Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[N:11]=[C:10]2[N:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][C:23]([F:26])([F:25])[F:24])[C:13](O)=[N:14][C:9]2=[CH:8][CH:7]=1)(=[O:4])=[O:3].P(Cl)(Cl)([Cl:29])=O>>[CH3:1][S:2]([O:5][C:6]1[N:11]=[C:10]2[N:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][C:23]([F:26])([F:25])[F:24])[C:13]([Cl:29])=[N:14][C:9]2=[CH:8][CH:7]=1)(=[O:4])=[O:3]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CS(=O)(=O)Oc1ccc2nc(O)n(-c3ccccc3OC(F)(F)F)c2n1
Product: CS(=O)(=O)Oc1ccc2nc(Cl)n(-c3ccccc3OC(F)(F)F)c2n1
Temperature: 80 °C

Procedure:
2-Hydroxy-3-(2-(trifluoromethoxy)phenyl)-3H-imidazo[4,5-b]pyridin-5-yl methanesulfonate (0.50 g, 1.3 mmol) taken up in phosphoryl trichloride (3.0 mL) was heated in a sealed tube to 80° C. for 48 h. The mixture was concentrated under reduced pressure and NaHCO3 was added to the residue until it turned basic. The solution was further diluted with water and extracted with EtOAc (3×). The combined organic extracts were dried over MgSO4 and concentrated under reduced pressure. The residue was purified column chromatography to give 2-chloro-3-(2-(trifluoromethoxy)phenyl)-3H-imidazo[4,5-b]pyridin-5-yl methanesulfonate, which was dissolved in a 1:4:1 solution of 1 M LiOH/THF/MeOH (10 mL) and stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure and the remaining was acidified with 1 N HCl. The resulting precipitate was collected by vacuum filtration and purified via preparative HPLC to give the title compound (0.11 g, 0.32 mmol, 25%). LCMS m/z=330.2 [M+H]+, 1H NMR (400 MHz, methanol-d4) δ ppm 6.70 (d, J=8.7 Hz, 1H), 7.58-7.68 (m, 3H), 7.73 (m, 1H), 7.90 (d, J=8.7 Hz, 1H).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:22]=2[NH2:28])=[CH:17][CH:16]=1>>[CH3:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:22]=2[NH:28][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)=[CH:19][CH:20]=1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Reactant: COc1ccc(-c2ccc(C)cc2N)cc1
Product: COc1ccc(-c2ccc(C)cc2Nc2ccnc3nc(C)ccc23)cc1

Procedure:
The product from Example 1d (0.088 g, 0.49 mmol) was reacted with the product from Example 214b (107 mg, 0.49 mmol) for 65 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid salt (0.106 g, 45%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 2.41 (s, 3 H) 2.72 (s, 3 H) 3.66 (s, 3 H) 6.29 (d, J=6.99 Hz, 1 H) 6.84 (d, J=8.82 Hz, 2 H) 7.27-7.53 (m, 5 H) 7.75 (d, J=8.46 Hz, 1 H) 8.32 (d, J=6.99 Hz, 1 H) 8.90 (d, J=8.46 Hz, 1 H) 10.88-11.05 (m, 1 H); MS (ESI+) m/z 356.0 (M+H)+; (ESI−) m/z 354.1 (M−H)−.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.C([O-])(O)=O.[Na+]>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCCCCOCc1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=CCCCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 75 %

Procedure:
The alcohol obtained in Step 1 (20.0 mmol) was dissolved in CH2Cl2 (100 mL). Dess-Martin periodinane (8.70 g, 20.5 mmol, 1 equiv.) was added, and the resulting solution stirred at room temperature for 18 h. The reaction mixture was then diluted with sat. aq. NaHCO3 (50 mL) and sat. aq. NaS2O3 (50 mL). The layers were separated, and the aqueous layer extracted with CH2Cl2 (2×100 mL. The combined organic layers were washed with sat. aq. NaHCO3 (100 mL) and brine (2×100 mL), dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, EtOAc:pet ether=1:2 to 2:3) to give the resulting aldehyde (2.85 g, 14.8 mmol, 75% yield from the alcohol) as a colorless oil. 1H NMR (500 MHz, CDCl3) δ=9.76 (t, J=1.7 Hz, 1H), 7.37-7.26 (m, 5H), 4.50 (s, 2H), 3.49 (t, J=6.2 Hz, 2H), 2.46 (td, J=7.2, 1.8 Hz, 2H), 1.79-1.71 (m, 2H), 1.70-1.61 (m, 2H) ppm; 13C NMR (125 MHz, CDCl3) δ=202.6, 138.7, 128.6, 127.84, 127.79, 73.2, 70.0, 43.8, 29.4, 19.2 ppm; LRMS (ESI+ve): 215 (M+Na+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][NH:6][C:7]1[C:12]([N+:13]([O-])=O)=[CH:11][CH:10]=[CH:9][N:8]=1)[CH3:2].[Cl:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[Cl:27])[C:21](Cl)=[O:22].C(N(CC)CC)C>O1CCCC1.[Pd]>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][NH:6][C:7]1[C:12]([NH:13][C:21](=[O:22])[C:20]2[CH:24]=[CH:25][C:26]([Cl:27])=[C:18]([Cl:17])[CH:19]=2)=[CH:11][CH:10]=[CH:9][N:8]=1)[CH3:2]
Reactant: CCOC(=O)CNc1ncccc1[N+](=O)[O-]
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)CNc1ncccc1NC(=O)c1ccc(Cl)c(Cl)c1
Reaction time: 8 h
Yield: 7.2 %

Procedure:
A solution of N-(3-nitro-2-pyridinyl)glycine ethyl ester (22.5 g, 0.1 mole) in 250 ml of tetrahydrofuran was hydrogenated in a small Parr bottle over 5% palladium on carbon (2.5 g) at room temperature for 1 hr. The reaction mixture was dried over magnesium sulfate and filtered through a Celite pad. Under nitrogen atmosphere, 3,4-dichlorobenzoyl chloride (20.95 g, 0.1 mole) and triethylamine (11.1 g, 0.11 mole) were added dropwise simultaneously to the above stirred filtrate at room temperature. After stirring overnight, the reaction mixture was filtered and the filtrate was evaporated to dryness. The residue was treated with acetone and water to obtain a crystalline solid, which was refrigerated overnight. The solid was collected by filtration, washed with water, and dried under high vacuum at 50° C. overnight (37.1 g). A 4-g sample was recrystallized from acetone/water and dried under high vacuum at 50° C. for 2 days to give 2.66 g of title compound, mp 137°-38° C.
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].[CH3:8][C:9]1[CH:10]=[C:11]([NH:21][C:22]2[N:27]=[C:26]([O:28][CH:29]3[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30]3)[CH:25]=[CH:24][N:23]=2)[CH:12]=[C:13]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:14]=1>ClCCl>[CH3:8][C:9]1[CH:10]=[C:11]([NH:21][C:22]2[N:27]=[C:26]([O:28][CH:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[CH:25]=[CH:24][N:23]=2)[CH:12]=[C:13]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:14]=1.[C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2]
Reactant: Cc1cc(Nc2nccc(OC3CCN(C(=O)OC(C)(C)C)CC3)n2)cc(-c2cccnc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(Nc2nccc(OC3CCNCC3)n2)cc(-c2cccnc2)c1
Reaction time: 2 h

Procedure:
TFA deprotection: 1:1 Dichloromethane:TFA (1.00 mL) solution was added to the isolated tert-butyl 4-[(2-{[3-methyl-5-(pyridin-3-yl)phenyl]amino}pyrimidin-4-yl)oxy]piperidine-1-carboxylate at room temperature and stirred for 2 hours. The reaction was concentrated under reduced pressure and the residue was purified by reverse phase chromatography (5-50% acetonitrile in water+0.05% TFA) to yield N-[3-methyl-5-(pyridin-3-yl)phenyl]-4-(piperidin-4-yloxy)pyrimidin-2-amine as a TFA salt. MS APCI calc'd for C21H24N5O [M+H]+ 362. found 362. 1H NMR (500 MHz, DMSO-d6) δ 9.67 (s, 1H), 8.91 (s, 1H), 8.65 (d, J=3.7 Hz, 1H), 8.47 (s, 2H), 8.25 (d, J=5.7 Hz, 1H), 8.19 (d, J=8.0 Hz, 1H), 7.87 (s, 1H), 7.71-7.61 (m, 1H), 7.59 (s, 1H), 7.17 (s, 1H), 6.31 (d, J=5.7 Hz, 1H), 5.24 (s, 1H), 3.19 (s, 2H), 2.97 (s, 2H), 2.36 (s, 2H), 2.09 (s, 3H), 1.90 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[S:24][CH:25]=[CH:26][C:27]=3[O:28][CH2:29][CH3:30])=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl.[C:33]([CH2:35][CH2:36][N:37]([CH3:47])[C:38](=[O:46])[CH2:39][N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)#[N:34]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20]([N:43]3[CH2:42][CH2:41][N:40]([CH2:39][C:38]([N:37]([CH2:36][CH2:35][C:33]#[N:34])[CH3:47])=[O:46])[CH2:45][CH2:44]3)=[O:21])[C:10]([C:23]3[S:24][CH:25]=[CH:26][C:27]=3[O:28][CH2:29][CH3:30])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CN(CCC#N)C(=O)CN1CCNCC1
Reactant: CCOc1ccsc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Agent: Cl
Product: CCOc1ccsc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N(C)CCC#N)CC1

Procedure:
2-{4-[(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-(3-ethoxy-thiophen-2-yl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 34) was reacted with N-(2-cyano-ethyl)-N-methyl-2-piperazin-1-yl-acetamide dihydrochloride to give 2-{4-[(4S,5R)-4,5-bis-(4-chloro-phenyl)-2-(3-ethoxy-thiophen-2-yl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-N-(2-cyano-ethyl)-N-methyl-acetamide in an analogous manner as described in example 1. LR-MS: 653.2 [(M+H)+].
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]2([C:24]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]([CH2:33][CH2:34][CH2:35][CH3:36])[C:25]=3[CH3:37])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:16](=[O:17])O2)=[C:6]1[CH3:38])[CH2:2][CH2:3][CH3:4].C(O)C.O.[NH2:43][NH2:44]>O>[CH2:1]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]2([C:24]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]([CH2:33][CH2:34][CH2:35][CH3:36])[C:25]=3[CH3:37])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:16](=[O:17])[NH:44][NH:43]2)=[C:6]1[CH3:38])[CH2:2][CH2:3][CH3:4]
Reactant: NN
Reactant: CCCCn1c(C)c(C2(c3c(C)n(CCCC)c4ccccc34)OC(=O)c3ccccc32)c2ccccc21
Solvent: CCO
Solvent: O
Product: CCCCn1c(C)c(C2(c3c(C)n(CCCC)c4ccccc34)NNC(=O)c3ccccc32)c2ccccc21
Yield: 92 %

Procedure:
With stirring, a mixture of 25.0 g of 3,3-bis(1-butyl-2-methylindol-3-yl)phthalide, 800.0 ml of ethyl alcohol, 200.0 ml of water and 29.4 g of 85 percent hydrazine hydrate was maintained at reflux temperature for approximately forty-eight hours. The resulting mixture was chilled in an external ice bath to a temperature in the range of 0°-5° C. The solid was collected by filtration, washed with chilled ethyl alcohol and dried in an air oven to obtain 23.65 g of 4,4-bis(1-butyl-2-methylindol-3-yl)-phthalazin-1(2H)-one (Formula V: R=R1 =R8 =R14 =H; R6 =R12 =C4H9 ; R7 =R13 =CH3), a pale orange-colored solid which melted at 205.5°-206.5° C. In the infrared spectrum maxima appeared at 3400 cm-1 (N-H;w) and 1670 cm-1 (C=O;s). The nuclear magnetic resonance spectrum was consistent with the assigned structure. Paper treated with an ink formulation of the product produced a purple-colored image when traced with an applied voltage stylus.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:13])[CH3:12])=[C:7]([OH:14])[C:6]=1[CH2:15][CH2:16][CH3:17])(=[O:3])[CH3:2].C(OC(=O)C)(=O)C.[N+:25]([O-])([OH:27])=[O:26]>C(O)(=O)C>[C:1]([NH:4][C:5]1[C:10]([N+:25]([O-:27])=[O:26])=[CH:9][C:8]([C:11](=[O:13])[CH3:12])=[C:7]([OH:14])[C:6]=1[CH2:15][CH2:16][CH3:17])(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CCCc1c(NC(C)=O)ccc(C(C)=O)c1O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CCCc1c(O)c(C(C)=O)cc([N+](=O)[O-])c1NC(C)=O

Procedure:
1-(4-Acetylamino-2-hydroxy-3-propylphenyl)ethanone (58.75 g) was suspended in glacial acetic acid (750 ml), and this suspension was treated with a mixture of glacial acetic acid (250 ml), acetic anhydride (48 ml) and conc. nitric acid (10.2 ml) with vigorous stirring. After 18 hours the insoluble material was collected and dried in vacuo to afford the title compound 29.1 g. The structure was confirmed by NMR and mass spectrometry.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][C:10]([C:13]3[CH:26]=[CH:25][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=4)=[CH:15][CH:14]=3)=[N:9]2)=[CH:4][CH:3]=1.Br[C:28]1([CH2:37][CH2:38][O:39][CH3:40])[C:33](=[O:34])[NH:32][C:31](=[O:35])[NH:30][C:29]1=[O:36]>>[CH3:40][O:39][CH2:38][CH2:37][C:28]1([O:24][C:21]2[CH:22]=[CH:23][C:18]([O:17][C:16]3[CH:25]=[CH:26][C:13]([C:10]4[CH:11]=[CH:12][N:8]([C:5]5[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=5)[N:9]=4)=[CH:14][CH:15]=3)=[CH:19][CH:20]=2)[C:29](=[O:36])[NH:30][C:31](=[O:35])[NH:32][C:33]1=[O:34]
Reactant: Oc1ccc(Oc2ccc(-c3ccn(-c4ccc(F)cc4)n3)cc2)cc1
Reactant: COCCC1(Br)C(=O)NC(=O)NC1=O
Product: COCCC1(Oc2ccc(Oc3ccc(-c4ccn(-c5ccc(F)cc5)n4)cc3)cc2)C(=O)NC(=O)NC1=O

Procedure:
By the same procedure as Example 1, Part C, 4-{4-[1-(4-Fluoro-phenyl)-1H-pyrazol-3-yl]-phenoxy}-phenol and 5-bromo-5-(2-methoxy-ethyl)-pyrimidine-2,4,6-trione (from Preparation 3B) were converted to the title compound. MS m/z: ESI+531.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:9]([C:13]2[NH:14][C:15](=[O:22])[NH:16][C:17](=[O:21])[C:18]=2[CH2:19][CH3:20])[C:10](=[O:12])[CH3:11])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[I-].[Li+].CS([CH2:29]/[CH:30]=[CH:31]/[CH3:32])(=O)=O>CN(C=O)C.CCOCC>[CH2:29]([N:14]1[C:13]([N:9]([C:4]2[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[CH:5]=2)[C:10](=[O:12])[CH3:11])=[C:18]([CH2:19][CH3:20])[C:17](=[O:21])[NH:16][C:15]1=[O:22])[CH:30]=[CH:31][CH3:32]
Reactant: C/C=C/CS(C)(=O)=O
Reactant: CCc1c(N(C(C)=O)c2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Agent: [I-]
Agent: [Li+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC=CCn1c(N(C(C)=O)c2cc(C)cc(C)c2)c(CC)c(=O)[nH]c1=O
Reaction time: 13 h
Yield: 40.9 %

Procedure:
To a stirred solution of N-(3,5-dimethyl-phenyl)-N-(5-ethyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidin-4-yl)-acetamide (109) (602 mg, 2 mmol) anhydrous powdered K2CO3 (276 mg, 2 mmol), and lithium iodide (268 mg, 2 mmol) in DMF (6 mL), was added 1-methanesulfonyl-trans-2-butene (283 μL, 2.4 mmol). After stirring for 13 hr., the reaction mixture was diluted with ether, washed with water, dried with MgSO4, filtered, and evaporated in vacuo. The residue was purified by silica gel column chromatography (eluent, ethyl acetate:hexane (1:1)) to afford 291 mg (40%) of a white solid. m.p. 218-220° C.; m/z (EI) 355(M+).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([S:10](Cl)(=[O:12])=[O:11])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21]([NH2:24])(=[O:23])=[O:22]>N1C=CC=CC=1>[S:21]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[NH:14][S:10]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[CH2:1][CH2:2][CH2:3]2)(=[O:12])=[O:11])(=[O:22])(=[O:23])[NH2:24]
Reactant: O=S(=O)(Cl)c1ccc2c(c1)CCC2
Reactant: Nc1ccccc1S(N)(=O)=O
Solvent: c1ccncc1
Product: NS(=O)(=O)c1ccccc1NS(=O)(=O)c1ccc2c(c1)CCC2
Reaction time: 8 h
Yield: 31.2 %

Procedure:
Indan-5-sulfonyl chloride (43 mg, 0.2 mmol) was added to a pyridine stock solution of 1.34M 2-amino-benzenesulfonamide (0.150 mL, 0.2 mmol). The reaction mixture was shaken overnight followed by solvent removal under vacuo. The crude mixture was dissolved in DMSO and purified by preparative HPLC (XTerra MS C8 column, acetonitrile/ammonium acetate buffer) to give the title compound (22 mg, 32%) as a white solid. MS m/z M−H 351. Rf 0.91 min (see above system in General procedure for Examples 23-43).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][CH2:12][CH:13]2[O:18][CH2:17][CH2:16][NH:15][CH2:14]2)=[O:10])=[CH:4][CH:3]=1.Cl[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:23][CH:22]=1>>[C:24]1([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:23]=[CH:22][C:21]([CH2:20][N:15]2[CH2:16][CH2:17][O:18][CH:13]([CH2:12][NH:11][C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[O:10])[CH2:14]2)=[CH:26][CH:25]=1
Reactant: O=C(NCC1CNCCO1)Nc1ccc(Cl)cc1
Reactant: ClCc1ccc(-c2ccccc2)cc1
Product: O=C(NCC1CN(Cc2ccc(-c3ccccc3)cc2)CCO1)Nc1ccc(Cl)cc1
Yield: 32.2 %

Procedure:
Example 30 was prepared in an analogous manner to Example 19 using a mixture of Intermediate 9 (0.01 g) and 4-(chloromethyl)-1,1′-biphenyl (0.0083 g) to give the title compound (0.0052 g). LC-MS (System A): Rt 2.95 mins, Mass Spectrum m/z 436 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([NH:12][C@@H:13]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)[C:14]([NH:16][CH2:17][C:18]([O:20]CC2C=CC=CC=2)=[O:19])=[O:15])=[O:11])=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([NH:12][C@@H:13]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)[C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(/C=C/c1ccc(Cl)cc1)N[C@@H](Cc1ccccn1)C(=O)NCC(=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CNC(=O)[C@H](Cc1ccccn1)NC(=O)/C=C/c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 94.1 %

Procedure:
To a suspension of benzyl {[(2S)-2-{[(2E)-3-(4-chlorophenyl)-2-propenoyl]amino}-3-(2-pyridyl)propanoyl]amino}-acetate (10.8 g) in methanol (200 ml) was added 1N aqueous sodium hydroxide solution (22.6 ml), and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated in vacuo, and the residue was treated with aqueous citric acid solution (10%, 100 ml). The resulting white precipitate was collected by filtration, washed with tetrahydrofuran-hexane (1:1, 150 ml), and dried in vacuo to give the title compound (8.25 g) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][C:10]2=O)=[CH:5][CH:4]=1.[CH3:14][NH:15][CH3:16]>C1(C)C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl.[Ti]>[CH3:14][N:15]([CH3:16])[C:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=2)[CH2:7][CH2:8][CH:9]=1
Reactant: CNC
Reactant: COc1ccc2c(c1)C(=O)CCC2
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Ti]
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)C(N(C)C)=CCC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.5 %

Procedure:
A solution of titanium tetrachloride (53.8 g, 31.2 ml) in dry toluene (200 ml) is added over a period of 45 minutes to a stirred solution of 7-methoxy-1-tetralone (100.5 g) and dimethyl amine (171 g) in dry toluene (2 l) while maintaining a reaction temperature of ≤10° C. When the addition of the titanium is complete, the ice bath is removed and the solution allowed to reach RT. The solution is stirred at RT for 3 hours. The solids are filtered, washed with dry toluene and the filtrate evaporated in vacuo, yielding 101.4 g of an amber oil which is used in the next step without further treatment.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][S:8][C:7]2[CH:11]=[CH:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][C:6]1=2)=[O:4].Cl.C(OCC)C.[NH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>O1CCOCC1.C(OCC)(=O)C.O>[N+:15]([C:13]1[CH:12]=[CH:11][C:7]2[S:8][CH2:9][CH2:10][N:5]([C:3](=[O:4])[CH2:2][N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)[C:6]=2[CH:14]=1)([O-:17])=[O:16]
Reactant: O=C(CCl)N1CCSc2ccc([N+](=O)[O-])cc21
Reactant: C1CCNC1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: O
Product: O=C(CN1CCCC1)N1CCSc2ccc([N+](=O)[O-])cc21
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 98 %

Procedure:
To a stirred solution of 2-chloro-1-(6-nitro-2H-benzo[b][1,4]thiazin-4(3H)-yl)ethanone (685 mg, 2.51 mmol) in dioxane (10 mL), cooled to 0° C. was added HCl, 1 M in diethyl ether (2.51 mL, 2.51 mmol) followed by pyrrolidine (0.21 mL, 2.51 mmol) dropwise. The resulting mixture was stirred at 0° C. for 5 minutes and then warmed to room temperature, stirring overnight. At this time, additional pyrrolidine (0.21 mL, 2.51 mmol) was added, followed by water (1 mL) to aid dissolution. After 1 hour of stirring at room temperature, the mixture was then diluted with ethyl acetate and washed with saturated sodium carbonate, water (3×), and brine. The organic phase was dried, filtered, and concentrated, giving a yellow/orange oil (756 mg, 98%). 1H NMR (DMSO-d6) δ 8.52 (brs, 1H), 7.93 (dd, J=9.0, 1.6 Hz, 1H), 7.49 (d, J=9.0 Hz, 1H), 4.01-3.91 (m, 4H), 3.56 (s, 2H), 3.45-3.35 (m, 2H), 2.55-2.50 (m, 2H), 2.22-2.14 (m, 4H); ESI-MS (m/z, %): 308 (MH+, 100).
Reaction SMILES: [Si:1](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]([O:26][C:27]1[CH:42]=[CH:41][C:30]([C:31]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:32])=[CH:29][C:28]=1[OH:43])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.N1C=CN=C1.O>ClCCl>[Si:1]([O:43][C:28]1[CH:29]=[C:30]([CH:41]=[CH:42][C:27]=1[O:26][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: O=C(OCc1ccccc1)c1ccc(OCc2ccccc2)c(O)c1
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)[Si](Oc1cc(C(=O)OCc2ccccc2)ccc1OCc1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 8 h
Yield: 116.3 %

Procedure:
A solution of tert-butyldiphenylsilyl chloride (850 mg, 3.09 mmol) in dichloromethane (10 cm3+5 cm3 rinse) was added to a stirred solution of benzyl 4-benzyloxy-3-hydroxybenzoate (827 mg, 2.47 mmol) and imidazole (421 mg, 6.18 mmol) in dichloromethane (15 cm3). After a few minutes a precipitate formed. The mixture was stirred overnight under an atmosphere of nitrogen, then was poured into water (50 cm3) The layers were shaken and separated, then the aqueous phase was further extracted with dichloromethane (2×50 cm3). The combined extracts were washed with brine (50 cm3) and evaporated to a pale yellow oil. This was filtered through a short silica column and eluted with 20% ethyl acetate in petroleum ether. Evaporation of the filtrate gave benzyl 3-(tert-butyldiphenylsilyloxy)-4-benzyloxybenzoate (1.646 g) as a very pale yellow oil, containing some tert-butyldiphenyl-silanol, which was used directly for the next step.
Reaction SMILES: [C:1]([C:3]1[CH:15]=[CH:14][C:6]2[O:7][CH2:8][C:9]([CH3:13])([CH3:12])[CH2:10][O:11][C:5]=2[CH:4]=1)#[CH:2].[CH2:16]([O:18][C:19](=[O:27])[C:20]1[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=1)[CH3:17].C(NC(C)C)(C)C.O=[Si]=O>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.CCOC(C)=O.C1COCC1>[CH2:16]([O:18][C:19](=[O:27])[C:20]1[CH:25]=[CH:24][C:23]([C:2]#[C:1][C:3]2[CH:15]=[CH:14][C:6]3[O:7][CH2:8][C:9]([CH3:12])([CH3:13])[CH2:10][O:11][C:5]=3[CH:4]=2)=[CH:22][CH:21]=1)[CH3:17]
Reactant: CCOC(=O)c1ccc(Br)cc1
Reactant: C#Cc1ccc2c(c1)OCC(C)(C)CO2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: O=[Si]=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)OCC(C)(C)CO3)cc1
Temperature: 57 °C
Yield: 43.7 %

Procedure:
To a mixture under Ar of 7-ethynyl-3,3-dimethyl-3,4-dihydro-2H-benzo[b][1,4]dioxepine (6) (1.0 g), ethyl-4-bromobenzoate (1.13 g), [PdCl2(PPh3)2] (174 mg) and copper(I) iodide (94 mg) is added a degassed solution of diisopropylamine (20 ml) and THF (20 ml). The reaction mixture is stirred over night at 57° C. After addition of AcOEt (100 ml) and filtration over dicalite, the solution is washed with 1 N aq. HCl sol. (3×50 ml) and H2O (3×50 ml). The organic layer is dried over MgSO4 and the solvent is evaporated. The crude product is purified by flash chromatography (silica gel, heptane/AcOEt 9:1) followed by preparative HPLC. 756 mg of 4-(3,3-dimethyl-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-ylethynyl)-benzoic acid ethyl ester are obtained as a white solid, MS (ESI) 350.2 (M•)+.