Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].[OH:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[OH:20][CH:21]1[CH2:26][CH2:25][N:24]([S:16]([C:14]2[S:15][C:11]([C:7]3[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=3[CH3:10])=[CH:12][CH:13]=2)(=[O:18])=[O:17])[CH2:23][CH2:22]1
Reactant: OC1CCNCC1
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)Cl)s2)s1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)N3CCC(O)CC3)s2)s1
Reaction time: 1 h

Procedure:
5-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]thiophene-2-sulfonyl chloride, prepared as in Step 1 of Example 9 (110 mg; 0.33 mmol; 1 eq.), is dissolved in DCM (10 ml). 4-Hydroxypiperidine (66.1 mg; 0.65 mmol; 2 eq.) and DIEA (0.17 ml; 0.98 mmol; 3 eq.) are added. After one hour, the solvents are evaporated. The crude product is dissolved in DCM and washed with NH4Cl saturated solution, water and dried over MgSO4. After evaporation of the solvents, Compound (10) is obtained as white-off solid (33 mg; 23%). 1H NMR (DMSO-d6) δ 1.40-1.60 (m, 2H), 1.72-1.85 (m, 2H), 2.14 (s, 3H), 2.42 (s, 3H), 2.80-2.92 (m, 2H), 3.15-3.30 (m, 2H), 3.59 (m, 1H), 4.71 (d, J=3 Hz, 1H), 7.30 (d, J=4.5 Hz, 1H), 7.58 (d, J=4.5 Hz, 1H), 12.18 (br s, 1H). M−(ESI): 400.20; M+(ESI): 402.10. HPLC, Rt: 2.86 min (purity: 100%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C@@H:10]([O:13]C(=O)C)[CH:11]=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:24]([Mg]Cl)[CH:25]([CH3:27])[CH3:26]>C1COCC1.CCOCC.CO>[C:1]([O:5][C:6]([NH:8][C@H:9]([C@@H:10]([OH:13])[C@@H:11]([OH:12])[CH2:24][CH:25]([CH3:27])[CH3:26])[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)C[Mg]Cl
Reactant: CC(=O)O[C@@H](C=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOCC
Product: CC(C)C[C@H](O)[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: -70 °C
Reaction time: 2 h

Procedure:
The oil prepared in Step 1 was dissolved under nitrogen in 100 mL of dry THF and cooled to -70° C. To this solution was added 13 mL (26 mmol) of a 2.0M solution of isobutylmagnesium chloride in ether and the stirred mixture was allowed to warm to room temperature and stir for 2 hrs. After decomposition with MeOH/H2Othe mixture was diluted with ether, washed with saturated NH4Cl solution twice, then dried and the solvents stripped off under vacuum. The residue was allowed to stand overnight in 80% MeOH-H2O containing excess ammonium hydroxide. The MeOH was stripped off and the mixture was extracted with ether. These extracts were combined, washed with water, dilute KHSO4, then dried and evaporated to give 2.36 g of a yellow glass which crystallized from 50 mL of pentane on standing overnight. The yellow-white powder obtained was recrystallized from ether-hexane and furnished the title compound (0.41 g) as white, hairy needles, mp 134-136° C., Rf (ether): single spot, 0.6. By chromatography of the mother liquors and crystallization of the appropriate fractions, an additional 0.22 g of product, mp 138-139° C., was obtained.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:11](CC#C)[C:10]2[CH:15]=[CH:16][C:17](=[O:24])[C:18]([O:20][CH2:21][C:22]#[CH:23])=[CH:19][C:9]=2[C:8](=[O:25])[CH:7]=1)=[O:5])C.Cl>>[O:25]=[C:8]1[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[NH:11][C:10]2[CH:15]=[CH:16][C:17](=[O:24])[C:18]([O:20][CH2:21][C:22]#[CH:23])=[CH:19][C:9]1=2
Reactant: C#CCOc1cc2c(=O)cc(C(=O)OCC)n(CC#C)c2ccc1=O
Agent: Cl
Product: C#CCOc1cc2c(=O)cc(C(=O)O)[nH]c2ccc1=O
Temperature: 25 °C

Procedure:
A mixture of 4,7-dihydro-4,7-dioxo-1-(2-propynyl)-6-(2-propynyloxy)-1H-cyclohepta[b]pyridine-2-carboxylic Acid ethyl ester (2.0 g, described in Example 20) and 19% hydrochloric acid (59 ml) is refluxed for 30 minutes and cooled to room temperature. The crystalline precipitate is collected and dried to obtain the title compound, mp 189° (darkens) and 250° C. (dec).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:7](I)[CH2:8][CH3:9].[Br:11][C:12]1[N:13]=[C:14]([C:21]([C:23]2[CH:24]=[C:25]3[C:30](=[CH:31][CH:32]=2)[NH:29][C:28](=[O:33])[N:27]([CH2:34][CH2:35][O:36][C:37]2[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=2)[C:26]3=[O:44])=[O:22])[N:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=12>CN(C=O)C>[Br:11][C:12]1[N:13]=[C:14]([C:21]([C:23]2[CH:24]=[C:25]3[C:30](=[CH:31][CH:32]=2)[N:29]([CH2:7][CH2:8][CH3:9])[C:28](=[O:33])[N:27]([CH2:34][CH2:35][O:36][C:37]2[CH:38]=[CH:39][C:40]([F:43])=[CH:41][CH:42]=2)[C:26]3=[O:44])=[O:22])[N:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=12
Reactant: O=C(c1ccc2[nH]c(=O)n(CCOc3ccc(F)cc3)c(=O)c2c1)c1nc(Br)c2ccccn12
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCn1c(=O)n(CCOc2ccc(F)cc2)c(=O)c2cc(C(=O)c3nc(Br)c4ccccn34)ccc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 91.6 %

Procedure:
7.22 g (22.16 mmol) of caesium carbonate and 5.65 g (33.24 mmol) of propyl iodide are added, under an inert atmosphere, to 5.6 g (11.08 mmol) of 6-[(1-bromoimidazo[1,5-a]pyridin-3-yl)carbonyl]-3-[2-(4-fluorophenoxy)ethyl]quinazoline-2,4(1H,3H)-dione in 300 ml of DMF. The reaction medium is stirred for 12 hours at ambient temperature under a nitrogen atmosphere and then concentrated under reduced pressure. The residue obtained is washed with 700 ml of water and then dried under reduced pressure at 40° C. overnight. 5.74 g of a yellow solid are obtained.
Reaction SMILES: [C:1](/[N:3]=[C:4](/[S-:7])\[S:5][CH3:6])#[N:2].[K+].Cl[CH2:10][C:11]([NH2:13])=[O:12].C[O-].[Na+].O>C(O)C>[NH2:2][C:1]1[N:3]=[C:4]([S:5][CH3:6])[S:7][C:10]=1[C:11]([NH2:13])=[O:12]
Reactant: NC(=O)CCl
Reactant: CS/C([S-])=N\C#N
Agent: C[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CSc1nc(N)c(C(N)=O)s1
Temperature: 25 °C
Yield: 30.4 %

Procedure:
A mixture of potassium (Z)-methyl cyanocarbonimidodithioate (10.0 g, 58.7 mmol) and 2-chloroacetamide (6.04 g, 64.6 mmol) in ethanol (20 mL) was refluxed for 1 h. After cooling to ambient temperature, sodium methoxide (3.49 g, 64.6 mmol) was added to the mixture. The mixture was stirred at reflux for 3 hours. The mixture was cooled to ambient temperature and water (50 mL) was added. The precipitate formed was collected by filtration. The precipitate was further washed with water and dried in vacuo. The product was obtained as a yellow solid (3.372 g, 30%). 1H NMR (300 MHz, d6-DMSO) δ 6.96 (s, 2H), 6.89 (s, 2H), 2.64 (s, 3H); LC-MS: 190 (MH+).
Reaction SMILES: [O:1]=[C:2]1[N:7]([CH2:8][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[CH2:6][CH2:5][N:4](C(OCC2C=CC=CC=2)=O)[CH2:3]1.[H][H]>[C].[Pd].CCO>[N:11]1[CH:12]=[CH:13][CH:14]=[C:9]([CH2:8][N:7]2[CH2:6][CH2:5][NH:4][CH2:3][C:2]2=[O:1])[CH:10]=1
Reactant: [H][H]
Reactant: O=C1CN(C(=O)OCc2ccccc2)CCN1Cc1cccnc1
Agent: [Pd]
Solvent: CCO
Product: O=C1CNCCN1Cc1cccnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.7 %

Procedure:
Benzyl 3-oxo-4-(pyridin-3-ylmethyl)piperazine-1-carboxylate (345 mg) was mixed with EtOH (7 ml), and 10% palladium carbon (70 mg) was added thereto under argon atmosphere to change the atmosphere to hydrogen atmosphere, followed by stirring at room temperature overnight. The reaction mixture was filtered using Celite as a filtration adjuvant, and the filtrate was concentrated under reduced pressure to obtain 1-(pyridin-3-ylmethyl)piperazin-2-one (190 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[CH:16][C:5]2[O:6][CH2:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH:10](Cl)[C:4]=2[CH:3]=1.[OH:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.Cl.[OH-].[Na+]>C1(C)C=CC=CC=1.C(OCC)C.O>[CH3:1][C:2]1[CH:17]=[CH:16][C:5]2[O:6][CH2:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH:10]([N:24]3[CH2:25][CH2:26][N:21]([CH2:20][CH2:19][OH:18])[CH2:22][CH2:23]3)[C:4]=2[CH:3]=1
Reactant: Cc1ccc2c(c1)C(Cl)c1ccccc1CO2
Reactant: OCCN1CCNCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: Cc1ccc2c(c1)C(N1CCN(CCO)CC1)c1ccccc1CO2
Temperature: 80 °C
Yield: 79 %

Procedure:
In this example, 3.7 g of crude crystals of 2-methyl-11-chloro-6,11-dihydrodibenz[b,e]oxepin obtained from 3.6 g of 2-methyl-6,11-dihydrodibenz[b,e]oxepinone-11 in the same manner as in Example 1 are dissolved in 60 ml of toluene and the solution is dropwise added to a solution of 9.8 g of 1-(2-hydroxyethyl)piperazine in 20 ml of toluene, followed by heating for 2 hours at 80° C. After completion of the reaction, 30 ml of water is added thereto, and the pH of the solution is adjusted to 2.0 with concentrated hydrochloric acid. Then, a toluene layer is discarded, and 20 ml of ethyl ether is added to an aqueous layer, followed by readjusting the pH of the solution to 10.5 with a 10 N sodium hydroxide aqueous solution. The aqueous layer is discarded, and the ethyl ether layer is dehydrated and concentrated under reduced pressure. The residue is purified through silica gel chromatography. Concentration of the main fractions gives 4.0 g of 2-methyl-11-[4-(2-hydroxyethyl)-1-piperazinyl]-6,11-dihydrodibenz[b,e]oxepin [compound 37] in an oily free base in a yield of 79%.
Reaction SMILES: ClC(OC(Cl)(Cl)Cl)=[O:3].[CH3:9][O:10][C:11](=[O:29])[C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[N:14][C:13]=1[NH:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1>O1CCOCC1>[Cl:18][C:16]1[CH:15]=[N:14][C:13]2[N:19]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[C:9](=[O:3])[O:10][C:11](=[O:29])[C:12]=2[CH:17]=1
Reactant: COC(=O)c1cc(Cl)cnc1NCc1ccc(OC)cc1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: COc1ccc(Cn2c(=O)oc(=O)c3cc(Cl)cnc32)cc1
Yield: 90.9 %

Procedure:
Trichloromethyl chloroformate (5.40 mL, 44.82 mmol) was added slowly to a solution of 5-chloro-2-(4-methoxy-benzylamino)-nicotinic acid methyl ester (72) (12.5 g, 40.75 mmol) in dioxane and refluxed for 4 h under nitrogen atmosphere. The solution was cooled and the solvent was removed under vacuum. The residue was recrystallized by ether to yield 11.80 g (91%) of 6-chloro-1-(4-methoxy-benzyl)-1H-pyrido[2,3-d][1,3]oxazine-2,4-dione (73) as white solids. MP: 173° C.; 1H-NMR (DMSO-d6): 3.71 (s, 3H), 5.25 (s, 2H), 6.85 (m, 2H), 7.33 (m, 2H), 8.49 (d, J=2.8 Hz, 1H), 8.82 (d, J=2.8 Hz, 1H); EIMS: 319 (M+1).
Reaction SMILES: [NH2:1][C@:2]12[CH2:37][CH2:36][C@@H:35]([CH:38]([CH3:40])[CH3:39])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:34])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C@@H:11]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=2)[CH2:10][CH2:9]3)[CH2:6][CH2:5]1.Cl[CH2:42][CH2:43][N:44]1[CH2:49][CH2:48][S:47](=[O:51])(=[O:50])[CH2:46][CH2:45]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[I-].[K+]>C(#N)C>[O:50]=[S:47]1(=[O:51])[CH2:48][CH2:49][N:44]([CH2:43][CH2:42][NH:1][C@:2]23[CH2:37][CH2:36][C@@H:35]([CH:38]([CH3:40])[CH3:39])[C@@H:3]2[C@@H:4]2[C@@:17]([CH3:20])([CH2:18][CH2:19]3)[C@@:16]3([CH3:21])[C@@H:7]([C@:8]4([CH3:34])[C@@H:13]([CH2:14][CH2:15]3)[C:12]([CH3:22])([CH3:23])[C@@H:11]([C:24]3[CH:25]=[CH:26][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:32][CH:33]=3)[CH2:10][CH2:9]4)[CH2:6][CH2:5]2)[CH2:45][CH2:46]1
Reactant: COC(=O)c1ccc([C@H]2CC[C@]3(C)[C@H]4CC[C@@H]5[C@H]6[C@H](C(C)C)CC[C@]6(N)CC[C@@]5(C)[C@]4(C)CC[C@H]3C2(C)C)cc1
Reactant: O=S1(=O)CCN(CCCl)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc([C@H]2CC[C@]3(C)[C@H]4CC[C@@H]5[C@H]6[C@H](C(C)C)CC[C@]6(NCCN6CCS(=O)(=O)CC6)CC[C@@]5(C)[C@]4(C)CC[C@H]3C2(C)C)cc1
Temperature: 120 °C
Yield: 62 %

Procedure:
A mixture of methyl 4-((1S,3aS,5aR,5bR,7aS,9S,11aS,11bR,13aR,13bR)-3a-amino-1-isopropyl-5a,5b,8,8,11a-pentamethylicosahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (50 mg, 0.091 mmol), 4-(2-chloroethyl)thiomorpholine 1,1-dioxide (54.1 mg, 0.274 mmol), potassium phosphate (77 mg, 0.365 mmol) and potassium iodide (36.4 mg, 0.219 mmol) in acetonitrile (2 mL) was heated up at 120° C. for 20 hours. The reaction mixture was quenched with distilled water (5 mL), extracted with dichloromethane (3×5 mL), the organic phases were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to provide the crude product as a yellow solid (40 mg, 62%). LCMS: m/e 709.53 (M+H)+, 2.46 min (method 11).
Reaction SMILES: B(C1C=CC(CCCC(O)=O)=CC=1)(O)O.CC1(C)C[O:21][B:20]([C:23]2[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[CH:25][CH:24]=2)[O:19]C1.[OH-].[Na+]>>[B:20]([C:23]1[CH:24]=[CH:25][C:26]([CH2:29][CH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[CH:27][CH:28]=1)([OH:21])[OH:19]
Reactant: CC1(C)COB(c2ccc(CCCCC(=O)O)cc2)OC1
Agent: O=C(O)CCCc1ccc(B(O)O)cc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCCCc1ccc(B(O)O)cc1
Yield: 76.1 %

Procedure:
Using a procedure analogous to that used to prepare 2B, 5A (429 mg, 1.48 mmol) was reacted with NaOH to afford 5B (250 mg, 76%) as an off-white solid.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[C:5]1(=O)[O:9][CH2:8][CH2:7][O:6]1>C(O)C>[OH:2][CH2:1][CH2:3][NH:4][C:5]([O:6][CH2:7][CH3:8])=[O:9]
Reactant: NCCO
Reactant: O=C1OCCO1
Solvent: CCO
Product: CCOC(=O)NCCO
Reaction time: 2 h

Procedure:
40.6 grams of ethanolamine were charged to a standard neck reaction vessel fitted with an agitator, packed column and a thermometer. 70.3 grams of ethylene carbonate was added, and the temperature was allowed to rise to 100° C. The mixture was then held at 100° C. for 2 hours. The crude 2-hydroxyethyl urethane of ethanol formed had a viscosity of 4.5 poise at 30° C. (as measured by an ICI cone and plate viscometer) and a base number of 3.0. The residual base number corresponded to a conversion of amine to urethane of 99.4%. The mixture was heated to 150° C. and 689.1 grams of dodecanedioic acid were added. The solution was heated slowly to 220° C., with water being removed continuously, over a 1.5 hour period. The reaction product was then cooled and poured out. The final product had a melting point of 81° C. to 84° C.
Reaction SMILES: Br[C:2]1[CH:39]=[CH:38][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][CH2:15][N:16]([CH2:27][C:28]2[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=2)[CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=2)=[CH:4][CH:3]=1.[F:40][C:41]([F:52])([F:51])[C:42]1[CH:47]=[CH:46][C:45](B(O)O)=[CH:44][CH:43]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:25]([C:22]1[CH:23]=[CH:24][C:19]([CH2:18][CH2:17][N:16]([CH2:27][C:28]2[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=2)[CH2:15][CH2:14][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][CH2:6][C:5]2[CH:38]=[CH:39][C:2]([C:45]3[CH:46]=[CH:47][C:42]([C:41]([F:52])([F:51])[F:40])=[CH:43][CH:44]=3)=[CH:3][CH:4]=2)=[CH:20][CH:21]=1)#[N:26]
Reactant: COC(=O)c1ccc(CN(CCc2ccc(C#N)cc2)CCc2ccccc2OCc2ccc(Br)cc2)cc1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)c1ccc(CN(CCc2ccc(C#N)cc2)CCc2ccccc2OCc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)cc1
Yield: 70.6 %

Procedure:
200 mg (0.34 mmol) of methyl 4-({{2-[2-(4-bromobenzyloxy)phenyl]ethyl}-[2-(4-cyanophenyl)ethyl]amino}methyl)benzoate from Example 9A are dissolved in 2 ml of 1,2-dimethoxyethane and, under argon, 78 mg (0.41 mmol) of 4-trifluoromethylphenylboronic acid, 2.5 mg of bis(triphenylphosphine)palladium(II) chloride and 0.38 ml of a 2 M aqueous sodium carbonate solution are added. The reaction mixture is then stirred under reflux for 12 hours. The mixture is subsequently cooled, filtered through 1 g of Extrelut, washed with dichloromethane and concentrated. The resulting crude product is purified by preparative HPLC. 158 mg (0.24 mmol, 71% yield) of a colorless oil are obtained.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][CH:5]=[N:4]1.Br[C:9]1([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:12][CH2:11][CH2:10]1.CN(P(N(C)C)(N(C)C)=O)C>CN(C)C=O.O1CCCC1>[N:3]1([C:9]2([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:12][CH2:11][CH2:10]2)[CH:7]=[CH:6][CH:5]=[N:4]1
Reactant: CCOC(=O)C1(Br)CCC1
Reactant: c1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C1(n2cccn2)CCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.2 %

Procedure:
Into a 50 mL round bottom flask was added sodium hydride (60% dispersion in mineral oil, 452 mg, 11 mmol) and anhydrous tetrahydrofuran (18 mL). To the mixture was added pyrazole (511.6 mg, 7.515 mmol) and anhydrous tetrahydrofuran (1 mL). The mixture was stirred at room temperature for 2 h and then cooled to 0° C. Ethyl 1-bromocyclobutanecarboxylate (1.3 mL, 7.5 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 45 minutes and at room temperature over three days. HMPA (1.35 mL, 7.5 mmol) was added and the mixture was stirred at room temperature for 2 h. The reaction mixture was warmed to 70° C. for 2 h followed by the addition of N,N-dimethylformamide (4 mL). The reaction mixture was stirred at 70° C. for another 2 h before more N,N-dimethylformamide (2 mL) was added and then stirred at 70° C. for 18 h. The solvent was removed under reduced pressure. To the residue was added water and extracted with a mixture of heptanes and ethyl acetate (3×). The combined organics were dried over magnesium sulfate, filtered and concentrated under reduced pressure. Flash chromatography (0-40% ethyl acetate in heptanes) provided impure ethyl 1-(1H-pyrazol-1-yl)cyclobutanecarboxylate (688 mg), which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[N:16]=[C:15]([C:24]([OH:26])=O)[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:7]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=C(C(N3CC(=O)NC3)=O)C=2)C=C(F)C=1.[S:54]1[CH2:58][CH2:57][NH:56][CH2:55]1>>[Br:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[N:16]=[C:15]([C:24]([N:56]3[CH2:57][CH2:58][S:54][CH2:55]3)=[O:26])[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:11])([F:12])[F:10])[CH:7]=1
Reactant: C1CSCN1
Reactant: O=C(O)c1cc(-c2cc(Br)cc(OC(F)(F)F)c2)n(-c2cccnc2)n1
Agent: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3ccccn3)n2)CN1
Product: O=C(c1cc(-c2cc(Br)cc(OC(F)(F)F)c2)n(-c2cccnc2)n1)N1CCSC1

Procedure:
130 mg (0.30 mmol) of the compound of Example 39A is reacted analogously to the synthesis of the compound of Example 1 with 0.03 ml (0.33 mmol) of thiazolidine. 116 mg (77% of theory) of the title compound is obtained.
Reaction SMILES: C([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[O:10][C:9]([C:18]2[N:23]=[CH:22][C:21]3[CH:24]=[CH:25][S:26][C:20]=3[CH:19]=2)=[CH:8]1)(C)(C)C.Cl.[Cl:28][CH2:29][CH2:30][N:31]1[CH:35]=[CH:34][N:33]=[CH:32]1>>[ClH:28].[N:31]1([CH2:30][CH2:29][O:17][C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[O:10][C:9]([C:18]2[N:23]=[CH:22][C:21]4[CH:24]=[CH:25][S:26][C:20]=4[CH:19]=2)=[CH:8][C:7]3=[N:6][OH:5])[CH:35]=[CH:34][N:33]=[CH:32]1
Reactant: ClCCn1ccnc1
Reactant: CC(C)(C)ON=c1cc(-c2cc3sccc3cn2)oc2ccc(O)cc12
Agent: Cl
Product: ON=c1cc(-c2cc3sccc3cn2)oc2ccc(OCCn3ccnc3)cc12

Procedure:
6-(2-imidazol-1-yl-ethoxy)2-thieno[3,2-c]pyridin-6-yl-chromen-4-one oxime, hydrochloride was prepared in 25% overall yield using the method described in example 127, starting from 6-Hydroxy-2-thieno[3,2-c]pyridin-6-yl-chromen-4-one O-tert-butyl-oxime (example 127B) and 1-(2-Chloro-ethyl)-1H-imidazole hydrochloride.
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[N:13]=[CH:12][NH:11][C:10]=2[C:9]2=[N:15][N:16]=[CH:17][N:8]2[C:7]1=[O:18])[CH2:2][CH2:3][CH2:4][CH3:5].[Br:19]N1C(=O)CCC1=O>C1COCC1>[Br:19][C:12]1[NH:11][C:10]2[C:9]3=[N:15][N:16]=[CH:17][N:8]3[C:7](=[O:18])[N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:14]=2[N:13]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCCn1c(=O)n2cnnc2c2[nH]cnc21
Solvent: C1CCOC1
Product: CCCCCn1c(=O)n2cnnc2c2[nH]c(Br)nc21
Temperature: 70 °C
Yield: 6.9 %

Procedure:
To a mixture of 6-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[3,4-i]purin-5-one (0.12 g, 0.487 mmol) in THF (5 mL) in a microwave reaction tube was added N-bromosuccinimide (0.20 g, 1.1 mmol). The mixture was heated at 70° C. in microwave oven for 12 min. After cooling down to room temperature, it was purified using preparative LCMS to provide the product (0.011 g). LCMS calculated for C11H14BrN6O (M+H): 325.0, 327.0; found: 325.0, 327.0.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][C@@H:10]([N:13]([CH2:21][CH2:22][CH3:23])[CH2:14][CH2:15][C:16]1[S:17][CH:18]=[CH:19][CH:20]=1)[CH2:9][CH2:8]2.CN(C)CC>CCCCCC.C(OCC)(=O)C>[OH:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][C@@H:10]([N:13]([CH2:21][CH2:22][CH3:23])[CH2:14][CH2:15][C:16]1[S:17][CH:18]=[CH:19][CH:20]=1)[CH2:9][CH2:8]2
Reactant: CCCN(CCc1cccs1)[C@H]1CCc2cccc(OC)c2C1
Agent: CCN(C)C
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCN(CCc1cccs1)[C@H]1CCc2cccc(O)c2C1

Procedure:
Synthesis worked according to the preparation of A7-1 when using 76 mg (0.23 mmol) (S)—N-(8-methoxytetralin-2-yl)-N-propyl-N-[2-(2-thienyl)ethyl]amine ((S)-A5-1: R═OMe, Cy=2-thienyl). Flash chromatography was done using hexane/ethyl acetate 10/1 in the presence of 1% (v/v) of dimethylethylamine to achieve compound 1b.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1)[C:6]([CH:24]([OH:26])[CH3:25])=[C:5]2[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C1COCC1.C(OC(C)C)(C)C>>[C:24]([C:6]1[N:7]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([S:20]([CH3:23])(=[O:21])=[O:22])=[CH:18][CH:19]=2)[C:8](=[O:12])[C:9]2[C:4]([C:5]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=2)(=[O:26])[CH3:25]
Reactant: CC(O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(S(C)(=O)=O)cc1
Solvent: CC(C)OC(C)C
Solvent: C1CCOC1
Product: CC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(S(C)(=O)=O)cc1

Procedure:
In the same manner as in Example 311, the title compound was synthesized using 6-bromo-3-(1-hydroxyethyl)-2-(4-methanesulfonylbenzyl)-4-phenyl-2H-isoquinolin-1-one. Crystals (THF-diisopropyl ether).
Reaction SMILES: [CH3:1][N:2]([CH2:10][CH:11]=O)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[NH:25][C:24]2[C:26]([CH:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)=[CH:27][CH:28]=[CH:29][C:23]=2[N:22]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CO>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[NH:25][C:24]2[C:26]([CH:30]3[CH2:35][CH2:34][N:33]([CH2:11][CH2:10][N:2]([CH3:1])[C:3](=[O:9])[O:4][C:5]([CH3:6])([CH3:7])[CH3:8])[CH2:32][CH2:31]3)=[CH:27][CH:28]=[CH:29][C:23]=2[N:22]=1
Reactant: CN(CC=O)C(=O)OC(C)(C)C
Reactant: COc1ccccc1-c1nc2cccc(C3CCNCC3)c2[nH]1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1ccccc1-c1nc2cccc(C3CCN(CCN(C)C(=O)OC(C)(C)C)CC3)c2[nH]1
Temperature: 25 °C
Yield: 25.8 %

Procedure:
To a solution of tert-butyl methyl(2-oxoethyl)carbamate (0.165 g, 0.950 mmol) in DCM (3 ml) was added a solution of 175 (0.292 g, 0.950 mmol) in MeOH (3.00 ml) followed by acetic acid (0.082 ml, 1.425 mmol) and after 1 hour of stirring at room temperature, sodium triacetoxyborohydride (0.242 g, 1.140 mmol) was added according to the procedure described for 59 (scheme 8, example 6, step 7) to give tert-butyl 2-(4-(2-(2-methoxyphenyl)-1H-benzo[d]imidazol-7-yl)piperidin-1-yl)ethyl(methyl)-carbamate (0.114 g, 0.245 mmol, 25.8% yield) as a white crusty solid. LRMS (ESI): (calc.) 464.6 (found) 465.5 (MH)+