Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22]([NH:24][CH2:25][C:26]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:27]=1[C:28]([O:30]C)=[O:29])=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC#N.[OH-].[Na+]>CO>[CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22]([NH:24][CH2:25][C:26]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:27]=1[C:28]([OH:30])=[O:29])=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(F)ccc1CNC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCOC2(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CO
Product: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1C(=O)O)c(OCc1ccccc1)c2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 19 %

Procedure:
To a suspension of intermediate 154, methyl 2-((3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamido)methyl)-5-fluorobenzoate. (500 mg, 1.01 mmol) in MeOH (10 mL) and CH3CN (5 mL) was added 1N NaOH (2 mL) and the mixture stirred at room temperature for 2 hrs. The mixture was concentrated in vacuo and the residue purified by reverse phase column chromatography (YMC, C-18 ODS, 10-25% CH3CN/H2O) to provide 90 mg (Yield 19%) of the title compound as an off-white powder: LC/MS m/z 482 (M+H).
Reaction SMILES: CC(C[AlH]CC(C)C)C.[NH2:10][C:11]1[N:16]=[C:15]([NH:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:14]([CH2:22][C:23]2[CH:32]=[CH:31][C:26]([C:27](OC)=[O:28])=[CH:25][C:24]=2[O:33][CH3:34])=[C:13]([CH3:35])[N:12]=1.C(O)(C)C.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1.C(Cl)Cl>[NH2:10][C:11]1[N:16]=[C:15]([NH:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:14]([CH2:22][C:23]2[CH:32]=[CH:31][C:26]([CH2:27][OH:28])=[CH:25][C:24]=2[O:33][CH3:34])=[C:13]([CH3:35])[N:12]=1
Reactant: CCCCNc1nc(N)nc(C)c1Cc1ccc(C(=O)OC)cc1OC
Agent: CC(C)C[AlH]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CC(C)O
Product: CCCCNc1nc(N)nc(C)c1Cc1ccc(CO)cc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of DIBAL-H (80 ml, 1M in hexanes) was added portion wise over 20 min to a stirred solution of the product from step (ii) (3.8 g) in THF (25 mL) at 0° C. The mixture was allowed to warm to rt, stirred for 2 h, then cooled to 0° C. Isopropanol (2 mL) was added, stirred for 10 min and then added to a saturated solution of sodium sulfate (50 mL). The mixture was diluted with DCM (100 mL) and then stirred for 1 h. The organic phase was separated and the aqueous was extracted with DCM. The combined organic extracts were dried and filtered. The crude product was purified via silica chromatography (10% MeOHIDCM) to give the subtitle compound as a cream solid, 2.2 g.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:10]=3[NH:11][C:12](=[O:15])[CH2:13][N:14]=2)=[CH:4][CH:3]=1.[Cl:24][C:25]1[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[C:26]=1[C:27](Cl)=[O:28].NC1C=CC(N2C(=O)CC(=O)NC3C(CC)=CC=CC2=3)=CC=1>>[Cl:24][C:25]1[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[C:26]=1[C:27]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:10]=3[NH:11][C:12](=[O:15])[CH2:13][N:14]=2)=[CH:6][CH:7]=1)=[O:28]
Reactant: Nc1ccc(C2=NCC(=O)Nc3c2ccc2ccccc32)cc1
Reactant: COc1cccc(Cl)c1C(=O)Cl
Agent: CCc1cccc2c1NC(=O)CC(=O)N2c1ccc(N)cc1
Product: COc1cccc(Cl)c1C(=O)Nc1ccc(C2=NCC(=O)Nc3c2ccc2ccccc32)cc1
Yield: 83.5 %

Procedure:
By using 5-(4-aminophenyl)-1,3-dihydronaphtho[1,2-e]-1,4-diazepin-2-one (40 mg, 0.13 mmol) obtained in Example 64, and 2-chloro-6-methoxybenzoyl chloride (0.2 mmol), the title compound (51 mg, yield 54%) was obtained in the same manner as that of Example 1, (4).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:6][N:5]=1)([O-])=O.[H][H]>C(O)C.[Pd]>[O:10]([C:7]1[CH:8]=[CH:9][C:4]([NH2:1])=[N:5][CH:6]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccccc2)cn1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(Oc2ccccc2)cn1
Reaction time: 18 h
Yield: 96.2 %

Procedure:
2-Nitro-5-phenoxy-pyridine (262 mg) was dissolved in dry ethanol (12 mL) and 10% palladium on charcoal (90 mg) was added. A hydrogen atmosphere was introduced by repeated evacuation/hydrogen introduction. The mixture was then allowed to stir for 18 hours. The catalyst was removed by filtration through celite and the filtrate was concentrated in vacuo to give 5-phenoxy-pyridin-2-ylamine (217 mg) as a yellow foam. This material was used without further purification. MS (EI): 186.1 (M+).
Reaction SMILES: I[C:2]1[Se:3][CH:4]=[CH:5][CH:6]=1.[F:7][C:8]([F:20])([F:19])[O:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)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>[F:7][C:8]([F:19])([F:20])[O:9][C:10]1[CH:15]=[CH:14][C:13]([C:2]2[Se:3][CH:4]=[CH:5][CH:6]=2)=[CH:12][CH:11]=1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: Ic1ccc[se]1
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: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: FC(F)(F)Oc1ccc(-c2ccc[se]2)cc1

Procedure:
A mixture of 15.1 g (58.7 mmol) of 2-iodoselenophene, 13.9 g (67.7 mmol) of 4-trifluoromethoxyphenylboronic acid, 3.90 g (3.38 mmol) of tetrakis(triphenylphosphine)palladium(0) and 150 ml of 2 N sodium carbonate soln. in 400 ml of toluene/ethanol (1:1) is heated under reflux for 23 h. After cooling, the organic phase is separated off, and the aqueous phase is extracted a number of times with MTBE. The combined organic phases are washed with 1 N hydrochloric acid and sat. sodium chloride soln. The solution is dried using sodium sulfate and concentrated to dryness. The residue is purified by column chromatography (SiO2, n-heptane:EtOAc=20:1→10:1→1:1). Further purification is carried out by recrystallisation from n-heptane; 2-(4-trifluoromethoxyphenyl)selenophene is obtained as a yellowish solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([SH:10])[CH:6]=[C:7]([CH3:9])[CH:8]=1.CS(O[CH2:16][C@@H:17]1[C@:26]2([CH3:27])[C@H:21]([C:22]([CH3:29])([CH3:28])[CH2:23][CH2:24][CH2:25]2)[CH2:20][CH2:19][C@:18]1([OH:31])[CH3:30])(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CC#N>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:10][CH2:16][C@@H:17]2[C@:26]3([CH3:27])[C@H:21]([C:22]([CH3:29])([CH3:28])[CH2:23][CH2:24][CH2:25]3)[CH2:20][CH2:19][C@@:18]2([CH3:30])[OH:31])[CH:6]=[C:7]([CH3:9])[CH:8]=1
Reactant: COc1cc(C)cc(S)c1
Reactant: CC1(C)CCC[C@]2(C)[C@@H](COS(C)(=O)=O)[C@](C)(O)CC[C@@H]12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COc1cc(C)cc(SC[C@@H]2[C@@]3(C)CCCC(C)(C)[C@@H]3CC[C@@]2(C)O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.2 %

Procedure:
A mixture of 3-methoxy-5-methylbenzenethiol (11) (3.14 g, 20.4 mmol), ((1S,2R,4aS,8aS)-2-hydroxy-2,5,5,8a-tetramethyldecahydronaphthalen-1-yl)methyl methanesulfonate (12) (6.48 g, 20.4 mmol), and Cs2CO3 (19.90 g, 61.08 mmol) in CH3CN (300 mL) was stirred at room temperature for 1 h, then refluxed for 24 h. After cooling, the mixture was concentrated. Purification by chromatography on silica gel (Hexanes/EtOAc, 4:1) gave (1R,2R,4aS,8aS)-1-{[(3-methoxy-5-methylphenyl)sulfanyl]methyl}-2,5,5,8a-tetramethyl-decahydronaphthalen-2-ol (13) (5.70 g, purity ˜75%) as a yellow sticky mass.
Reaction SMILES: [CH3:1][S:2]([C:4]1[N:8]2[C:9](=[O:21])[C:10]3[NH:11][CH:12]=[N:13][C:14]=3[N:15]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:7]2=[N:6][N:5]=1)=[O:3].CS(C1N2C(=O)C3NC=NC=3N(CCCCC)C2=NN=1)(=O)=O.[Br:44]N1C(=O)CCC1=O>C1COCC1.O>[Br:44][C:12]1[NH:11][C:10]2[C:9](=[O:21])[N:8]3[C:4]([S:2]([CH3:1])=[O:3])=[N:5][N:6]=[C:7]3[N:15]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:14]=2[N:13]=1
Reactant: CCCCCn1c2nc[nH]c2c(=O)n2c(S(C)=O)nnc12
Reactant: O=C1CCC(=O)N1Br
Agent: CCCCCn1c2nc[nH]c2c(=O)n2c(S(C)(=O)=O)nnc12
Solvent: O
Solvent: C1CCOC1
Product: CCCCCn1c2nc(Br)[nH]c2c(=O)n2c(S(C)=O)nnc12
Temperature: 70 °C
Reaction time: 3 h

Procedure:
To a mixture of 3-(methylsulfinyl)-9-pentyl-6,9-dihydro-5h-[1,2,4]triazolo[4,3-a]purin-5-one and 3-(methylsulfonyl)-9-pentyl-6,9-dihydro-5h-[1,2,4]triazolo[4,3-a]purin-5-one (3:2, 125 mg, 0.40 mmol) in THF (3 mL) was added N-bromosuccinimide (82.3 mg, 0.462 mmol). The mixture was stirred at 70° C. for 3 hours. The reaction was diluted with water and extracted with ethyl acetate three times, dried with sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by Prep LCMS to yield the desired product. LCMS calculated for: C12H15BrN6O2S (M+H) 387.0; found: 387.0, 389.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].Br[C:12]1[CH:21]=[N:20][CH:19]=[CH:18][C:13]=1[C:14]([O:16][CH3:17])=[O:15]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH:6][C:18]1[CH:19]=[N:20][CH:21]=[CH:12][C:13]=1[C:14]([O:16][CH3:17])=[O:15]
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: COC(=O)c1ccncc1Br
Product: COC(=O)c1ccncc1NCc1ccc(Cl)c(Cl)c1
Yield: 73 %

Procedure:
The title compound was prepared in 73% yield from 3,4-dichlorobenzylamine and methyl 3-bromoisonicotinate according to the procedure for Preparation 4A. 1H NMR (400 MHz, CDCl3): δ 8.10 (s, 1H), 7.95 (d, 1H, J=5.1 Hz), 7.87 (br s, 1H), 7.65 (d, 1H, J=5.1 Hz), 7.42 (d, 1H, J=8.7 Hz), 7.39 (s, 1H), 7.18 (dd, 1H, J=8.2 Hz), 4.48 (d, 2H, J=6.0 Hz), 3.91 (s, 3H). [M+H] calc'd for C14H12Cl2N2O2, 311, 313. found 311, 313.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:8][C:9]=2[Cl:11])[CH2:4][CH:3]1[CH3:17].[Cl:18]Cl>Cl.C(O)(=O)C>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:8][C:9]=2[Cl:11])[CH2:4][C:3]1([CH3:17])[Cl:18]
Reactant: CC1Cc2cc(OCC(=O)O)cc(Cl)c2C1=O
Reactant: ClCl
Agent: Cl
Solvent: CC(=O)O
Product: CC1(Cl)Cc2cc(OCC(=O)O)cc(Cl)c2C1=O

Procedure:
By following substantially the procedure described in Example 12, Step B, using as the reactants (1-oxo-2-methyl-7-chloro-5-indanyloxy)acetic acid (2.55 g., 0.01 mole), chlorine (710 mg., 0.01 mole), glacial acetic acid (50 ml.) and concentrated hydrochloric acid (1 drop) there is obtained (1-oxo-2-methyl-2,7-dichloro-5-indanyloxy)acetic acid.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.Cl.Cl.[CH2:14]([NH:16][CH:17]([CH3:21])[CH2:18][CH2:19][NH2:20])[CH3:15]>C(Cl)Cl.[OH-].[Na+]>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([N:16]([CH2:14][CH3:15])[CH:17]([CH3:21])[CH2:18][CH2:19][NH:20][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: CCNC(C)CCN
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCN(C(C)CCNS(=O)(=O)c1ccc(C)cc1)S(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 14 h
Yield: 39.4 %

Procedure:
A solution of p-toluenesulfonyl chloride (17.01 g, 89.2 mmol) in CH2Cl2 (300 mL) was added to a solution of II (8.89 g, 47.0 mmol) in 1 N NaOH (300 mL) which had been cooled to 0° C. After addition was complete, the biphasic mixture was stirred for 14 hours (0° C. to room temperature). The layers were separated and the aqueous portion was extracted with CH2Cl2 (2×50 mL). The combined organic phase was washed with 1 N HCl (2×100 mL) and H2O (100 mL) and evaporated in vacuo. Column chromatography on silica gel eluting with 3% EtOH/CHCl3 produced 7.46 g (39%) of III. NMR δ 0.77 (d, 3 H, J=7), 1.15 (t, 3 H, J=7), 1.45-1.76 (m, 2 H), 2.40 (s, 6 H), 2.79-3.25 (m, 4 H), 3.70-4.08 (m, 1 H), 5.47 (t, 1 H, J=7), 7.13-7.81 (m, 8 H). Anal. calcd. for C20H28N2O4S2: C, 56.58; H. 6.65; N, 6.60. Found: C, 56.60; H, 6.64; N, 6.65.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])/[C:7](=[CH:11]/[C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH:22]=[C:21]([CH3:23])[N:20]=[CH:19]2)=[C:14]([O:24][CH3:25])[CH:13]=1)/[CH2:8][CH2:9]O)([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:46]1(=[O:56])[NH:50][C:49](=[O:51])[C:48]2=[CH:52][CH:53]=[CH:54][CH:55]=[C:47]12.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[C:1]([O:5][C:6](=[O:26])/[C:7](=[CH:11]/[C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH:22]=[C:21]([CH3:23])[N:20]=[CH:19]2)=[C:14]([O:24][CH3:25])[CH:13]=1)/[CH2:8][CH2:9][N:50]1[C:46](=[O:56])[C:47]2[C:48](=[CH:52][CH:53]=[CH:54][CH:55]=2)[C:49]1=[O:51])([CH3:2])([CH3:4])[CH3:3]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: COc1cc(/C=C(\CCO)C(=O)OC(C)(C)C)ccc1-n1cnc(C)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cc(/C=C(\CCN2C(=O)c3ccccc3C2=O)C(=O)OC(C)(C)C)ccc1-n1cnc(C)c1
Yield: 87.5 %

Procedure:
To an anhydrous THF (3.0 mL) solution of (E)-4-hydroxy-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]butyric acid tert-butyl ester (100 mg), triphenylphosphine (87.8 mg), phthalimide (49.3 mg) and diisopropyl azodicarboxylate (77.0 μL) were added one by one. After agitating reaction solution at room temperature for 1.5 hours, reaction solution was concentrated under reduced pressure as it was, the residue was purified by silica gel chromatography (elution solvent:ethyl acetate), and 119 mg of the title compound was obtained. The physical properties of the compound are as follows.
Reaction SMILES: [C:1]1([CH:7]([CH2:11]Br)[C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:13][N:14]1[C:19]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:18][C:17](=[O:26])[N:16]([CH3:27])[C:15]1=[O:28].[CH2:29](N(CC)CC)[CH3:30].C(O)C>O1CCOCC1>[CH3:13][N:14]1[C:19]([N:20]2[CH2:25][CH2:24][N:23]([CH2:11][CH:7]([C:8]([O:10][CH2:29][CH3:30])=[O:9])[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:22][CH2:21]2)=[CH:18][C:17](=[O:26])[N:16]([CH3:27])[C:15]1=[O:28]
Reactant: O=C(O)C(CBr)c1ccccc1
Reactant: CCN(CC)CC
Reactant: Cn1c(N2CCNCC2)cc(=O)n(C)c1=O
Solvent: CCO
Solvent: C1COCCO1
Product: CCOC(=O)C(CN1CCN(c2cc(=O)n(C)c(=O)n2C)CC1)c1ccccc1
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
8.1 g of α-phenyl-β-bromopropionic acid and 1,3-dimethyl-6-(1-piperazinyl)-2,4(1H,3H)-pyrimidinedione were dissolved in 90 ml of dioxane, and the solution was stirred at 90° C. for 30 minutes. 12 ml of triethylamine was added to this solution, followed by stirring at 90° C. for 1 hour. Afterward, 60 ml of ethanol was added, and the solution was then heated under reflux for 3 hours. The solvent was distilled off from the reaction solution under reduced pressure, and the resulting residue was then dissolved in chloroform. The obtained solution was washed with water and then dried over anhydrous sodium sulfate. Afterward, the solvent was distilled off under reduced pressure, and the resulting residue was then purified through a silica gel column chromatograph (chloroform), thereby obtaining 4.5 g of 1,3-dimethyl-6-[4-(2-ethoxycarbonyl-2-phenylethyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidinedione.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[N:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:12]=2[Cl:18])=[C:4]([O:19][Si](C(C)(C)C)(C)C)[C:3]=1[S:27]([N:30]([CH3:32])[CH3:31])(=[O:29])=[O:28].[N:33]#[C:34]N.C([N:39](CC)C(C)C)(C)C.[F-].[Cs+]>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:34]#[N:33])[C:9]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:12]=2[Cl:18])=[NH:39])=[C:4]([OH:19])[C:3]=1[S:27]([N:30]([CH3:31])[CH3:32])(=[O:28])=[O:29]
Reactant: N#CN
Reactant: CCN(C(C)C)C(C)C
Reactant: CN(C)S(=O)(=O)c1c(Cl)ccc(N=C=Nc2cccc(Cl)c2Cl)c1O[Si](C)(C)C(C)(C)C
Agent: [Cs+]
Agent: [F-]
Solvent: CC#N
Product: CN(C)S(=O)(=O)c1c(Cl)ccc(N(C#N)C(=N)Nc2cccc(Cl)c2Cl)c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.1 %

Procedure:
To a solution of N-[4-chloro-2-tert-butyldimethylsilyloxy-3-(N″,N″-dimethylaminosulfonyl)phenyl]-N′-(2,3dichlorophenyl)carbodiimide (270 mg, 0.47 mmol) in acetonitrile (5 mL) at room temperature, cyanamide (79 mg, 1.88 mmol) and N,N-diisopropylethylamine (76 mg, 0.56 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was diluted with a mixture of tetrahydrofuran (3 mL) and methanol (1 mL). Cesium fluoride (86 mg, 0.56 mmol) was added at 0° C. The reaction mixture was stirred at 0° C. for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by Gilson HPLC to give the desired product (98 mg, 48%). EI-MS m/z 473.75(M+).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:25]=[CH:24][C:8]2[C:9]([CH3:23])([CH2:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15][CH:14]=3)[CH2:10][O:11][C:7]=2[CH:6]=1)=[O:4].[OH-].[Na+].C(O)C.Cl>O1CCCC1.O>[CH3:23][C:9]1([CH2:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15][CH:14]=2)[C:8]2[CH:24]=[CH:25][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=2[O:11][CH2:10]1
Reactant: COC(=O)c1ccc2c(c1)OCC2(C)Cc1cccc2ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: CC1(Cc2cccc3ccccc23)COc2cc(C(=O)O)ccc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 3-Methyl-3-naphthalen-1-ylmethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (150 mg, 0.45 mmol), sodium hydroxide (150 mg, 3.75 mmol), ethanol (5 ml) and water (1 ml) in tetrahydrofuran (5 ml), was stirred for 12 h at room temperature. The reaction medium was acidified by adding a 1.2 M hydrochloric acid solution and extracted with ethyl acetate. The organic phase was washed with water, dried (Na2SO4), and concentrated in a rotary evaporator. The product was obtained as a brown oil (M: 128 mg, 89%).
Reaction SMILES: N1C=CC=CC=1.[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][N:9]=1.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>O>[CH3:27][C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][N:9]=2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc([N+](=O)[O-])cn1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2ccc([N+](=O)[O-])cn2)cc1
Temperature: 100 °C
Yield: 79.4 %

Procedure:
A pyridine suspension (40 ml) containing 2-amino-5-nitropyridine (4.0 g) and p-toluenesulfonyl chloride (5.7 g) was stirred for a day and night at 100° C. The reaction liquid was poured in water (200 ml), the precipitated solid was recovered by filtration, and successively washed with water and diethyl ether by the order stated. Drying the solid under reduced pressure, 4-methyl-N-(5-nitro-2-pyridinyl)benzenesulfonamide (6.7 g) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([O:15][CH3:16])=[CH:9][CH:8]=3.C([O:19][CH:20]=[C:21]([C:27](OCC)=O)[C:22]([O:24][CH2:25][CH3:26])=[O:23])C>C1(C)C(C)=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:27]=[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:20](=[O:19])[C:8]4[CH:9]=[C:10]([O:15][CH3:16])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4
Reactant: COc1ccc2[nH]c3ccc(Br)cc3c2c1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: Cc1ccccc1C
Product: CCOC(=O)c1cn2c3ccc(Br)cc3c3cc(OC)cc(c1=O)c32
Yield: 50 %

Procedure:
3-bromo-6-methoxycarbazole (2.5 g) produced in Example 1, step 1 and diethyl ethoxymethylenemalonate (9.16 ml) were dissolved in xylene, and the solution was heated under reflux in an argon atmosphere for 120 hours, and allowed to cool. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: chloroform) to obtain the title compound (2 g, 50%).
Reaction SMILES: [C:1]1([CH3:14])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[O:9][CH2:10][C:11]([OH:13])=O.C([N:18](C(C)C)CC)(C)C.N[N:25]([CH:33]=[NH:34])[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29].O.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[NH:18]=[C:33]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[NH:34][C:11](=[O:13])[CH2:10][O:9][C:2]1[C:1]([CH3:14])=[CH:6][C:5]([CH3:7])=[CH:4][C:3]=1[CH3:8]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)N(N)C=N
Reactant: Cc1cc(C)c(OCC(=O)O)c(C)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C)c(OCC(=O)NC(=N)NC(=O)OC(C)(C)C)c(C)c1
Temperature: 25 °C
Reaction time: 25 h
Yield: 87.6 %

Procedure:
Mesityloxyacetic acid (89.3 g; 460 mmol), diisopropylethylamine (297.1 g; 2.3 mol), tert-butyl amino(imino)methylcarbamate (76.8 g; 480 mmol), and 1-hydroxybenzotriazole monohydrate (62.4 g; 460 mmol) were dissolved in N,N-dimethylformamide (1.0 L), 2-(1H)-benzotriazol-1-yl-1,1,3,3-tetramethyluronium hexafluorophosphate (183.1 g; 460 mmol) was added thereto, and the mixture was stirred for 25 hours at room temperature. The precipitated crystals were collected by filtration, washed with ethyl acetate and then dried to give 135.2 g of the title compound (yield 88%).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([CH2:6][C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)=[N:2]1.C([N-]C(C)C)(C)C.[Li+].[C:23]1(=[O:29])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.O>O1CCCC1>[OH:29][C:23]1([CH:6]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[C:3]2[N:4]=[CH:5][NH:1][N:2]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=C1CCCCC1
Reactant: N#Cc1ccc(Cc2nc[nH]n2)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc(C(c2nc[nH]n2)C2(O)CCCCC2)cc1
Reaction time: 0.5 h
Yield: 94.5 %

Procedure:
5 g of 4-[1-(1,2,4-triazolyl)methyl]benzonitrile is dissolved in 100 ml of tetrahydrofuran and combined at -50° with 20 ml of 1.5-molar solution of lithium diisopropylamide in tetrahydrofuran, stirred for 0.5 hour, further agitated with 2.9 g of cyclohexanone for 1 hour at -70°, and heated to 25°. Then water is added, the mixture is extracted with ethyl acetate, washed neutral with water, dried over sodium sulfate, and concentrated to dryness under vacuum, thus obtaining 7.24 g of crude 4-[1-hydroxycyclohex-1-yl-1-(1,2,4-triazolyl)methyl]benzonitrile.
Reaction SMILES: C([O:5][C:6](=[O:27])/[CH:7]=[CH:8]/[C:9]1[CH:26]=[N:25][C:12]2[NH:13][C:14](=[O:24])[CH2:15][N:16]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:17][C:11]=2[CH:10]=1)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)[Cl:36]>>[ClH:36].[CH2:22]([O:21][C:19]([CH2:18][N:16]1[CH2:17][C:11]2[CH:10]=[C:9](/[CH:8]=[CH:7]/[C:6]([OH:27])=[O:5])[CH:26]=[N:25][C:12]=2[NH:13][C:14](=[O:24])[CH2:15]1)=[O:20])[CH3:23]
Reactant: ClCCl
Reactant: CCOC(=O)CN1CC(=O)Nc2ncc(/C=C/C(=O)OC(C)(C)C)cc2C1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Product: Cl
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 88 %

Procedure:
A solution of (E)-3-(4-ethoxycarbonylmethyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid tert-butyl ester (1.14 g, 3.04 mmol) in CH2Cl2 (8 mL) was treated with TFA (8 mL). After stirring at room temperature under N2 for 45 min, the clear tan solution was concentrated in vacuo. The resulting oil was treated with anhydrous HCl in dioxane (10 mL, 4.0 M) and sonicated until the oil was converted to a fine off-white solid. The resulting mixture was diluted with Et2O (100 mL) and stirred under N2 for 20 min. The solid was isolated by filtration, washed with Et2O, and dried under vacuum at 50° C. overnight to give the title compound (1.05 g, 88%) as an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ 10.57 (s, 1H), 8.56-8.55 (m, 1H), 8.10 (s, 1H), 6.57 (d, J=16.0 Hz, 1H), 6.57 (d, J=16.0 Hz, 1H), 4.14-4.05 (m, 3H), 3.62-3.56 (m, 6H), 1.18 (t, J=7.1 Hz, 3H); MS (EST) m/e 320 (M+H)+.