Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:14][CH:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][CH2:23][CH2:24][OH:25])[CH2:17][CH2:16]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:26]([C:29]1[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=1)([O-:28])=[O:27].Cl.CN(C)CCCN=C=NCC.Cl>CN(C)C1C=CN=CC=1.O.C(Cl)(Cl)Cl>[CH:1]([O:14][CH:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:33](=[O:34])[C:32]2[CH:31]=[CH:30][C:29]([N+:26]([O-:28])=[O:27])=[CH:37][CH:36]=2)[CH2:17][CH2:16]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: OCCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(OCCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1)c1ccc([N+](=O)[O-])cc1
Yield: 76 %

Procedure:
To 4 mL of chloroform was added 4-[4-benzhydryloxy]piperidino]-1-butanol obtained from step 2 (0.11 g), 4-nitrobenzoic acid (0.1 g), 4-dimethylaminopyridine (DMAP, 0.12 g), and 1-[3-(dimethylamino)propyl]-3-ethylcarbodimide hydrochloride (0.1 g). The resulting mixture was allowed to react at room temperature for 3 hrs. before adding water to end the reaction. The resulting solution was acidified with 1N hydrochloric acid, and extracted by using chloroform. An organic solution layer was washed with 1N sodium hydroxide, dehydrated over magnesium sulfate, filtered, and concentrated under reduced pressure. The column chromatography was performed thereon, thereby obtaining crude yellowish liquid product (0. 12 g, 76% yield) of the title.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[C@@H:21]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[C:20]([CH3:29])([CH3:28])[O:19][C:18]4=[O:30])=[CH:13][CH:12]=3)=[N:9][N:10]=[C:4]2[CH:3]=1.[C:31]([Zn]C#N)#[N:32]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:29][C:20]1([CH3:28])[O:19][C:18](=[O:30])[N:17]([C:14]2[CH:13]=[CH:12][C:11]([C:8]3[N:5]4[CH:6]=[CH:7][C:2]([C:31]#[N:32])=[CH:3][C:4]4=[N:10][N:9]=3)=[CH:16][CH:15]=2)[C@H:21]1[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC1(C)OC(=O)N(c2ccc(-c3nnc4cc(I)ccn34)cc2)[C@H]1c1ccccc1
Reactant: N#C[Zn]C#N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC1(C)OC(=O)N(c2ccc(-c3nnc4cc(C#N)ccn34)cc2)[C@H]1c1ccccc1
Temperature: 85 °C
Yield: 35.6 %

Procedure:
To a 2 mL sealable tube were added (S)-3-(4-(7-iodo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)phenyl)-5,5-dimethyl-4-phenyloxazolidin-2-one (70 mg, 0.137 mmol), dicyanozinc (16.11 mg, 0.137 mmol, commercially available from Sigma-Aldrich, Milwaukee, Wis.) and Pd(Ph3P)4 (15.85 mg, 0.014 mmol, commercially available from Sigma-Aldrich, Milwaukee, Wis.) in DMF (457 μL). The mixture was purged with nitrogen for 5 minutes and then the tube was sealed. The vessel was heated to 85° C. in a microwave oven for 1 hour. LC-MS indicated complete conversion to the desired product. The final reaction mixture was passed through a syringe filter, and the material thus obtained was purified by reverse-phase preparative HPLC using 0.1% TFA in ACN/H2O, gradient 15% to 90% over 20 minutes to provide (S)-3-(4-(5,5-dimethyl-2-oxo-4-phenyloxazolidin-3-yl)phenyl)-[1,2,4]triazolo[4,3-a]pyridine-7-carbonitrile (20 mg, 0.049 mmol, 35.6% yield) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ 8.71 (t, J=1.37 Hz, 1H), 8.66 (dd, J=1.17, 7.34 Hz, 1H), 7.84-7.90 (m, 2H), 7.72-7.78 (m, 2H), 7.37-7.44 (m, 2H), 7.28-7.37 (m, 3H), 7.22 (dd, J=1.56, 7.34 Hz, 1H), 5.56 (s, 1H), 1.67 (s, 3H), 0.94 (s, 3H). m/z (ESI) 410.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[O:8][CH:7]=[C:6]([OH:9])[C:4](=[O:5])[CH:3]=1.CN(C)C.[F:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1>C1COCC1>[F:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([O:9][C:6]2[C:4](=[O:5])[CH:3]=[C:2]([CH3:1])[O:8][CH:7]=2)=[O:20])=[CH:17][CH:16]=1
Reactant: Cc1cc(=O)c(O)co1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: CN(C)C
Solvent: C1CCOC1
Product: Cc1cc(=O)c(OC(=O)c2ccc(F)cc2)co1
Reaction time: 0.08 h
Yield: 88 %

Procedure:
Allomaltol (600 mg; 4.76 mmol) was weighed out into a round bottom flask (100 ml) containing a stir-bar. The contents were diluted with anhydrous THF (˜20 ml) and stirred (˜5 min) to afford a solution. Next, trimethyl amine (840 μl) was added drop-wise and the contents stirred (˜5 min). 4-Fluorobenzoyl chloride (600 μl) was then added drop-wise, capped and stirred at room temperature. The reaction was monitored via silica gel TLC. Once complete, the reaction mixture was concentrated under reduced pressure and the contents purified by silica gel chromatography to afford 1.04 g crystalline product (4.19 mmol; 88% yield). This compound was found to have an EC50 of >1 mM. 1H NMR (DMSO-d6) δ 8.59 (s, 1H; 2-H); 8.18-8.13 (dd, 2H); 7.47-7.41 (t, 2H); 6.44 (s, 1H; 5-H); 2.34 (s, −3H; 6-CH3).
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][NH:11][C:10]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[C:9]=2[C:8]1=[O:30].[O:40]=[C:41]1[CH2:45][CH2:44][CH2:43][N:42]1[CH:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1>>[F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][NH:11][C:10]2[N:15]=[C:16]([N:49]3[CH2:48][CH2:47][CH:46]([N:42]4[CH2:43][CH2:44][CH2:45][C:41]4=[O:40])[CH2:51][CH2:50]3)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[C:9]=2[C:8]1=[O:30]
Reactant: O=C1CCCN1C1CCNCC1
Reactant: Cc1ccccc1-c1nc(S(C)(=O)=O)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCN2
Product: Cc1ccccc1-c1nc(N2CCC(N3CCCC3=O)CC2)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCN2
Yield: 96.8 %

Procedure:
In a similar manner to Example 1, 6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-2-(methylsulfonyl)-5-oxopyrimido[4,5-b][1,5]diazocine (Compound of Reference Example 19; 85.9 mg) was reacted with 4-(2-oxopyrrolidine-1-yl)piperidine (30.3 mg) to obtain 6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-5-oxo-2-[4-(2-oxopyrrolidine-1-yl)piperidine-1-yl]pyrimido[4,5-b][1,5]diazocine (96.0 mg, 97%).
Reaction SMILES: CN.C(CN)O.[NH:7]1[C:15]2[C:10](=[CH:11][C:12]([O:16][C@@H:17]3[CH2:22][CH2:21][C@H:20]([N:23]4C(=O)C5C(=CC=CC=5)C4=O)[CH2:19][CH2:18]3)=[CH:13][CH:14]=2)[CH:9]=[N:8]1>O>[NH:7]1[C:15]2[C:10](=[CH:11][C:12]([O:16][C@@H:17]3[CH2:22][CH2:21][C@H:20]([NH2:23])[CH2:19][CH2:18]3)=[CH:13][CH:14]=2)[CH:9]=[N:8]1
Reactant: O=C1c2ccccc2C(=O)N1[C@H]1CC[C@@H](Oc2ccc3[nH]ncc3c2)CC1
Agent: CN
Solvent: NCCO
Solvent: O
Product: N[C@H]1CC[C@@H](Oc2ccc3[nH]ncc3c2)CC1
Reaction time: 22 h
Yield: 56.2 %

Procedure:
A 30%-methylamine-ethanolamine solution (1.0 ml) was added to the cis-2-[4-(1H-indazol-5-yloxy)cyclohexyl]-1H-isoindole-1,3(2H)-dione (100 mg, 0.277 mmol) obtained in Example 380. After 22 hours, the mixture thus obtained was poured into water (20 ml) and extracted with ethyl acetate (20 ml×2), and the organic layer was dried over anhydrous magnesium sulfate. The organic layer dried was concentrated under reduced pressure, and the resulting residue was purified by a silica gel column chromatography (eluent: chloroform/methanol→chloroform/methanol/(1%-aqueous ammonia)) to obtain cis-4-(1H-indazol-5-yloxy)cyclo-hexanamine (36 mg, 57%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[CH:5][C:6]=1[C:7](OCC)=[O:8].Cl.Cl[C:21]([NH2:23])=[NH:22].CS(C)(=O)=O.[OH-].[NH4+]>O>[NH2:22][C:21]1[NH:23][C:7](=[O:8])[C:6]2[CH:5]=[C:4]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[S:3][C:2]=2[N:1]=1
Reactant: CCOC(=O)c1cc(-c2ccc(F)cc2)sc1N
Reactant: N=C(N)Cl
Agent: CS(C)(=O)=O
Agent: Cl
Agent: [NH4+]
Solvent: O
Product: Nc1nc2sc(-c3ccc(F)cc3)cc2c(=O)[nH]1
Temperature: 125 °C
Yield: 94.8 %

Procedure:
A mixture of ethyl 2-amino-5-(4-fluorophenyl)thiophene-3-carboxylate (0.3 g, 1.13 mmol), chloroformamidine hydrochloride (0.33 g, 2.83 mmol) and dimethylsulfone (0.53 g, 5.65 mmol) was heated at 120-130° C. for 30 minutes. After cooling down to room temperature, water (10 ml) was added and ammonium hydroxide was used to neutralize the suspension. The solid was filtered off, washed with water and dried. The crude residue was purified by flash chromatography on silica gel (CH2Cl2/MeOH 10:1) to yield the title compound as a white solid (0.28 g, 95%).
Reaction SMILES: [O:1]1[C:3]2([CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][CH3:12])=[O:10])[CH2:4]2)[CH2:2]1.[CH2:13]([NH2:15])[CH3:14]>>[CH2:13]([NH:15][CH2:2][C:3]1([OH:1])[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][CH3:12])=[O:10])[CH2:4]1)[CH3:14]
Reactant: CCN
Reactant: COC(=O)N1CCCC2(CO2)C1
Product: CCNCC1(O)CCCN(C(=O)OC)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
9.3 g (54.3 mmol) of methyl 5-aza-1-oxaspiro[2,5]octane-5-carboxylate are added dropwise to 50 ml of ethylamine solution (50% strength in water) and the mixture is stirred overnight at room temperature. It is then concentrated and the reside is distilled.
Reaction SMILES: [C:1](OCC)(=[O:3])[CH3:2].[H-].[Na+].[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:19])[CH3:18])=[CH:13][CH:12]=1.S(=O)(=O)(O)O>C1COCC1.C(O)C.C1OCCOCCOCCOCCOCCOC1>[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:19])[CH2:18][C:1](=[O:3])[CH3:2])=[CH:13][CH:12]=1
Reactant: CCOC(C)=O
Reactant: COc1ccc(C(C)=O)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=S(=O)(O)O
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(C(=O)CC(C)=O)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60.5 %

Procedure:
To 9.80 mL of ethyl acetate (100 mmol) in 40 mL dry THF at room temperature was added 2.0 g of 60% sodium hydride (49.9 mmol), 7.50 g of 4′-methoxyacetophenone (49.9 mmol), 100.0 mg of 18-crown-6 (0.40 mmol), and 2 drops of ethanol. After 30 minutes, the reaction was refluxed for 1 h, and then 100 mL of dry THF was added. After an additional 1 h, 30 mL THF was added. After 1 h the reaction was cooled to 0° C. and 25 mL of 10% aqueous sulfuric acid was added. The product was extracted with diethyl ether. The ether extracts were dried with Na2SO4, filtered, and concentrated in vacuo. The crude material was purified via silica gel chromatography eluting with 4:1 hexane:ethyl acetate to give 5.8 g of 1-(4-methoxyphenyl)butane-1,3-dione containing 30% starting material (via 1H NMR 42% yield).
Reaction SMILES: [CH2:1]([NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH:21]=O)=[CH:17][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[NH2:24][CH:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:26][OH:27]>>[CH2:1]([NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][NH:24][CH:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:26][OH:27])=[CH:17][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCNC(=O)c1ccc(C=O)cc1
Reactant: NC(CO)c1ccccc1
Product: CCCCCCCCCCCCNC(=O)c1ccc(CNC(CO)c2ccccc2)cc1
Yield: 83 %

Procedure:
The same procedure as employed in the preparation of Example 226 (step a) but using N-dodecyl-4-formylbenzamide and 2-amino-2-phenylethanol gave the title compound as a white powder (83%). 1H NMR (CD3OD, 300 MHz) δ 7.79 (d, J=8.3 Hz, 2H), 7.44-7.26 (m, 7H), 3.85-3.56 (m, 5H), 3.39 (t, J=7.2 Hz, 2H), 1.71-1.58 (m, 2H), 1.47-1.25 (m, 18H), 0.92 (t, J=6.8 Hz, 3H) M−(LC/MS(ESI)): 437.5; M+(LC/MS(ESI)): 439.6 HPLC (Condition A), Rt: 4.26 min (HPLC purity: 98.8%).
Reaction SMILES: C(OC([NH:8][C:9]([CH2:31][CH3:32])([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:16][CH:15]=1)[CH2:10][OH:11])=O)(C)(C)C.[ClH:33]>O1CCCC1.O1CCOCC1>[ClH:33].[NH2:8][C:9]([CH2:31][CH3:32])([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[CH:16][CH:15]=1)[CH2:10][OH:11]
Reactant: CCC(CO)(CCc1ccc(OCCCCc2ccccc2)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CCC(N)(CO)CCc1ccc(OCCCCc2ccccc2)cc1
Reaction time: 3 h

Procedure:
To a solution of 2-tert-butoxycarbonylamino-2-ethyl-4-(4-(4-phenylbutyloxy)phenyl)butanol (3.2 g) in tetrahydrofuran (10 ml) was added a solution of 4M hydrochloric acid in dioxane (10 ml) and the mixture was stirred for 3 hours. The solvent was distilled away to give the subject compound (3 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH-].[K+].Cl.Cl[CH2:15][CH2:16][N:17]([CH2:20][CH3:21])[CH2:18][CH3:19].O>CN(C)C=O>[CH2:16]([N:17]([CH2:20][CH3:21])[CH2:18][CH2:19][S:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)[CH3:15]
Reactant: O=[N+]([O-])c1ccc(S)cc1
Reactant: CCN(CC)CCCl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)CCSc1ccc([N+](=O)[O-])cc1
Temperature: 100 °C

Procedure:
To a solution of 7.0 g (45 mmol) of 4-nitrothiophenol and 22.5 mL of 4N aqueous potassium hydroxide in 40 mL of dimethylformamide add a solution of 9.53 g (55 mmol) of 2-chloro-N,N-diethylethanamine hydrochloride in 40 mL of dimethylformamide. Heat the reaction mixture for about 3 h at 100° C. After this time, cool the mixture to room temperature and add 150 mL of water. Extract th aqueous mixture with 3×200 mL of methylene chloride. Combine the methylene chloride extracts and extract these with 200 mL of 1N aqueous hydrochloric acid. Make the acid extract basic with saturated aqueous sodium bicarbonate solution
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:16][CH2:17][CH2:18][CH3:19])=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[S:25](Cl)(=[O:27])=[O:26]>N1C=CC=CC=1>[CH2:17]([S:16][C:5]1[CH:4]=[CH:3][C:2]([NH:1][S:25]([C:21]2[S:20][CH:24]=[CH:23][CH:22]=2)(=[O:27])=[O:26])=[C:10]2[C:6]=1[CH:7]=[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:9]2)[CH2:18][CH3:19]
Reactant: CCCSc1ccc(N)c2[nH]c(C(=O)OCC)cc12
Reactant: O=S(=O)(Cl)c1cccs1
Solvent: c1ccncc1
Product: CCCSc1ccc(NS(=O)(=O)c2cccs2)c2[nH]c(C(=O)OCC)cc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.6 %

Procedure:
To a mixed solution of ethyl 7-amino-4-(propylthio)-1H-indole-2-carboxylate (0.90 g) and pyridine (10 mL) was added 2-thiophenesulfonyl chloride (0.72 g) under ice-cooling, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate, washed with aqueous citric acid solution, aqueous sodium hydrogencarbonate solution and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:9-1:3), and the obtained crystals were recrystallized from ethyl acetate-hexane to give the title compound (0.64 g, yield 47%) as colorless needle crystals. melting point 150-151° C.
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:6]=2[NH:5][CH2:4][CH:3]1[NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].Br[CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26].C(=O)([O-])[O-].[K+].[K+]>CO>[O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:6]=2[N:5]([CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])[CH2:4][CH:3]1[NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]
Reactant: CC(C)=CCBr
Reactant: Cc1ccc2c(c1)NC(=O)C(NC(=O)OC(C)(C)C)CN2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)=CCN1CC(NC(=O)OC(C)(C)C)C(=O)Nc2cc(C)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
2-Oxo-3-tert-butoxycarbonylamino-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (2.00 g) obtained from Referential Example 7 was suspended in methanol (20 ml), 1-bromo-3-methyl-2-butene (1.18 g) and potassium carbonate (997 mg) were added, the mixture was stirred for 2 hours at room temperature. The reaction mixture was concentrated under reduced pressure, water (100 ml) was added, and extracted with methylene chloride. The organic layer was washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure, to thereby obtain 1.85 g of the titled compound (Yield: 71.4%).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:10]1([CH3:19])[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+].C1C=C(S([O-])(=O)=O)C=C(P(C2C=CC=C(S([O-])(=O)=O)C=2)C2C=CC=C(S([O-])(=O)=O)C=2)C=1.[Na+].[Na+].[Na+].O>CC1C=CC(C)=CC=1.N(CCO)(CCO)CCO.O.CS(C)=O.[Pd](Cl)Cl>[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[C:13]1[CH:14]=[CH:15][C:10]([CH3:19])=[CH:11][CH:12]=1)#[N:5]
Reactant: Cc1ccc(B(O)O)cc1
Reactant: N#Cc1ccccc1Cl
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])c1cccc(P(c2cccc(S(=O)(=O)[O-])c2)c2cccc(S(=O)(=O)[O-])c2)c1
Solvent: OCCN(CCO)CCO
Solvent: Cc1ccc(C)cc1
Solvent: CS(C)=O
Product: Cc1ccc(-c2ccccc2C#N)cc1
Yield: 84.6 %

Procedure:
15 g of 2-chlorobenzonitrile, 14.8 g of p-tolueneboronic acid and 28.9 g of sodium carbonate in 50 ml of p-xylene, 40 ml of triethanolamine and 10 ml of water were heated to 120° C. At 80° C., a mixture of 38.66 g of palladium(II) chloride and 1.1 ml of TPPTS/H2O solution (0.6 molar) in 2.5 ml of DMSO was added. After the reaction was complete, the phases were separated. The aqueous phase was washed with 50 ml of toluene. The combined organic phases were washed with 20 ml of water and subsequently dried over sodium sulfate. Crystallization from n-heptane gave 17.8 g of 2-cyano-4'-methylbiphenyl.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]([O:17]CC)=[O:16])=[C:10]3[CH2:9][N:8]([CH3:20])[C:7](=[O:21])[C:6]=2[CH:22]=1.[OH-].[Na+].Cl>C(O)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]([OH:17])=[O:16])=[C:10]3[CH2:9][N:8]([CH3:20])[C:7](=[O:21])[C:6]=2[CH:22]=1
Reactant: CCOC(=O)c1ncn2c1CN(C)C(=O)c1cc(F)ccc1-2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CN1Cc2c(C(=O)O)ncn2-c2ccc(F)cc2C1=O

Procedure:
A solution of 3.03 g (10 mmol) of ethyl 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]-benzodiazepine-3-carboxylate and 0.44 g (11 mmol) of sodium hydroxide in 20 ml of ethanol and 10 ml of water is heated to boiling under reflux for 30 minutes. Subsequently, the mixture is treated with 11 ml of 1 N hydrochloric acid and concentrated to half of the volume. The precipitated crystals are filtered off under suction and dried. There is obtained 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid of decomposition point 279°.
Reaction SMILES: IC1C=CC=CC=1S([O-])(=O)=O.[Na+].OOS([O-])=O.[K+].[CH3:19][CH2:20][CH2:21][CH2:22][CH:23]([OH:28])[CH2:24][CH2:25][CH2:26][CH3:27]>C(#N)C>[CH3:19][CH2:20][CH2:21][CH2:22][C:23](=[O:28])[CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCC(O)CCCC
Agent: O=S(=O)([O-])c1ccccc1I
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CC#N
Product: CCCCC(=O)CCCC
Temperature: 70 °C
Reaction time: 3 h

Procedure:
9.2 mg (0.03 mmol) of sodium 2-iodobenzenesulfonate prepared by Preparation Example 4, 1.48 g (2.4 mmol) of Oxone (registered trademark) and 433 mg (3 mmol) of 5-nonanol were added to 3.75 ml of acetonitrile, and the mixture was heated at 70° C. while being stirred for three hours. The later treatment was carried out in the same way as in Example 1, and then 5-nonanone was obtained. The yield of the obtained 5-nonanone was determined and the result is shown in Table 1.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=2)[O:6][CH:7]=1.[NH:20]1[CH2:26][CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[CH3:19][O:18][C:10]1[CH:9]=[C:8]([C:5]2[O:6][CH:7]=[C:3]([CH2:2][N:20]3[CH2:26][CH2:25][CH2:24][N:23]([CH2:2][C:3]4[N:4]=[C:5]([C:8]5[CH:9]=[C:10]([O:18][CH3:19])[C:11]([O:16][CH3:17])=[C:12]([O:14][CH3:15])[CH:13]=5)[O:6][CH:7]=4)[CH2:22][CH2:21]3)[N:4]=2)[CH:13]=[C:12]([O:14][CH3:15])[C:11]=1[O:16][CH3:17]
Reactant: C1CNCCNC1
Reactant: COc1cc(-c2nc(CCl)co2)cc(OC)c1OC
Product: COc1cc(-c2nc(CN3CCCN(Cc4coc(-c5cc(OC)c(OC)c(OC)c5)n4)CC3)co2)cc(OC)c1OC

Procedure:
4-Chloromethyl-2-(3,4,5-trimethoxyphenyl)oxazole (111 mg) and homopiperazine (18 mg) were treated in the same manner in Example 1 to obtain the title compound as a free base.
Reaction SMILES: CN.[CH2:3]([N:5](CC)CC)C.[S:10](F)(=[O:19])([C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=1)=[O:11]>C(O)C>[CH3:3][NH:5][S:10]([C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=1)(=[O:19])=[O:11]
Reactant: Nc1ccc(S(=O)(=O)F)cc1
Reactant: CCN(CC)CC
Agent: CN
Solvent: CCO
Product: CNS(=O)(=O)c1ccc(N)cc1
Temperature: 80 °C
Reaction time: 18 h
Yield: 78.1 %

Procedure:
Methylamine (3 ml of a 33% solution in ethanol) and then triethylamine (0.159 ml, 1.1 mmol) was added to sulphanilyl fluoride (200 mg, 1.1 mmol), and the mixture heated at 80° C. for 6 hours then at ambient temperature for 18 hours. The volatiles were removed by evaporation and the residue azeotroped with toluene to give the title compound (160 mg, 76% yield). NMR: 2.30 (s, 3H), 5.85 (s, 2H), 6.60 (d, 2H), 7.39 (d, 2H); m/z: 187 [MH]+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][CH2:11][C@H:12]([OH:24])[CH2:13][N:14]2[CH2:23][CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:9])[CH:3]=1.[NH2:25][CH:26]1[CH2:31][CH2:30][N:29]([C:32](=[O:34])[CH3:33])[CH2:28][CH2:27]1.CCN(CC)CC>CC(O)C>[C:32]([N:29]1[CH2:30][CH2:31][CH:26]([NH:25][C:2]2[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][CH2:11][C@H:12]([OH:24])[CH2:13][N:14]3[CH2:23][CH2:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH2:15]3)=[O:9])[CH:3]=2)[CH2:27][CH2:28]1)(=[O:34])[CH3:33]
Reactant: CC(=O)N1CCC(N)CC1
Reactant: O=C(NC[C@H](O)CN1CCc2ccccc2C1)c1cc(Cl)ncn1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CC(=O)N1CCC(Nc2cc(C(=O)NC[C@H](O)CN3CCc4ccccc4C3)ncn2)CC1
Yield: 130573.4 %

Procedure:
The solution of (S)-6-chloro-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)pyrimidine-4-carboxamide (190 g, 0.55 mmol) and 1-(4-aminopiperidin-1-yl)ethanone (78 g), Et3N (100 g, 1 mol) in i-PrOH (2000 mL) was stirred at 60° C. for 16 h, at which time LCMS showed completed conversion. The mixture was concentrated and the residue was purified by flash chromatography to give the crude product. Four batches were run in parallel and produced a combined crude product weight of 482 g. This crude was further purified on preparative HPLC to give the title compound (325 g, >98% purity, free base form). 1H NMR (400 MHz, MeOD-d4) 8.26 (s, 1H), 7.15-7.02 (m, 5H), 4.46 (m, 1H), 4.15-4.07 (m, 2H), 3.88 (m, 1H), 3.74 (s, 2H), 3.53 (m, 2H), 3.33 (m, 1H), 2.95-2.86 (m, 5H), 2.68 (m, 2H), 2.14-2.01 (m, 5H), 1.48-1.42 (m, 2H); LCMS (m/z): 453.3 [M+H]+
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([C:11]([OH:13])=O)=[CH:7][CH:8]=2)[NH:3]1.[NH:14]1[CH2:19][CH2:18][CH2:17][C@@H:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[CH2:26][C@H:15]12.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[N:14]1([C:11]([C:6]2[CH:5]=[C:4]3[C:9]([CH2:10][C:2](=[O:1])[NH:3]3)=[CH:8][CH:7]=2)=[O:13])[CH2:19][CH2:18][CH2:17][C@@H:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[CH2:26][C@H:15]12
Reactant: c1ccc2c(c1)C[C@@H]1NCCC[C@H]21
Reactant: O=C1Cc2ccc(C(=O)O)cc2N1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C1Cc2ccc(C(=O)N3CCC[C@@H]4c5ccccc5C[C@@H]43)cc2N1
Yield: 34 %

Procedure:
The title compound is prepared from 2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid and cis-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 34% of theory; LC (method 4): tR=1.88 min; Mass spectrum (ESI+): m/z=333 [M+H]+.