Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][NH2:21])=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].I.[NH2:24][C:25]1[C:26]([C:33]([NH:35][C:36](=[NH:39])SC)=[O:34])=[N:27][C:28]([Cl:32])=[C:29]([NH2:31])[N:30]=1.C(N(CC)CC)C>C1COCC1>[C:1]([O:5][C:6](=[O:22])[NH:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:36]([NH2:39])=[N:35][C:33]([C:26]2[C:25]([NH2:24])=[N:30][C:29]([NH2:31])=[C:28]([Cl:32])[N:27]=2)=[O:34])=[CH:13][CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCOc1ccc(CCCCN)cc1
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Agent: I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCOc1ccc(CCCCNC(N)=NC(=O)c2nc(Cl)c(N)nc2N)cc1
Yield: 92.5 %

Procedure:
{2-[4-(4-Aminobutyl)phenoxy]ethyl}carbamic acid tert-butyl ester 2 (1.7 g, 5.5 mmol), 1-(3,5-diamino-6-chloropyrazine-2-carbonyl)-2-methylisothiourea hydriodide (2.6 g, 6.6 mmol), and triethylamine (3.1 mL) were combined in THF (18 mL). The reaction was stirred at reflux under argon for 1.5 h. The product mixture was allowed to cool, and the solvent was evaporated. Chromatography (silica gel, methylene chloride/methanol/concentrated ammonium hydroxide, 100:10:1) afforded 2.65 g (92%) of the pure product as a yellow foamy solid. 1H NMR (300 MHz, CDCl3) δ 1.44 (s, 9H), 1.62 (m, 2H), 1.61 (m, 2H), 1.75 (br s, 2H), 2.56 (t, 2H), 2.71 (t, 2H), 3.51 (m, 2H), 3.99 (t, 2H), 5.07 (br s, 1H), 6.80 (d, 2H), 7.08 (d, 2H).
Reaction SMILES: [H-].[Na+].[CH2:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH:4]1[OH:12].[C:13]([O:17][C:18]([N:20]1[CH2:24][CH2:23][CH2:22][C@H:21]1[CH2:25]OS(C)(=O)=O)=[O:19])([CH3:16])([CH3:15])[CH3:14]>CN(C=O)C>[C:13]([O:17][C:18]([N:20]1[CH2:24][CH2:23][CH2:22][C@H:21]1[CH2:25][O:12][CH:4]1[CH2:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:3]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: OC1Cc2ccccc2C1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COC1Cc2ccccc2C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 17.5 %

Procedure:
Sodium hydride (60%) (0.6 g, 14.4 mmol) is added to a flame dried flask charged with indan-2-ol (0.965 g, 7.2 mmol) and N,N′-dimethylformamide (DMF) (20 mL), cooled to 0° C. under N2 and stirred for 30 minutes. A solution of (S)-2-Methanesulfonyloxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (P) (1 g, 3.6 mmol) in DMF (5 mL) is added dropwise to the reaction mixture in such a manner as to maintain 0° C. The reaction is stirred at 60° C. for one hour, cooled to 0° C., quenched with brine, diluted with EtOAc, washed repeatedly with brine (6×), dried and concentrated in vacuo. The residue is purified by chromatography on SiO2 (5% EtOAc/Hexanes) to give 0.20 g of indanyl ether (Q) as a clear colorless oil: LCMS (ES) 340.17 (MNa+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[C:11]2[NH2:14])=[CH:6][CH:5]=1)[CH3:2].[Li].CO.N>O1CCCC1.O>[CH2:1]([O:3][C:4]1[CH2:13][C:12]2[C:11]([NH2:14])=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc2cccc(N)c2c1
Agent: N
Agent: [Li]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCOC1=CCc2cccc(N)c2C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 75.3 %

Procedure:
Next, to a flask containing a mixture of (7-ethoxy-1-naphthyl)amine (1.80 g, 9.61 mmol) and t-buthanol (2.13 g, 28.8 mmol) in tetrahydrofuran (20 mL) was collected liquid ammonia (300 mL) at −78° C. To the mixture was added lithium (0.200 g, 28.8 mmol) over 30 minutes and stirred at −78° C. for 1 hour. Methanol and water was added, and the mixture was stirred at room temperature for 16 hours to allow ammonia to evaporate. To the obtained residue was added ethylacetate. The organic layer was washed with water, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford (7-ethoxy-5,8-dihydronaphthalen-1-yl)amine (1.37 g, 76% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][C:14]([CH3:20])([CH3:19])[CH2:13][C:12]2=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:23][OH:24]>C(O)C.N1C=CC=CC=1.CC(=O)OCC>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][C:14]([CH3:20])([CH3:19])[CH2:13][C:12]2=[N:23][OH:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: CC1(C)CC(=O)c2cc(OCc3ccccc3)ccc2O1
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC1(C)CC(=NO)c2cc(OCc3ccccc3)ccc2O1

Procedure:
By heating 11.3 g (40 mmol) of 6-benzyloxy-2,2-dimethylchroman-4-one with 3.1 g (44 mmol) of hydroxylamine hydrochloride in 27 ml of ethanol and 27 ml of pyridine for 3 h at 70° C., after distilling off the solvent in vacuo and precipitating with water, 12.5 g of product, m.p. 105-108° C., were obtained. The product was dissolved in EA, the solution was dried and concentrated, and the residue was crystallized using petroleum ether; m.p. 118-120° C.
Reaction SMILES: [OH-:1].[K+].[CH3:3][C:4]([C:7]1[CH:12]=[C:11]([SH:13])[CH:10]=[C:9]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:8]=1[OH:18])([CH3:6])[CH3:5].[OH2:19]>CC(C)=O>[CH3:6][C:4]([C:7]1[CH:12]=[C:11]([S:13][CH2:3][CH2:4][CH2:7][C:8]([OH:19])=[O:1])[CH:10]=[C:9]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:8]=1[OH:18])([CH3:3])[CH3:5]
Reactant: [OH-]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: O
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)c1cc(SCCCC(=O)O)cc(C(C)(C)C)c1O
Reaction time: 1.5 h

Procedure:
Potassium hydroxide flakes (2.52 g, 0.045 mole) were added to a clear solution of 2,6-bis(1,1-dimethylethyl)-4-mercaptophenol (3.57 g, 0.015 mole) and ethyl 4-bromo butyrate (3.23 g, 0.0165 mole) in acetone (10 ml). Water (20 ml) was added and the solution stirred for 1.5 hours, the solvent removed on a rotary evaporator and water (50 ml) added. The organic layer was extracted with ethyl ether (3×75 ml). The aqueous layer was acidified with concentrated hydrochloric acid, extracted with ethyl ether (2×50 ml), washed with water (50 ml), dried over sodium sulfate, filtered and the solvents removed, leaving an oil, which was purified by chromatography on silica, recrystallized from ethyl ether/Skellysolve B, filtered and the product dried in vacuo at room temperature for 12 hours, m.p. ca. 112°-113.5° C. Analysis calc. for C18H28O3S(324.48): Calc.: C, 66.63; H, 8.70; S, 9.88. Found: C, 66.71; H, 8.74; S, 9.57.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[O:11][C:10]([C:12]3[CH:13]=[C:14]4[C:18](=[CH:19][CH:20]=3)[C:17](=[N:21][OH:22])[CH2:16][CH2:15]4)=[C:9]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[CH:8]=2)[CH2:3][CH2:2]1.Br[CH2:30][C:31]#[N:32].C(N(CC)CC)C>ClCCl.CN(C)C=O>[OH:22][N:21]=[C:17]1[C:18]2[C:14](=[CH:13][C:12]([C:10]3[O:11][C:7]([CH:4]4[CH2:3][CH2:2][N:1]([CH2:30][C:31]#[N:32])[CH2:6][CH2:5]4)=[CH:8][C:9]=3[C:23]3[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=3)=[CH:20][CH:19]=2)[CH2:15][CH2:16]1
Reactant: ON=C1CCc2cc(-c3oc(C4CCNCC4)cc3-c3ccncc3)ccc21
Reactant: N#CCBr
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#CCN1CCC(c2cc(-c3ccncc3)c(-c3ccc4c(c3)CCC4=NO)o2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
A solution of the product of Example 40 Step 5 (0.13 g, 0.35 mmol) in dry dichloromethane (10 ml) and dry dimethylformamide (0.5 ml) was treated with bromoacetonitrile (0.027 ml, 0.39 mmol) and triethylamine (0.054 ml, 0.39 mmol) and stirred at ambient temperature overnight. The crude reaction mixture was poured onto an SCX column and eluted with methanol followed by a mixture of 0.880 ammonia/methanol (1:10). The basic fractions were combined, concentrated in vacuo and triturated with diethyl ether to afford the title compound (0.13 g, 90%); MS(ES+) m/e 413 [M+H]+.
Reaction SMILES: C([C:4]1[CH:12]=[CH:11][C:10]2[NH:9][CH2:8][C@H:7]3C[C@@H](N(CCC)CCC)C[C:5]=1[C:6]=23)(=O)C.C([N:25]([CH2:28]C)CC)C.ClC(OCC(Cl)(Cl)Cl)=[O:32]>C(Cl)Cl>[C:28]([N:9]1[C:10]2[C:6](=[CH:5][CH:4]=[CH:12][CH:11]=2)[CH2:7][CH2:8]1)(=[O:32])[NH2:25]
Reactant: CCCN(CCC)[C@H]1Cc2c(C(C)=O)ccc3c2[C@@H](CN3)C1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: NC(=O)N1CCc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 270.4 %

Procedure:
To a solution of (+) (2aS,4R) -6-acetyl-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole (1.7 g, 5.7 mmol) and triethylamine (0.8 ml, 6 mmol) in 90 ml CH2Cl2 was added dropwise a solution of 2,2,2-trichloroethyl chloroformate (1.3 g, 6 mmol) in 10 ml CH2Cl2. The reaction mixture was stirred at room temperature for one hour and then extracted with water and 1N HCl. The organic solution was washed with a saturated NaHCO3 solution, a saturated brine solution, dried over MgSO4 and then concentrated to dryness in vacuo to give 2.5 g of the 1-carbamylindoline.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11][CH2:12][C:13](Cl)=C)([CH3:4])([CH3:3])[CH3:2].[C:16]1(N(CC)CC)C=CC=CC=1>CCOC(C)=O>[C:1]([C:5]1[C:6]2[S:11][C:12]([CH3:13])=[CH:16][C:7]=2[CH:8]=[CH:9][CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCN(CC)c1ccccc1
Reactant: C=C(Cl)CSc1ccccc1C(C)(C)C
Solvent: CCOC(C)=O
Product: Cc1cc2cccc(C(C)(C)C)c2s1
Temperature: 25 °C
Yield: 98 %

Procedure:
A solution of 1-tert-Butyl-2-(2-chloro-allylsulfanyl)-benzene (5.66 g, 23.58 mmol) in PhNEt2 (50 mL) is refluxed overnight. It is cooled to rt, diluted with EtOAc (100 mL), washed with 1.0 M HCl (3×100 mL); dried with Na2SO4; filtered and concentrated. The resulting crude material is purified by chromatography gives the title compound (4.69 g, 23.01 mmol, 98%). 1H NMR (CDCl3): δ 1.54 (s, 9H), 2.59 (d, J=1.3 Hz, 3H), 6.99 (q, J=1.3 Hz, 1H), 7.21-7.29 (m, 2H), 7.53 (dd. J=7.4, 1.3 Hz, 1H) ppm. ES-MS (m/z): calcd for C13H16S (M+1)+: 205.3. found: 205.0.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][OH:8])=[CH:5][N:4]=[CH:3]1.C(Cl)(=O)C(Cl)=O.[H-].[Na+].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[S:25][C:26]3[C:27](=[O:42])[N:28]([C:33]4[CH:38]=[CH:37][C:36](O)=[C:35]([O:40][CH3:41])[CH:34]=4)[CH:29]=[CH:30][C:31]=3[N:32]=2)=[CH:20][CH:19]=1>C(Cl)Cl.CN(C=O)C.O>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[S:25][C:26]3[C:27](=[O:42])[N:28]([C:33]4[CH:38]=[CH:37][C:36]([O:8][CH2:7][C:6]5[N:2]([CH3:1])[CH:3]=[N:4][CH:5]=5)=[C:35]([O:40][CH3:41])[CH:34]=4)[CH2:29][CH2:30][C:31]=3[N:32]=2)=[CH:20][CH:19]=1
Reactant: Cn1cncc1CO
Reactant: COc1cc(-n2ccc3nc(-c4ccc(Cl)cc4)sc3c2=O)ccc1O
Agent: O=C(Cl)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(N2CCc3nc(-c4ccc(Cl)cc4)sc3C2=O)ccc1OCc1cncn1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 41.6 %

Procedure:
Treat a solution of (3-methyl-3H-imidazol-4-yl)-methanol (60.0 mg, 0.54 mmol) in CH2Cl2 with oxalyl chloride (0.15 g, 1.2 mmol) and 2 drops of DMF. Stir at room temperature for 4 h, concentrate, and dissolve in DMF (5.0 mL). Add this solution to a suspension of NaH (62.5 mg, 1.6 mmol) and 2-(4-chloro-phenyl)-5-(4-hydroxy-3-methoxy-phenyl)-5H-thiazolo[5,4-c]pyridin-4-one (200.0 mg, 0.5 mmol) in DMF (5 mL). Stir at room temperature for 2 h, dilute with water, and extract with CH2Cl2 (2×). Combine the organics, dry, and concentrate. Purify by flash chromatography, using 0-10% 2N NH3/MeOH in CH2Cl2, to give the title compound (100.0 mg, 40%). MS (ES+) 481.0 (M+1)+. 1H NMR (400 MHz, CDCl3): δ7.90 (d, 2H, J=8.4 Hz), 7.44 (d, 2H, J=4.0 Hz), 7.41 (s, 1H), 7.07 (s, 1H), 6.97 (d, 1H, J=8.8 Hz), 6.94 (d, 1H, J=2.2 Hz), 6.81 (dd, 1H, J=8.6, 2.4 Hz), 5.04 (s, 2H), 4.07 (t, 2H, J=7.0 Hz), 3.83 (s, 3H), 3.72 (s, 3H), 3.27 (t, 2H, J=6.8 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:18]2[CH:22]=[CH:21][CH:20]=[N:19]2)[CH:6]=[CH:7][C:8]=1B1OC(C)(C)C(C)(C)O1.Br[C:24]1[S:28][C:27]([N:29]2[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]2)=[N:26][N:25]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:18]2[CH:22]=[CH:21][CH:20]=[N:19]2)[CH:6]=[CH:7][C:8]=1[C:24]1[S:28][C:27]([N:29]2[CH2:30][CH2:31][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:33][CH2:34]2)=[N:26][N:25]=1
Reactant: COc1cc(-n2cccn2)ccc1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nnc(Br)s2)CC1
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: C1COCCO1
Solvent: O
Product: COc1cc(-n2cccn2)ccc1-c1nnc(N2CCN(C(=O)OC(C)(C)C)CC2)s1
Temperature: 120 °C
Yield: 77.8 %

Procedure:
To a stirred suspension of 1-(3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazole [Intermediate 1] (132 mg, 0.441 mmol) and tert-butyl 4-(5-bromo-1,3,4-thiadiazol-2-yl)piperazine-1-carboxylate (140 mg, 0.401 mmol) in dioxane (2 mL) was added Pd(PPh3)4 (23 mg, 20 μmol) followed by a solution of Na2CO3 (85 mg, 0.802 mmol) in water (0.5 mL). The reaction mixture was purged with nitrogen, sealed, and heated at 120° C. for 30 minutes under microwave irradiation. The reaction mixture was cooled to room temperature, diluted with DCM (20 mL), washed with water (10 mL), then the organic phase was separated and concentrated in vacuo to afford the crude product as a pale brown solid. The crude material was purified by flash chromatography using a 12 g silica cartridge running an EtOAc/heptane gradient to afford the title compound as a pale yellow/off-white solid (138 mg, 78% yield). LC-MS: Rt 1.34 min; MS m/z 443.3 [M+H]+ [Method A]. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.65 (d, J=2.53 Hz, 1H), 8.21 (d, J=8.59 Hz, 1H), 7.80 (d, J=1.52 Hz, 1H), 7.66 (d, J=2.02 Hz, 1H), 7.60 (dd, J=8.59, 2.02 Hz, 1H), 6.59-6.62 (m, 1H), 4.05 (s, 3H), 3.51 (s, 8H), 1.43 (s, 9H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[CH2:10]1[O:13][C@H:11]1[CH3:12].CC(C)([O-])C.[K+].CC(O)(C)C>C1COCC1>[N:1]1([CH2:10][C@H:11]([CH3:12])[OH:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: c1ccc2[nH]ncc2c1
Reactant: C[C@H]1CO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: C[C@H](O)Cn1ncc2ccccc21
Yield: 33.6 %

Procedure:
A mixture of 0.5 g (4.23 mmol) indazole, 0.3 mL (S)-propylene oxide (4.4 mmol), 0.53 g potassium t-butoxide (4.3 mmol) and 15 mL of 25:1 t-BuOH:THF was stirred in a sealed tube at 70° C. overnite. The solvent was removed in vacuo, 50 mL ethyl acetate was added to the residue, the mixture was filtered, concentrated and the residue purified by chromatography over silica eluting with 1:1 EtOAc:hexanes to yield 0.250 g (1.42 mmol, 67%) of the title compound as a viscous oil. MS (APCI) m/z 177 (M+1).
Reaction SMILES: C([O:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:18]1[CH:28]=[CH:27][C:21]2[CH2:22][CH2:23][S:24](=[O:26])(=[O:25])[C:20]=2[CH:19]=1)(C)(C)C>C(Cl)Cl.CCCCC>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:29])=[O:5])=[C:10]([C:16]#[C:17][C:18]2[CH:28]=[CH:27][C:21]3[CH2:22][CH2:23][S:24](=[O:26])(=[O:25])[C:20]=3[CH:19]=2)[CH:11]=1
Reactant: CC(C)(C)OC(=O)COc1ccc(Cl)cc1C#Cc1ccc2c(c1)S(=O)(=O)CC2
Solvent: CCCCC
Solvent: ClCCl
Product: O=C(O)COc1ccc(Cl)cc1C#Cc1ccc2c(c1)S(=O)(=O)CC2
Yield: 93 %

Procedure:
Following the general method as outlined in Example 15, starting from tert-butyl{4-chloro-2-[(1,1-dioxido-2,3-dihydro-1-benzothien-6-yl)ethynyl]phenoxy}acetate (Intermediate 235), the title compound was obtained as a beige solid in 93% yield after trituration in DCM/pentane.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[NH:6]2.[H-].[Na+].CN(C)C=O.[CH3:26][O:27][CH2:28]Cl>O1CCCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:6]2[CH2:26][O:27][CH3:28]
Reactant: CCOC(=O)c1cc2c(F)ccc([N+](=O)[O-])c2[nH]1
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(F)ccc([N+](=O)[O-])c2n1COC
Temperature: 4 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
A mixture of ethyl 4-fluoro-7-nitro-1H-indole-2-carboxylate (0.48 g), 60% sodium hydride (0.12 g) and N,N-dimethylformamide (20 mL) was stirred at 4° C. for 30 min. A solution (5 mL) of chloromethyl methyl ether (0.25 mL) in tetrahydrofuran was added dropwise under ice-cooling. After stirring at room temperature for 18 hr, the reaction solution was diluted with ethyl acetate, washed with aqueous citric acid solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:5) to give the title compound (0.46 g, yield 81%) as pale-brown needle crystals.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:20]=[C:19]([NH2:21])[C:18]([O:22][CH3:23])=[C:17]3[C:13]=2[C:14]2[CH:27]=[C:26]([CH3:28])[CH:25]=[N:24][C:15]=2[NH:16]3)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2].NC1C(OC)=C2C(C3C=C(C)C=NC=3N2)=C(C2C=C(N[C:53]([CH:55]3[CH2:57][CH2:56]3)=[O:54])C=CC=2)C=1>>[CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:20]=[C:19]([NH:21][C:53]([CH:55]3[CH2:57][CH2:56]3)=[O:54])[C:18]([O:22][CH3:23])=[C:17]3[C:13]=2[C:14]2[CH:27]=[C:26]([CH3:28])[CH:25]=[N:24][C:15]=2[NH:16]3)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: COc1c(N)cc(-c2cccc(NC(=O)C3CC3)c2)c2c1[nH]c1ncc(C)cc12
Reactant: CCS(=O)(=O)c1cccc(-c2cc(N)c(OC)c3[nH]c4ncc(C)cc4c23)c1
Product: CCS(=O)(=O)c1cccc(-c2cc(NC(=O)C3CC3)c(OC)c3[nH]c4ncc(C)cc4c23)c1

Procedure:
The title compound was prepared from Compound 239 by using an analogous procedure to that outlined in the preparation of Compound 241. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.82 (br. s., 4 H) 1.16 (t, J=7.33 Hz, 3 H) 2.17 (m., 1 H) 2.25 (s, 3 H) 3.95 (s, 3 H) 7.44 (br. s., 1 H) 7.78 (br. s., 1 H) 7.87 (d, J=7.58 Hz, 1 H) 7.96 (d, J=3.28 Hz, 1 H) 8.01 (d, J=7.33 Hz, 1 H) 8.07 (br. s., 1 H) 8.23 (br. s., 1 H) 9.88 (br. s., 1 H) 12.07 (br. s., 1 H); [M+H] calc'd for C25H26N3O4S, 464.2; found, 464.3.
Reaction SMILES: [H-].[Na+].[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[S:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]([NH:24][C:25]2[C:30]([CH:31]([CH3:33])[CH3:32])=[CH:29][CH:28]=[C:27]([OH:34])[C:26]=2[CH:35]([CH3:37])[CH3:36])=[O:23])[CH2:17][CH2:16]1.I[CH3:39]>CN(C=O)C.O>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[S:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]([NH:24][C:25]2[C:30]([CH:31]([CH3:32])[CH3:33])=[CH:29][CH:28]=[C:27]([O:34][CH3:39])[C:26]=2[CH:35]([CH3:37])[CH3:36])=[O:23])[CH2:17][CH2:16]1
Reactant: CC(C)c1ccc(O)c(C(C)C)c1NC(=O)CN1CCN(CCSc2nc3ccccc3o2)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C(C)C)c(NC(=O)CN2CCN(CCSc3nc4ccccc4o3)CC2)c1C(C)C
Temperature: 40 °C
Reaction time: 0.17 h
Yield: 23 %

Procedure:
Sodium hydride (21 mg, 0.48 mmol) was added to a solution of 2-[4-[2-(benzoxazol-2-ylthio)ethyl]piperazin-1-yl]-N-(2,6-diisopropyl-3-hydroxyphenyl)acetamide (200 mg, 0.40 mmol) in DMF (2 ml), the mixture was stirred at 40° C. for 10 minutes and iodomethane (68 mg, 0.48 mmol) was added thereto followed by stirring for 1 hour. The reaction solution was diluted with water and extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution and dried over sodium sulfate and the solvent was evaporated therefrom. The residue was purified by a silica gel column chromatography (developing solvent, chloroform:methanol=50:1) to provide 47 mg (yield 23%) of 2-[4-[2-(benzoxazol-2-ylthio)ethyl]-piperazin-1-yl]-N-(2,6diisopropyl-3-methoxyphenyl)acetamide. This was made into a dihydrochloride and recrystallized to provide the desired compound as colorless powdery crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1.[C:21]([O-])([O-])(OCC)[CH3:22].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:21]([CH3:22])=[N:13][N:12]=[C:10]3[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1
Reactant: CCOC(C)([O-])[O-]
Reactant: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Product: Cc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Reaction time: 6 h

Procedure:
To a solution of 2.84 parts of 7-chloro-2-hydrazino-5-phenyl-3-H-1,4-benzodiazepine in 50 parts by volume of chloroform are added 10 parts of ethyl orthoacetate and 4 parts of p-toluenesulfonic acid. The solution is left standing at room temperature for 6 hours and heated for a while on a water-bath to complete the reaction. The mixture is washed with saturated aqueous sodium bicarbonate, then with water and dried over anhydrous sodium sulfate. After evaporation of the solvent, the residue is treated in a similar manner to Example 18 to give 8-chloro-1-methyl-6-phenyl-4H-s-triazolo [4,3-a][1,4] benzodiazepine as colorless needles. Melting point: 224° C to 225° C.
Reaction SMILES: [OH-].[Na+].[CH3:3][N:4]([C:13]1[CH:14]=[C:15]([C:19]2[CH:20]=[N:21][C:22]([CH:25]=[CH:26][C:27]([O-:29])=[O:28])=[N:23][CH:24]=2)[CH:16]=[CH:17][CH:18]=1)[C:5]([NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:6]>O1CCCC1.O>[CH3:3][N:4]([C:13]1[CH:14]=[C:15]([C:19]2[CH:20]=[N:21][C:22]([CH:25]=[CH:26][C:27]([OH:29])=[O:28])=[N:23][CH:24]=2)[CH:16]=[CH:17][CH:18]=1)[C:5]([NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:6]
Reactant: CCCCCNC(=O)N(C)c1cccc(-c2cnc(C=CC(=O)[O-])nc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCNC(=O)N(C)c1cccc(-c2cnc(C=CC(=O)O)nc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.1 %

Procedure:
10 mg (242.5 μmol, 2.5 eq) of sodium hydroxide pellets are added to a solution of 37.6 mg (97 μmol, 1 eq) of 3-{5-[3-(1-methyl-3-pentylureido)phenyl]pyrimidine-2-acrylate in 2 ml of tetrahydrofuran and 4 drops of water. The reaction mixture is stirred for 8 hours at room temperature. The reaction medium is concentrated and then diluted with 10 ml of water and washed with twice 10 ml of dichloromethane. The aqueous phase is acidified with 1N hydrochloric acid and then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are evaporated off and the residue is then chromatographed on a preparative silica plate (95/5/0.5% dichloromethane/methanol/aqueous ammonia). 7.9 mg of 3-{5-[3-(1-methyl-3-pentylureido)phenyl]pyrimidin-2-yl}acrylic acid are obtained in the form of beige-colored crystals. Yield=22%.
Reaction SMILES: [CH3:1][O:2][C:3](OC)([CH2:14][CH2:15][CH3:16])[CH2:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6].C(OC(C)C)(C)C>CO>[CH3:1][O:2][C:3]([CH2:14][CH2:15][CH3:16])=[CH:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6]
Reactant: CCCC(CC(=O)Nc1ccccc1)(OC)OC
Solvent: CC(C)OC(C)C
Solvent: CO
Product: CCCC(=CC(=O)Nc1ccccc1)OC
Yield: 45.8 %

Procedure:
60 g of 3,3-dimethoxy-hexananilide were heated at 145° C until the distillation of methanol ceased and after cooling, isopropyl ether was added thereto. The precipitate formed was recovered by vacuum filtration to obtain 24 g of 3-methoxy-2-hexenanilide melting at 104° C.