Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:13][CH3:14])=[C:8]([CH:12]=1)[C:9]([OH:11])=O)#[N:2].CN(C)C=O.[F:20][C:21]([F:31])([F:30])[C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1.C(P(=O)(OCC)OCC)#N>O.C(N(CC)CC)C>[C:1]([CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:13][CH3:14])=[C:8]([CH:12]=1)[C:9]([NH:27][CH2:26][C:25]1[CH:24]=[CH:23][C:22]([C:21]([F:20])([F:30])[F:31])=[CH:29][CH:28]=1)=[O:11])#[N:2]
Reactant: COc1ccc(CC#N)cc1C(=O)O
Reactant: NCc1ccc(C(F)(F)F)cc1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CC#N)cc1C(=O)NCc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To 2.55 g of publicly known 5-cyanomethyl-2-methoxybenzoic acid were added 50 ml of dimethylformamide, 2.57 g of 4-trifluoromethylbenzylamine, 2.66 g of diethyl cyanophosphonate and 2.00 ml of triethylamine, and the mixture was stirred for 20 minutes under cooling with ice and for 6 hours at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. After washed with water, then with saturated brine, the organic layer was dried over anhydrous sodium sulfate. Solvent was distilled off under reduced pressure, and the residue was crystallized from hexane-diethyl ether and collected by filtration to obtain 4.44 g of 5-cyanomethyl-2-methoxy-N-(4-trifluoromethylbenzyl)benzamide as colorless crystals. Melting point 124-125° C. Elemental analysis (%) C16H15F3N2O2 Calcd.(%) C, 62.07; H, 4.34; N, 8.04 Found (%) C, 62.03; H, 4.27; N, 7.99
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH:15]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Br:25])[CH:20]=2)[C:16](O)=[O:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:26][C:27]1[C:32]([F:33])=[C:31]([F:34])[CH:30]=[C:29]([NH2:35])[C:28]=1[NH2:36].[I-].ClC1C=CC=C[N+]=1C.C(N(C(C)C)CC)(C)C>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH:15]([C:16](=[O:17])[NH:36][C:28]2[C:29]([NH2:35])=[CH:30][C:31]([F:34])=[C:32]([F:33])[C:27]=2[F:26])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Br:25])[CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: Nc1cc(F)c(F)c(F)c1N
Reactant: CC(C)(C)OC(=O)N1CCC(OC(C(=O)O)c2cccc(Br)c2)CC1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(OC(C(=O)Nc2c(N)cc(F)c(F)c2F)c2cccc(Br)c2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-[(3-bromophenyl)carboxymethoxy]piperidine-1-carboxylic acid tert-butyl ester (general procedure 165D+saponification)(1 g) in acetonitrile (10 mL) are added 3,4,5-trifluorobenzene-1,2-diamine (470 mg), 2-chloro-1-methylpyridinium iodide (802 mg) and dropwise diisopropylethylamine (1.1 mL). The reaction mixture is stirred at room temperature for 2 hours. Solvent is removed under reduced pressure and the residue diluted with ethyl acetate. The organic phase is washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography over silica gel (gradient dichloromethane/methanol/ammonia from 98/2/0.2 to 90/10/1) to get 4-[(6-amino-2,3,4-trifluorophenylcarbamoyl)(3-bromophenyl)methoxy]piperidine-1-carboxylic acid tert-butyl ester. This intermediate is dissolved in acetic acid (15 mL) and the reaction mixture is refluxed for 3 hours. Acetic acid is removed under reduced pressure. Water is added to the residue and the solution is basified by adding a solution of saturated sodium hydrogencarbonate to pH 10. The aqueous phase is extracted with ethyl acetate. The pooled organic extracts are dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography over silica gel (gradient dichloromethane/methanol/ammonia from 98/2/0.2 to 90/10/1) to yield 2-[(3-bromophenyl)(piperidin-4-yloxy)methyl]-5,6,7-trifluoro-1H-benzimidazole.
Reaction SMILES: Br[C:2]1[C:12]2[C:13]3[C:5]([CH2:6][CH2:7][C:8]=3[CH:9]=[CH:10][CH:11]=2)=[CH:4][CH:3]=1.CCCCCC.C([Li])CCC.C([O:28][B:29](OC(C)C)[O:30]C(C)C)(C)C.Cl>C1(C)C=CC=CC=1.CCOCC>[CH2:7]1[C:8]2=[C:13]3[C:12](=[CH:11][CH:10]=[CH:9]2)[C:2]([B:29]([OH:30])[OH:28])=[CH:3][CH:4]=[C:5]3[CH2:6]1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Brc1ccc2c3c(cccc13)CC2
Agent: Cl
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: CCOCC
Product: OB(O)c1ccc2c3c(cccc13)CC2
Yield: 45 %

Procedure:
Commercially available 5-bromo acenaphthene in an amount of 11.7 g was dissolved into a mixed solution of dehydrated toluene in an amount 50 milliliter and dehydrated ether in an amount of 50 milliliter, and the resultant solution was cooled down to −40° C. under an atmosphere of argon gas. Thirty five milliliter of 1.6M-normal butyllithium hexane solution was dripped into the resultant solution, followed by elevating the temperature up to −10° C. Two hours later, the resultant solution was cooled down to −70° C. and further, another solution prepared by dissolving triisopropoxyborane in an amount of 35 milliliter into 50 milliliter of ether was dripped into the solution. After stirring the resultant solution for 3 hours at the temperature of −70° C., it was left standing for one night. After the night, the resultant solution was acidified in a dilute hydrochloric acid of 10% by weight and an organic layer was extracted with the use of toluene. Washing with the use of both dilute hydrochloric acid and a saturated sodium chloride solution, the organic layer was dried with anhydrous sodium sulfate, and the organic solvent was distillated by means of an evaporator. Crystallizing the residues with the use of toluene/hexane, 4.5 g of 5-acenaphthene boronic acid was obtained (yield: 45%).
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][C@H:3]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[NH:2]1.C(N(CC)CC)C.[C:26](=[S:28])=[S:27].[C:29]1([CH2:34]Cl)[S:33][CH:32]=[CH:31][CH:30]=1>C(O)C>[C:29]1([CH2:34][S:27][C:26]([N:2]2[C@@H:3]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:4][C:5]3[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[NH:12][C:13]=3[CH2:1]2)=[S:28])[S:33][CH:32]=[CH:31][CH:30]=1
Reactant: CCOC(=O)[C@H]1Cc2c([nH]c3ccccc23)CN1
Reactant: S=C=S
Reactant: ClCc1cccs1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)[C@H]1Cc2c([nH]c3ccccc23)CN1C(=S)SCc1cccs1
Yield: 63 %

Procedure:
In the same manner as described in Example 53, ethyl (3R)-1,2,3,4-tetrahydro-β-carboline-3-carboxylate (2.24 g), triethylamine (1.25 g), carbon disulfide (0.76 ml), ethanol (50 ml) and 2-thenyl chloride (1.65 g) are reacted and treated. The product is recrystallized from ethyl acetate-n-hexane to give the title compound (2.60 g, 63%) as colorless needles, m.p. 205°-207° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5](B2OC(C)(C)C(C)(C)O2)[CH:4]=[N:3]1.Cl[C:17]1[CH:22]=[C:21]([O:23][C:24]2[CH:25]=[CH:26][C:27]([C:31]3[C:32]([O:39][CH3:40])=[N:33][C:34]([S:37][CH3:38])=[N:35][CH:36]=3)=[N:28][C:29]=2[CH3:30])[CH:20]=[CH:19][N:18]=1.C([O-])([O-])=O.[K+].[K+]>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.O1CCOCC1.O>[CH3:40][O:39][C:32]1[C:31]([C:27]2[CH:26]=[CH:25][C:24]([O:23][C:21]3[CH:22]=[CH:17][N:18]=[C:19]([C:5]4[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=4)[CH:20]=3)=[C:29]([CH3:30])[N:28]=2)=[CH:36][N:35]=[C:34]([S:37][CH3:38])[N:33]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: COc1nc(SC)ncc1-c1ccc(Oc2ccnc(Cl)c2)c(C)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1nc(SC)ncc1-c1ccc(Oc2ccnc(-c3cnn(C)c3)c2)c(C)n1
Temperature: 90 °C
Yield: 98 %

Procedure:
A mixture of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.30 g, 1.44 mmol), 5-(5-((2-chloropyridin-4-yl)oxy)-6-methylpyridin-2-yl)-4-methoxy-2-(methylthio)pyrimidine (0.49 g, 1.31 mmol), and K2CO3 (0.54 g, 3.92 mmol) in 5:1 dioxane/water (18 mL) was sparged with Ar, treated with Pd(PPh3)4 (0.15 g, 0.13 mmol), sparged again with Ar and heated at 90° C. for 4 h. The mixture was cooled to RT, treated with satd. NaHCO3, extracted with EtOAc (3×) and the combined organics were dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to obtain 4-methoxy-5-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-(methylthio)pyrimidine (0.54 g, 98%). 1H NMR (400 MHz, DMSO-d6): δ 8.93 (s, 1H), 8.39 (d, J=5.7 Hz, 1H), 8.28 (s, 1H), 7.99 (d, J=0.7 Hz, 1H), 7.88 (d, J=8.5 Hz, 1H), 7.65 (d, J=8.6 Hz, 1H), 7.30 (d, J=2.4 Hz, 1H), 6.66 (dd, J=5.7, 2.4 Hz, 1H), 4.06 (s, 3H), 3.85 (s, 3H), 2.58 (s, 3H), 2.42 (s, 3H); MS (ESI) m/z: 421.1 (M+H+).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([C:13]([C:28]4[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=4)=[C:14](/[CH:16]=[CH:17]/[C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)[N:15]=3)[N:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1.N1C=CC=CC=1.[CH3:41][S:42](Cl)(=[O:44])=[O:43]>C(Cl)Cl>[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[C:8]3[N:9]([C:13]([C:28]4[CH:29]=[CH:30][C:31]([NH:32][S:42]([CH3:41])(=[O:44])=[O:43])=[CH:33][CH:34]=4)=[C:14](/[CH:16]=[CH:17]/[C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)[N:15]=3)[N:10]=[CH:11][CH:12]=2)[CH2:5][CH2:6]1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(-c2c(/C=C/c3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc(-c2c(/C=C/c3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a mixture of compound 10b (66 mg, 0.15 mmol) and pyridine (24 μL, 0.29 mmol) in DCM (5 mL) was added methanesulfonyl chloride (23 μL, 0.29 mmol). The resulting mixture was stirred at rt for 3 days. The mixture was then diluted with DCM (20 mL), and washed with 1 N HCl solution and brine. The organic layer was dried over MgSO4, filtered, and concentrated. The orange solid obtained was washed with methanol (2×5 mL), and dried in vacuo to give the title compound 47. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 10.09-10.17 (m, 1H), 8.64-8.83 (br.s., 1H), 8.25 (br.s, 1H), 8.06-8.22 (m, 3H), 7.83-8.06 (m, 3H), 7.63-7.80 (m, 3H), 7.36-7.48 (m, 2H), 6.46 (d, J=5.9 Hz, 1H), 4.04-4.18 (m, 4H), 3.79-3.97 (m, 4H), 3.14 (s, 3H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C28H26N6O3S: 527.2 (M+H). Found 527.1.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:22]([CH2:23][C:24]([OH:26])=O)[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[N:15]=2)=[CH:10][CH:9]=1.[C:27]1([NH:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N(CC)CC)C>CN(C)C=O.O>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[N:22]([CH2:23][C:24]([N:33]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:26])[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[N:15]=2)=[CH:12][CH:13]=1
Reactant: c1ccc(Nc2ccccc2)cc1
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(Cn1c(-c2ccc(Cl)cc2)nc2cccnc21)N(c1ccccc1)c1ccccc1
Temperature: 60 °C
Yield: 70.1 %

Procedure:
Under a nitrogen atmosphere, oxalyl chloride (1.73 g, 0.0137 mole) was added dropwise, slowly, to a stirred and chilled (10° C.) solution of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (3.7 g, 0.013 mole) in anhydrous dimethylformamide (50 ml). The reaction mixture was heated at 60° C. for 4 hr under nitrogen, cooled and added dropwise to a stirred and chilled (10° C.) solution of diphenylamine (2.37 g, 0.014 mole) and triethylamine (1.42 g, 0.014 mole) in anhydrous dimethylformamide (75 ml). The reaction mixture was stirred at room temperature overnight and then poured into water (400 ml). The mixture was extracted with ethyl acetate (2×75 ml). The aqueous layer was saturated with sodium chloride and extracted again with ethyl acetate (75 ml). The combined organic layers were washed with 5% potassium hydroxide solution (2×50 ml), water (50 ml) and saturated sodium chloride solution (50 ml). The combined layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give 4.0 g of an oil (70%). The oil was crystallized from isopropyl ether-isopropyl alcohol to give 2.2 g (39%) of a white solid, mp. 176°-178° C.
Reaction SMILES: [Br:1]Br.[CH2:3]([O:5][C:6]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH3:19])=[CH:13][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:4]>C(O)(=O)C>[Br:1][C:15]1[C:14]([O:17][CH2:18][CH3:19])=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([O:5][CH2:3][CH3:4])[CH:16]=1
Reactant: BrBr
Reactant: CCOC(=O)c1cc(OCC)ccc1OCC
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(OCC)c(Br)cc1OCC
Reaction time: 1 h
Yield: 31.9 %

Procedure:
A solution of bromine (0.338 mL, 6.60 mmol) in acetic acid (6 mL) was added dropwise to a mixture of ethyl 2,5-diethoxybenzoate (1.36 mL, 6.02 mmol) and acetic acid (24 mL) cooled in a water bath. After stirring 1 h, more bromine (0.102 mL, 1.99 mmol) was added dropwise to the reaction mixture. After stirring an additional 4 h, the reaction mixture was concentrated under reduced pressure and the residue was purified by flash column chromatography (eluting with 10% diethyl ether in hexanes) to give ethyl 4-bromo-2,5-diethoxybenzoate as an off-white solid (0.610 g, 32%).
Reaction SMILES: N1C=CC=CC=1NC1C=CC=CC=1N.CC(C)C=CC([Cl:21])=O.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[N:31]=[C:30]1/[CH:38]=[CH:39]/[C:40]1[CH:45]=CC=C[CH:41]=1.Cl>CO>[ClH:21].[CH3:41][CH:40]([CH3:45])/[CH:39]=[CH:38]/[C:30]1[N:29]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=2)[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[N:31]=1
Reactant: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Reactant: CC(C)C=CC(=O)Cl
Agent: Cl
Agent: Nc1ccccc1Nc1ccccn1
Solvent: CO
Product: CC(C)/C=C/c1nc2ccccc2n1-c1ccccn1

Procedure:
Free base of the titled compound was prepared from N-(2-pyridyl)-o-phenylenediamine and 4-methyl-2-pentenoyl chloride (Yamada, T.; Takashima, K.; Miyazawa, T.; Kuwata, S.; Watanabe, H. Bull. Chem. Soc. Jpn. 1978, 51, 878) according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method A). The free base was treated with a 10% methanol solution of hydrogen chloride and concentrated to dryness. The residue was recrystallized from ethyl acetate/n-hexane to give the titled compound.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([Br:9])[C:3]=1[O:10][CH3:11].[C:12]1([CH2:18][SH:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CCN(C(C)C)C(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:18]([S:19][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([Br:9])[C:3]=1[O:10][CH3:11])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COc1c(Br)cc(F)cc1Br
Reactant: SCc1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(Br)cc(F)cc1SCc1ccccc1

Procedure:
1,3-Dibromo-5-fluoro-2-methoxy-benzene (14.2 g, 50 mmol), phenyl-methanethiol (5.86 ml, 50 mmol), Pd2dba3 (1.145 g, 1.25 mmol, 2.5 mol-%), Xantphos (1.447 g, 2.5 mmol, 5 mol-%) and DIPEA (17.5 ml, 100 mmol) were dissolved in 130 ml dry, degassed 1,4-dioxane and heated to reflux for 3 h. After cooling down the mixture was filtrated and evaporated. The remaining solid (22 g) is chromatographed on silica gel using n-heptane-MTBE as eluent. Yield: 12.42 g, 76%.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1.[N:16]1([CH2:22][CH:23]2[N:28]3[C:29]([CH3:35])=[CH:30][C:31]4[CH:32]=[CH:33][CH:34]=[C:26]([C:27]=43)[O:25][CH2:24]2)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>C(Cl)Cl>[N:16]1([CH2:22][CH:23]2[N:28]3[C:29]([CH3:35])=[C:30]([C:11](=[O:12])[C:10]4[CH:14]=[CH:15][C:7]([O:6][CH3:5])=[CH:8][CH:9]=4)[C:31]4[CH:32]=[CH:33][CH:34]=[C:26]([C:27]=43)[O:25][CH2:24]2)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: Cc1cc2cccc3c2n1C(CN1CCOCC1)CO3
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(=O)c2c(C)n3c4c(cccc24)OCC3CN2CCOCC2)cc1
Temperature: 0 °C
Yield: 47.6 %

Procedure:
To a suspension of 7.5 g (0.056 mole) of aluminum chloride in 100 ml of methylene dichloride (MDC) was added, rapidly with stirring, a solution of 6.2 ml (0.038 mole) of 4-methoxybenzoyl chloride. When addition was complete the mixture was stirred for one hour at room temperature and the resulting solution then added dropwise over a ten minute period with stirring to a solution of 8.5 g (0.031 mole) of 3-(4-morpholinylmethyl)-5-methyl-2,3-dihydropyrrolo[1,2,3-de]-1,4-benzoxazine in 100 ml of MDC. The resulting mixture was then heated under reflux for thirty minutes, cooled and poured into 300 ml of ice water with stirring. The organic solvent was removed in vacuo, and the residual aqueous medium was diluted with ethyl acetate and neutralized by the addition of saturated aqueous sodium bicarbonate. The organic layer was separated, dried over magnesium sulfate, filtered through silica, taken to dryness in vacuo and chromatographed. There was thus obtained about 7 g of crude product which was recrystallized from ethyl acetate/hexane to give 6.0 g of 3-(4-morpholinylmethyl)-5-methyl-6-(4-methoxybenzoyl)2,3-dihydropyrrolo[1,2,3-de]-1,4-benzoxazine, m.p. 182°-189° C.
Reaction SMILES: [CH:1]([O:4][CH:5]1[CH2:10][CH2:9][C:8]([C:11]2[O:15][N:14]=[C:13]([C:16]([OH:18])=O)[C:12]=2[CH3:19])=[CH:7][CH2:6]1)([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:44][C:45]1[C:46](=[O:58])[N:47]([CH:52]2[CH2:57][CH2:56][CH2:55][CH2:54][CH2:53]2)[N:48]([CH3:51])[C:49]=1[CH3:50].C(N(CC)CC)C>CN1C(=O)CCC1>[CH:52]1([N:47]2[C:46](=[O:58])[C:45]([NH:44][C:16]([C:13]3[C:12]([CH3:19])=[C:11]([C:8]4[CH2:9][CH2:10][CH:5]([O:4][CH:1]([CH3:2])[CH3:3])[CH2:6][CH:7]=4)[O:15][N:14]=3)=[O:18])=[C:49]([CH3:50])[N:48]2[CH3:51])[CH2:53][CH2:54][CH2:55][CH2:56][CH2:57]1
Reactant: Cc1c(N)c(=O)n(C2CCCCC2)n1C
Reactant: Cc1c(C(=O)O)noc1C1=CCC(OC(C)C)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: Cc1c(C(=O)Nc2c(C)n(C)n(C3CCCCC3)c2=O)noc1C1=CCC(OC(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 5-(4-isopropoxycyclohex-1-en-1-yl)-4-methylisoxazole-3-carboxylic acid (174 mg, 0.656 mmol) in dry NMP (3 mL), HATU (274 mg, 0.721 mmol) was added followed by 4-amino-2-cyclohexyl-1,5-dimethyl-1H-pyrazol-3(2H)-one (Intermediate D) (151 mg, 0.721 mmol) and triethylamine (0.201 mL, 1.443 mmol). The mixture was stirred at room temperature overnight. The resulting mixture was partitioned between EtOAc (20 mL) and 1M NaOH (aq) (20 mL) and the organic phase was washed with water (30 mL), brine (30 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was dissolved in DMSO and purified using a UV-directed reverse phase chromatography with a gradient of 40-80% MeCN in water (0.1% formic acid) over 9.5 minutes. The product fraction was added to EtOAc (50 mL) and washed with a saturated aqueous NaHCO3 solution (50 mL). The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure to afford the title compound;
Reaction SMILES: [CH3:1][C:2]1[C:7](=[O:8])[C@@H:6]([OH:9])[CH2:5][C:4]([CH3:11])([CH3:10])[C:3]=1[CH:12]=[CH:13][C:14]([CH3:18])=[CH:15][CH:16]=[O:17].N1C=CC=CC=1.[Cl:25][CH2:26][C:27](Cl)=[O:28].O>C(OCC)C>[CH3:1][C:2]1[C:7](=[O:8])[C@@H:6]([O:9][C:27](=[O:28])[CH2:26][Cl:25])[CH2:5][C:4]([CH3:10])([CH3:11])[C:3]=1[CH:12]=[CH:13][C:14]([CH3:18])=[CH:15][CH:16]=[O:17]
Reactant: O=C(Cl)CCl
Reactant: CC(C=CC1=C(C)C(=O)[C@@H](O)CC1(C)C)=CC=O
Solvent: CCOCC
Solvent: c1ccncc1
Solvent: O
Product: CC(C=CC1=C(C)C(=O)[C@@H](OC(=O)CCl)CC1(C)C)=CC=O
Reaction time: 1 h

Procedure:
13 grams of 5-[2,6,6-trimethyl-oxo-4(S)-hydroxy-cyclohex-1-en-1-yl]-3-methyl-penta-2,4-dien-1-al (XIII) are dissolved in 200 ml of diethyl ether. 20 ml of pyridine are added to the solution at 0° C. and 12 g of chloroacetic acid chloride are then added dropwise. The mixture is stirred for 1 hour and then poured into water and extracted with diethyl ether. The 5-[2,6,6-trimethyl-3-oxo-4(S)-(chloroacetoxy)-cyclohex-1-en-1-yl]-3-methyl-penta-2,4-dien-1-al is isolated from the ether extract (IIA).
Reaction SMILES: O=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]([C:12]([O:14][CH3:15])=[O:13])=[CH:3]1.C1(P([N:30]=[N+:31]=[N-:32])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>CN(C)C=O>[N:30]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:3]=1)=[N+:31]=[N-:32]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1cc(=O)c2ccccc2[nH]1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1cc(N=[N+]=[N-])c2ccccc2n1
Temperature: 100 °C

Procedure:
A solution of the compound prepared in Example 272 (0.032 g) in N,N-dimethylformamide (1 mL) was treated with diphenyl phosphoryl azide (0.037 mL), followed by triethylamine (0.028 mL) at room temperature. The mixture was heated at 100° C. overnight. The solvent was evaporated in vacuo and the resulting oil was purified by column chromatography on silica gel (1-10% diethyl ether in dichloromethane) to obtain the title compound (0.016 g) having the following physical data.
Reaction SMILES: [CH2:1]([N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)[C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1.P(Cl)(Cl)Cl.[NH2:21][C:22]1[S:23][C:24]([C:30]2[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=2)=[C:25]([C:27](O)=[O:28])[N:26]=1>N1C=CC=CC=1>[NH2:21][C:22]1[S:23][C:24]([C:30]2[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=2)=[C:25]([C:27]([N:14]2[CH2:15][CH2:16][N:11]([CH2:1][C:2]3[CH:10]=[CH:9][C:8]4[O:7][CH2:6][O:5][C:4]=4[CH:3]=3)[CH2:12][CH2:13]2)=[O:28])[N:26]=1
Reactant: Nc1nc(C(=O)O)c(-c2ccncc2)s1
Reactant: c1cc2c(cc1CN1CCNCC1)OCO2
Solvent: ClP(Cl)Cl
Solvent: c1ccncc1
Product: Nc1nc(C(=O)N2CCN(Cc3ccc4c(c3)OCO4)CC2)c(-c2ccncc2)s1
Temperature: 80 °C
Reaction time: 3 h
Yield: 19 %

Procedure:
To a mixture of 1-piperonylpiperazine (2.72 g) and phosphorus trichloride (0.49 ml) in pyridine (20 ml) was added 2-amino-5-(4-pyridyl)-4-thiazolecarboxylic acid (1.24 g) and the mixture was stirred at 80° C. for 3 hours. The reaction mixture was evaporated in vacuo and the residue was dissolved in a mixture of ethyl acetate and water. The resultant mixture was adjusted to pH 8.0 with saturated aqueous potassium carbonate. The organic extract was dried over magnesium sulfate. The solvent was evaporated in vacuo to give a crystalline residue, which was recrystallized from ethyl acetate to afford 2-amino-5-(4-pyridyl)-4-[(4-piperonyl-1-piperazinyl)carbonyl]thiazole (0.45 g). mp 216°-217° C.