Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]3([C:26]([O:28]CC)=[O:27])[CH2:25][CH2:24]3)[CH:8]=2)[N:3]=1.[OH-].[Na+]>O1CCCC1>[NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:15][C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:22]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]3([C:26]([OH:28])=[O:27])[CH2:24][CH2:25]3)[CH:8]=2)[N:3]=1
Reactant: CCOC(=O)C1(c2ccc3nc(N)nc(C(=O)N4Cc5ccccc5C4)c3c2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(C3(C(=O)O)CC3)ccc2n1
Temperature: 23 °C
Reaction time: 12 h

Procedure:
400 mg of ethyl 1-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]cyclopropanecarboxylate are dissolved in 14 ml of tetrahydrofuran, and 3.5 ml of 2N sodium hydroxide solution are added. The mixture is stirred at 23° C. for 12 h, evaporated to dryness in vacuo, taken up in 10 ml of water and adjusted to pH 2 using 1 ml of 25% hydrochloric acid. The resultant precipitate is filtered off and dried in vacuo. Yield: 250 mg (67%) of 1-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]cyclopropanecarboxylic acid;
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([C:13]#[N:14])=[C:6]2[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)=O.[S:21]1[CH2:27][C:25](=[O:26])[NH:24][C:22]1=[S:23].C([O-])(=O)C.[Na+]>C(O)(=O)C>[O:26]=[C:25]1[C:27](=[CH:1][C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][CH:12]=2)[N:9]=[CH:8][C:7]([C:13]#[N:14])=[C:6]3[C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[S:21][C:22](=[S:23])[NH:24]1
Reactant: O=C1CSC(=S)N1
Reactant: N#Cc1cnc2ccc(C=O)cc2c1-c1cccnc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: N#Cc1cnc2ccc(C=C3SC(=S)NC3=O)cc2c1-c1cccnc1

Procedure:
Similar procedure as described in example 61j was used, starting from 6-formyl-4-pyridin-3-yl-quinoline-3-carbonitrile (example 63c), rhodanine, sodium acetate, and acetic acid to give 6-(4-oxo-2-thioxo-thiazolidin-5-ylidenemethyl)-4-pyridin-3-yl-quinoline-3-carbonitrile. LC-MS m/e 375 (MH+).
Reaction SMILES: I[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[O:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH:11]=[C:10]1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCO.O>[O:9]1[C:10]2=[CH:11][CH:12]=[CH:17][C:16]2=[CH:15][CH:14]=[C:13]1[NH:6][C:5]1[CH:7]=[CH:8][CH:2]=[CH:3][CH:4]=1
Reactant: OB(O)c1cc2ccccc2o1
Reactant: Nc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Solvent: O
Product: c1ccc(Nc2ccc3cccc-3o2)cc1
Temperature: 125 °C
Yield: 99.6 %

Procedure:
A mixture of 4-iodo-aniline (25.0 g, 114.1 mmol), 2-benzofuran-boronic acid (27.7 g, 171.2 mmol), PdCl2(O-tolylphosphine) (11.66 g, 14.8 mmol), and Na2CO3 (60.49 g, 570.7 mmol) in DME/EtOH/H2O (4:2:1) (700 mL) was heated at 125° C. for 2 h. The reaction mixture was cooled to room temperature, filtered and washed. The solvent was removed under reduced pressure. The residue was partitioned (ethyl acetate/water) and the organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The resulting crude was purified by column chromatography on silica gel, eluting with dichloromethane to afford 4-benzofuran-2-yl-phenylamine (11) as a pale yellow solid (23.78 g, 99.5%): 1H NMR (300 MHz, CDCl3): δ 7.66 (d, J=9.0 Hz, 2H), 7.51-7.55 (m, 2H), 7.20-7.23 (m, 2H), 6.81 (s, 1H), 6.73 (d, J=9.0 Hz, 2H), 3.83 (bs, 2H) TLC conditions: Uniplate silica gel, 250 microns; mobile phase=ethyl acetate/hexanes (2:1); Rf=0.45.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:5]=[C:6]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:8][CH:9]=1.[I-].C[N+:17](C)(C)N.CC([O-])(C)C.[K+].Cl>CS(C)=O>[N+:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([O:3][C:2]([F:13])([F:14])[F:1])[C:5]=1[NH2:17])([O-:12])=[O:11]
Reactant: C[N+](C)(C)N
Reactant: O=[N+]([O-])c1cccc(OC(F)(F)F)c1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [I-]
Solvent: CS(C)=O
Product: Nc1c(OC(F)(F)F)cccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a solution of 3-trifluoromethoxy nitrobenzene (4.0 g, 20 mmol) in DMSO (60 ml), trimethylhydrazinium iodide (4.4 g, 22 mmol) is added and cooled to 0° C. KOt-Bu is added in portions. After stirring for 4 h at 25° C., ice water is added, pH is adjusted to 2-3 with HCl solution, the mixture extracted with EtOAc and washed with brine, followed by drying (Na2SO4) and evaporation of the solvent. Chromatography (silica gel, CH2Cl2/hexane=1:1) gave 2-nitro-6-trifluoromethoxy-phenylamine.
Reaction SMILES: CN(/[CH:4]=[N:5]/[C:6]([C:8]1[CH:9]=[C:10]2[C:19](=[CH:20][CH:21]=1)[C:18]1[N:14]([CH:15]=[C:16]([C:22]3[N:26]([CH:27]([CH3:29])[CH3:28])[N:25]=[C:24]([CH3:30])[N:23]=3)[N:17]=1)[CH2:13][CH2:12][O:11]2)=O)C.Cl.[NH:32]([CH:34]1[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]1)[NH2:33]>C(O)(=O)C>[CH:27]([N:26]1[C:22]([C:16]2[N:17]=[C:18]3[C:19]4[CH:20]=[CH:21][C:8]([C:6]5[N:32]([CH:34]6[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]6)[N:33]=[CH:4][N:5]=5)=[CH:9][C:10]=4[O:11][CH2:12][CH2:13][N:14]3[CH:15]=2)=[N:23][C:24]([CH3:30])=[N:25]1)([CH3:28])[CH3:29]
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(C(=O)/N=C/N(C)C)cc2OCC3)n(C(C)C)n1
Reactant: CN1CCC(NN)CC1
Agent: Cl
Solvent: CC(=O)O
Product: Cc1nc(-c2cn3c(n2)-c2ccc(-c4ncnn4C4CCN(C)CC4)cc2OCC3)n(C(C)C)n1
Temperature: 100 °C
Yield: 34.3 %

Procedure:
A mixture of N-[(1E)-(dimethylamino)methylidene]-4-[3-methyl-1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca1(14),2,4,10,12-pentaene-12-carboxamide (100 mg, 0.246 mmol) and 4-hydrazinyl-1-methylpiperidine hydrochloride (81 mg, 0.49 mmol) in acetic acid (10 mL) was heated at 100° C. for 1 h. The solvent was removed under reduce pressure, and the residue was purified by prep-HPLC (Gilson GX 281, Shim-pack PRC-ODS 250 mm×20 mm×2, gradient: CH3CN/10 mm/L NH4HCO3, 17 min) to afford 255 (40 mg, 34% yield) as a white solid. LCMS (ESI): RT=4.28 min, m/z: 474.3 [M+H+]. 1H NMR (500 MHz, DMSO-d6) δ 8.58-8.57 (d, J=8.0 Hz, 1H), 8.08 (s, 1H), 7.99 (s, 1H), 7.44-7.42 (dd, J=8.0, 1.5 Hz, 1H), 7.31 (d, J=1.5 Hz, 1H), 5.86 (m, 1H), 4.58 (s, 4H), 4.31 (m, 1H), 2.86-2.84 (m, 2H), 2.26 (s, 3H), 2.18 (s, 3H), 2.13-2.07 (m, 2H), 2.01-1.96 (m, 2H), 1.91-1.89 (m, 2H), 1.47 (d, J=6.5 Hz, 6H)
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[C@@H:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([OH:24])[CH:19]=4)[CH2:16][NH:15][C:14]3=[O:25])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:35][CH2:36][O:37]C1CCCCO1.O>C(#N)C>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([N:13]3[C@@H:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:35][CH2:36][OH:37])[CH:19]=4)[CH2:16][NH:15][C:14]3=[O:25])=[CH:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: BrCCOC1CCCCO1
Reactant: O=C1NC[C@H](c2cccc(O)c2)N1c1ccc(Oc2ccc(Cl)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: O=C1NC[C@H](c2cccc(OCCO)c2)N1c1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of (S)-1-(4-(4-chlorophenoxy)phenyl)-5-(3-hydroxyphenyl)-imidazolidin-2-one (26 mg, 0.068 mmol) in acetonitrile (2 mL) is added Cs2CO3 (50 mg, 0.15 mmol) followed by 2-(2-bromoethoxy)tetrahydro-2H-pyran (30 mg, 0.14 mmol). The resulting mixture is stirred at room temperature for 24 h and is then treated with water (5 mL) and extracted with EtOAc (3×3 mL). The combined organic layers are concentrated and the residue is dissolved in MeOH (1 mL). To the MeOH solution is added catalytic amount of pTSA (˜1 mg). The resulting mixture is stirred at room temperature for 1 h and is then treated with sat. NaHCO3 solution (3 mL). After extracting with EtOAc (3×3 mL), the combined organic layers are concentrated and purified by preparative thin layer chromatography (silica gel, 85% EtOAc/hexane) to provide the title compound as a white solid. 1H NMR (CDCl3, 400 MHz) δ 7.33 (d, J=9.2 Hz, 2H), 7.22-7.27 (m, 3H), 6.89 (d, J=7.6 Hz, 1H), 6.81-6.88 (m, 6H), 5.23 (dd, J=8.8, 6.0 Hz, 1H), 4.90 (br s, 1H), 3.92-4.08 (m, 5H), 2.34 (dd, J=8.8, 6.4 Hz, 1H), 2.03 (t, J=5.6 Hz, 1H); HPLC-MS calculated for C23H21ClN2O4 (M+H+) 425.1, found 425.1.
Reaction SMILES: C(S[CH:5]1[N:8]([C:9](=[C:23]([O:30][C:31]2[CH:36]=[CH:35][C:34]([S:37]([CH3:39])=[O:38])=[CH:33][CH:32]=2)[C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[S:11])[C:7](=[O:40])[CH2:6]1)C=C.[Cl:41]Cl>ClCCl.C(Cl)(Cl)(Cl)Cl>[Cl:41][CH:5]1[N:8]([C:9](=[C:23]([O:30][C:31]2[CH:36]=[CH:35][C:34]([S:37]([CH3:39])=[O:38])=[CH:33][CH:32]=2)[C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[S:11])[C:7](=[O:40])[CH2:6]1
Reactant: ClCl
Reactant: C=CCSC1CC(=O)N1C(C(=S)OCc1ccc([N+](=O)[O-])cc1)=C(Oc1ccc(S(C)=O)cc1)C(=O)C(C)(C)C
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: CS(=O)c1ccc(OC(C(=O)C(C)(C)C)=C(C(=S)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)CC2Cl)cc1
Temperature: 25 °C
Yield: 52.5 %

Procedure:
To a solution of 0.488 g of 4-nitrobenzyl 2-(4-allylthioazetidin-2-on-1-yl)-3-(4-methylsulphinylphenoxy)-3-trimethylacetylthiopropenate in dichloromethane at -20°, was added dropwise a solution of 1.58 mmol of chlorine in carbon tetrachloride. After 30 minutes the mixture was warmed to room temperature, evaporated in vacuo, and the residual oil was chromatographed over silica gel. Elution with hexane-ethyl acetate mixtures afforded 0.24 g of the title compound as a pale yellow foam (53% of the theoretical yield).
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]([O:7][CH2:8][CH2:9]Cl)=[O:6])[CH3:3].C1CCC(NC2CCCCC2)CC1.[C:24]([OH:31])(=[O:30])/[CH:25]=[CH:26]/[C:27]([OH:29])=[O:28]>CN1CCCC1=O>[CH3:1][CH:2]([O:4][C:5]([O:7][CH2:8][CH2:9][O:29][C:27](/[CH:26]=[CH:25]/[C:24]([OH:31])=[O:30])=[O:28])=[O:6])[CH3:3]
Reactant: CC(C)OC(=O)OCCCl
Reactant: O=C(O)/C=C/C(=O)O
Agent: C1CCC(NC2CCCCC2)CC1
Solvent: CN1CCCC1=O
Product: CC(C)OC(=O)OCCOC(=O)/C=C/C(=O)O
Yield: 9.7 %

Procedure:
Following general procedure A, chloroethyl (methylethoxy)formate (0.25 g, 1.50 mmol) was reacted overnight with the pre-formed bis-dicyclohexylamine salt (DCHA) of fumaric acid (FA) (0.50 g, 1.26 mmol) in N-methylpyrrolidinone (NMP) at ca. 100° C. The crude material was purified by mass-guided preparative HPLC to afford (0.030 g, 10% yield) of the title compound (50) as a white, waxy, semi-solid. 1H NMR (CD3CN, 400 MHz): δ 6.86 (q, J=5.6 Hz, 1H), 6.81 (d, J=16.0 Hz, 1H), 6.73 (d, J=16.0 Hz, 1H), 2.57-2.50 (heptet, J=7.2 Hz, 1H), 1.48 (d, J=5.6 Hz, 3H), 1.13 (m, 6H). MS (ESI): m/z=244.99 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:6][CH:7]=1.[Br:19]N1C(=O)CCC1=O>CN(C=O)C.C(OCC)(=O)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:6][C:7]=1[Br:19]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1cccc(-c2ccc(N)cn2)c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc(-c2ccc(N)c(Br)n2)c1
Yield: 86.2 %

Procedure:
To a solution of ethyl 3-(5-aminopyridin-2-yl)benzoate (7.52 g, 31.06 mmol) in DMF (150 mL) was added N-bromosuccinimide (5.58 g, 31.37 mmol) at 0° C. for 5 min. The reaction mixture was quenched with satd. NaHCO3 solution (150 mL) at 0° C. The mixture was partitioned between ethyl acetate and water. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by flash column chromatography using a 85:15 v/v hexane:ethyl acetate as solvent to afford ethyl 3-(5-amino-6-bromopyridin-2-yl)benzoate (8.6 g, 86% yield) as a reddish brown solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.Cl[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([O:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][N:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C1CCNCC1
Reactant: ClCCCCCCOCc1ccccc1
Product: O=C1CCN(CCCCCCOCc2ccccc2)CC1

Procedure:
1-(6-Benzyloxyhexyl)-4-piperidone is prepared from 4-piperidone and 1-chloro-6-benzyloxyhexane essentially as described above in Example 38, Scheme C, step a.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.[F:15][C:16]([F:34])([F:33])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]Br>>[F:15][C:16]([F:33])([F:34])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:13][CH:14]=1
Reactant: FC(F)(F)CCCCCCCCCCCCCCCBr
Reactant: CCOC(=O)CCc1ccc(N)cc1
Product: CCOC(=O)CCc1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1

Procedure:
In a manner directly analogous to that described in Example 8, ethyl 4-aminohydrocinnamate is alkylated with 15-(trifluoromethyl)pentadecyl bromide to form ethyl 4-[15-(trifluoromethyl)pentadecylamino]hydrocinnamate. Subsequently, in a manner directly analogous to that described in Example 9, ethyl 4-[15-(trifluoromethyl)pentadecylamino]hydrocinnamate is hydrolyzed to 4-[15-(trifluoromethyl)pentadecylamino]hydrocinnamic acid.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][C:4]1=[O:12])[CH3:2].[CH3:13][O:14]C(Cl)Cl>[Ti](Cl)(Cl)(Cl)Cl.C(Cl)Cl>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([CH:13]=[O:14])=[CH:9][CH:10]=2)[CH2:5][C:4]1=[O:12])[CH3:2]
Reactant: CCN1C(=O)Cc2ccccc21
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CCN1C(=O)Cc2cc(C=O)ccc21
Temperature: 25 °C
Reaction time: 252 h
Yield: 76 %

Procedure:
To a solution of 32.2 g. (0.2 mole) of 1-ethyloxindole in 200 ml. of methylene chloride was added 44 ml. (0.4 mole) of titanium tetrachloride followed by 22.6 ml. (0.25 mole) of dichloromethyl methyl ether. The reaction was stirred for 10.5 days at 25° C. followed by the addition of additional titanium tetrachloride and dichloromethyl methyl ether every 48 hours. The reaction was poured onto 1 l. of ice and water and extracted with methylene chloride. Concentration of the dried extract gave the crude product which was recrystallized from diethyl ether, 28.6 g. (76% yield), m.p. 126°-127° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C@H:28]([O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:13][CH2:14][CH:15]1[O:17][CH:16]1[C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(O)C>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C@H:28]([O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[CH2:13][CH2:14][C:15](=[O:17])[CH2:16][C:18]1[CH:19]=[CH:20][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:26][CH:27]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(C2OC2CC[C@@H](NC(=O)OCc2ccccc2)[C@H](O[Si](C)(C)C(C)(C)C)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Product: COC(=O)c1ccc(CC(=O)CC[C@@H](NC(=O)OCc2ccccc2)[C@H](O[Si](C)(C)C(C)(C)C)c2ccccc2)cc1
Yield: 50 %

Procedure:
A mixture of the title compound from Step F above (1.00 g, 1.69 mmol) and palladium acetate Pd(OAc)2 (0.064 g, 0.28 mmol) in ethanol (15 ml) was degassed and flushed with N2, and then triphenylphosphine (0.298 g, 1.137 mmol) was added. The reaction mixture was refluxed overnight. After removal of the solvent, the residue was purified by column chromatography (0-20% then 20% ethyl acetate in hexanes). 0.50 g (50%) of the title compound was obtained. 1H NMR (CDCl3, 400 MHz): δ8.14 (d, J=8.6 Hz, 2H), 7.53-7.28 (m, 12H), 5.13 (s, 2H), 4.97 (d, J=9.4 Hz, 1H), 4.86 (s, 1H), 4.06 (s, 3H), 3.85 (s, 2H), 2.77-2.64 (m, 2H), 2.07 (m, 1H), 1.85-1.79 (m, 2H), 1.05 (s, 9H), 0.19 (s, 3H), 0.00 (s, 3H). MS: m/z (ESI) 590 (M+1).
Reaction SMILES: [CH3:1][C:2]([S:5](/[N:7]=[CH:8]/[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:11][N:10]=1)=O)([CH3:4])[CH3:3].[CH:21]([Mg]Br)=[CH2:22]>O1CCCC1>[C:2]([S:5][NH:7][C@@H:8]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:11][N:10]=1)[CH:21]=[CH2:22])([CH3:4])([CH3:3])[CH3:1]
Reactant: C=C[Mg]Br
Reactant: CC(C)(C)S(=O)/N=C/c1ccc(OCC(F)(F)F)cn1
Solvent: C1CCOC1
Product: C=C[C@@H](NSC(C)(C)C)c1ccc(OCC(F)(F)F)cn1
Temperature: -78 °C
Yield: 73.5 %

Procedure:
To a mixture of 2-methyl-N-{(1E)-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]methylidene}propane-2-sulfinamide (10.0 g, 32.4 mmol) and tetrahydrofuran (150 ml) at −78° C. was added dropwise 1.0M vinylmagnesium bromide in tetrahydrofuran (58.4 ml, 58.4 mmol), maintaining temperature during addition below −70° C. Reaction was stirred at −78° C. for an hour. To complete reaction, an additional amount of 1.0M vinylmagnesium bromide (19.4 ml, 19.4 mmol) was required. The reaction was then quenched by pouring mixture into a cold solution of saturated NH4Cl (800 ml) and ethyl acetate (600 ml) with vigorous stirring at 0° C. Layers were separated and organic extracts were combined, dried over Na2SO4, filtered and concentrated in vacuum. The resulting brown oil was purified by flash chromatography (Si2O, 25-100% ethyl acetate in hexanes, gradient) to give 2-{(1R)-1-[(tert-butylthio)amino]prop-2-enyl}-5-(2,2,2-trifluoroethoxy)pyridine as a white solid (8.10 g, 73.5%). 1H NMR (400 MHz, CDCl3) 8.30 (d, J=2.8 Hz, 1H), 7.28 (m, 2H), 5.92-5.83 (m, 1H), 5.34 (dd, J=16 Hz and 33 Hz, 2H), 5.01 (m, 1H), 4.99 (bs, 1H), 4.39 (q, J=8.0 Hz, 2H), 1.28 (s, 9H); MS(Electrospray): m/z 337.1 (M+H).
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH2:5][N:6]([CH2:11][C:12]([N:14]3[CH2:19][CH2:18][N:17]([CH:20]4[CH2:23][CH2:22][CH2:21]4)[CH2:16][CH2:15]3)=[O:13])[CH2:7][CH2:8][C:9]=2[N:10]=1.C([Sn](CCCC)(CCCC)[C:29]1[N:30]=[N:31][CH:32]=[CH:33][CH:34]=1)CCC>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>[CH:20]1([N:17]2[CH2:18][CH2:19][N:14]([C:12](=[O:13])[CH2:11][N:6]3[CH2:7][CH2:8][C:9]4[N:10]=[C:2]([C:29]5[N:30]=[N:31][CH:32]=[CH:33][CH:34]=5)[S:3][C:4]=4[CH2:5]3)[CH2:15][CH2:16]2)[CH2:23][CH2:22][CH2:21]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnn1
Reactant: O=C(CN1CCc2nc(Br)sc2C1)N1CCN(C2CCC2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: O=C(CN1CCc2nc(-c3cccnn3)sc2C1)N1CCN(C2CCC2)CC1
Temperature: 110 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2-bromo-5-[2-(4-cyclobutylpiperazin-1-yl)-2-oxoethyl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine (300 mg, 0.75 mmol), 3-(tributylstannyl)pyridazine (369 mg, 1 mmol) and Pd(PPh3)4 (92 mg, 0.08 mmol) in toluene (15 mL) is degassed by Ar and heated at 110° C. in a sealed tube overnight. The mixture is cooled and saturated KF solution (10 mL) is added. The mixture is stirred at rt for 30 min then the layers are separated. The aqueous layer is extracted with EtOAc (15 ml) and the combined extracts are dried and evaporated. The residue is purified by PTLC to give the title compound as white solid. MS (M+1): 399.2; 1H NMR (δ, CDCl3): 9.63-9.64 (m, 1H), 9.23 (dd, 1H), 7.84 (dd, 1H), 3.90 (s, 2H), 3.62 (td, 4H), 3.45 (s, 2H), 3.00 (s, 4H), 2.64-2.74 (m, 1H), 2.29 (t, 4H), 1.64-2.06 (m, 6H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].C1(C)C=CC=CC=1.[C:12]([NH:20][C:21]1[CH:30]=[C:29]([O:31]C)[CH:28]=[CH:27][C:22]=1[C:23]([O:25][CH3:26])=[O:24])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl>C(OCC)(=O)C>[C:12]([NH:20][C:21]1[CH:30]=[C:29]([OH:31])[CH:28]=[CH:27][C:22]=1[C:23]([O:25][CH3:26])=[O:24])(=[O:19])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)c1ccc(OC)cc1NC(=O)c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(O)cc1NC(=O)c1ccccc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 36.1 %

Procedure:
0.94 g of aluminum chloride was added to 7 mL of toluene solution containing 0.67 g of methyl 2-(benzamido)-4-methoxybenzoate at room temperature and stirred at 80° C. for 2 hours and 30 minutes. After the reaction mixture was cooled to room temperature, ethyl acetate and 1.0 mol/L hydrochloric acid were added and a solid substance was separated by filtration to obtain 0.23 g of methyl 2-(benzamido)-4-hydroxybenzoate as white solid.
Reaction SMILES: CS[C:3]1[NH:12][C:11](=[O:13])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]=1.Cl.[Cl:15][C:16]1[CH:17]=[C:18]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:19]=[CH:20][CH:21]=1.C(N(CC)CC)C>C(O)CC(C)C>[Cl:15][C:16]1[CH:17]=[C:18]([N:22]2[CH2:27][CH2:26][N:25]([C:3]3[NH:12][C:11](=[O:13])[C:10]4[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=4[N:4]=3)[CH2:24][CH2:23]2)[CH:19]=[CH:20][CH:21]=1
Reactant: Clc1cccc(N2CCNCC2)c1
Reactant: CSc1nc2c(c(=O)[nH]1)CCCC2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)CCO
Product: O=c1[nH]c(N2CCN(c3cccc(Cl)c3)CC2)nc2c1CCCC2

Procedure:
2-Methylsulfanyl-5,6,7,8-tetrahydro-3H-quinazolin-4-one (100 mg; 0.51 mmol), 1-(3-chlorophenyl)piperazine hydrochloride (118.8 mg; 0.51 mmol) and triethylamine (141.3 μl; 1.02 mmol) are reacted in isoamyl alcohol (1 ml) in accordance with the procedure for Example 1 (reaction time 4 h) and worked up; yield: 51 mg (29%), crystals;
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([N+:16]([O-])=O)[CH:14]=3)[C:9]([C:19]3[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=3)=[CH:8]2)[CH2:3][CH2:2]1.C([O-])([O-])=O.[Cs+].[Cs+].[N+](C1C=C2C(C(C3C=CC(C#N)=CC=3)=CN2)=CC=1)([O-])=O.CC1C=C[C:57]([S:60](OC2CCOCC2)(=[O:62])=[O:61])=CC=1.Cl>CN(C=O)C>[O:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([NH:16][S:60]([CH3:57])(=[O:62])=[O:61])[CH:14]=3)[C:9]([C:19]3[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=3)=[CH:8]2)[CH2:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)OC2CCOCC2)cc1
Reactant: N#Cc1ccc(-c2cn(C3CCOCC3)c3cc([N+](=O)[O-])ccc23)cc1
Agent: Cl
Agent: N#Cc1ccc(-c2c[nH]c3cc([N+](=O)[O-])ccc23)cc1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1ccc2c(-c3ccc(C#N)cc3)cn(C3CCOCC3)c2c1
Temperature: 60 °C

Procedure:
4-(1-(4-tetrahydropyranyl)-6-nitro-1H-indol-3-yl)-benzonitrile: Add Cs2CO3 (2.54 g, 7.8 mmol) to a mixture of 4-(6-nitro-1H-indol-3-yl)-benzonitrile (1.591 g, 6 mmol), 4-(4-methylphenylsulfonyloxy)tetrahydropyran (2 g, 7.8 mmol) in DMF (25 ml) and under N2 atmosphere; heat the resulting mixture to 60° C. for 14 hours. After cooling, the reaction is poured into ice/water (200 ml) and 5N HCl (6 ml), sonicated, and filtered with Et2O wash to give 1:1 mixture of the title compound:starting material as a brownish red solid (1.202 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[C:6]([CH3:13])=[CH:5][C:4]=1[OH:14].O[CH2:16][CH:17]=[C:18]([CH3:27])[CH2:19][CH2:20][CH:21]=[C:22]([CH3:26])[C:23]([OH:25])=[O:24]>C1C=CC=CC=1>[C:23]([C:22]([CH3:26])=[CH:21][CH2:20][CH2:19][C:18]([CH3:27])=[CH:17][CH2:16][C:5]1[C:4]([OH:14])=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[C:6]=1[CH3:13])([OH:25])=[O:24]
Reactant: CC(=CCO)CCC=C(C)C(=O)O
Reactant: COc1c(C)cc(O)c(OC)c1OC
Solvent: c1ccccc1
Product: COc1c(C)c(CC=C(C)CCC=C(C)C(=O)O)c(O)c(OC)c1OC
Yield: 36.5 %

Procedure:
5 g of 2,3,4-trimethoxy-5-methylphenol was dissolved in 10 ml of benzene and 10 g of silica alumina was added thereto. 1.8 g of 8-hydroxy-2,6-dimethyl-2,6-octadienoic acid dissolved in 4 ml of benzene was added to the above solution. The obtained solution was heated to 40° to 50° C. for two hours to allow reaction. The reaction mixture was then filtered and the precipitate was washed with ethyl ether while the filtrate was washed with water, dried over anhydrous magnesium sulfate and concentrated. The concentrate was purified by silica gel chromatography with the use of ether/n-hexane as the eluent to give 1.3 g of the title compound as a colorless oil.