Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:12]=1[C:13]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)=[O:14]>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[CH3:9][O:10][C:11]1[C:25]([CH2:26][Br:1])=[CH:24][CH:23]=[CH:22][C:12]=1[C:13]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)=[O:14]
Reactant: COc1c(C)cccc1C(=O)c1ccc(Cl)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1c(CBr)cccc1C(=O)c1ccc(Cl)cc1
Yield: 98 %

Procedure:
A mixture of 1.78 g of N-bromo-succinimide and 10 mg of benzoyl peroxide was added to a suspension of 2.6 g of 2-methoxy-3-methyl-4'-chlorobenzophenone in 15 ml of carbon tetrachloride and the solution was refluxed for 4 hours. The insolubles were removed by filtration and the filtrate was evaporated to dryness to obtain 3.32 g of 2-methoxy-3-bromomethyl-4'-chlorobenzophenone in the form of a clear yellow oil.
Reaction SMILES: OC1C=C(CNC=C2C3C(=CC=C(I)C=3)C(=O)NC2=O)C=CC=1C1C=CC=CC=1.[CH:30]1([C:35]2[CH:36]=[C:37]3[C:42](=[CH:43][CH:44]=2)[C:41](=[O:45])[NH:40][C:39](=[O:46])[C:38]3=[CH:47]OC)[CH2:34][CH2:33][CH2:32][CH2:31]1.[NH2:50][CH2:51][C:52]1[CH:53]=[CH:54][C:55]([C:59]2[CH:63]=[CH:62][O:61][CH:60]=2)=[C:56]([OH:58])[CH:57]=1>>[CH:30]1([C:35]2[CH:36]=[C:37]3[C:42](=[CH:43][CH:44]=2)[C:41](=[O:45])[NH:40][C:39](=[O:46])[C:38]3=[CH:47][NH:50][CH2:51][C:52]2[CH:53]=[CH:54][C:55]([C:59]3[CH:63]=[CH:62][O:61][CH:60]=3)=[C:56]([OH:58])[CH:57]=2)[CH2:31][CH2:32][CH2:33][CH2:34]1
Reactant: COC=C1C(=O)NC(=O)c2ccc(C3CCCC3)cc21
Reactant: NCc1ccc(-c2ccoc2)c(O)c1
Agent: O=C1NC(=O)c2ccc(I)cc2C1=CNCc1ccc(-c2ccccc2)c(O)c1
Product: O=C1NC(=O)c2ccc(C3CCCC3)cc2C1=CNCc1ccc(-c2ccoc2)c(O)c1
Yield: 78 %

Procedure:
Following the same procedure for the preparation of 4-{[(2-hydroxy-biphenyl-4-ylmethyl)-amino]-methylene}-6-iodo-4H-isoquinoline-1,3-dione, the title compound (purified through chromatography) is prepared from 6-cyclopentyl-4-methoxymethylene-4H-isoquinoline-1,3-dione (108 mg, 0.398 mmol) and 5-Aminomethyl-2-furan-3-yl-phenol (109 mg, 0.57 mmol) in 78% yield: MS (ESI): 427.1 (M−1)−1.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]([C:25]1([C:28](O)=[O:29])[CH2:27][CH2:26]1)#[N:24]>>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([NH:20][C:28]([C:25]2([C:23]#[N:24])[CH2:27][CH2:26]2)=[O:29])=[CH:21][CH:22]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CC1(C(=O)O)CC1
Reactant: Nc1ccc(CCCCCCCOCc2ccccc2)cc1
Product: N#CC1(C(=O)Nc2ccc(CCCCCCCOCc3ccccc3)cc2)CC1
Yield: 98.1 %

Procedure:
General procedure E was used to convert 1.05 mmol of 13a and 1.575 mmol of 1-cyanocyclopropanecarboxylic acid to 1.03 mmol (98%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]([OH:10])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[Cl:44][C:45]1[CH:50]=[CH:49][C:48]([CH2:51][N:52]2[CH:56]=[CH:55][C:54]([NH2:57])=[N:53]2)=[C:47]([C:58]([F:61])([F:60])[F:59])[CH:46]=1>CN(C=O)C.CO>[Cl:44][C:45]1[CH:50]=[CH:49][C:48]([CH2:51][N:52]2[CH:56]=[CH:55][C:54]([NH:57][C:8]([C:7]3[CH:6]=[CH:5][N:4]=[CH:3][C:2]=3[F:1])=[O:10])=[N:53]2)=[C:47]([C:58]([F:59])([F:61])[F:60])[CH:46]=1
Reactant: Nc1ccn(Cc2ccc(Cl)cc2C(F)(F)F)n1
Reactant: O=C(O)c1ccncc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccn(Cc2ccc(Cl)cc2C(F)(F)F)n1)c1ccncc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 3-fluoro-4-pyridinecarboxylic acid (27 mg, 0.191 mmol, Aldrich) was added a solution of HATU (24 mg, 0.189 mmol, Advanced asymmetrics) in DMF (0.5 ml), DIPEA (0.076 ml, 0.435 mmol) and then a solution of 1-{[4-chloro-2-(trifluoromethyl)phenyl]methyl}-1H-pyrazol-3-amine (for a preparation see Intermediate 37)(40 mg, 0.145 mmol) in DMF (0.5 ml). The resulting yellow solution was stirred at ambient temperature overnight. Further amounts of HATU (72 mg, 0.189 mmol), 3-fluoro-4-pyridinecarboxylic acid (27 mg, 0.191 mmol) and DIPEA (0.076 ml, 0.435 mmol) were added. The reaction mixture was stirred at ambient temperature for a further 2 h. The reaction mixture was diluted with methanol and purified by MDAP on Sunfire C18 column (Method B) using Acetonitrile-Water with a Formic acid modifier. The solvent was evaporated in vacuo to give the title compound as a white solid (49 mg); LCMS: (System 4) MH+=399 tRET=2.82 min.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Br:23]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[NH2:1][C:2]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([Br:23])[N:6]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrBr
Reactant: CCCCNc1nc(N)c2ncn(Cc3ccccc3)c2n1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCNc1nc(N)c2nc(Br)n(Cc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
6-Amino-9-benzyl-2-butylaminopurine (101 mg, 0.34 mmol) and bromine (0.5 ml) were dissolved in 50 ml of methylene chloride and the solution was stirred at room temperature for 1 hour. Aqueous sodium thiosulfate was added to the reaction mixture. The organic layer was separated, dried on sodium sulfate and filtered. The solvent in the filtrate was evaporated in vacuo. The residue was purified with silica gel chromatography (1% methanol/chloroform) to give the subject compound (116 mg, yield 91%).
Reaction SMILES: C([N:20]1[C:24]2[CH:25]=[N:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:32]=3[C:23]=2[N:22]=[CH:21]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.[CH:38]1([C:41](Cl)=[O:42])[CH2:40][CH2:39]1.FC(F)(F)C(O)=O>C1COCC1.CCCCCC>[CH:38]1([C:41]([C:21]2[NH:22][C:23]3[C:32]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[N:26]=[CH:25][C:24]=3[N:20]=2)=[O:42])[CH2:40][CH2:39]1
Reactant: O=C(Cl)C1CC1
Reactant: c1ccc(C(c2ccccc2)(c2ccccc2)n2cnc3c4ccccc4ncc32)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: O=C(c1nc2cnc3ccccc3c2[nH]1)C1CC1
Reaction time: 0.5 h
Yield: 55.7 %

Procedure:
To a cold solution (-70° C.) of 1.23 g of 3-trityl-3H-imidazo[4,5-c]quinoline (III-1) in 25 ml of THF was added dropwise a mixture of 3 ml of 1.6M solution of n-butyl lithium in hexane and 3 ml of THF while being kept at -72°~-68° C. The mixture was stirred at the same temperature for 30 min., whereby a yellow solution of 2-lithio form (III-1') was obtained. All the 2-lithio form used in the Examples hereafter are prepared according to the same reaction conditions. To the yellow solution of the compound (III-1') was added 1.04 g of cyclopropanecarbonyl chloride all at once. The temperature of the reaction solution was gradually elevated to room temperature, and the solvent was evaporated under reduced pressure. The residue was partitioned between ethyl acetate and aqueous ammonia. The organic layer was washed with water and saturated brine, successively, and dried. The ethyl acetate was removed by evaporation, and the residue was crystallized from n-hexane--ethyl acetate to give 900 mg of the crude crystals (Ib-1). The compound (Ib-1) was deprotected by mixing with 4 ml of trifluoroacetic acid. After stirring for 30 min. at room temperature, the reaction mixture was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate. The organic layer was washed with water and saturated brine, and dried. The ethyl acetate was removed by evaporation, and the residue was chromatographed on a column of silica gel for purification. The fraction eluted with chloroform--methanol (30:1 v/v) was concentrated and crystallized from -hexane to give 395 mg (yield: 56%) of the titled compound (Ic-1). This was recrystallized from ethanol to give colorless crystals melting at 230° C. (dec.).
Reaction SMILES: [O-2].[Mg+2:2].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>>[C:3]1([O-:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Mg+2:2].[C:3]1([O-:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Oc1ccccc1
Agent: [Mg+2]
Agent: [O-2]
Product: [O-]c1ccccc1

Procedure:
A powder of commercial magnesium oxide (80 g) calcined at 550° C. and 282 g of phenol were charged in a ball mill and mixed at 150° C. for 16 hours. Phenol was thoroughly removed by vacuum evaporation to give magnesium phenolate-containing magnesium oxide of particle sizes 10-16 mesh.
Reaction SMILES: [CH3:1][NH:2][C@@H:3]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C@H:6]([C:13]2[CH:14]=[CH:15][C:16]([Cl:20])=[C:17]([Cl:19])[CH:18]=2)[CH2:5][CH2:4]1.ClC1C=C(C(C2C=CC=CC=2)CCC(O)=O)C=CC=1Cl.ClC1C=C(C2C3C(=CC=CC=3)C(=O)CC2)C=CC=1Cl>>[CH3:1][NH:2][C@H:3]1[C:8]2[C:7](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C@@H:6]([C:13]2[CH:14]=[CH:15][C:16]([Cl:20])=[C:17]([Cl:19])[CH:18]=2)[CH2:5][CH2:4]1
Reactant: CN[C@H]1CC[C@@H](c2ccc(Cl)c(Cl)c2)c2ccccc21
Agent: O=C(O)CCC(c1ccccc1)c1ccc(Cl)c(Cl)c1
Agent: O=C1CCC(c2ccc(Cl)c(Cl)c2)c2ccccc21
Product: CN[C@@H]1CC[C@H](c2ccc(Cl)c(Cl)c2)c2ccccc21

Procedure:
As previously indicated, the 4-(3,4-dichlorophenyl)-4-phenylbutanoic acid final product afforded by the process of this invention is a valuable intermediate that ultimately leads to the antidepressant agent known as sertraline or cis-(1S) (4S)-N-methyl-4-(3,4-dichlorophenyl)-1, 2,3,4-tetrahydro-1-naphthaleneamine as disclosed in the previously discussed prior art. More specifically, 4-(3,4-dichlorophenyl)-4-phenylbutanoic acid is first converted to 4-(3,4-dichlorophenyl)-3, 4-dihydro-1-(2H)-naphthalenone and then finally to racemic cis-N-methyl-4-(3,4-dichlorophenyl)-1, 2,3,4-tetrahydro-1-naphthaleneamine prior to ultimately yielding the desired cis-(1S) (4S)-N-methyl-4-(3,4-dichlorophenyl)-1, 2,3,4-tetrahydro-1-naphthaleneamine by the multi-step method of the prior art process as earlier described by W.M. Welch, Jr. et al. in U.S. Pat. No. 4,536,518 and the Journal of Medicinal Chemistry, Vol. 27, No. 11, p. 1508 (1984).
Reaction SMILES: [CH2:1]([O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][Cl:19])=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].S(Cl)(Cl)=O.[CH2:26](OC1C=CC(CO)=CC=1)[CH2:27]CCCCCCCCCCCC>C(Cl)Cl>[CH2:1]([O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][Cl:19])=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:26][CH3:27]
Reactant: CCCCCCCCCCCCOc1ccc(CCl)cc1
Reactant: CCCCCCCCCCCCCCOc1ccc(CO)cc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCCCCCCCCCCCCCOc1ccc(CCl)cc1

Procedure:
This one was synthesized following the same general procedure as that for the preparation of 4-dodecyloxybenzyl chloride; thionyl chloride (7.45 g, 63.1 mmol), 4-tetradecyloxybenzyl alcohol (18.4 g, 57.4 mmol), CH2Cl2 (150 mL). 16.28 g (84%) white solid which decomposes upon melting.
Reaction SMILES: [CH3:1][CH:2]([C:8]([CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])=[CH2:9])[CH2:3][CH2:4][CH2:5][CH2:6][OH:7].P(=O)(O)(O)O>>[CH3:1][C:2]1([CH:8]2[CH2:10][CH2:11][CH2:12][C:13]([CH3:14])([CH3:15])[CH2:9]2)[CH2:3][CH2:4][CH2:5][CH2:6][O:7]1
Reactant: C=C(CCC=C(C)C)C(C)CCCCO
Agent: O=P(O)(O)O
Product: CC1(C)CCCC(C2(C)CCCCO2)C1

Procedure:
The procedure of Example I was applied to a sample of 5-methyl-6-(4-methyl-3-pentenyl)-6-hepten-1-ol. This was stirred with 85 percent phosphoric acid for one hour at room temperature, and the ether-soluble, water-insoluble reaction product was chromatographed on alumina. A relatively non-polar material was eluted from the column immediately (polar materials such as alcohols remained on the column). The eluted product was identified by means of NMR and IR as 2-methyl-2-(3',3'-dimethylcyclohexyl)-tetrahydropyran.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13](/[CH:15]=[CH:16]/[C:17]2[N:18](COCC3C=CC=CC=3)[N:19]=[CH:20][CH:21]=2)[CH:12]=[CH:11][C:10]=1[N:31]1[S:35](=[O:37])(=[O:36])[NH:34][C:33](=[O:38])[CH2:32]1)C1C=CC=CC=1>CO.[Pd]>[OH:8][C:9]1[CH:14]=[C:13]([CH2:15][CH2:16][C:17]2[NH:18][N:19]=[CH:20][CH:21]=2)[CH:12]=[CH:11][C:10]=1[N:31]1[S:35](=[O:37])(=[O:36])[NH:34][C:33](=[O:38])[CH2:32]1
Reactant: O=C1CN(c2ccc(/C=C/c3ccnn3COCc3ccccc3)cc2OCc2ccccc2)S(=O)(=O)N1
Agent: [Pd]
Solvent: CO
Product: O=C1CN(c2ccc(CCc3ccn[nH]3)cc2O)S(=O)(=O)N1

Procedure:
5-{2-Benzyloxy-4-[(E)-2-(2-benzyloxymethyl-2H-pyrazol-3-yl)-vinyl]-phenyl} 1,1-dioxo-1,2,5-thiadiazolidin-3-one (240 mg, 0.40 mmol) is dissolved in methanol (5 mL). 10% Pd/C is added periodically (7×50 mg) at intervals over 4 days. The mixture is stirred under an atmosphere of hydrogen at balloon pressure. The catalyst is removed by filtering the mixture through Celite and the filtrate is concentrated. The residue is chromatographed (reverse phase, 0-25% EtOH/water) to afford the title compound as a grey solid: 1H NMR (CD3OD) δ 7.46 (s, 1H), 7.31 (d, J=8.0 Hz, 1H), 6.75 (s, 1H), 6.71 (d, J=8.0 Hz, 1H) 6.10 (s, 1H) 4.29 (s, 2H), 2.89 (m, 4H); (M+1)+=323.
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1)(N1C=CN=C1)=O.[F:13][C:14]1[CH:15]=[C:16]2[C:21](=[C:22]([OH:25])C=1F)[N:20]([NH:26][CH3:27])[CH:19]=[C:18]([C:28]([OH:30])=[O:29])[C:17]2=[O:31]>CN(C)C=O>[F:13][C:14]1[CH:15]=[C:16]2[C:21](=[C:22]([OH:25])[C:1]=1[N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1)[N:20]([NH:26][CH3:27])[CH:19]=[C:18]([C:28]([OH:30])=[O:29])[C:17]2=[O:31]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CNn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(O)c21
Solvent: CN(C)C=O
Product: CNn1cc(C(=O)O)c(=O)c2cc(F)c(-n3ccnc3)c(O)c21
Reaction time: 2 h
Yield: 59.4 %

Procedure:
Carbonyldiimidazole (32 mg) was added to a stirred solution of 6,7-difluoro-8-hydroxy-1-(methylamino)-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid (50 mg) obtained in Reference example (i) in dry dimethylformamide (2 ml). Stirring was continued at room temperature for 2 hours and then at 80° C. for 5 hours. The solvent was removed under reduced pressure and the residue was suspended in water and the pH was adjusted to pH 5 with acetic acid. The precipitate which separated out was filtered and washed with methanol to give 35 mg of 6-fluoro-8-hydroxy-7-(1-imidazolyl)-1-(methylamino)-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid as pale yellow powder, FAB-MS m/z 319 (MH+); 1H-NMR (d6 -DMSO) δ: 2.82 (3H, s), 7.10 (1H, d, J=10.7 Hz), 7.61 (1H, d), 7.75 (1H, d), 8.62 (1H, s), 8.92 (1H, s), 15.33 (1H, br.s)
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([NH:14][C:15]1[C:16](=[O:35])[N:17]([C:21]2[CH:22]=[C:23]([CH:30]=[C:31]([F:34])[C:32]=2[CH3:33])[C:24]([NH:26][CH:27]2[CH2:29][CH2:28]2)=[O:25])[CH:18]=[CH:19][N:20]=1)([CH3:13])[CH3:12].[CH3:36][NH2:37]>>[CH:27]1([NH:26][C:24](=[O:25])[C:23]2[CH:22]=[C:21]([N:17]3[CH:18]=[CH:19][N:20]=[C:15]([NH:14][C:11]([CH3:13])([C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=4[O:4][CH2:3][CH2:2][NH:37][CH3:36])[CH3:12])[C:16]3=[O:35])[C:32]([CH3:33])=[C:31]([F:34])[CH:30]=2)[CH2:29][CH2:28]1
Reactant: CN
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-n1ccnc(NC(C)(C)c2ccccc2OCCCl)c1=O
Product: CNCCOc1ccccc1C(C)(C)Nc1nccn(-c2cc(C(=O)NC3CC3)cc(F)c2C)c1=O

Procedure:
The title product was prepared from 3-[3-[[1-[2-(2-chloroethoxy)phenyl]-1-methylethyl]amino]-2-oxo-1(2H)-pyrazinyl]-N-cyclopropyl-5-fluoro-4-methyl-benzamide (Example 169h) and methylamine using a similar method to that described for example 167f. Purification was by RPHPLC (0.2% ammonia/MeCN gradient on a Phenominex column).
Reaction SMILES: C[O:2][C:3](=[O:23])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[O:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[NH:19][C:20](=[O:22])[CH3:21])[N:12]=1.C1COCC1.[OH-].[Na+]>CCO>[C:20]([NH:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:11]1[N:12]=[C:8]([CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:23])=[O:2])[O:9][CH:10]=1)(=[O:22])[CH3:21]
Reactant: COC(=O)CCCCc1nc(-c2ccccc2NC(C)=O)co1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(=O)Nc1ccccc1-c1coc(CCCCC(=O)O)n1

Procedure:
Combine 5-[4-(2-acetylamino-phenyl)-oxazol-2-yl]-pentanoic acid methyl ester (3.26 g, 10.3 mmol) with THF (3 mL), EtOH (3 mL) and 1 N NaOH (40 mL) and stir at room temperature until hydrolysis is complete. Concentrate the mixture and dilute the residue with water before adjusting to pH 3.5-4.0 with aq HCl. Extract the mixture with 1-2% MeOH/EtOAc and concentrate the combined extracts in vacuo. Chromatograph the resulting residue over silica gel (MeOH/CH2Cl2) which allows for isolation of 5-[4-(2-acetylamino-phenyl)-oxazol-2-yl]-pentanoic acid (2.76 g, 89%). MS (ES): (M−1)− 301.2, 302.3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.[O-]P(OP(OP([O-])([O-])=O)([O-])=O)(=O)[O-].[K+].[K+].[K+].[K+].[K+].Br[C:30]1[CH:39]=[CH:38][C:37]2[NH:36][C:35](=[O:40])[C:34]3[NH:41][CH:42]=[CH:43][C:33]=3[C:32]=2[CH:31]=1.[CH2:44]([C:46]([O-:48])=[O:47])[CH3:45].O>O1CCOCC1.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>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:30]1[CH:39]=[CH:38][C:37]2[NH:36][C:35](=[O:40])[C:34]3[NH:41][CH:42]=[CH:43][C:33]=3[C:32]=2[CH:31]=1.[CH2:44]([C:46]([O-:48])=[O:47])[CH3:45]
Reactant: OB(O)c1ccccc1Cl
Reactant: O=c1[nH]c2ccc(Br)cc2c2cc[nH]c12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCC(=O)[O-]
Agent: O=P([O-])([O-])OP(=O)([O-])OP(=O)([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: O=c1[nH]c2ccc(-c3ccccc3Cl)cc2c2cc[nH]c12
Temperature: 110 °C
Reaction time: 20 h
Yield: 15 %

Procedure:
68 mg (0.01 mmol) of dichlorobis(triphenylphosphine)-palladium (II), 92 mg (0.59 mmol) of 2-chlorophenylboronic acid and 1 mL (2 mmol) of a 2M aqueous solution of tribasic potassium triphosphate are added to a degassed solution of 200 mg (0.49 mmol) of 8-bromo-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate dissolved in 10 mL of anhydrous dioxan. The reaction mixture is stirred at 110° C. for 20 hours. Water is added and the product is extracted with ethyl acetate. The organic phases are washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and evaporated. The residue is purified by chromatography on silica (eluent dichloromethane/methanol 98/2) to give 27 mg (15%) of 8-(2-chlorophenyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate in the form of a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([NH2:9])[C:6]([N+:10]([O-])=O)=[CH:5][CH:4]=1.[H][H]>CCO.[Pd]>[CH3:1][O:2][C:3]1[N:8]=[C:7]([NH2:9])[C:6]([NH2:10])=[CH:5][CH:4]=1
Reactant: COc1ccc([N+](=O)[O-])c(N)n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(N)c(N)n1

Procedure:
6-(Methyloxy)-3-nitro-2-pyridinamine (26 g, 129 mmol) was suspended in EtOH (500 ml) at room temperature under argon and then treated with palladium on carbon (15 g, 14.10 mmol) (10% paste). The reaction was stirred under 1 atmosphere of hydrogen overnight. The reaction was filtered through a Celite pad and the pad washed with EtOH (500 ml). EtOH was evaporated to afford the product as a purple oil (20.68 g, slightly impure).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.[H-].[Na+].CS(O[CH:14]1[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]1)(=O)=O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH:18]2[CH2:19][CH2:14][CH2:15][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:17]2)[CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(OS(C)(=O)=O)C1
Reactant: Brc1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC(n2cc(Br)cn2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 29.8 %

Procedure:
4-Bromopyrazole (2.94 g, 20 mmol) dissolved in DMF (20 mL) was cooled to 0° C., sodium hydride (900 mg, 22.5 mmol) was added portion-wise over 1 h. After warmed to room temperature and stirred for 1 h, tert-butyl 3-(methylsulfonyloxy)-piperidine-1-carboxylate (5.03 g, 20 mmol) was added, and the reaction mixture was heated at 100° C. overnight. The reaction mixture was quenched with saturated NH4Cl, and extracted with EtOAc. The organic layer was washed with H2O, brine, dried and concentrated. Crude mixture was column purified with mixture of EtOAc and hexane to give tert-butyl 3-(4-bromo-1H-pyrazol-1-yl)piperidine-1-carboxylate (1.97 g) as white solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]2[CH2:14][CH:9]1[CH2:10][N:11]2[C:15]1[C:16]2[C:17](=[C:21]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)[N:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])[N:23]=2)[N:18]=[CH:19][N:20]=1)=O)(C)(C)C.Cl>O1CCOCC1>[ClH:30].[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([C:21]2[N:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])[N:23]=[C:16]3[C:15]([N:11]4[CH2:10][CH:9]5[CH2:14][CH:12]4[CH2:13][NH:8]5)=[N:20][CH:19]=[N:18][C:17]=23)=[CH:32][CH:33]=1
Reactant: CC(C)(C)OC(=O)N1CC2CC1CN2c1ncnc2c(-c3ccc(Cl)cc3)n(-c3ccccc3Cl)nc12
Agent: Cl
Solvent: C1COCCO1
Product: Clc1ccc(-c2c3ncnc(N4CC5CC4CN5)c3nn2-c2ccccc2Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
To the solution of 5-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester 2A-46 (595 mg, 1.11 mmol) in dioxane (8 ml) was added HCl (2.22 ml, 4 N in dioxane, 8.88 mmol). The reaction mixture was stirred for 3 hours under nitrogen at room temperature. Then, the reaction mixture was concentrated and co-evaporated with diethyl ether (25 ml). The residue was further dried in a drying pistol under vacuum at 65° C. to give Rac-(S,S)-3-(4-chlorophenyl)-2-(2-chlorophenyl)-7-(2,5-diazabicyclo[2.2.1]hept-2-yl)-2H-pyrazolo[4,3-d]pyrimidine HCl salt 4A-1 (522 mg, 92%): MS: 437.1 (M+1)+; 1H NMR (400 MHz, CD3OD) δ 8.6 (d, J=6.2 Hz, 1H), 7.7 (dd, J=15.8, 7.1 Hz, 1H), 7.6 (m, 2H), 7.5 (m, 1H), 7.4 (dd, J=8.3, 3.3 Hz, 2H), 7.3 (t, J=7.5 Hz, 2H), 6.3 (s, 0.5H), 5.8 (s, 0.5H), 4.7 (m, 1H), 4.6 (d, J=13.7 Hz, 0.5H), 4.5 (dd, J=13.7, 2.5 Hz, 0.5H), 4.2 (ddd, J=29.5, 14.1, 1.7 Hz, 1H), 3.6 (m, 2H), 2.5 (dd, J=24.0, 12.0 Hz, 1H), 2.3 (t, J=11.2 Hz, 1H).
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([CH:29]=[CH:30][C:31]=3[O:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH3:38])[C:14]([NH:16][C:17]3[CH:28]=[CH:27][C:20]([C:21]([O:23][CH2:24][CH:25]=[CH2:26])=[O:22])=[CH:19][CH:18]=3)=[O:15])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.I[CH3:40]>>[CH3:40][N:16]([C:17]1[CH:28]=[CH:27][C:20]([C:21]([O:23][CH2:24][CH:25]=[CH2:26])=[O:22])=[CH:19][CH:18]=1)[C:14](=[O:15])[C:13]1[CH:29]=[CH:30][C:31]([O:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH3:38])=[C:11]([C:1]23[CH2:10][CH:5]4[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]4)[CH2:8]2)[CH2:2]3)[CH:12]=1
Reactant: C=CCOC(=O)c1ccc(NC(=O)c2ccc(OCOCCOC)c(C34CC5CC(CC(C5)C3)C4)c2)cc1
Reactant: CI
Product: C=CCOC(=O)c1ccc(N(C)C(=O)c2ccc(OCOCCOC)c(C34CC5CC(CC(C5)C3)C4)c2)cc1

Procedure:
In a manner analogous to that of Example 16(a), 1.35 g (2.6 mmol) of allyl 4-[3-(1-adamantyl)-4-methoxyethoxymethoxybenzamido]-benzoate prepared in Example 10(d) was reacted with 190 μl (3.1 mmol) of iodomethane and 1.38 g (100%) of the expected allylic ester was recovered.