Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C[AlH]CC(C)C)C.C[O:11][C:12](=[O:26])[CH2:13][O:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([Cl:25])=[CH:17][CH:16]=1.[NH2:27][CH2:28][CH2:29][NH:30][S:31]([C:34]1[C:35]2[CH:36]=[CH:37][N:38]=[CH:39][C:40]=2[CH:41]=[CH:42][CH:43]=1)(=[O:33])=[O:32]>>[C:13]([OH:32])(=[O:14])[C:12]([OH:11])=[O:26].[C:13]([OH:32])(=[O:14])[C:12]([OH:11])=[O:26].[Cl:25][C:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:15]([O:14][CH2:13][CH2:12][NH:27][CH2:28][CH2:29][NH:30][S:31]([C:34]2[C:35]3[CH:36]=[CH:37][N:38]=[CH:39][C:40]=3[CH:41]=[CH:42][CH:43]=2)(=[O:33])=[O:32])=[CH:16][CH:17]=1
Reactant: COC(=O)COc1ccc(Cl)c2ccccc12
Reactant: NCCNS(=O)(=O)c1cccc2cnccc12
Agent: CC(C)C[AlH]CC(C)C
Product: O=C(O)C(=O)O
Product: O=S(=O)(NCCNCCOc1ccc(Cl)c2ccccc12)c1cccc2cnccc12

Procedure:
By following similar procedure as described in Example 34, DIBAL-H reduction of (4-chloro-naphthalen-1-yloxy)-acetic acid methyl ester and subsequent reductive amination with isoquinoline-5-sulfonic acid (2-amino-ethyl)-amide gives the free amine product as a gum. The free amine is converted to the di-oxalic acid salt of the title compound as a white powder. ESIMS: m/z 456 [(M+H)+, 35Cl], 458 [(M+H)+, 37Cl].
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[N:22][N:23](CC3C=CC(OC)=CC=3)[CH:24]=2)=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Cl:15])=[O:5].FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>ClCCl>[Cl:1][C:2]1[CH:19]=[CH:18][C:17]([C:20]2[CH:24]=[N:23][NH:22][CH:21]=2)=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Cl:15])=[O:5]
Reactant: COc1ccc(Cn2cc(-c3ccc(Cl)c(C(=O)NCCc4ccccc4Cl)c3)cn2)cc1
Solvent: ClCCl
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCCc1ccccc1Cl)c1cc(-c2cn[nH]c2)ccc1Cl
Temperature: 110 °C
Reaction time: 16 h
Yield: 112.4 %

Procedure:
To as solution of 2-chloro-N-[2-(2-chloro-phenyl)-ethyl]-5-[1-(4-methoxy-benzyl)-1H-pyrazol-4-yl]-benzamide (20 mg, 0.042 mmol) in dichloromethane (0.2 mL) was added trifluoroacetic acid (24 mg, 0.21 mmol) and anisole (45 mg, 0.42 mmol). The mixture was stirred at 110° C., for 16 h. A second portion of trifluoroacetic acid (0.2 mL) and anisole (45 μL) was added and the mixture was stirred at 110° C. for a further 6 h. The mixture was concentrated in vacuo to dryness and triturated with hexane to afford the title compound as an orange solid (17 mg). LCMS (m/z) 358.5 M+1.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1Cl.[C:10]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)([CH3:13])([CH3:12])[CH3:11].[OH-].[Na+].Cl>O.CS(C)=O.ClC1C=CC=CC=1Cl>[Cl:8][C:6]1[N:5]=[N:4][C:3]([O:20][C:17]2[CH:18]=[CH:19][C:14]([C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:15][CH:16]=2)=[C:2]([OH:1])[CH:7]=1
Reactant: Oc1cc(Cl)nnc1Cl
Reactant: CC(C)(C)c1ccc(O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: Clc1ccccc1Cl
Solvent: O
Product: CC(C)(C)c1ccc(Oc2nnc(Cl)cc2O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.1 %

Procedure:
3.0 g (purity: 90%; 16.4 mmol) of 4-hydroxy-3,6-dichloropyridazine, 7.45 g (49.1 mmol) of 4-t-butylphenol, and 2.03 g (purity: 97%; 49.1 mmol) of sodium hydroxide were added to a mixture of 19.1 g of 1,2-dichlorobenzene and 3.0 g of dimethyl sulfoxide and matured at 180° C. for 8 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, and 50 g of pure water was added to the cooled mixture. A 35% aqueous hydrochloric acid solution was added to the resultant mixture so that the pH of the aqueous phase was adjusted to 2.1, and then the deposited solids were taken out by filtration. The solids were dried under nitrogen gas for 24 hours, and then 25 mL of methyl t-butyl ether was added to the solids to obtain a slurry. After stirring for 1.5 hour, the obtained slurry was subjected to filtration, and the resultant solids were dried under a reduced pressure to obtain 2.61 g of 6-chloro-3-(4-t-butylphenoxy)-4-pyridazinol in the form of pale brown solids (yield: 57.2%).
Reaction SMILES: C([N:3]([CH2:6][CH3:7])CC)C.[C:8](O[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])(OC(C)(C)C)=[O:9].[O:23]1C[CH2:26][CH2:25][CH2:24]1>O>[NH2:3][C@H:6]([CH3:7])[CH2:8][OH:9].[OH:23][CH2:24][C@H:25]([NH:3][C:16](=[O:17])[O:18][C:19]([CH3:20])([CH3:21])[CH3:22])[CH3:26]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: CCN(CC)CC
Reactant: C1CCOC1
Solvent: O
Product: C[C@@H](N)CO
Product: C[C@H](CO)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
A solution of 24.3 g (0.323 mol) of 2(R)-aminopropanol is prepared in 450 ml of tetrahydrofuran and 8 ml of water. 32.6 g (0.323 mol) of triethylamine are added and a solution of 70.5 g (0.323 mol) of ditertbutyl dicarbonate (i.e. O[COC(CH3)3 ]2) in 150 ml of tetrahydrofuran is then added slowly. The reaction medium is stirred for 1 hour at room temperature and then concentrated under reduced pressure. The oily residue is taken up with 400 ml of ethyl ether and washed with 2 times 100 ml of a 0.1N solution of hydrochloric acid containing sodium chloride and then with a solution of sodium bicarbonate. The organic phase is dried over magnesium sulfate and concentrated under reduced pressure. The residue is taken up with 200 ml of cyclohexane and crystallized. The crude product is finally recrystallized from 350 ml of cyclohexane to give 49.3 g (yield=87%) of the expected product in the form of white crystals.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][NH:8]2)=[CH:4][CH:3]=1.[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>C(O)(=O)C.CO>[CH2:15]([N:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH:7]1[CH2:6][C:5]1[CH:13]=[CH:14][C:2]([Br:1])=[CH:3][CH:4]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Brc1ccc(CC2CCCCN2)cc1
Reactant: O=Cc1ccccc1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Brc1ccc(CC2CCCCN2Cc2ccccc2)cc1
Temperature: 25 °C
Yield: 51.7 %

Procedure:
To a 100 mL round-bottomed flask equipped with N2 inlet were added 250 mg (0.984 mmol) 2-(4-bromobenzyl)-piperidine (prepared as described in Tetrahedron Letters, 7, 631 (1977)), 110 uL (1.08 mmol) benzaldehyde, 7 mL methanol, 74 mg (1.18 mmol) sodium cyanoborohydride, and a few drops of acetic acid. The reaction was stirred at room temperature, followed by additional benzaldehyde, sodium cyanoborohydride, and acetic acid, for a total of 16 hours then poured into dilute aqueous sodium bicarbonate solution, and extracted into ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and evaporated. The residue was chromatographed on silica gel using methanol/methylene chloride as eluant, and the product further purified by conversion to the hydrochloride salt in ether followed by basification using aqueous sodium hydroxide solution to afford 175 mg (52%) of an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:11][C:12](=[O:17])[CH2:13][C:14](=O)[CH3:15])[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[CH:28]=O.[NH2:30][C:31]([NH2:33])=[O:32].[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:11][C:12]([C:13]2[CH:28]([C:19]3[CH:20]=[CH:21][C:22]4[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:18]=3)[NH:30][C:31](=[O:32])[NH:33][C:14]=2[CH3:15])=[O:17])[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2
Reactant: CC(=O)CC(=O)Nc1cc(Cl)c2[nH]ncc2c1
Reactant: O=Cc1ccc2ccccc2c1
Reactant: NC(N)=O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: O
Product: CC1=C(C(=O)Nc2cc(Cl)c3[nH]ncc3c2)C(c2ccc3ccccc3c2)NC(=O)N1
Temperature: 25 °C
Yield: 51.9 %

Procedure:
The product from Example 139, Step (b) (87.3 mg, 0.348 mmol, 1.00 equiv), 2-naphthaldehyde (54 mg, 0.348 mmol, 1.00 equiv), urea (32 mg, 0.53 mmol, 1.0 equiv), and ytterbium triflate (22 mg, 0.035 mmol, 0.10 equiv) and heated to 80° C. for 2 hours. The reaction was cooled to room temperature and water was added. The precipitate was collected by filtration and washed alternately with CH3CN and Et2O, affording 78 mg (52%) of the title compound. MS (ES+) m/e 432 [M+H].
Reaction SMILES: Cl[Si:2]([C:5]1[CH2:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)([CH3:4])[CH3:3].[CH2:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15]1.[Li].O>C(OCC)C>[CH:14]1([CH:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:13]=[C:5]2[SiH:2]([CH3:4])[CH3:3])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15]1
Reactant: C[Si](C)(Cl)C1=Cc2ccccc2C1
Reactant: C1=Cc2ccccc2C1
Agent: [Li]
Solvent: O
Solvent: CCOCC
Product: C[SiH](C)C1=Cc2ccccc2C1C1C=Cc2ccccc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 50.9 %

Procedure:
Chloro-2-indenyldimethylsilane (4.95 g, 0.023 mol.) according to Example 1 was dissolved in 20 ml of diethyl ether. The solution was cooled to 0° C., and a solution of lithium indene (1.94 g, 0.022 mol.) in 25 ml of diethyl ether was added dropwise. The mixture was stirred for 2 hours at 25° C. and then heated to reflux. For working up, 60 ml of water were added and the organic phase was washed with water again and dried over Na2SO4. After removal of the solvents under an oil pump vacuum, the light-yellow oil that remained was purified by means of column chromatography. 3.23 g (47%) of 1-indenyl-2-indenyl-dimethylsilane were obtained in the form of a colorless oil which crystallized in the refrigerator at 4° C. M.p.: 45° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)O)[CH:7]=1.C([SiH](CC)CC)C.B(F)(F)F.CCOCC>ClCCl.C(#N)C>[Cl:16][C:13]1[CH:12]=[CH:11][C:10]([CH2:8][C:6]2[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=2[F:17])=[CH:15][CH:14]=1
Reactant: OC(c1ccc(Cl)cc1)c1cc(Br)ccc1F
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: CC#N
Solvent: ClCCl
Solvent: CCOCC
Product: Fc1ccc(Br)cc1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 34.8 %

Procedure:
To a solution of the above (5-bromo-2-fluorophenyl)-(4-chlorophenyl)-methanol (15.0 g, 48 mmol) and triethylsilane (18.5 mL, 116 mmol) in dichloromethane (40 mL) and acetonitrile (20 mL) at 0° C. under nitrogen, was slowly added boron trifluoride diethyl etherate (22.7 mL, 181 mmol). The resulting solution was stirred for 18 hours, while slowly warming to room temperature. The reaction was cooled in an ice-water bath, quenched by slow addition of 7 M aqueous potassium hydroxide solution (30 mL) and extracted with methyl tert-butyl ether (200 mL×2). The combined organic solution was washed with water (25 mL×2), brine (25 mL×2), dried (sodium sulfate), filtered and concentrated under reduced pressure. Purification by flash column chromatography over silica gel eluting with a gradient of ethyl acetate in heptane gave 2-(4-chlorobenzyl)-4-bromo-1-fluorobenzene (5.0 g, 35% yield) as a colorless oil. 1H NMR (400 MHz, chloroform-d) delta ppm 7.33-7.22 (m, 4H), 7.13 (d, J=8.4 Hz, 2H), 6.93 (dd, J=9.2, 9.2 Hz, 1H), 3.92 (s, 2H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[N:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)[CH2:14][C:15](OC(C)(C)C)=[O:16]>O1CCCC1.C(OCC)C>[N:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)[CH2:14][CH2:15][OH:16]
Reactant: CC(C)(C)OC(=O)CN(c1ccccn1)c1ccccn1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: OCCN(c1ccccn1)c1ccccn1
Temperature: 25 °C

Procedure:
To a slurry of LAH (lithium aluminum hydride) (1.17 g, 30.8 mmol, 3.0 equiv) in THF (tetrahydrofuran) (45 ml) was added Tert-butyl 2-(di(pyridine-2-yl)amino)acetate (2.9 g, 10.2 mmol) at 0° C. under 1 atm argon (Ar). The reaction was slowly warmed to room temperature over 4 h. The reaction mixture was then diluted with diethyl ether and cooled to 0° C. The reaction was quenched via careful addition of water (4.0 ml) and then dried with magnesium sulfate. The solvent was removed in vacuo, and the crude product was purified by flash chromatography (SiO2, hexane/ethyl acetate=1:1) to afford DPAE as a pale yellow oil. DPAE was obtained (Yield: 1.2 g (55%)), and confirmed by 1H NMR (DMSO-d6, 300 MHz): δ 8.27 (m, 2H), 7.62 (m, 2H), 7.16 (d, J=8.4 Hz, 2H), 6.93 (m, 2H), 4.92 (t, J=5.4 Hz, 1H), 4.16 (t, J=6.5 Hz, 2H), 3.58 (q, J=6.5 Hz, 2H). ESI-MS (cation): 216.1 m/z (M+H+) obsd, 215 m/z calcd.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.OC1C=CC(C2C=CC(Cl)=CC=2)=CC=1C=O.[CH2:31]([C:33](CC)([C:37]([O-])=[O:38])[C:34]([O-:36])=[O:35])C.N1CCCCC1.Cl>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[C:12]3[C:11](=[CH:10][CH:9]=2)[O:14][C:37](=[O:38])[C:33]([C:34]([OH:36])=[O:35])=[CH:31]3)=[CH:6][CH:7]=1
Reactant: Oc1ccc(-c2ccc(Cl)cc2)cc1
Reactant: CCC(CC)(C(=O)[O-])C(=O)[O-]
Agent: Cl
Agent: O=Cc1cc(-c2ccc(Cl)cc2)ccc1O
Solvent: C1CCNCC1
Product: O=C(O)c1cc2cc(-c3ccc(Cl)cc3)ccc2oc1=O
Reaction time: 2 h

Procedure:
4-(p-Chlorophenyl)phenol is converted via the Duff reaction [J. Chem. Soc., 547 (1941)] to 2-hydroxy-5-(p-chlorphenyl)benzaldehyde, mp. 74°-78° C. i.r. 6.02μ. A solution of 233 mg. (1 mmole) of this aldehyde, 0.4 ml. (2.63 mmole) of diethylmalonate and 0.2 ml. (2 mmole) of piperidine is heated for 10 minutes and kept at 25° C. for 2 hours. Then 5 ml. of 9 N HCl is added and the mixture stirred at reflux overnight. The mixture is cooled in an ice bath and filtered to yield 238 mg. of the desired compound, i.r. 5.74, 5.9μ.
Reaction SMILES: [NH:1](C(OC(C1C=C(OC)C=C(OC)C=1)(C)C)=O)[C@H:2]([C:24]([NH:26][C@H:27]([C:49]([NH:51][C@H:52]([C:60]([NH:62][C@H:63]([C:70]([OH:72])=[O:71])[CH2:64][O:65]C(C)(C)C)=[O:61])[C@@H:53]([CH3:59])[O:54]C(C)(C)C)=[O:50])[CH2:28][S:29]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:25])[CH2:3][S:4]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.[F:90][C:91]([F:96])([F:95])[C:92]([OH:94])=[O:93]>C(S)C>[NH2:1][C@H:2]([C:24]([NH:26][C@H:27]([C:49]([NH:51][C@H:52]([C:60]([NH:62][C@H:63]([C:70]([OH:72])=[O:71])[CH2:64][OH:65])=[O:61])[C@@H:53]([CH3:59])[OH:54])=[O:50])[CH2:28][SH:29])=[O:25])[CH2:3][SH:4].[F:90][C:91]([C:92]([OH:94])=[O:93])([F:96])[F:95]
Reactant: COc1cc(OC)cc(C(C)(C)OC(=O)N[C@@H](CSC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)N[C@@H](CSC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)N[C@H](C(=O)N[C@@H](COC(C)(C)C)C(=O)O)[C@@H](C)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: CCS
Solvent: O
Product: C[C@@H](O)[C@H](NC(=O)[C@H](CS)NC(=O)[C@@H](N)CS)C(=O)N[C@@H](CO)C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
615.8 mg (0.5 mmole) of Ddz-Cys(Trt)-Cys(Trt)-Thr(But)-Ser(But)-OH are dissolved in a mixture of 2.5 ml of ethylmercaptan and 2.5 ml of trifluoroacetic acid. The reaction mixture is stirred for 4 hours at room temperature and is then poured into 50 ml of water. The aqueous phase is extracted three times with ether and is then freeze-dried.
Reaction SMILES: [C:1]([CH2:4][N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:8][CH:7]([NH:22][C:23]([C:25]2[NH:26][C:27]3[C:32]([CH:33]=2)=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])[C:6]1=[O:34])([OH:3])=[O:2].[C:35]([O:41][CH2:42]Cl)(=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37].C(N(CC)CC)C>CN(C)C=O>[C:35]([O:41][CH2:42][O:2][C:1]([CH2:4][N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[N:8][CH:7]([NH:22][C:23]([C:25]2[NH:26][C:27]3[C:32]([CH:33]=2)=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])[C:6]1=[O:34])=[O:3])(=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)(C)C(=O)OCCl
Reactant: O=C(O)CN1C(=O)C(NC(=O)c2cc3ccccc3[nH]2)N=C(c2ccccc2)c2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)OCOC(=O)CN1C(=O)C(NC(=O)c2cc3ccccc3[nH]2)N=C(c2ccccc2)c2ccccc21
Reaction time: 48 h

Procedure:
A mixture of 1-carboxymethyl-1,3-dihydro-3-(2-indolecarbonylamino)-5-phenyl-2H-1,4-benzodiazepin-2-one (85 mg, 0.20 mmol), pivaloyloxymethylchloride (32 μl, 0.22 mmol) and triethylamine (28 μl, 0.20 mmol) was combined in 2 ml of dry dimethylformamide and allowed to stand at room temperature for 48 hours. Solvent was removed under reduced pressure and the residue partitioned between ethyl acetate and water. Extractive work-up gave 100 mg of crude Product which was chromatographed on silica gel (CH3OH-CHCl3, 3:97 v/v elution) to give a white solid after trituration with ether: m.p. 225°-226° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15]3[C:16]4[CH2:29][CH2:28][CH2:27][C:17]=4[C:18](=[O:26])[NH:19][C:20]=3[CH:21]=[CH:22][C:23]=2[O:24][CH3:25])=[CH:10][CH:9]=1)(=[O:7])=[O:6].C(N(CC)CC)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>O1CCCC1>[CH3:37][S:38]([O:1][CH2:2][CH2:3][NH:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15]3[C:16]4[CH2:29][CH2:28][CH2:27][C:17]=4[C:18](=[O:26])[NH:19][C:20]=3[CH:21]=[CH:22][C:23]=2[O:24][CH3:25])=[CH:10][CH:9]=1)(=[O:7])=[O:6])(=[O:40])=[O:39]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc2[nH]c(=O)c3c(c2c1-c1ccc(S(=O)(=O)NCCO)cc1)CCC3
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc2[nH]c(=O)c3c(c2c1-c1ccc(S(=O)(=O)NCCOS(C)(=O)=O)cc1)CCC3
Temperature: 25 °C
Reaction time: 20 h
Yield: 51.6 %

Procedure:
To a stirred solution of N-(2-hydroxyethyl)-4-(8-methoxy-4-oxo-2,3,4,5-tetrahydro-1H-cyclopenta[c]quinolin-9-yl)benzenesulfonamide (230 mg, 0.555 mmol) and triethylamine (168 mg, 1.66 mmol) in anhydrous tetrahydrofuran (10 mL) was added methane sulfonyl chloride (88 mg, 0.666 mmol). The reaction mixture was stirred for 20 h at room temperature. After this time the reaction mixture was filtered to remove a white precipitate, which was washed with tetrahydrofuran (30 mL). The filtrate was concentrated under reduced pressure to an orange solid. The residue was purified by flash chromatography to afford the desired product as a brown solid (141 mg, 51%). ESI MS m/z 493 [C22H24N2O7S2+H]+
Reaction SMILES: [CH3:1][C:2]1([C:12]2[N:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[CH2:11][CH2:10][C:5]2([O:9][CH2:8][CH2:7][O:6]2)[CH2:4][CH2:3]1.[CH3:19][C:20]1[N:24]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=2)[N:23]=[CH:22][C:21]=1[C:35](Cl)=[O:36].C(N(CC)CC)C.O>N1C=CC=CC=1>[CH3:19][C:20]1[N:24]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=2)[N:23]=[CH:22][C:21]=1[C:35]([NH:18][C:15]1[CH:16]=[N:17][C:12]([C:2]2([CH3:1])[CH2:3][CH2:4][C:5]3([O:6][CH2:7][CH2:8][O:9]3)[CH2:10][CH2:11]2)=[CH:13][CH:14]=1)=[O:36]
Reactant: Cc1c(C(=O)Cl)cnn1-c1ccc(C(F)(F)F)cn1
Reactant: CC1(c2ccc(N)cn2)CCC2(CC1)OCCO2
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: O
Product: Cc1c(C(=O)Nc2ccc(C3(C)CCC4(CC3)OCCO4)nc2)cnn1-c1ccc(C(F)(F)F)cn1
Temperature: 50 °C
Yield: 90 %

Procedure:
[6-(8-Methyl-1,4-dioxaspiro[4.5]dec-8-yl)pyridin-3-yl]amine (340 mg) was added to a solution of 5-methyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxylic acid chloride (491 mg) described in Reference Example 180 in pyridine (7.0 ml) and stirred at 50° C. for an hour. After completion of the reaction, triethylamine (1.5 ml) and water was added and the precipitated solid was collected by filtration to give 5-methyl-N-[6-(8-methyl-1,4-dioxaspiro[4.5]dec-8-yl)pyridin-3-yl]-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxamide (618 mg) as a white solid.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH2:7]([O:11][CH2:12][C:13]1[O:17][CH:16]=[CH:15][CH:14]=1)[CH:8]1[O:10][CH2:9]1.C(N(CC)CC)C>CCOCC>[C:1]([O:6][CH2:9][CH:8]([OH:10])[CH2:7][O:11][CH2:12][C:13]1[O:17][CH:16]=[CH:15][CH:14]=1)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: c1coc(COCC2CO2)c1
Reactant: C=C(C)C(=O)O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C=C(C)C(=O)OCC(O)COCc1ccco1
Temperature: 100 °C
Reaction time: 2 h
Yield: 94.8 %

Procedure:
A mixture of methacrylic acid (10 g), furfuryl glycidyl ether (15 g) and triethylamine (0.3 g) was heated to 100° C. for 2 hours then to 105° C. for an additional 2 hours. GC analysis showed 96% conversion. The mixture was taken up into ether, washed with water, followed by saturated sodium bicarbonate, dried with MgSO4 filtered and rotary evaporated to provide 23.7 g of a faintly yellow oil (94.8%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:9])[C:5](=[O:8])[NH:6][CH:7]=1.Br[CH2:11][CH:12]1[CH2:14][CH2:13]1>>[Br:1][C:2]1[CH:3]=[C:4]([CH3:9])[C:5](=[O:8])[N:6]([CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH:7]=1
Reactant: Cc1cc(Br)c[nH]c1=O
Reactant: BrCC1CC1
Product: Cc1cc(Br)cn(CC2CC2)c1=O

Procedure:
5-bromo-3-methyl-1H-pyridin-2-one was N-alkylated with bromomethylcyclopropane to give 5-bromo-1-(cyclopropylmethyl)-3-methylpyridin-2-one. 5-bromo-1-(cyclopropylmethyl)-3-methylpyridin-2-one (100 mg, 0.41 mmol), [2-(2,4-difluorophenoxy)-5-(ethylsulfonylamino)phenyl]boronic acid (217 mg, 0.5 mol), K3PO4 (263 mg, 1.24 mmol) and Pd(dppf)Cl2 (30 mg, 41.3 umol) in dioxane (8 mL)/water (1 mL) were purged with N2 and heated at 70-80° C. for 12 h. Preparative HPLC gave the title compound (56.0 mg, 28.6% yield) as dull-red semisolid. 1H NMR (CDCl3, 400 MHz): δ 7.74 (s, 1H), 7.61 (s, 1H), 7.28 (d, J=2.0 Hz, 1H), 7.10-7.15 (m, 1H), 6.92-7.00 (m, 2H), 6.82-6.89 (m, 1H), 6.80 (d, J=8.8 Hz, 1H), 6.71 (br. s., 1H), 3.93 (d, J=7.2 Hz, 3H), 3.12-3.21 (m, 2H), 2.24 (s, 3H), 1.42 (t, J=7.2 Hz, 3H), 1.22-1.33 (m, 1H), 0.57-0.67 (m, 2H), 0.36-0.43 (m, 2H). LCMS: 475.1 (M+1)+
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][N:3]=1.[OH2:8].C[OH:10].C(Cl)(Cl)Cl>N1C=CC=CC=1.C(Cl)Cl>[N:5]1[CH:6]=[CH:7][C:2]([C:1]([OH:10])=[O:8])=[N:3][CH:4]=1
Reactant: Cc1ccncn1
Reactant: O
Reactant: CO
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: O=C(O)c1ccncn1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To a solution of 4-methylpyrimidine (4 g, 46.5 mmol) in pyridine (20 mL) was added SeO2 (8.7 g, 79.06 mmol) at room temperature. The reaction mixture was then heated to 60° C. for 2 h, and then stirred at room temperature for 16 h. The reaction mixture was diluted with DCM (50 mL) and filtered to remove selenium waste. The filtrate was concentrated to give a residue that was stirred with H2O (20 mL), the precipitated solid was filtered and washed with acetone (2×20 mL) and dried to provide (BB12) (3.1 g, 58%) as a brown solid. Rf: 0.2 (40% MeOH/CHCl3). 1H NMR (400 MHz, DMSO-d6): δ 13.8 (1H, br s), 9.37 (1H, s), 9.07 (1H, d, J=5.2 Hz), 8.01 (1H, d, J=4 Hz); m/z 123 (M−H)−.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:16])[CH:4]=[C:5]([CH2:8][O:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)[O:6][CH:7]=1.[C:17]([O-])([O-])=O.[Cs+].[Cs+].BrC[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][Br:30]>CN(C=O)C>[Br:30][CH:29]([CH3:17])[CH2:28][CH2:27][CH2:26][CH2:25][O:1][C:2]1[C:3](=[O:16])[CH:4]=[C:5]([CH2:8][O:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)[O:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=c1cc(COC2CCCCO2)occ1O
Reactant: BrCCCCCCBr
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(Br)CCCCOc1coc(COC2CCCCO2)cc1=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 7.4 %

Procedure:
5-Hydroxy-2-(tetrahydro-pyran-2-yloxymethyl)-4H-pyran-4-one (1.50 g, 6.60 mmol) was charged in a 30 mL sealed tube equipped with a magnetic stirrer and under inert atmosphere. Anhydrous DMF (10 mL), Cs2CO3 (2.30 g, 7.00 mmol) and 1,6-dibromo-hexane (3.20 g, 13.30 mmol) were successively added. The reaction mixture was stirred 2 h at 60° C. After evaporation of DMF, the crude compound was purified by column chromatography (SiO2; CH2Cl2:EtOAc=8:2) to give after evaporation 5-(6-bromo-hexyloxy)-2-(tetrahydro-pyran-2-yloxymethyl)-4H-pyran-4-one 3 as an oil (190 mg, 52% yield).