Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH:2]1[C:8]2=[C:9]([CH3:16])[C:10](=[O:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C@:7]32[O:17][C@:4]([CH3:18])([CH2:5][O:6]3)[CH2:3]1.[H][H].S(=O)(=O)(O)O>Cl(O)(=O)(=O)=O.CO>[OH:15][C:10]1[C:9]([CH3:16])=[C:8]2[C:7](=[C:12]([CH3:13])[C:11]=1[CH3:14])[O:17][C@:4]([CH3:18])([CH2:5][OH:6])[CH2:3][CH2:2]2
Reactant: [H][H]
Reactant: CC1=C(C)[C@]23OC[C@](C)(CC(O)C2=C(C)C1=O)O3
Agent: O=S(=O)(O)O
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CO
Product: Cc1c(C)c2c(c(C)c1O)CC[C@@](C)(CO)O2
Reaction time: 15 h
Yield: 111.3 %

Procedure:
A mixture of 0.59 g of (3S,9aR)-(-)-2,3,4,5,7,9a-hexahydro-5-hydroxy-3,6,8,9-tetramethyl-3,9a-epoxy-1-benzoxepin-7-one, 0.7 g of palladium-on-barium sulfate (5% by weight) and 3 drops of concentrated perchloric acid in 20 ml of methanol was hydrogenated with ca 120 ml of hydrogen under normal pressure. Subsequently, 2 ml of 2-N sulfuric acid were added and air was conducted into the mixture for 15 hours. The reaction mixture was again hydrogenated with ca 25 ml of hydrogen. After removal of the catalyst by filtration over Hyflo, the filtrate was treated with dilute sodium bicarbonate solution and extracted with ether. The combined organic phases were dried over magnesium sulfate. After distillation of the solvent on a rotary evaporator, there were obtained 0.62 g of brown crystals, which, for purification, was chromatographed on Kieselgel with acetic ester/toluene (1/1 parts by volume). The resulting (S)-(+)-6-hydroxy-hydroxy-2,5,7,8-tetramethylchroman-2-methanol crystallized from methylene chloride/hexane at a yield of 487 mg; melting point 126.5°- 128.5°.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3]1[C:4]([S:12][C:13]2[NH:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH2:21])[C:16]=3[N:22]=2)=[CH:5][C:6]2[O:10][CH2:9][O:8][C:7]=2[CH:11]=1.[C:24]([O:27][C@@H:28]([CH3:50])[C:29]([N:31]1[CH2:36][CH2:35][CH:34]([CH2:37][CH2:38]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:33][CH2:32]1)=[O:30])(=[O:26])[CH3:25]>>[C:24]([O:27][C@@H:28]([CH3:50])[C:29]([N:31]1[CH2:36][CH2:35][CH:34]([CH2:37][CH2:38][N:14]2[C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH2:21])[C:16]=3[N:22]=[C:13]2[S:12][C:4]2[C:3]([N:2]([CH3:23])[CH3:1])=[CH:11][C:7]3[O:8][CH2:9][O:10][C:6]=3[CH:5]=2)[CH2:33][CH2:32]1)=[O:30])(=[O:26])[CH3:25]
Reactant: CN(C)c1cc2c(cc1Sc1nc3c(N)nccc3[nH]1)OCO2
Reactant: CC(=O)O[C@@H](C)C(=O)N1CCC(CCOS(=O)(=O)c2ccc(C)cc2)CC1
Product: CC(=O)O[C@@H](C)C(=O)N1CCC(CCn2c(Sc3cc4c(cc3N(C)C)OCO4)nc3c(N)nccc32)CC1

Procedure:
The title compound was prepared by a similar procedure described for step 7 of example 1 using 2-{[6-(dimethylamino)-1,3-benzodioxol-5-yl]sulfanyl}-1H-imidazo[4,5-c]pyridin-4-amine (150 mg, 0.45 mmol) and (2S)-1-[4-(2-{[(4-methylphenyl)sulfonyl]oxy}ethyl)piperidin-1-yl]-1-oxopropan-2-yl acetate (542 mg, 1.36 mmol). TOF LC-MS [M+H]+ 555.238.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH:15]2[O:17][CH2:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=1[N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.C(N(CC)CC)C>O1CCOCC1>[CH2:1]([O:8][C:9]1[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH:15]([OH:17])[CH2:16][N:35]2[CH2:34][CH2:33][N:32]([C:25]3[CH:26]=[C:27]([O:30][CH3:31])[CH:28]=[CH:29][C:24]=3[O:23][CH3:22])[CH2:37][CH2:36]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(COc2ccc(OCC3CO3)cc2)cc1
Reactant: COc1ccc(OC)c(N2CCNCC2)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COc1ccc(OC)c(N2CCN(CC(O)COc3ccc(OCc4ccccc4)cc3)CC2)c1
Yield: 33.9 %

Procedure:
2.56 g of 1-(4-benzyloxyphenoxy)-2,3-epoxypropane was dissolved in 100 ml of dioxane, and to this were added 2.95 g of 1-(2,5-dimethoxyphenyl)piperazine dihydrochloride and 3.5 ml of triethylamine and reaction and workup were carried out as in Example 1-A. The residue obtained was purified by column chromatography (silica gel, elution with ethyl acetate:hexane=1:1) to give 1.62 g of brown oil.
Reaction SMILES: [CH2:1]([CH:11]1[NH:16][CH2:15][CH2:14][CH2:13][S:12]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[Br:17][C:18]1[CH:19]=[C:20]([N:24]=[C:25]=[S:26])[CH:21]=[CH:22][CH:23]=1>>[Br:17][C:18]1[CH:19]=[C:20]([NH:24][C:25]([N:16]2[CH2:15][CH2:14][CH2:13][S:12][CH:11]2[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[S:26])[CH:21]=[CH:22][CH:23]=1
Reactant: S=C=Nc1cccc(Br)c1
Reactant: CCCCCCCCCCC1NCCCS1
Product: CCCCCCCCCCC1SCCCN1C(=S)Nc1cccc(Br)c1

Procedure:
The procedure of Example 25 was repeated, except that the reactants consisted of 0.9 g. of 2-decyltetrahydro-2H-1,3-thiazine and 0.7 g. of 3-bromophenyl isothiocyanate. The product was recrystallized from ethanol to give N-(3-bromophenyl)-2-decyltetrahydro-2H-1,3-thiazine3-carbothioamide, m.p. 73°-4°. The following elemental microanalysis was obtained:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:15]3[C:14]([CH3:16])=[N:13][N:12]([C:17]4[C:18]([O:23][CH3:24])=[N:19][CH:20]=[CH:21][CH:22]=4)[C:11]=3[C:10](=[O:25])[N:9]2CC2C=CC(OC)=CC=2)=[CH:4][CH:3]=1.O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>CC#N.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:15]3[C:14]([CH3:16])=[N:13][N:12]([C:17]4[C:18]([O:23][CH3:24])=[N:19][CH:20]=[CH:21][CH:22]=4)[C:11]=3[C:10](=[O:25])[NH:9]2)=[CH:4][CH:3]=1
Reactant: COc1ccc(CN2C(=O)c3c(c(C)nn3-c3cccnc3OC)C2c2ccc(Cl)cc2)cc1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: COc1ncccc1-n1nc(C)c2c1C(=O)NC2c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.7 %

Procedure:
To a stirred solution of 4-(4-chlorophenyl)-5-(4-methoxybenzyl)-1-(2-methoxypyridin-3-yl)-3-methyl-4,5-dihydropyrrolo[3,4-c]pyrazol-6(1H)-one (Step 71.3) (2.8 g, 5.90 mmol) in CH3CN (80 mL) and H2O (20 mL) was added CAN (9.70 g, 17.69 mmol) and the reaction mixture was stirred at RT for 16 hr. The reaction mixture was quenched with brine and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 and evaporated under reduced pressure. The crude material was purified by silica gel column chromatography (CH2Cl2/MeOH 1-2.5%). The residue was triturated in CH2Cl2 to afford the title product (1.06 g, 2.93 mmol, 50% yield) as white solid. tR: 4.36 min (HPLC 1); tR: 0.98 min (LC-MS 2); ESI-MS: 355 [M+H]+ (LC-MS 2); Rf=0.39 (CH2Cl2/MeOH 9:1).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[CH:6]1[O:8][CH2:7]1.[CH2:18]([OH:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[H-].[Na+]>O1CCCC1>[CH2:18]([O:25][CH2:7][CH:6]([C:5]1[CH:4]=[C:3]([C:2]([F:1])([F:16])[F:17])[CH:11]=[C:10]([C:12]([F:14])([F:13])[F:15])[CH:9]=1)[OH:8])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: OCc1ccccc1
Reactant: FC(F)(F)c1cc(C2CO2)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OC(COCc1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a cooled (0° C.) solution of 3,5-bis(trifluoromethyl)styrene oxide (Description 12, 0.5 g) and benzyl alcohol (1 g) in tetrahydrofuran (10 ml) was added sodium hydride (50% in mineral oil, 48 mg). The solution was stirred at room temperature for 16 hours. A further addition of sodium hydride (20 mg) was made and the solution heated to reflux for 2 hours. The cooled solution was evaporated to dryness and the residue purified by chromatography on silica (eluting with increasing concentrations of ethyl acetate in isohexane 0-20%) to provide the title compound. 1H NMR (360 MHz, CDCl3) δ 3.22 (1H, d J 3.1 Hz), 3.48 (1H, dd J 8.2 Hz and 9.6 Hz), 3.67 (1H, dd J 9.7 Hz and 3.5 Hz), 4.57 (1H, s), 4.98 (1H, m), 7.23-7.37 (5H, m), 7.80 (1H, s), 7.83 (2H, s).
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[CH2:7]([O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][NH:20][C:21]2[C:26]([C:27]([OH:29])=[O:28])=[C:25]([CH2:30][CH3:31])[N:24]=[CH:23][N:22]=2)=[CH:14][CH:13]=1)[CH2:8][CH2:9][CH3:10].CI>CC(CC)=O>[CH2:7]([O:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][CH2:19][NH:20][C:21]2[C:26]([C:27]([O:29][CH3:1])=[O:28])=[C:25]([CH2:30][CH3:31])[N:24]=[CH:23][N:22]=2)=[CH:16][CH:17]=1)[CH2:8][CH2:9][CH3:10]
Reactant: O=C([O-])[O-]
Reactant: CCCCOc1ccc(CCNc2ncnc(CC)c2C(=O)O)cc1
Agent: [K+]
Solvent: CI
Solvent: CCC(C)=O
Product: CCCCOc1ccc(CCNc2ncnc(CC)c2C(=O)OC)cc1
Temperature: 65 °C
Reaction time: 3 h
Yield: 73.5 %

Procedure:
Potassium carbonate (0.27 g, 1.95 mmol) was added to a solution of 4-(2-(4-butoxyphenyl)ethylamino)-6-ethylpyrimidine-5-carboxylic acid (0.34 g, 0.99 mmol) in ethyl methyl ketone (20 ml), and methyl iodide (0.42 g, 2.96 mmol) was added. After stirring at 65° C. for 3 hours, the mixture was cooled to room temperature. The resulting solid was filtered off and the solvent was evaporated. The residue was purified by column chromatography on silica gel eluting with n-hexane/ethyl acetate (=8/2) to give the desired methyl 4-(2-(4-butoxyphenyl)ethylamino)-6-ethylpyrimidine-5-carboxylate (0.26 g, 73%).
Reaction SMILES: CC(C)([O-])C.[K+].C(O)(C)(C)C.[CH3:12][O:13][C:14](=[O:20])[CH2:15][C:16](=[O:19])[CH2:17][CH3:18].Br[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)(=[O:31])=[O:30])=[CH:25][CH:24]=1>O1CCCC1>[CH3:12][O:13][C:14](=[O:20])[CH:15]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)(=[O:31])=[O:30])=[CH:25][CH:24]=1)[C:16](=[O:19])[CH2:17][CH3:18]
Reactant: CCC(=O)CC(=O)OC
Reactant: O=S(=O)(c1ccc(CBr)cc1)N1CCOCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: CCC(=O)C(Cc1ccc(S(=O)(=O)N2CCOCC2)cc1)C(=O)OC
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
A suspension of potassium tert-butoxide (0.26 g) in anhydrous tetrahydrofuran (40 mL) at 0° C. was treated with a mixture of tert-butanol (1.0 mL) and 3-oxopentanoic acid methyl ester (0.25 mL). The mixture was stirred at 0° C. for 45 minutes and then a solution of 4-(4-bromomethylbenzenesulfonyl)morpholine (0.53 g) in tetrahydrofuran (10 mL) was added and the resulting mixture warmed to room temperature over 1 hour and then stirred at this temperature for 17 hours. The mixture was concentrated under reduced pressure and the residue diluted with water and extracted with ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane (1:1 by volume) to afford title compound, 0.41 g.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH2:8][N:9]2[CH2:14][CH2:13][CH2:12][C:11]3([CH2:19][CH2:18][N:17]([C:20]4[CH:29]=[N:28][C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[N:21]=4)[CH2:16][CH2:15]3)[C:10]2=[O:30])[CH:5]=[CH:4][N:3]=1.[CH3:31][O-:32].[Na+]>CO>[CH3:31][O:32][C:2]1[CH:7]=[C:6]([CH2:8][N:9]2[CH2:14][CH2:13][CH2:12][C:11]3([CH2:19][CH2:18][N:17]([C:20]4[CH:29]=[N:28][C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[N:21]=4)[CH2:16][CH2:15]3)[C:10]2=[O:30])[CH:5]=[CH:4][N:3]=1
Reactant: O=C1N(Cc2ccnc(Br)c2)CCCC12CCN(c1cnc3ccccc3n1)CC2
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(CN2CCCC3(CCN(c4cnc5ccccc5n4)CC3)C2=O)ccn1
Temperature: 25 °C
Yield: 68 %

Procedure:
The title compound was synthesized from 2-((2-bromopyridin-4-yl)methyl)-9-(quinoxalin-2-yl)-2,9-diazaspiro[5.5]undecan-1-one (prepared according to method D) as follows: A stirred solution of 2-((2-bromopyridin-4-yl)methyl)-9-(quinoxalin-2-yl)-2,9-diazaspiro[5.5]undecan-1-one (synthesized according to method D) (70 mg, 0.15 mmol) and NaOMe (40.6 mg, 0.75 mmol) in MeOH (2 mL) was heated at 100° C. for 18 h. The reaction mixture was cooled to rt and the solvent was evaporated under reduced pressure. Water was added and the mixture was extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was washed with hexane to yield the title compound (55 mg, 68%). [1H NMR (300 MHz, CDCl3) ♀ ppm 8.60 (s, 1H), 8.12 (d, 1H), 7.85 (d, 1H), 7.68 (d, 1H), 7.56 (t, 1H), 7.38 (t, 1H), 6.75 (d, 1H), 6.55 (s, 1H), 4.56 (s, 2H), 4.31-4.13 (m, 2H), 3.92 (s, 3H), 3.70-3.55 (m, 2H), 3.25 (br s, 2H), 2.40-2.25 (m, 2H), 1.98-1.80 (m, 4H), 1.78-1.50 (m, 2H); LCMS RtF=1.30 min, [M+H]+=418.0].
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10].Cl[C:39]([O:41][CH2:42][CH3:43])=[O:40]>ClCCl.CO>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:39]([O:41][CH2:42][CH3:43])=[O:40])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: CCOC(=O)Cl
Reactant: COC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)NC(=N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)OC)c4ccccn4)ccc3n2C)cc1
Yield: 72 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)-amide-hydrochloride and ethyl chloroformate. Yield: 72% of theory, C29H31N7O5 (557.6) Rf value: 0.58 (silica gel; dichloromethane/methanol=9:1) ##EQU70##
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[CH:10][N:11]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29]CC)=[O:28])[C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19].[OH-].[Na+]>>[C:27]([CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][N:11]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[N:9]=[CH:10]1)([OH:29])=[O:28]
Reactant: CCOC(=O)CCCCCCCn1cnc(-c2ccccc2Cl)c1-c1ccccc1Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCCCCCCn1cnc(-c2ccccc2Cl)c1-c1ccccc1Cl
Yield: 66.6 %

Procedure:
4,5-Bis(2-chlorophenyl)-1-(7-ethoxycarbonylheptyl)-imidazole (0.4 g) was reacted with 2N sodium hydroxide in a method similar to Example 10. Work-up and chromatography on silica gel eluted with a dichloromethane:methanol gradient followed by recrystallisation from dichloro-methane and hexane gave 1-(7-carboxyheptyl)-4,5-bis-(2-chlorophenyl)imidazole (0.25 g, 67%) as a white solid, m.p. 145°-6°.
Reaction SMILES: Cl.[CH:2]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH:15]3[CH2:20][CH2:19][N:18]([CH:21]([CH3:23])[CH3:22])[CH2:17][CH2:16]3)=[CH:11][CH:12]=2)[CH:7]=[C:6]1[C:24]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:25])([CH3:4])[CH3:3].[CH3:32][S:33](Cl)(=[O:35])=[O:34]>>[CH:2]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH:15]3[CH2:20][CH2:19][N:18]([CH:21]([CH3:23])[CH3:22])[CH2:17][CH2:16]3)=[CH:11][CH:12]=2)[CH:7]=[C:6]1[C:24]([N:26]1[CH2:27][CH2:28][N:29]([S:33]([CH3:32])(=[O:35])=[O:34])[CH2:30][CH2:31]1)=[O:25])([CH3:3])[CH3:4]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCNCC2)n3C(C)C)CC1
Agent: Cl
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCN(S(C)(=O)=O)CC2)n3C(C)C)CC1

Procedure:
The title compound was prepared in analogy to example 51, from [1-isopropyl-5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-piperazin-1-yl-methanone hydrochloride and methanesulfonyl chloride. Light-yellow foam. MS (m/z): 491.2 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[O:4][CH2:3]1.O=[C:15]([CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17].C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[C:16]([CH:15]([NH:1][CH:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[O:4][CH2:3]1)[CH2:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)([O:18][CH2:19][CH3:20])=[O:17]
Reactant: NC1COc2ccccc2NC1=O
Reactant: CCOC(=O)C(=O)CCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)C(CCc1ccccc1)NC1COc2ccccc2NC1=O
Reaction time: 8 h

Procedure:
The 3-amino-2,3-dihydro-1,5-benzoxazepin-4(5H)-one (0.250 g) is dissolved in 5 ml of methanol and 2.88 g of ethyl 2-oxo-4-phenylbutyrate is added. This is followed by the addition of a solution of 88 mg of sodium cyanoborohydride in 3 ml of methanol and 0.8 ml of glacial acetic acid. The reaction is stirred overnight under nitrogen and concentrated. The residue is dissolved in 20 ml of methylene chloride and washed with 10 ml of cold saturated sodium carbonate. After drying over magnesium sulfate the solution is concentrated to an oil which is purified by flash chromatography on silica gel [solvent, acetone, hexane (1:4)] to afford 3-[N-(1-carboethoxy-3-phenylpropyl)amino]-2,3-dihydro-1,5-benzoxazepin-4(5H)-one; NMR (CDCl3) δ 9.35 (s (broad, 1], 6.50-7.30 (m, 10, 4.10 (q, 2), 2.67 (t (broad), 2], 1.21 (t, 3); IR (neat) 3220 (NH), 1730 (C=O, ester), 1685 (C=O, lactam) cm-1.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=3)=[CH:9][N:10]=2)[CH:7]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[C:30](B3OC(C)(C)C(C)(C)O3)=[CH:29][CH:28]=[N:27]2)=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([N:26]2[C:30]([C:2]3[CH:3]=[CH:4][C:5]4[N:6]([C:8]([C:11]5[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=5)=[CH:9][N:10]=4)[CH:7]=3)=[CH:29][CH:28]=[N:27]2)=[CH:24][CH:25]=1
Reactant: CC1(C)OB(c2ccnn2-c2ccc(Cl)cc2)OC1(C)C
Reactant: N#Cc1ccc(-c2cnc3ccc(Br)cn23)cc1
Product: N#Cc1ccc(-c2cnc3ccc(-c4ccnn4-c4ccc(Cl)cc4)cn23)cc1

Procedure:
The title compound, white solid (78 mg, 59%), MS (ISP) m/z=396.5 [(M+H)+], mp 208° C., was prepared in accordance with the general method of example 1 from 4-(6-bromo-imidazo[1,2-a]pyridin-3-yl)-benzonitrile (intermediate N) (0.1 g, 0.335 mmol) and 1-(4-chloro-phenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (intermediate B) (0.13 g, 0.44 mmol).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[C:15]([NH2:17])=[O:16])[C:5]([Cl:18])=[CH:4][N:3]=1.[NH2:19][C:20]1[CH:32]=[CH:31][C:23]2[N:24]([CH3:30])[C:25](=[O:29])[CH2:26][CH2:27][CH2:28][C:22]=2[CH:21]=1.Cl>CC(O)C.O1CCOCC1>[Cl:18][C:5]1[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[C:15]([NH2:17])=[O:16])=[N:7][C:2]([NH:19][C:20]2[CH:32]=[CH:31][C:23]3[N:24]([CH3:30])[C:25](=[O:29])[CH2:26][CH2:27][CH2:28][C:22]=3[CH:21]=2)=[N:3][CH:4]=1
Reactant: CN1C(=O)CCCc2cc(N)ccc21
Reactant: NC(=O)[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: CN1C(=O)CCCc2cc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4C(N)=O)n3)ccc21
Yield: 82.2 %

Procedure:
2-(2,5-Dichloro-pyrimidin-4-ylamino)-trans-cyclohexanecarboxylic acid amide (50.1 mg, 0.173 mmol) and 7-amino-1-methyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (35.9 mg, 0.190 mmol) were slurried in iPrOH (2.0 mL) prior to adding ˜0.2 mL of 4N HCl in dioxane. This mixture was heated in a microwave reactor (sealed vessel) at 120° C. for 50 min. After quenching with saturated aqueous NaHCO3 solution (2 mL), the resulting precipitate was collected by filtration, successively washed with iPrOH (1×1 mL), water (4×2 mL) and ether (2×2 mL) to afford product (63 mg, 82%) as a white powder that had the following properties: m.p.=280-283° C.; LC/MS (ESI+): 443 (M+H); 1H-NMR (DMSO-d6, 400 MHz): δ 9.25 (s, 1H), 7.92 (s, 1H), 7.77 (s, 1H), 7.55 (d, 1H, J=8.6), 7.17 (d, 1H, J=8.3), 7.06 (s, 1H), 6.77 (s, 1H), 6.56 (d, 1H, J=8.6), 4.17 (m, 1H), 3.19 (s, 3H), 2.65 (m, 2H), 2.41 (m, 1H), 2.16 (m, 2H), 2.04 (m, 3H), 1.90-1.65 (m, 3H), 1.45 (m, 1H), 1.40-1.15 (m, 3H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].O1[C:22]2([CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[O:21]CC1>CS(C)=O.C(OCC)C>[F:9][C:8]([F:11])([F:10])[C:7]1[C:2]([N:25]2[CH2:26][CH2:27][C:22](=[O:21])[CH2:23][CH2:24]2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: FC(F)(F)c1cccnc1Cl
Reactant: C1CC2(CCN1)OCCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOCC
Product: O=C1CCN(c2ncccc2C(F)(F)F)CC1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
2-Chloro-3-(trifluoromethyl)pyridine (11.92 g, 65.7 mmol)), K2CO3(19.10 g, 138 mmol), and 1,4-dioxa-8-azaspiro[4.5]decane (8.85 mL, 69.0 mmol) were combined in DMSO (65 mL) and stirred at 100° C. for 3 hours. The mixture was treated with additional 1,4-dioxa-8-azaspiro[4.5]decane (2.0 mL, 16 mmol), stirred for 2 hours, treated with additional 1,4-dioxa-8-azaspiro[4.5]decane (1.0 mL, 7.8 mmol), and stirred for 1 hour. The mixture was diluted with diethyl ether (200 mL), washed with water (250 mL), washed with brine (100 mL), dried (Na2SO4), filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in concentrated HCl (25 mL), stirred for 3 hours, basified with concentrated NH4OH, extracted with CH2Cl2, and the phases separated. The organic phase was dried (Na2SO4), filtered, and the filtrate concentrated under reduced pressure. The residue was purified via flash chromatography (20% to 40% diethyl ether/hexanes) to provide the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.CN(C(ON1N=NC2[CH:22]=[CH:23][CH:24]=[N:25]C1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C1(N)CC1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:25][CH:24]2[CH2:22][CH2:23]2)=[O:8])=[CH:9][CH:10]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1ccc(Br)cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NC1CC1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
4-Bromo-benzoic acid (2.5116 g, 12.5 mmol) and HATU (5.2213 g, 13.7 mmol) were dissolved in DMF (40 mL). DIEA (4.572 mL, 26.2 mmol) was added, and the mixture was allowed to stir at ambient temperature for 15 minutes. Then cyclopropylamine (0.866 mL, 12.5 mmol) was added, and the reaction was stirred at ambient temperature overnight. The solvent was removed, and the crude was purified via silica gel chromatography to give the desired product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]2[N:13]=[C:14]([SH:17])[CH:15]=[CH:16][C:11]2=[N:10][N:9]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH:25]([CH2:31][CH3:32])[C:26]([O:28][CH2:29][CH3:30])=[O:27]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]2[N:13]=[C:14]([S:17][CH:25]([CH2:31][CH3:32])[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:15]=[CH:16][C:11]2=[N:10][N:9]=1
Reactant: CCOC(=O)C(Br)CC
Reactant: Fc1ccccc1-c1nnc2ccc(S)nn12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CC)Sc1ccc2nnc(-c3ccccc3F)n2n1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
To a solution of 3-(2-fluorophenyl)-[1,2,4]triazolo[4,3-b]pyridazine-6-thiol (1 mmol) and cesium carbonate (1.5 equiv.) in DMF (5 mL) was added ethyl 2-bromobutyrate (1.5 equiv.) and the mixture was stirred at 70° C. for 3 hours. The reaction was monitored by thin-layer chromatography and was shown to be complete at this time. The solvent was removed in vacuo and the residue was chromatographed on a silica gel column, to furnish ethyl 2-((3-(2-fluorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)thio)butanoate.