR (CDCl3) 4.8-4.65 (m, 1H), 3.60-3.50 (m, 1H), 3.3-3.2 (m, 1H), 3.35, 3.32 (2s, 3H), 3.22-3.08 (m, 1H), 2.18-1.82 (m, 2H) 1.65-1.35 (m, 2H), 1.35-1.20 (m, 14H), 0.90-0.80 (m, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=3)=[CH:11][C:10]([C:23]([OH:25])=O)=[N:9]2)=[CH:4][CH:3]=1.ClC1C=C(N2C(C3C=C(F)C=C(Cl)C=3)=CC(C([N:49]3[CH2:53][C:52](=[O:54])[NH:51][CH2:50]3)=O)=N2)C=CC=1F>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:20])([F:21])[F:22])[CH:14]=3)=[CH:11][C:10]([C:23]([N:49]3[CH2:53][C:52](=[O:54])[NH:51][CH2:50]3)=[O:25])=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc(-c2cccc(C(F)(F)F)c2)n(-c2ccc(F)cc2)n1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3ccc(F)c(Cl)c3)n2)CN1
Product: O=C1CN(C(=O)c2cc(-c3cccc(C(F)(F)F)c3)n(-c3ccc(F)cc3)n2)CN1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 87A in analogy to the synthesis of the compound of Example 1. 28 mg (74% of theory) of the title compound are obtained.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][C:6]1[S:7][CH:8]=[C:9]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:10]=1)=[O:4].C(N(CC)C(C)C)(C)C.Cl[C:27]1[N:32]=[C:31]([N:33]2[CH:38]=[C:37]([CH:39]3[C:45]4[CH:46]=[CH:47][C:48]([CH3:50])=[CH:49][C:44]=4[CH:43]=[CH:42][C:41]4[CH:51]=[C:52]([CH3:55])[CH:53]=[CH:54][C:40]3=4)[C:36](=[O:56])[NH:35][C:34]2=[O:57])[CH:30]=[CH:29][N:28]=1>CN1CCCC1=O>[CH3:50][C:48]1[CH:47]=[CH:46][C:45]2[CH:39]([C:37]3[C:36](=[O:56])[NH:35][C:34](=[O:57])[N:33]([C:31]4[CH:30]=[CH:29][N:28]=[C:27]([NH:1][CH2:2][C:3]([NH:5][C:6]5[S:7][CH:8]=[C:9]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:10]=5)=[O:4])[N:32]=4)[CH:38]=3)[C:40]3[CH:54]=[CH:53][C:52]([CH3:55])=[CH:51][C:41]=3[CH:42]=[CH:43][C:44]=2[CH:49]=1
Reactant: CCOC(=O)Cc1csc(NC(=O)CN)n1
Reactant: Cc1ccc2c(c1)C=Cc1cc(C)ccc1C2c1cn(-c2ccnc(Cl)n2)c(=O)[nH]c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CCOC(=O)Cc1csc(NC(=O)CNc2nccc(-n3cc(C4c5ccc(C)cc5C=Cc5cc(C)ccc54)c(=O)[nH]c3=O)n2)n1

Procedure:
A mixture of the product from step (i) (0.194 g), N,N-diisopropylethylamine (0.35 ml) and the product from example 8 step (ii) (0.25 g) in 1-methyl-2-pyrrolidinone (5 ml) was heated at 90° C. for 10 hours. The mixture was partitioned between ethyl acetate and water. The organic phase was washed with water, dried (MgSO4) and evaporated. Purification was by chromatography eluting with 70% ethyl acetate in isohexane. Yield 0.175 g.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9](=[O:11])[CH3:10])=[C:4]([CH3:12])[CH:3]=1.Cl[C:14]1[N:19]=[CH:18][CH:17]=[CH:16][N:15]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.[Cu]>[CH3:12][C:4]1[CH:3]=[C:2]([O:1][C:14]2[N:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:7]=[C:6]([CH3:8])[C:5]=1[C:9](=[O:11])[CH3:10]
Reactant: Clc1ncccn1
Reactant: CC(=O)c1c(C)cc(O)cc1C
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1c(C)cc(Oc2ncccn2)cc1C
Temperature: 100 °C
Reaction time: 3 h
Yield: 54.8 %

Procedure:
A mixture of 1-(4-hydroxy-2,6-dimethylphenyl)ethanone (4-2, 2.15 g, 13.1 mmol), 2-chloropyrimidine (1.00 g, 8.73 mmol), copper (55.0 mg, 0.87 mmol), and potassium carbonate (3.62 g, 26.2 mmol) in 17.5 mL of DMF was stirred at 100° C. for 3.0 h. The reaction mixture was cooled to room temperature, added with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4(s), and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (50% EtOAc in hexanes as eluant) to give 1-(2,6-dimethyl-4-(pyrimidin-2-yloxy)phenyl)ethanone (6-1, 1.16 g) as white solids in 55% yield: 1H NMR (500 MHz, CDCl3) δ 8.58 (d, J=4.5 Hz, 2 H), 7.05 (t, 1 H), 6.87 (s, 2 H), 2.49 (s, 3 H), 2.27 (s, 6 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:6]([OH:8])=O.[C:13]([C:17]1[CH:32]=[CH:31][C:20]([C:21]([NH:23][C:24]2[C:25]([NH2:30])=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:22])=[CH:19][CH:18]=1)([CH3:16])([CH3:15])[CH3:14]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:6]([NH:30][C:25]1[C:24]([NH:23][C:21](=[O:22])[C:20]2[CH:31]=[CH:32][C:17]([C:13]([CH3:15])([CH3:14])[CH3:16])=[CH:18][CH:19]=2)=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:8]
Reactant: COc1cc(C(=O)O)ccc1C
Reactant: CC(C)(C)c1ccc(C(=O)Nc2ccccc2N)cc1
Product: COc1cc(C(=O)Nc2ccccc2NC(=O)c2ccc(C(C)(C)C)cc2)ccc1C
Yield: 28 %

Procedure:
Using the procedure described in Example 102, Part A, 3-methoxy-4-methylbenzoic acid (3.6 mmol) and N1-(4-tert-butylbenzoyl)-1,2-benzenediamine (1.8 mmol) yielded 210 mg (28%) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[N:11](CC2C=CC(OC)=CC=2OC)[CH2:10][C:9]2[CH:23]=[C:24]([Br:26])[S:25][C:8]=2[C:7]1=[O:27])=[O:5])[CH3:2].S(Cl)(Cl)=O>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[N:11]=[CH:10][C:9]2[CH:23]=[C:24]([Br:26])[S:25][C:8]=2[C:7]=1[OH:27])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1C(=O)c2sc(Br)cc2CN1Cc1ccc(OC)cc1OC
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)c1ncc2cc(Br)sc2c1O
Reaction time: 5 h

Procedure:
2-Bromo-5-(2,4-dimethoxy-benzyl)-7-oxo-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine-6-carboxylic acid ethyl ester (example 21.c, 5.66 g, 12.5 mmol) was dissolved in 85 mL of anhydrous dichloromethane. To the solution was added 1.37 mL of thionyl chloride, and the reaction mixture was stirred for 5 hours. The solution was filtered on a fine glass frit filter to collect a white solid precipitate. The solid was washed twice with cold dichloromethane and then partitioned between saturated sodium bicarbonate solution and ethyl acetate. The organic fraction was washed with brine, dried over anhydrous sodium sulfate, and concentrated to 3.1 g of off-white solid: MS: (+) m/z 300.0, 301.9 (M+1, 79Br/81Br)
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.O[C:16]1[CH:17]=[C:18]([C:22](=[O:24])[CH3:23])[CH:19]=[CH:20][CH:21]=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>O1CCCC1.O>[C:22]([C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[O:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1)(=[O:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: CC(=O)c1cccc(O)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1cccc(OC2CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 73.9 %

Procedure:
To a stirred solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (4.00 g, 19.9 mmol), 1-(3-hydroxyphenyl)ethanone (2.71 g, 19.9 mmol), and triphenylphosphine (5.73 g, 21.9 mmol) in tetrahydrofuran (100 mL) was added slowly diisopropyl azodicarboxylate (4.25 mL, 21.9 mmol) at 0° C. under Nitrogen. The resulting mixture was stirred at room temperature for 17 hours. The mixture was poured into water (200 mL) and extracted with ethyl acetate (200 mL). The organic layer was washed with water (200 mL) and dried over sodium sulfate. After removal of the solvent, the residue was purified by column chromatography on silica gel eluting with n-hexane/ethyl acetate (4:1) to give 4.70 g (74%) of the title compound as colorless oil.
Reaction SMILES: Br[C:2]1[C:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[S:10][C:6]=2[CH:5]=[C:4]([O:19][CH3:20])[CH:3]=1.[C:21](=O)([O-])[O-].[K+].[K+].CB(O)O>C1(C)C=CC=CC=1.C(OC(=O)C)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:21][C:2]1[C:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[S:10][C:6]=2[CH:5]=[C:4]([O:19][CH3:20])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(-c2nc3c(Br)cc(OC)cc3s2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CB(O)O
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1ccc(-c2nc3c(C)cc(OC)cc3s2)cc1
Temperature: 100 °C
Yield: 77.2 %

Procedure:
To a solution of 4-bromo-6-methoxy-2-(4-methoxy-phenyl)-benzothiazole (1.0 g, 2.86 mmol) in dry toluene (25 mL) was added potassium carbonate (4.2 g, 30.4 mmol), methylboronic acid (0.92 g, 15.3 mmol) and tetrakis(triphenylphosphine)palladium (0.44 g, 0.38 mmol). The mixture was heated to 100° C. for 24 h, then cooled to room temperature. The mixture was diluted with ethylacetate and washed with water, saturated sodium carbonate and brine. After chromatographic purification gave 4-methyl-6-methoxy-2-(4-methoxy-phenyl)-benzothiazole as a white solid (0.63 g, 77% yield). Mass spec: MH+=286.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[CH:12]([CH:14]=[CH2:15])=[O:13].[N:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:17]>ClCCl>[OH:17][N:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12](=[O:13])[CH:14]=[CH2:15]
Reactant: C=CC=O
Reactant: O=Nc1ccccc1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: C=CC(=O)N(O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
DBU (15 mg, 0.1 mmol) was added under argon to a solution of acrolein (56 mg, 1 mmol), nitrosobenzene (107 mg, 1 mmol) and catalyst (36.4 mg, 0.1 mmol) in dichloromethane (5 mL). The reaction mixture was stirred at room temperature for 10 min. The solvent was removed under vacuum, and the residue was purified by flash silica gel column chromatography using hexane and ethyl acetate as the eluents.
Reaction SMILES: [CH2:1]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2Br)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([Sn](CCCC)(CCCC)C=C)[CH2:19]CC>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[CH:18]=[CH2:19])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cccc2c1CN(Cc1ccccc1)C2
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1cccc2c1CN(Cc1ccccc1)C2
Temperature: 100 °C

Procedure:
A solution of 2-benzyl-4-bromoisoindoline (16.7 g, 58.0 mmol) and tributyl(vinyl)tin (20.3 mL, 69.6 mmol) in toluene (400 mL) was degassed by bubbling nitrogen gas through the solution for 0.25 h. Tetrakis(triphenylphosphine)palladium (0) (1.30 g, 1.16 mmol) was added and the resulting solution heated in a 100° C. oil bath under nitrogen for 24 h. The contents of the reaction flask were cooled, evaporated and subjected to flash column chromatography eluting with hexane/ethyl acetate 95/5 to give after evaporation the title compound as a pale oil that turned pink on standing. LRMS (ESI) m/z 236 [(M+H)+; calcd for C17H18N: 236].
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:11]=[C:10]([I:12])[CH:9]=[C:8]2[C:4]=1[C:5](=[O:14])[C:6](=[O:13])[NH:7]2.[H-].[Na+].[CH3:19][Si:20]([CH3:27])([CH3:26])[CH2:21][CH2:22][O:23][CH2:24]Cl.O>CN(C)C=O>[CH3:19][Si:20]([CH3:27])([CH3:26])[CH2:21][CH2:22][O:23][CH2:24][N:7]1[C:8]2[C:4](=[C:3]([C:2]([F:15])([F:1])[F:16])[CH:11]=[C:10]([I:12])[CH:9]=2)[C:5](=[O:14])[C:6]1=[O:13]
Reactant: C[Si](C)(C)CCOCCl
Reactant: O=C1Nc2cc(I)cc(C(F)(F)F)c2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[Si](C)(C)CCOCN1C(=O)C(=O)c2c1cc(I)cc2C(F)(F)F
Reaction time: 0.5 h
Yield: 82.6 %

Procedure:
A solution of 4-trifluoromethyl-6-iodo-1H-indole-2,3-dione (12.0 g, 35.2 mmol) in N,N-dimethylformamide (120 mL) was cooled to 0° C. under nitrogen, and thereto was added 55% sodium hydride (1.70 g, 39.0 mmol) and the mixture was stirred for 30 minutes. Then, to the reaction solution was added dropwise 2-(trimethylsilyl)-ethoxymethyl chloride (7.00 mL, 39.6 mmol), and the mixture was stirred at room temperature for 5 minutes. To the reaction solution was added water, and the mixture was extracted with ethyl acetate-toluene (1:1) twice, washed with water twice, and then dried over magnesium sulfate, and filtered. The filtrate was evaporated and purified by silica gel column chromatography (hexane/ethyl acetate=5/1) to give the titled compound (13.7 g, 83%).