Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([CH:20]([CH3:22])[CH3:21])[N:15]=2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH:20]([C:16]1[N:15]=[C:14]([CH:10]2[O:11][CH2:12][CH2:13][NH:8][CH2:9]2)[CH:19]=[CH:18][N:17]=1)([CH3:22])[CH3:21]
Reactant: CC(C)c1nccc(C2CN(C(=O)OC(C)(C)C)CCO2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1nccc(C2CNCCO2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.4 %

Procedure:
2-(2-Isopropylpyrimidin-4-yl)-morpholine-4-carboxylic acid tert-butyl ester (256 mg, 833 μmol) was dissolved in 5 mL of dichloromethane and TFA (2 mL) was added. The solution was stirred at room temperature for 2 h. The solvents were evaporated. The residue was extracted with dichloromethane and 1N NaOH solution. The organic layer was dried over Na2SO4 and concentrated. The residue was dried under vacuum to afford 2-(2-isopropylpyrimidin-4-yl)-morpholine (175 mg) as a colorless oil. (M+H)+=208 m/e.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1[N:9]2[C:10]3[CH:16]=[C:15]([C:17]4[C:25]5[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH3:27])[CH:24]=5)[N:19]([CH3:28])[CH:18]=4)[N:14]([CH2:29][OH:30])[C:11]=3[N:12]=[CH:13][C:8]2=[CH:7][N:6]=1.[CH3:31][C:32](OC(C)=O)=[O:33].N1C=CC=CC=1>C1COCC1.C([O-])(O)=O.[Na+]>[OH:30][CH2:29][N:14]1[C:11]2[N:12]=[CH:13][C:8]3[N:9]([C:5]([CH2:4][CH2:3][CH2:2][NH:1][C:32](=[O:33])[CH3:31])=[N:6][CH:7]=3)[C:10]=2[CH:16]=[C:15]1[C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]([CH3:28])[CH:18]=1
Reactant: COc1ccc2c(c1)c(-c1cc3c(ncc4cnc(CCCN)n43)n1CO)cn2C
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COc1ccc2c(c1)c(-c1cc3c(ncc4cnc(CCCNC(C)=O)n43)n1CO)cn2C
Reaction time: 0.17 h
Yield: 99.9 %

Procedure:
To a solution of (1-(3-aminopropyl)-7-(5-methoxy-1-methyl-1H-indol-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-6-yl)methanol (0.116 g, 0.287 mmol) in THF (3 mL) at rt was added Ac2O (0.032 mL, 0.344 mmol) and pyridine (1.0 mL, 12.36 mmol). After about 10 min, additional Ac2O (0.027 mL, 0.287 mmol) was added. After about 15 min the mixture was diluted with aqueous NaHCO3 (10 mL) and extracted with EtOAc (20 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo to give N-(3-(6-(hydroxymethyl)-7-(5-methoxy-1-methyl-1H-indol-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)propyl)acetamide (0.128 g, 100%): LC/MS (Table 2, Method c) Rt=1.26 min; MS m/z 447 (M+H)+.
Reaction SMILES: [Li]C(C)(C)C.[CH:6]([Si:9]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[C:10]1[O:11][CH:12]=[CH:13][N:14]=1)([CH3:8])[CH3:7].[Sn:21](Cl)([CH2:30][CH2:31][CH2:32][CH3:33])([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][CH2:23][CH2:24][CH3:25]>C1COCC1.C(OCC)(=O)C>[CH2:30]([Sn:21]([CH2:22][CH2:23][CH2:24][CH3:25])([CH2:26][CH2:27][CH2:28][CH3:29])[C:12]1[O:11][C:10]([Si:9]([CH:6]([CH3:8])[CH3:7])([CH:15]([CH3:17])[CH3:16])[CH:18]([CH3:20])[CH3:19])=[N:14][CH:13]=1)[CH2:31][CH2:32][CH3:33]
Reactant: CC(C)[Si](c1ncco1)(C(C)C)C(C)C
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCC[Sn](CCCC)(CCCC)c1cnc([Si](C(C)C)(C(C)C)C(C)C)o1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
tert-BuLi (1.7M, 8.4 mL, 14.3 mmol) was added dropwise over 30 min. to a stirred solution of 2-(triisopropylsilyl)-1,3-oxazole* (3 g, 13 mmol) in THF (75 mL) at −78° C. under argon. The solution was allowed to stir for 20 min. at −78° C. and Bu3SnCl (5.2 mL, 19.5 mmol) was then added over 20 min. The reaction mixture was warmed up to room temperature and stirred for an additional 16 h. The reaction was diluted with ethyl acetate and washed with water. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The crude product was dissolved in n-pentane, filtered through Celite and the solvent evaporated to give the title compound in quantitative yield as a pale-yellow oily residue, which was used without further purification in the next step. *Prepared according to Ross A, et al. Tetrahedron Letters 2002, 43, 935.
Reaction SMILES: [O:1]1[CH2:13][CH:2]1[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]#[N:12].[NH2:14][CH2:15][CH2:16][NH:17][C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[S:19]>C(O)(C)C>[OH2:1].[C:11]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[O:4][CH2:3][CH:2]([OH:1])[CH2:13][NH:14][CH2:15][CH2:16][NH:17][C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[S:19])#[N:12]
Reactant: N#Cc1ccccc1OCC1CO1
Reactant: NCCNC(=S)Nc1ccccc1
Solvent: CC(C)O
Product: N#Cc1ccccc1OCC(O)CNCCNC(=S)Nc1ccccc1
Product: O
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.7 %

Procedure:
A solution was prepared of 1.75 g (0.01 mole) of 2,3-epoxy-1-(2-cyanophenoxy)propane, 7, in 50 ml of isopropyl alcohol, assisted by gentle warming and sonication. To this was next added 2.95 g (0.01 mole) of 12 all at once. The solution was refluxed for one hour then stirred overnight at room temperature. The solution was concentrated in vacuo to 5.6 of gum, which was chromatographed over 150 g of silica gel using 10% CH3OH/CHCl3 (saturated with NH3) and taking 10 ml fractions. Fractions 12-41 gave 1.8 g of a foam which was found to be nonhomogeneous. This material was rechromatographed over 200 g of silica gel using the same solvent system as before and taking 10 ml cuts. Fractions 12-30 gave 400 mg (12%) of yellow sticky 13, m.p. 41°-47° C. Rf =0.64 (silica gel GF, 10% CH 3 OH/CHCl3 (NH3)). Mass spectrum, m/e 370 (M+); liquid chromatography showed 98% pure. Analysis satisfactory for C19H22N4O2S.1.6H2O.
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[C:10]([CH2:12][C:13](OC)=[O:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1>[Pt]>[OH:14][CH2:13][CH2:12][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2](=[O:1])[CH:11]=1.[OH:14][CH2:13][CH2:12][CH:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2](=[O:1])[CH2:11]1
Reactant: COC(=O)Cc1cc(=O)[nH]c2ccccc12
Agent: [Pt]
Product: O=C1CC(CCO)c2ccccc2N1
Product: O=c1cc(CCO)c2ccccc2[nH]1

Procedure:
4-(2-Hydroxyethyl)-2(1H)-quinolinone is prepared from methyl 2-oxo-1,2-dihydro-4-quinolineacetate (prepared in 3.3.) according to the procedure described in 1.3. It is a solid, melting point 213°-5° C. A catalytic hydrogenation of this compound is performed with Adams+ platinum to obtain (±)-4-(2-hydroxyethyl)-3,4-dihydro-2(1H)-quinolinone.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][Si:10]([CH:17]([CH3:19])[CH3:18])([CH:14]([CH3:16])[CH3:15])[CH:11]([CH3:13])[CH3:12])[CH:5]=[C:6]([Br:8])[CH:7]=1.[C:20]([O-])([O-])=O.[Cs+].[Cs+].[NH2:26][C:27]1[CH:28]=[CH:29][C:30]([C:33]#[N:34])=N[CH:32]=1>O1CCOCC1.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.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[Br:8][C:6]1[CH:7]=[C:2]([NH:26][C:27]2[CH:32]=[CH:20][C:30]([C:33]#[N:34])=[CH:29][CH:28]=2)[CH:3]=[C:4]([O:9][Si:10]([CH:17]([CH3:19])[CH3:18])([CH:14]([CH3:16])[CH3:15])[CH:11]([CH3:13])[CH3:12])[CH:5]=1
Reactant: CC(C)[Si](Oc1cc(Br)cc(Br)c1)(C(C)C)C(C)C
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ccc(N)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: [Cs+]
Solvent: C1COCCO1
Product: CC(C)[Si](Oc1cc(Br)cc(Nc2ccc(C#N)cc2)c1)(C(C)C)C(C)C
Temperature: 100 °C
Yield: 46.4 %

Procedure:
To 1.0 g (2.45 mmol) of 3,5-dibromotriisopropylsiloxybenzene in 20.0 mL of anhydrous 1,4-dioxane was added 1.12 g (3.43 mmol) of Cs2CO3, 0.32 g (2.7 mmol) of 5-amino-pyridine-2-carbonitrile and 43 mg (0.074 mmol) Xantphos. The reaction mixture was deoxygenated by bubbling argon for 30 mins and then treated with 57 mg (0.049 mmol) of Pd(PPh3)4. The reaction vial was capped and heated at 100° C. for 4 hours. The reaction mixture was cooled to room temperature, filtered through Celite®, and the filter cake was washed with ethyl acetate. The ethyl acetate layer was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was chromatographed on silica gel using 5:1 hexane:ethyl acetate to give 506 mg of 4-(3-bromo-5-triisopropylsilanyloxy-phenylamino)-benzonitrile.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([CH2:13][O:14][C:15]([NH:17][NH:18][C:19]3[C:20]([NH2:25])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:16])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[CH3:26][C:27]1[CH:35]=[CH:34][C:30]([C:31]([Cl:33])=[O:32])=[CH:29][CH:28]=1>>[ClH:33].[CH3:26][C:27]1[CH:35]=[CH:34][C:30]([C:31]([NH:25][C:20]2[C:19]([NH:18][NH:17][C:15]([O:14][CH2:13][CH:10]3[CH2:9][CH2:8][N:7]([C:4]4[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=4)[CH2:12][CH2:11]3)=[O:16])=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:32])=[CH:29][CH:28]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: Nc1ccccc1NNC(=O)OCC1CCN(c2ccncc2)CC1
Product: Cc1ccc(C(=O)Nc2ccccc2NNC(=O)OCC2CCN(c3ccncc3)CC2)cc1
Product: Cl
Yield: 54.2 %

Procedure:
Using the procedure described in Example 48, Part C, N1-[[1-(4-pyridyl)piperidin-4-yl]methoxycarbonylamino]-1,2-benzenediamine (0.61 mmol) and 4-methylbenzoyl chloride (1.2 mmol) yielded 164 mg (56%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:44])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][CH:17]([CH:29]3[C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=4[CH2:33][S:32][C:31]4[CH:40]=[CH:41][CH:42]=[CH:43][C:30]3=4)[CH2:18][NH:19][C:20](=O)OC3C=CC=CC=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:45][CH2:46][CH2:47][CH2:48][OH:49].C(=O)([O-])[O-].[K+].[K+].[OH2:56]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:44])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][CH:17]([CH:29]3[C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=4[CH2:33][S:32][C:31]4[CH:40]=[CH:41][CH:42]=[CH:43][C:30]3=4)[CH2:18][NH:19][C:20]([NH:45][CH2:46][CH2:47][CH2:48][OH:49])=[O:56])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C(NCC(CCCN1CCC(O)(c2ccc(Cl)cc2)CC1)C1c2ccccc2CSc2ccccc21)Oc1ccccc1
Reactant: O
Reactant: NCCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(NCCCO)NCC(CCCN1CCC(O)(c2ccc(Cl)cc2)CC1)C1c2ccccc2CSc2ccccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution phenyl N-[2-[3-[4-(4-chlorophenyl)-4-hydroxypiperidino]propyl]-2-(6,11-dihydrodibenzo[b,e]thiepin-11-yl)ethyl]carbamate (300 mg) in DMF (10 ml) were added 3-amino-1-propanol (70 mg), potassium carbonate (130 mg) and the mixture was stirred at room temperature for 16 hours. Water and ethyl acetate were added to the reaction mixture, the organic layer was separated and washed with saturated aqueous sodium chloride, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography eluting with ethyl acetate-methanol (9:1) to give the titled compound (200 mg). 1H-NMR (CDCl3) d: 1.40-1.70(6H,m), 2.01-2.08(2H,m), 2.30-2.63(8H,m), 3.12 (2H,q), 3.42(2H,t), 4.00-4.12(2H,m), 4.22-4.28(2H,m), 4.82(1H,brt), 4.99(1H,brs), 6.98-7.45(12H,m).MS m/z: 594(M+1)
Reaction SMILES: [C:1]1([C:14](O)=[O:15])[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.CN(C)C=O.[N:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH:35]=[C:36]([NH2:40])[CH:37]=[CH:38][CH:39]=2)=[CH:30][N:29]=1>ClCCl.N1C=CC=CC=1>[N:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH:35]=[C:36]([NH:40][C:14]([C:1]3[C:13]4[CH2:12][C:11]5[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=5)[C:5]=4[CH:4]=[CH:3][CH:2]=3)=[O:15])[CH:37]=[CH:38][CH:39]=2)=[CH:30][N:29]=1
Reactant: Nc1cccc(-c2ccnnc2)c1
Reactant: O=C(O)c1cccc2c1Cc1ccccc1-2
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(-c2ccnnc2)c1)c1cccc2c1Cc1ccccc1-2
Reaction time: 2 h
Yield: 64.1 %

Procedure:
To a suspension of 1-fluorenecarboxylic acid (120 mg) and oxalyl chloride (0.12 ml) in dichloromethane (2.5 ml) was added N,N-dimethylformamide (0.01 ml) and the mixture was stirred for 2 hours. The resultant solution was evaporated to give a crude acid chloride. To a suspension of 3-(pyridazin-4-yl)phenylamine (98 mg) and pyridine (0.14 ml) in dichloromethane (2 ml) was dropwise added a solution of the acid chloride obtained above in dichloromethane (5 ml), and the mixture was stirred for an hour. The mixture was diluted with dichloromethane and washed with an aqueous solution of sodium hydrogen carbonate and brine. The separated organic layer was dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by a silica gel column chromatography eluting with 2% methanol in dichloromethane to give N-(3-(pyridazin-4-yl)-phenyl)-9H-fluorene-1-carboxamide (133 mg, 63.9%)
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[C@@H:8]([C:9](=[O:34])[NH:10][C@@H:11]([CH2:27][C:28]2[N:29]=[CH:30][N:31]([CH3:33])[CH:32]=2)[C:12]([NH:14][C:15]2[S:16][CH:17]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[N:19]=2)=[O:13])[O:7]1)=[O:5])C.[Li+].[OH-]>C1COCC1.CO.O>[F:26][C:23]1[CH:22]=[CH:21][C:20]([C:18]2[N:19]=[C:15]([NH:14][C:12](=[O:13])[C@@H:11]([NH:10][C:9]([C@H:8]3[O:7][C@@H:6]3[C:4]([OH:5])=[O:3])=[O:34])[CH2:27][C:28]3[N:29]=[CH:30][N:31]([CH3:33])[CH:32]=3)[S:16][CH:17]=2)=[CH:25][CH:24]=1
Reactant: CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](Cc1cn(C)cn1)C(=O)Nc1nc(-c2ccc(F)cc2)cs1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cn1cnc(C[C@H](NC(=O)[C@H]2O[C@@H]2C(=O)O)C(=O)Nc2nc(-c3ccc(F)cc3)cs2)c1
Yield: 33.2 %

Procedure:
Synthesized following general saponification procedure using the following quantities: the corresponding peptidomimetic epoxide ethyl ester 21 (93 mg, 0.19 mmol); LiOH (4.5 mg, 0.19 mmol); THF/MeOH/H2O (1.5 mL: 0.5 mL: 0.5 mL); yielded 36 as a white solid (29 mg, 33.1%). 1H NMR (400 MHz, DMSO-d6): 12.50 (bs, 1H), 8.82-8.80 (d, 1H): 7.93-7.91 (m, 2H); 7.76 (s, 1H); 7.63 (s, 1H); 7.46-7.24 (t, 2H); 6.99 (s, 1H); 4.79-4.74 (m, 1H); 3.67-3.66 (d, 1H); 3.62 (s, 3H); 3.49-3.48 (d, 1H); 3.12-2.90 (m, 2H). 13C NMR (400 MHz, DMSO-d6): 169.72, 168.60, 165.56, 162.97, 160.54, 157.78, 147.88, 137.17, 130.84, 127.71, 127.63, 118.35, 115.68, 115.47, 108.08, 53.07, 52.98, 51.56, 33.11, 29.60. ESI-HRMS (m/z): [M+H+] calcd. for C20H18FNO5S: 460.1085, observed: 460.1090. Rt=18.1 min, purity=95.3%.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11](=[O:13])[CH3:12])([CH3:3])[CH3:2].[Br:14]Br>CCOCC>[Br:14][CH2:12][C:11]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[O:4][CH:1]([CH3:3])[CH3:2])=[O:13]
Reactant: CC(=O)c1ccccc1OC(C)C
Reactant: BrBr
Solvent: CCOCC
Product: CC(C)Oc1ccccc1C(=O)CBr
Yield: 97.2 %

Procedure:
Dissolve 1-(2-isopropoxyphenyl)ethanone (1.0 g, 6 mmol) in Et2O (25 mL) and add bromine (0.3 mL, 6 mmol) drop-wise while stirring stir the mixture in the dark at ambient temperature. Wash the reaction mixture with a saturated aqueous Na2CO3 solution. Dry it over MgSO4; filter; collect the filtrate; removed the volatiles under reduced pressure to provide the title compound (1.5 g, 83%). MS (m/z): 258 (M+1).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[NH:7][CH2:6][C:5]=12.C(N(CC)C(C)C)(C)C.[CH3:24][C:25]1[CH:43]=[CH:42][C:41]([F:44])=[CH:40][C:26]=1[C:27]([NH:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[C:32]([Cl:39])[CH:31]=1)=[O:28].O>C(Cl)Cl>[CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:34]([C:33]3[CH:37]=[CH:38][C:30]([NH:29][C:27](=[O:28])[C:26]4[CH:40]=[C:41]([F:44])[CH:42]=[CH:43][C:25]=4[CH3:24])=[CH:31][C:32]=3[Cl:39])=[O:35])[CH2:6][C:5]=12
Reactant: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)Cl)c(Cl)c1
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 1.84 g of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine in 25 ml of methylene chloride is added 1.30 g of N,N-diisopropylethylamine. While cooling in an ice bath, a solution of 3.45 g of [4-[(2-methyl-5-fluorobenzoyl)amino]-2-chlorobenzoyl chloride in 50 ml of methylene chloride is added. The reaction mixture becomes homogeneous after 5 minutes and is stirred at room temperature for 18 hours. Water is added and the separated organic layer washed with saturated sodium bicarbonate, dried with Na2SO4 and passed through a short pad of hydrous magnesium silicate. The methylene chloride is removed in vacuo to give 4.60 g of the desired product as a glass. A sample is crystallized from ethyl acetate to give crystalline solid, m.p. 191°-195° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9]O)[CH:5]=[C:6]([F:8])[CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:30]N1C(=O)CCC1=O>O1CCCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([CH2:9][Br:30])[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: OCc1cc(F)cc(Br)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Fc1cc(Br)cc(CBr)c1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
(3-Bromo-5-fluorophenyl)methanol (0.78 g, 3.8 mmol) and triphenylphosphine (2.0 g, 7.6 mmol) were combined in tetrahydrofuran (20 mL) and cooled to 0° C. N-Bromosuccinimide (1.4 g, 7.98 mmol) was introduced in portions and the reaction allowed to warm to room temperature. After 16 h, the reaction mixture was diluted with ethyl acetate, washed with concentrated sodium bicarbonate (2×), then brine (2×), dried over sodium sulfate, and concentrated. Column chromatography on silica gel (5% ethyl acetate/hexanes) gave 0.8 g (79%) as a white powder. 1H-NMR (CDCl3, 300 MHz) 7.30 (s, 1H), 7.14-7.18 (m, 1H), 7.01-7.05 (m, 1H), 4.36 (s, 2H).
Reaction SMILES: C(OC([NH:8][C@H:9]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=2)=[CH:19][CH:18]=1)[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=O)(C)(C)C.Cl.O1CCOCC1>>[ClH:29].[NH2:8][C@H:9]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=2)=[CH:19][CH:18]=1)[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)C[C@H](N)Cc1ccc(-c2cccc(Cl)c2)cc1
Reaction time: 0.5 h
Yield: 205.4 %

Procedure:
To (R)-ethyl 3-(tert-butoxycarbonylamino)-4-(3′-chlorobiphenyl-4-yl)butanoate (3.33 g, 7.97 mmol) is added a solution of 4 M HCl in 1,4-dioxane (19.9 mL, 18.0 mmol) at room temperature. After stirring for 0.5 hours, the reaction mixture is concentrated under reduced pressure to give (R)-ethyl 3-amino-4-(3′-chlorobiphenyl-4-yl)butanoate hydrochloride (2.90 g). HPLC retention time=0.70 minutes (condition B); MS (m+1)=318.26; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.19-1.24 (m, 3 H) 2.73-2.78 (m, 1 H) 2.84-2.91 (m, 1 H) 3.05-3.11 (m, 1 H) 3.50-3.54 (m, 1 H) 3.92 (br s, 1 H) 4.14-4.17 (m, 2 H) 7.29-7.53 (m, 8 H) 8.73 (br. s., 3 H).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.[CH2:20]([O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:21]1[O:23][CH2:22]1>O1CCCC1.O>[C:25]1([O:24][CH2:20][CH:21]([OH:23])[CH2:22][CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: c1ccc(OCC2CO2)cc1
Reactant: Cc1cccnc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: OC(CCc1cccnc1)COc1ccccc1
Reaction time: 0.5 h
Yield: 78.5 %

Procedure:
Under argon gas, a solution of diisopropylamine (1.67 g, 16.5 mmol) in tetrahydrofuran (5 mL) was added dropwise to n-butyllithium (1.53 M in hexane, 9.8 mL, 15 mmol) at 5° C. and the mixture was stirred for 30 minutes. To this was further added a solution of 3-methylpyridine (2.794 g, 30 mmol) in tetrahydrofuran (5 mL) dropwise at 5° C., and the mixture was stirred for 30 minutes. Then, a solution of phenyl glycidyl ether (1.50 g, 10 mmol) in tetrahydrofuran (5 mL) was added at 5° C. and the reaction was carried out for 2 hours. This reaction mixture was diluted with 20 mL of water for hydrolysis, and extracted with 30 mL of ethyl acetate. The organic layer was washed with 20 mL of water twice and the solvent was distilled off under reduced pressure to give a deep-red oil. This oil was purified by silica gel column chromatography (Merck's Kieselgel 60, hexane/ethyl acetate=1/2) to give 1.911 g (isolation yield: 79%) of 1-O-phenyl-4-(3-pyridyl)-1,2-butanediol (yellow oil).
Reaction SMILES: C(O)(=O)/C=C\C(O)=O.[CH3:9][N:10]1[C@H:24]2[C@@H:14]([C:15]3[CH:16]=[CH:17][CH:18]=[C:19]4[C:25]=3[C:22]([CH2:23]2)=[CH:21][NH:20]4)[CH2:13][C:12](=O)[CH2:11]1.[NH2:27][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1.C.[H][H]>CO.[Pd]>[CH3:9][N:10]1[C@H:24]2[C@@H:14]([C:15]3[CH:16]=[CH:17][CH:18]=[C:19]4[C:25]=3[C:22]([CH2:23]2)=[CH:21][NH:20]4)[CH2:13][CH:12]([NH:27][C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)[CH2:11]1
Reactant: [H][H]
Reactant: Nc1cccnc1
Reactant: CN1CC(=O)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Agent: [Pd]
Agent: O=C(O)/C=C\C(=O)O
Solvent: CO
Product: CN1CC(Nc2cccnc2)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21

Procedure:
17.8 g of 6-methyl-8-oxo-ergoline hydrogen maleate and 23.5 g of 3-aminopyridine in 500 cc of methanol are hydrogenated with the addition of 12 g of 10% palladium on active charcoal under normal conditions. After the hydrogen take up is complete (approx. 120 hours), the catalyst is filtered off, the filtrate is concentrated in a vacuum at a water bath temperature of 60°, and the resulting residue is purified and separated by chromatography on a 30-fold quantity of silica gel with methylene chloride and the addition of increasing amounts of methanol.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH:11]12[CH2:17]C[CH:15]1[CH2:14][NH:13][CH2:12]2.C(N(CC)CC)C>O1CCOCC1>[CH:15]12[CH2:17][CH:11]1[CH2:12][N:13]([C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1)[CH2:14]2
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: C1CC2CNCC12
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccc(N2CC3CC3C2)nc1
Temperature: 65 °C
Yield: 97.5 %

Procedure:
A mixture of 0.5 g (3.15 mmol) of 2-chloro-5-nitropyridine, 0.452 g (3.78 mmol) of 3-aza-bicyclo[3.2.0]heptane (J. Med. Chem. 1967, 10(4), 621) and 1.32 mL (6.94 mmol) of triethylamine in 10 mL of dioxane, is heated at 65° C. for 4 h. The reaction mixture is then poured into 50 mL of ice water. The mixture is stirred until the ice has melted completely, then a yellow precipitate is collected by filtration and is dried at reduced pressure. In this way we isolate 0.63 g of the expected product in the form of a yellow powder.
Reaction SMILES: [OH:1][C:2]12[CH2:9][CH2:8][C:5]([C:10]3[NH:18][C:17]4[C:16](=O)[NH:15][C:14](=[O:20])[N:13]([CH2:21][CH2:22][CH3:23])[C:12]=4[N:11]=3)([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:25]>N1C=CC=CC=1>[OH:1][C:2]12[CH2:9][CH2:8][C:5]([C:10]3[NH:18][C:17]4[C:16](=[S:25])[NH:15][C:14](=[O:20])[N:13]([CH2:21][CH2:22][CH3:23])[C:12]=4[N:11]=3)([CH2:6][CH2:7]1)[CH2:4][CH2:3]2
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CCCn1c(=O)[nH]c(=O)c2[nH]c(C34CCC(O)(CC3)CC4)nc21
Solvent: c1ccncc1
Product: CCCn1c(=O)[nH]c(=S)c2[nH]c(C34CCC(O)(CC3)CC4)nc21
Temperature: 25 °C
Yield: 19 %

Procedure:
8-(4-Hydroxy-bicyclo[2.2.2]oct-1-yl)-3-propyl-3,7-dihydro-purine-2,6-dione (500 mg, 1.57 mmol) was dissolved in 10 mL of pyridine. P4S10 (1.05 g, 1.5 eq) was added and the reaction mixture was stirred under reflux for 6 h. The reaction mixture was then cooled to rt and quenched slowly with 5 mL of H2O. The mixture was then acidified at 0° C. to pH 5 with 6 N HCl. The aqueous layer was extracted with EtOAc. The combined organic layer was dried (Na2SO4) and concentrated under reduced pressure. Purification by preparative HPLC afforded 100 mg of the titled compound.