Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1=[C:3]([Cl:9])[C:4]([O:6][C:7]1=[O:8])=[O:5].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([CH:20]([CH3:22])[CH3:21])[CH2:18][NH2:19])=[CH:13][CH:12]=1.O>C(O)(=O)C>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([CH:17]([CH:20]([CH3:22])[CH3:21])[CH2:18][N:19]=[C:4]([OH:5])/[C:3](/[Cl:9])=[C:2](/[Cl:1])\[C:7]([OH:6])=[O:8])=[CH:15][CH:16]=1
Reactant: O=C1OC(=O)C(Cl)=C1Cl
Reactant: CC(C)C(CN)c1ccc(Cl)cc1
Solvent: O
Solvent: CC(=O)O
Product: CC(C)C(CN=C(O)/C(Cl)=C(/Cl)C(=O)O)c1ccc(Cl)cc1
Temperature: 20 °C
Yield: 58.1 %

Procedure:
16.7 g (0.1 mol) of dichloromaleic anhydride and 19.7 g (0.1 mol) of 2-(4-chlorophenyl)-3-methylbutylamine are stirred in 100 ml glacial acetic acid at 120° C. for 4 hours. The mixture is cooled to 20° C. and 10 ml of water are added. A colorless precipitate separates out, and is filtered off with suction and dried. 21.2 g of dichloromaleic acid N-[2-(4-chlorophenyl)-3-methylbutyl]imide of melting point 91°-92° C. are obtained. A further 10.4 g of imide can also be isolated by stirring the mother liquor with water. The total yield is: 91.3% of theory.
Reaction SMILES: [NH:1]([C:13]([O:15][CH2:16][CH:17]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]2[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:14])[C@H:2]([C:10](O)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.ON1C(=O)CCC1=O.C1CCC(N=C=NC2CCCCC2)CC1.C(N(CC)CC)C.[NH2:60][C@H:61]([C:74]([O:76][C:77]([CH3:80])([CH3:79])[CH3:78])=[O:75])[CH2:62][CH2:63][CH2:64][CH2:65][NH:66][C:67]([O:69][C:70]([CH3:73])([CH3:72])[CH3:71])=[O:68].Cl>ClCCl>[NH:1]([C:13]([O:15][CH2:16][CH:17]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]2[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:14])[C@H:2]([C:10]([NH:60][C@H:61]([C:74]([O:76][C:77]([CH3:80])([CH3:79])[CH3:78])=[O:75])[CH2:62][CH2:63][CH2:64][CH2:65][NH:66][C:67]([O:69][C:70]([CH3:71])([CH3:72])[CH3:73])=[O:68])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](N)C(=O)OC(C)(C)C
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of Fmoc-Phe-OH (6, 5.00 g, 12.9 mmol) in dichloromethane (100 mL) were added HOSu (1.56 g, 13.6 mmol) and DCC (2.93 g, 14.2 mmol). The resulting suspension was stirred at room temperature for 3 h. Then, triethylamine (1.83 mL, 13.2 mmol) and H-Lys(Boc)-OtBu.HCl (4.46 g, 13.2 mmol) were added consecutively, and the resulting suspension was stirred overnight. The reaction mixture was filtered, and the filtrate was washed with 10% aqueous citric acid, water, a saturated aqueous NaHCO3 solution, and brine. The organic layer was dried over Na2SO4, filtered, and concentrated. This gave crude 8 (8.97 g, max. 12.91 mmol, 100%) as a white solid. 1H NMR (300 MHz, CDCl3) δ: 1.10-1.90 (m, 6H, CH2-Lys), 1.41 (s, 18H, tBu), 3.01-3.15 (m, 4H, N—CH2-Lys+CH2-Phe), 4.19 (t, 1H, J=6.8 Hz, CH-Fmoc), 4.25-4.55 (m, 4H, 2×α-H+ CH2-Fmoc), 7.19-7.35 (m, 7H, HAr), 7.38 (t, 2H, J=7.4 Hz, HAr), 7.51 (m, 2H, HAr), 7.72 (d, 2H, J=7.5 Hz, HAr).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH:15]=O)[O:10][N:9]=2)=[CH:4][CH:3]=1.[CH2:17]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][N:27]3[CH2:28][CH2:29][N:24]([CH2:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:25][CH2:26]3)[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: O=CCCc1cc(-c2ccc(F)cc2)no1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Fc1ccc(-c2cc(CCCN3CCN(Cc4ccccc4)CC3)on2)cc1
Yield: 75 %

Procedure:
About 2 min after dissolving 3-[3-(4-fluorophenyl)isoxazol-5-yl]propanal (20 mg, 0.09 mmol) and 1-benylpiperazine (15.9, 0.09 mmol) in 2 mL of dry methylene chloride, were added NaBH(OAc)3 (58 mg, 0.27 mmol) and molecular sieves (5 beads). The reaction mixture was reacted for 22.5 hr and followed the same processes as in Example 1 to obtain 25.6 mg (74.0%) of the target compound.
Reaction SMILES: [NH2:1][N:2]1[C:6]([C:7]#[N:8])=[CH:5][CH:4]=[C:3]1[CH:9]1[CH2:12][N:11]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:10]1.C(O)(=O)C.[CH:27](N)=[NH:28]>C(O)CCC>[NH2:8][C:7]1[C:6]2=[CH:5][CH:4]=[C:3]([CH:9]3[CH2:10][N:11]([C:13]([O:15][CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[O:14])[CH2:12]3)[N:2]2[N:1]=[CH:27][N:28]=1
Reactant: N=CN
Reactant: N#Cc1ccc(C2CN(C(=O)OCc3ccccc3)C2)n1N
Solvent: CCCCO
Solvent: CC(=O)O
Product: Nc1ncnn2c(C3CN(C(=O)OCc4ccccc4)C3)ccc12
Temperature: 25 °C
Yield: 39.8 %

Procedure:
A solution of benzyl 3-(1-amino-5-cyano-1H-pyrrol-2-yl)azetidine-1-carboxylate (575 mg, 1.94 mmoL) and formamidine acetate (2.02 g, 19.4 mmol) in 1-butanol (8 mL) was stirred at 120° C. for 4 hours. The mixture was then cooled to rt and was partitioned between EtOAc (25 mL) and H2O (25 mL). The layers were separated and the aqueous layer was further extracted with EtOAc (2×25 mL). The combined organic layers were washed with brine, dried (Na2SO4) and concentrated. The crude material was purified by ISCO® chromatography using 3:1 ethyl acetate/hexanes to obtain 250 mg (40%) of the desired product. ES-MS m/z 324.34 [M+H]+, HPLC RT (min) 2.30.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][C:10]2[C:11]3[N:19]=[C:18]([NH:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([C:27]([OH:29])=O)[CH2:23][CH2:22]4)[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)=[CH:4][C:3]=1[Cl:30].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=[CH:42][CH:43]=[CH:44][C:39]=2[N:38]=N1.N1CCCC1>C(N(CC)CC)C>[NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][C:10]2[C:11]3[N:19]=[C:18]([NH:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([C:27]([N:38]5[CH2:39][CH2:44][CH2:43][CH2:42]5)=[O:29])[CH2:23][CH2:22]4)[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)=[CH:4][C:3]=1[Cl:30]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Nc1c(Cl)cc(Nc2ncnc3cnc(N[C@H]4CC[C@H](C(=O)O)CC4)nc23)cc1Cl
Agent: F[B-](F)(F)F
Solvent: C1CCNC1
Solvent: CCN(CC)CC
Product: Nc1c(Cl)cc(Nc2ncnc3cnc(N[C@H]4CC[C@H](C(=O)N5CCCC5)CC4)nc23)cc1Cl

Procedure:
Prepared from 4-[(4-amino-3,5-dichlorophenyl)amino]-6-[(trans-4-carboxycyclohexyl)amino]pyrimido[5,4-d]pyrimidine by reaction with O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate, triethylamine and pyrrolidine. Melting point: 228°-230° C,; Rf : 0.43 (silica gel; petroleum ether/ethyl acetate/methanol=10:10:4) Calculated: C 55.09 H 5.23 N 22.35; Found: 55.07 5.19 22.33 14.22
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH:9]([CH3:11])[CH3:10])[C:6](=[S:12])[NH:5][C:4](=[O:13])[CH:3]=1.[N:14]([O-])=[O:15].[Na+].O>C(O)(=O)C>[NH2:1][C:2]1[N:7]([CH2:8][CH:9]([CH3:11])[CH3:10])[C:6](=[S:12])[NH:5][C:4](=[O:13])[C:3]=1[N:14]=[O:15]
Reactant: CC(C)Cn1c(N)cc(=O)[nH]c1=S
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)Cn1c(N)c(N=O)c(=O)[nH]c1=S
Temperature: 75 °C
Yield: 96.4 %

Procedure:
6-Amino-1-isobutyl-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (1.0 g, 5.0 mmol) was suspended in 10% acetic acid (20 mL). Sodium nitrite (0.38 g, 5.5 mmol) was added and the resulting mixture was heated at 75° C. for 1 h. The reaction mixture became first pink and then purple. The purple mixture was cooled to room temperature. Then water (20 mL) was added and the purple solid was collected by filtration and washed with water to give the title compound (1.1 g, 92% yield). This solid was used in the following step without further purification.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]([OH:24])=[O:23])=[CH:17][CH:16]=2)=[CH:10][CH:9]=1>O.[OH-].[Na+]>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]([OH:24])=[O:23])=[CH:17][CH:16]=2)=[O:2])=[CH:10][CH:9]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: O=C(O)Cc1ccc(Sc2ccc(Cl)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)Cc1ccc(S(=O)c2ccc(Cl)cc2)cc1
Reaction time: 8 h

Procedure:
To a solution of 4.49 g of sodium metaperiodate in 80 ml of water is added a solution of 5.57 g of [p-(p-chlorophenylthio)phenyl]acetic acid in 75 ml of 1.75% NaOH. A white solid precipitates immediately. After stirring overnight the mixture is filtered and the filtrate is acidified with concentrated HCl to give a white solid. This product, which contains some starting material, is reworked, as above, to yield the pure product. Recrystallization from chloroform-hexane affords white crystals, mp 139°-141° C. and 144°-148.5° C.
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[C:10]([C:26]#[N:27])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[CH:12]=2)=[O:7])CCC.[NH2:28][CH2:29][C:30]1([C:34]([OH:36])=[O:35])[CH2:33][CH2:32][CH2:31]1.C[O-].[Na+].CO.Cl>O>[C:26]([C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[C:13]([O:19][CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:12]=2)[C:17]([OH:18])=[C:8]([C:6]([NH:28][CH2:29][C:30]2([C:34]([OH:36])=[O:35])[CH2:33][CH2:32][CH2:31]2)=[O:7])[N:9]=1)#[N:27]
Reactant: CCCCOC(=O)c1nc(C#N)c2cc(OC3CCCCC3)ccc2c1O
Reactant: NCC1(C(=O)O)CCC1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: N#Cc1nc(C(=O)NCC2(C(=O)O)CCC2)c(O)c2ccc(OC3CCCCC3)cc12
Yield: 35.2 %

Procedure:
A mixture of 1-cyano-7-cyclohexyloxy-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester (20 mg, 0.054 mmol) and 1-aminomethyl-cyclobutanecarboxylic acid (37 mg, 0.22 mmol) in 0.5 M NaOMe/MeOH solution (0.84 mL, 0.42 mmol) was microwaved at 120° C. for 2 h. Reaction mixture was diluted with water (50 mL) and acidified by 1 N HCl to pH=3-4. Precipitate was collected, rinsed with water and dried. Crude product was purified by silica gel chromatography, eluting with 10-100% EtOAc/hexanes, to provide the title compound 8 mg (0.019 mmol) in 35% yield. LC-MS ESI−: 422.03 (M−1)−.
Reaction SMILES: CC(C)([O-])C.[K+:6].[C:7]([C:9]1([CH2:15][C:16]([OH:18])=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)#[N:8]>O1CCCC1>[C:7]([C:9]1([CH2:15][C:16]([O-:18])=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)#[N:8].[K+:6]
Reactant: N#CC1(CC(=O)O)CCCCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#CC1(CC(=O)[O-])CCCCC1
Reaction time: 0.17 h
Yield: 100.7 %

Procedure:
To a 250-mL flask under nitrogen is added 14.8 g (0.13 mol) of potassium tertiary butoxide followed by 74 mL of tetrahydrofuran. The solution is stirred for 10 minutes, suction filtered, and washed using 50 mL of tetrahydrofuran. The filtrates are combined and transferred into an additional funnel on a separate 250-mL flask containing 20 g (0.12 mol) of dried 1-cyanocyclohexaneacetic acid and 100 mL of tetrahydrofuran. The potassium tertiary butoxide solution is added dropwise over 5 minutes to the previous solution. The precipitate is cooled in an ice bath, suction filtered, and washed with 25 mL of cold tetrahydrofuran. The filter cake is dried in a vacuum oven at 50° C. for 16 hours to give 24.8 g of potassium 1-cyanocyclohexaneacetate as a white crystalline solid; mp 196°-199° C.
Reaction SMILES: [CH3:1][C:2]([CH3:4])=O.C(O)(=O)C.[NH2:9][C:10]1[N:15]=[CH:14][CH:13]=[CH:12][N:11]=1>C(O)C>[CH:2]([NH:9][C:10]1[N:15]=[CH:14][CH:13]=[CH:12][N:11]=1)([CH3:4])[CH3:1]
Reactant: CC(C)=O
Reactant: Nc1ncccn1
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)Nc1ncccn1
Reaction time: 8 h

Procedure:
Ethanol (200 mL), acetone (21 mL, 1.5 eq.), and glacial acetic acid (3.0 mL, 0.28 eq.) were added to the aminopyrimidine solution in the hydrogenation flask. After evacuating and purging, the flask was pressurized with H2 (60 psi). The reductive amination was allowed to proceed overnight. TLC on silica using EtOAc as the eluant gave an Rf=0.41 (streaky) for the isopropylamino-pyrimidine and an Rf=0.11 for the starting aminopyrimidine carbamate. Both TLC and LC/MS confirmed complete reaction with virtually no bis-isopropylaminopyrimidine produced. If necessary, HPLC can be used as an alternative means to monitor progress of the reaction. The crude reaction solution was diluted with EtOAc (1 L) and filtered through a pad of basic alumina (400 mL). The alumina was rinsed with EtOAc (200 mL) and EtOH (200 mL) and the combined organic solutions were concentrated in vacuo. The flask was vented under N2. The viscous oil was redissolved in anhydrous toluene (700 mL) and concentrated. After venting the flask under nitrogen, the product was dried again by azeotropic removal of another 400 mL of toluene. A viscous reddish-brown oil was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([CH:13]2[O:18][CH2:17][CH2:16][NH:15][CH2:14]2)[NH:11][CH:12]=1.[Cl:19][C:20]1[CH:25]=[C:24](Cl)[N:23]=[C:22]([NH2:27])[N:21]=1.CCN(C(C)C)C(C)C>C(O)C>[Cl:19][C:20]1[CH:25]=[C:24]([N:15]2[CH2:16][CH2:17][O:18][CH:13]([C:10]3[NH:11][CH:12]=[C:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])[N:9]=3)[CH2:14]2)[N:23]=[C:22]([NH2:27])[N:21]=1
Reactant: Clc1ccccc1-c1c[nH]c(C2CNCCO2)n1
Reactant: Nc1nc(Cl)cc(Cl)n1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(Cl)cc(N2CCOC(c3nc(-c4ccccc4Cl)c[nH]3)C2)n1
Yield: 30.7 %

Procedure:
A solution of 2-[4-(2-chlorophenyl)-1H-imidazol-2-yl]morpholine (250 mg, 0.833 mmol), 4,6-dichloro-2-pyrimidinamine (137 mg, 0.833 mmol) and Hunig's base (0.36 mL, 2.08 mmol) in ethanol (80 mL) was heated at 85° C. for 3 hours. The reaction mixture was filtered, and the filtrate was concentrated. The resulting residue was purified by silica gel chromatography using 50% EtOAc in petroleum ether to afford the title compound (100 mg) as a white solid. LC-MS (ES) m/z=391, 393 [M+H]+.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH2:5]([O:7][C:8]([CH:10]1[O:14][C:13]2[CH:15]=[CH:16][C:17]([CH3:19])=[CH:18][C:12]=2[O:11]1)=[O:9])[CH3:6].[CH2:20]([N:23]([CH2:36][CH2:37][CH3:38])[S:24]([C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1)(=[O:26])=[O:25])[CH2:21][CH3:22]>ClCCCl>[CH2:5]([O:7][C:8]([CH:10]1[O:11][C:12]2[CH:18]=[C:17]([CH3:19])[C:16]([C:31](=[O:32])[C:30]3[CH:34]=[CH:35][C:27]([S:24](=[O:25])(=[O:26])[N:23]([CH2:20][CH2:21][CH3:22])[CH2:36][CH2:37][CH3:38])=[CH:28][CH:29]=3)=[CH:15][C:13]=2[O:14]1)=[O:9])[CH3:6]
Reactant: CCCN(CCC)S(=O)(=O)c1ccc(C(=O)Cl)cc1
Reactant: CCOC(=O)C1Oc2ccc(C)cc2O1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CCCN(CCC)S(=O)(=O)c1ccc(C(=O)c2cc3c(cc2C)OC(C(=O)OCC)O3)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
46.6 g (0.35 mol) of aluminum chloride are added portionwise within 25 minutes at 5° to 10° C., with stirring, to a solution of 31.2 g (0.15 mol) of 5-methyl-1,3-benzodioxole-2-carboxylic acid ethyl ester and 54.7 g (0.18 mol) of 4-(dipropylsulfamoyl)-benzoyl chloride in 350 ml of 1,2-dichloroethane. The reaction mixture is then stirred for a further 90 minutes at 5°-10° C. and for 30 minutes at room temperature, after which time all the aluminum chloride has been dissolved. After standing for about 24 hours at room temperature, the reaction mixture is poured into about 2 kg of an ice/water mixture. The organic phase is separated; it is subsequently washed once with 2N hydrochloric acid, twice with water, once with 1N sodium bicarbonate solution and again twice with water; it is afterwards dried over sodium sulfate and concentrated by evaporation in vacuo. The 5-[4-(dipropylsulfamoyl)-benzoyl]-6-methyl- 1,3-benzodioxole-2-carboxylic acid ethyl ester obtained as residue melts at 97°-99° C. after recrystallisation.
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[S:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:6][CH:5]=1.[OH-].[K+]>C1COCC1.O>[CH2:21]([S:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH2:13][CH2:12][CH2:11][NH:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:28])=[O:2])=[CH:5][N:6]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COC(=O)c1ccc(NCCCc2ccccc2SCc2ccccc2)nc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(NCCCc2ccccc2SCc2ccccc2)nc1
Temperature: 50 °C

Procedure:
To a solution of the ester of Example 6 in THF (0.8 mL) was added a solution of KOH (14 mg, 0.255 mmol) in H2O (0.2 mL). The mixture was stirred at 50° C., then concentrated to remove THF. The aqueous phase was washed with ethyl ether, then the aqueous phase was acidified until pH 3-4 was reached. The acidified solution was extracted with Et2O or EtOAc (3×), dried over MgSO4, filtered and concentrated in vacuo to give a white solid.
Reaction SMILES: [ClH:1].[N:2]1([C:9]2[CH:10]=[C:11]([NH:17][S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][CH:28]([F:30])[F:29])(=[O:20])=[O:19])[CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH2:8][CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH2:31]=O>[BH4-].[Na+].C(#N)C>[ClH:1].[F:29][CH:28]([F:30])[O:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[S:18]([NH:17][C:11]1[CH:12]=[CH:13][C:14]([O:15][CH3:16])=[C:9]([N:2]2[CH2:8][CH2:7][CH2:6][N:5]([CH3:31])[CH2:4][CH2:3]2)[CH:10]=1)(=[O:20])=[O:19]
Reactant: COc1ccc(NS(=O)(=O)c2ccccc2OC(F)F)cc1N1CCCNCC1
Reactant: C=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC#N
Product: COc1ccc(NS(=O)(=O)c2ccccc2OC(F)F)cc1N1CCCN(C)CC1

Procedure:
The title compound was prepared from the title compound of Example 3 under reductive amination conditions employing an aqueous solution of formaldehyde and sodium borohydride in acetonitrile as solvent.
Reaction SMILES: [CH3:1][O:2][C:3]1(/[CH:9]=[CH:10]/[CH2:11]O)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.[S:13]([O-])(=[O:16])(=[O:15])[CH3:14]>>[CH3:1][O:2][C:3]1(/[CH:9]=[CH:10]/[CH2:11][S:13]([CH3:14])(=[O:16])=[O:15])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1
Reactant: CS(=O)(=O)[O-]
Reactant: COC1(/C=C/CO)CCOCC1
Product: COC1(/C=C/CS(C)(=O)=O)CCOCC1

Procedure:
4-methoxy-4-(3-hydroxy-trans-prop-1-enyl)tetrahydropyran, prepared as in step 4, was convened to the corresponding mesylate according to the methodof Crossland and Servis, J. Org. Chem., 35, 3195-3196 (1970).
Reaction SMILES: ClC1[CH:24]=[CH:23][C:5]2N(C)[C:7](=[O:21])[C:8]3[CH:15]=[N:14][C:13]4[N:16]([CH2:19][CH3:20])[N:17]=[CH:18][C:12]=4[C:9]=3[N:10](C)[C:4]=2C=1.CCCCC[C@H](O)/C=C/[C@@H]1[C@@H](CCCCCC[C:45]([OH:47])=[O:46])C(=O)C[C@H]1O>>[CH2:4]([NH:10][C:9]1[C:8]2[C:7](=[O:21])[O:46][CH:45]([OH:47])[C:15]=2[N:14]=[C:13]2[N:16]([CH2:19][CH3:20])[N:17]=[CH:18][C:12]=12)[CH2:5][CH2:23][CH3:24]
Reactant: CCCCC[C@H](O)/C=C/[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(=O)O
Reactant: CCn1ncc2c3c(cnc21)C(=O)N(C)c1ccc(Cl)cc1N3C
Product: CCCCNc1c2c(nc3c1cnn3CC)C(O)OC2=O

Procedure:
10-Chloro-3-ethyl-7,12-dimethyl-7,12-dihydropyrazolo-[4',3':5,6]pyrido[4,3-b][1,5]benzodiazepin-6(3H)-one, said PGE1 being present in a concentration of from about 10-6 molar to about 10-9 molar, and said compound being present in a concentration of from about 0.1 mM to about 4 mM.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][CH:3]=1.[Li]CCCC.[Br:14][C:15]1[CH:16]=[CH:17][C:18]([O:23][CH3:24])=[C:19]([CH:22]=1)[CH:20]=[O:21]>C1COCC1>[Br:14][C:15]1[CH:16]=[CH:17][C:18]([O:23][CH3:24])=[C:19]([CH:20]([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)[OH:21])[CH:22]=1
Reactant: COc1ccc(Br)cc1C=O
Reactant: Brc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(Br)cc1C(O)c1ccc(Br)cc1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
1,4-Dibromobenzene (15.3 g; 65 mmol) in THF (350 ml) is cooled to −78° C. and treated with nBuLi (44.7 ml; 71.5 mmol of a 1.6M solution). The white precipitate is stirred for 15 minutes at −78° C. 5-Bromo-2-methoxy-benzaldehyde (6.98 g; 32.5 mmol) in THF (32 ml) is added, stirred for 5 min at −78° C. and then poured on water. The aqueous phase is extracted twice with TBME, the organic phase dried over Na2SO4, evaporated to dryness and the residue purified via SiO2 chromatography (Cyclohexane/acetone 98:2>96:4) to yield the title compound as white crystals recrystallised from ether/hexanes (9.25 g; 73.8%).
Reaction SMILES: [NH:1]([CH:8]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]12([C:32](Cl)=[O:33])[CH2:31][CH:26]3[CH2:27][CH:28]([CH2:30][CH:24]([CH2:25]3)[CH2:23]1)[CH2:29]2>>[C:2]1([N:1]([CH:8]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][C:15]3[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=3)[CH2:9]2)[C:32]([C:22]23[CH2:31][CH:26]4[CH2:25][CH:24]([CH2:30][CH:28]([CH2:27]4)[CH2:29]2)[CH2:23]3)=[O:33])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: Fc1ccc(CCN2CCC(Nc3ccccc3)C2)cc1
Product: O=C(N(c1ccccc1)C1CCN(CCc2ccc(F)cc2)C1)C12CC3CC(CC(C3)C1)C2

Procedure:
3-Anilino-1-(2-(4-fluorophenyl)ethyl)pyrrolidine and 1-adamantanecarbonyl chloride were reacted under the same conditions as in Example 53 to give N-phenyl-N-(1-(2-(4-fluorophenyl)ethyl)pyrrolidin-3-yl)-1-adamantanecarboxamide.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([CH3:11])[CH:5]=1.Cl[C:13]1[C:18]([CH3:19])=[CH:17][C:16]([N+:20]([O-:22])=[O:21])=[CH:15][N:14]=1>O1CCCC1>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:13]2[C:18]([CH3:19])=[CH:17][C:16]([N+:20]([O-:22])=[O:21])=[CH:15][N:14]=2)=[C:6]([CH3:11])[CH:5]=1
Reactant: Cc1cc(Cl)ccc1O
Reactant: Cc1cc([N+](=O)[O-])cnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(Cl)ccc1Oc1ncc([N+](=O)[O-])cc1C
Reaction time: 0.33 h

Procedure:
Sodium hydride (60% in mineral oil, 1.08 g, 27 mmol) was washed 3× with hexanes then a solution of 4-chloro-2-methylphenol (3.50 g, 24.5 mmol) dissolved in tetrahydrofuran (40 mL) was added. The solution was stirred for 20 minutes then 2-chloro-3-methyl-5-nitropyridine (4.02 g, 23.3 mmol) was added and the reaction mixture was heated to reflux for 3 hours. After cooling, the mixture was concentrated in vacuo then dissolved in ethyl acetate and washed with water, 3× with saturated NaHCO3 and saturated NaCl then dried over Na2So4 and concentrated in vacuo.
Reaction SMILES: [NH2:1][C@H:2](C(N)=O)[CH2:3][C:4]1C=CC(O)=C[CH:5]=1.Cl.C([N:17]([CH2:20]C)[CH2:18][CH3:19])C>O1CCOCC1>[N:17]1[C:18]2[CH:19]=[CH:5][CH:4]=[CH:3][C:2]=2[NH:1][CH:20]=1
Reactant: NC(=O)[C@@H](N)Cc1ccc(O)cc1
Reactant: CCN(CC)CC
Agent: Cl
Solvent: C1COCCO1
Product: c1ccc2[nH]cnc2c1
Reaction time: 8 h
Yield: 72 %

Procedure:
To a room temperature solution of intermediate 2 in anhydrous dioxane (200 mL) were added triethylamine (6 mL, 40 mmol) and tert-butyldimethylsilyltrifluoro methanesulfonate (8.6 g, 32 mmol). The resulting solution was then stirred overnight and quenched with saturated aqueous sodium bicarbonate solution. It was extracted with dichloromethane (3×100 mL), and the combined organic layers were dried over sodium sulfate and concentrate in vacuo. The residue was purified by flash chromatography (silica gel, hexane/ethyl acetate) to provide intermediate 3 (9.2 g, 72% overall), which was characterized by LC/MS (LRMS (M+H+) m/z: 458.16).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10](=[N:12][C:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[C:34]4[C:29](=[CH:30][C:31]([O:37][CH3:38])=[C:32]([O:35][CH3:36])[CH:33]=4)[CH:28]4[CH:23]([CH2:24][CH2:25][CH:26]([O:39]C(=O)C)[CH2:27]4)[N:22]=3)=[CH:17][CH:16]=2)=[O:14])[NH2:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+]>CO>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10](=[N:12][C:13](=[O:14])[C:15]2[CH:16]=[CH:17][C:18]([C:21]3[C:34]4[C:29](=[CH:30][C:31]([O:37][CH3:38])=[C:32]([O:35][CH3:36])[CH:33]=4)[CH:28]4[CH:23]([CH2:24][CH2:25][CH:26]([OH:39])[CH2:27]4)[N:22]=3)=[CH:19][CH:20]=2)[NH2:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: COc1cc2c(cc1OC)C1CC(OC(C)=O)CCC1N=C2c1ccc(C(=O)N=C(N)N2CCN(C(C)=O)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Product: COc1cc2c(cc1OC)C1CC(O)CCC1N=C2c1ccc(C(=O)N=C(N)N2CCN(C(C)=O)CC2)cc1
Yield: 52.4 %

Procedure:
484 mg of acetic acid (2RS,4aRS,10bRS)-6-(4-{[1-(4-acetyl-piperazin-1-yl)-1-amino-methylene]-carbamoyl}-phenyl)-8,9-dimethoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-yl ester (compound 10) and 137 mg of cesium carbonate are stirred in 10 ml of methanol for 16 h at room temperature. The solvent is removed and the solid residue purified by chromatography on silica gel to yield 235 mg of the title compound.