Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:13]=[C:14]([CH:21]=[CH:22][C:23]=3[CH3:24])[C:15]([NH:17][CH:18]3[CH2:20][CH2:19]3)=[O:16])=[CH:9][CH:10]=2)[CH:5]=[N:4][N:3]=1.[F:25][C:26]([F:41])([F:40])[C:27]1[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][C:28]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].O>COCCOC.CCO.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>[F:25][C:26]([F:40])([F:41])[C:27]1[CH:32]=[C:31]([C:33]([F:34])([F:35])[F:36])[CH:30]=[CH:29][C:28]=1[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:13]=[C:14]([CH:21]=[CH:22][C:23]=3[CH3:24])[C:15]([NH:17][CH:18]3[CH2:20][CH2:19]3)=[O:16])=[CH:9][CH:10]=2)[CH:5]=[N:4][N:3]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1C(F)(F)F
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(Cl)nncc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCO
Solvent: O
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(-c3ccc(C(F)(F)F)cc3C(F)(F)F)nncc2c1
Temperature: 120 °C

Procedure:
In a microwave tube was placed 3-(1-chlorophthalazin-6-yl)-N-cyclopropyl-4-methylbenzamide (0.097 g, 0.29 mmol), 2,4-bis(trifluoromethyl)benzeneboronic acid (0.074 g, 0.29 mmol), tetrakis(triphenylphosphine)palladium (0) (0.033 g, 0.029 mmol) and 2M potassium carbonate (0.43 mL, 0.86 mmol) in 1.5 mL of DME/EtOH (4/1). The mixture was heated in the microwave at 120° C. for 20 minutes. After cooling, water was added and the mixture was extracted with DCM. The combined organic layers were dried over sodium sulfate, filtered and concentrated. The crude product was purified by HPLC to give 3-(1-(2,4-bis(trifluoromethyl)phenyl)phthalazin-6-yl)-N-cyclopropyl-4-methylbenzamide as an off-white solid. MS (ES+)=516.2 (M+H).
Reaction SMILES: IC1C=CC([C@H]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C@H:11]3[CH2:18][CH2:19][CH2:20][N:10]3C2)=CC=1.[Br:21][C:22]1[CH:32]=[CH:31][C:25]([CH:26]([OH:30])[C:27]([OH:29])=[O:28])=[CH:24][CH:23]=1.C1(C2CCCN2)C=CC=CC=1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>>[Br:21][C:22]1[CH:23]=[CH:24][C:25]([CH:26]([OH:30])[C:27]([O:29][N:10]2[CH2:20][CH2:19][CH2:18][CH:11]2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:28])=[CH:31][CH:32]=1
Reactant: O=C(O)C(O)c1ccc(Br)cc1
Reactant: Ic1ccc([C@@H]2CN3CCC[C@@H]3c3ccccc32)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc(C2CCCN2)cc1
Product: O=C(ON1CCCC1c1ccccc1)C(O)c1ccc(Br)cc1

Procedure:
Trans-1,2,3,5,6,10b-hexahydro-6-(4'-iodophenyl)pyrrolo[2,1-a]isoquinoline (trans-6), was synthesized by a four step reaction sequence outlined in FIG. 1A. 4-Bromomandelic acid (1) was coupled with 2-phenylpyrrolidine (2) in the presence of BOP reagent to yield 2-phenylpyrrolidino 4-bromophenyl-α-hydroxyacetate (3). Upon treatment with PPA, the amide 3 was cyclized to the lactam (4) which was reduced with aluminum hydride to provide a pair of diastereomers (5) with a trans-to-cis ratio of 2. The desired trans-6-(4'-bromophenol)-1,2,3,5,6,10b-hexahydropyrrolo[2,1-a]-isoquinoline (trans 5) was separated by flash chromatography. Trans-5 was treated with butyllithium followed by iodination to afford trans-1,2,3,5,6,10b-hexahydro-6-(4'-iodophenyl) pyrrolo [2,1-a]isoquinoline (trans-6). Enantiomeric enriched (+)-(6S, 10bR)-1,2,3,5,6,10b-hexahydro-6-(4'-iodophenyl)pyrrolo[2,1-a]isoquinoline was obtained by the same reaction sequence starting with (+)-2(R)-phenylpyrrolidine.
Reaction SMILES: [C:1]([S:5][CH2:6][C:7]1([CH3:14])[NH:11][C:10](=[O:12])[NH:9][C:8]1=[O:13])([CH3:4])([CH3:3])[CH3:2].[OH-:15].[K+]>C1(C)C=CC=CC=1>[C:10]([NH:11][C@:7]([CH3:14])([C:8]([OH:15])=[O:13])[CH2:6][S:5][C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:12])[NH2:9]
Reactant: [OH-]
Reactant: CC(C)(C)SCC1(C)NC(=O)NC1=O
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(C)(C)SC[C@](C)(NC(N)=O)C(=O)O
Temperature: 95 °C
Reaction time: 51 h
Yield: 90 %

Procedure:
First, 5-tert-butylthiomethyl-5-methylhydantoin (5 g, 23 mmol) was mixed with a 73% aqueous potassium hydroxide solution (5.7 g) and toluene (10 ml), and the mixture was heated to 95° C. and stirred for 51 hours. The HPLC analysis of the reaction solution showed the production of the title compound in a reaction yield of 90%.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:12][C:13]2[CH:18]=[C:17]([N+:19]([O-])=O)[CH:16]=[C:15]([Cl:22])[C:14]=2[Cl:23])=[N:4][N:5]([CH3:11])[C:6]=1[O:7][CH:8]([F:10])[F:9].C(O)(=O)C.C(O)C>[Fe].C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([CH2:12][C:13]2[CH:18]=[C:17]([NH2:19])[CH:16]=[C:15]([Cl:22])[C:14]=2[Cl:23])=[N:4][N:5]([CH3:11])[C:6]=1[O:7][CH:8]([F:9])[F:10]
Reactant: Cn1nc(Cc2cc([N+](=O)[O-])cc(Cl)c2Cl)c(Cl)c1OC(F)F
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cn1nc(Cc2cc(N)cc(Cl)c2Cl)c(Cl)c1OC(F)F

Procedure:
At 70—75° C., 2.2 g (5.7 mmol) of 4-chloro-3-(2,3-dichloro-5-nitrobenzyl)-5-difluoromethoxy-1-methyl-1H-pyrazole were added to a mixture of 1.7 g (30 mmol) of iron, 5 ml of acetic acid and 10 ml of ethanol. The mixture was then heated under reflux for 1 hour. The reaction mixture was then admixed with 50 ml of ethyl acetate and filtered through a bed of diatomaceous earth. Finally, the mixture was concentrated. Yield: 2 g;
Reaction SMILES: Br.[NH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][NH:8][C:7](=[O:11])[CH:6]=1.[C:12]1(=O)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](=[O:21])[O:13]1.CCN(C(C)C)C(C)C>C1(C)C(C)=CC=CC=1>[O:11]=[C:7]1[CH:6]=[C:5]([CH2:4][CH2:3][N:2]2[C:12](=[O:13])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]2=[O:21])[CH:10]=[CH:9][NH:8]1
Reactant: NCCc1cc[nH]c(=O)c1
Reactant: O=C1OC(=O)c2ccccc21
Agent: Br
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1C
Product: O=C1c2ccccc2C(=O)N1CCc1cc[nH]c(=O)c1
Temperature: 140 °C
Reaction time: 6 h
Yield: 75.4 %

Procedure:
A mixture of 4-(2-aminoethyl)pyridin-2(1H)-one hydrobromide (400 mg, 1.83 mmol), isobenzofuran-1,3-dione (271 mg, 1.83 mmol) and DIEA (472 mg, 3.66 mmol) in 30 mL of xylene was stirred at 140° C. for 6 hours. The solvent was removed under reduce pressure. The residue was purified by silica gel chromatography, eluting with DCM/MeOH (30/1) to give 2-(2-(2-oxo-1,2-dihydropyridin-4-yl)ethyl)isoindoline-1,3-dione (370 mg, 76%) as a white sold. LC-MS: 269 [M+H]+, tR=1.23 min.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH:32]([CH3:34])[CH3:33])=[CH:27][CH:26]=2)[C:8]2[C:13]([C:14]=1[Cl:15])=[CH:12][C:11](B1OC(C)(C)C(C)(C)O1)=[CH:10][CH:9]=2)=[O:5])C.Br[C:36]1[CH:37]=[CH:38][C:39]([O:42][CH:43]2[CH2:47][CH2:46][CH2:45][CH2:44]2)=[N:40][CH:41]=1>>[Cl:15][C:14]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:36]3[CH:41]=[N:40][C:39]([O:42][CH:43]4[CH2:47][CH2:46][CH2:45][CH2:44]4)=[CH:38][CH:37]=3)[CH:12]=2)[N:7]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH:32]([CH3:33])[CH3:34])=[CH:27][CH:26]=2)[C:6]=1[C:4]([OH:3])=[O:5]
Reactant: CCOC(=O)c1c(Cl)c2cc(B3OC(C)(C)C(C)(C)O3)ccc2n1-c1ccc(OC(C)C)cc1
Reactant: Brc1ccc(OC2CCCC2)nc1
Product: CC(C)Oc1ccc(-n2c(C(=O)O)c(Cl)c3cc(-c4ccc(OC5CCCC5)nc4)ccc32)cc1

Procedure:
The title compound was prepared in accordance with Example 8(b) from 3-chloro-1-(4-isopropoxyphenyl)-5-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-1H-indole-2-carboxylic acid ethyl ester (see Example 35(c)) and 5-bromo-2-cyclopentoxypyridine (see Example 36(b)), followed by ester hydrolysis in accordance with Example 1(c).
Reaction SMILES: [Br-].[Br:2][CH2:3][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[C:29]([N:33]1[CH2:38][CH2:37][C:36](=O)[CH2:35][CH2:34]1)([CH3:32])([CH3:31])[CH3:30]>C1COCC1>[Br:2][CH:3]=[C:36]1[CH2:37][CH2:38][N:33]([C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:34][CH2:35]1
Reactant: BrC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)N1CCC(=O)CC1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)N1CCC(=CBr)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of (bromomethyl)triphenylphosphonium bromide (1.52 g, 3.48 mmol) in dry THF (15 mL) at −78° C. was added potassium tert-butoxide (3.5 mL, 1.0M) slowly. After stirring 20 minutes, 1-tert-butylpiperidin-4-one (COMPOUND PPA-1) (595 mg, 3.83 mmol) in THF (2 mL) was added, and the reaction mixture was warmed up to rt slowly over 2 h. The reaction mixture was quenched with brine, and it was extracted with CH2Cl2. The combined extracts were dried over Na2SO4 then concentrated in vacuo. The crude material was purified by flash chromatography eluting first with hexane then gradually increasing to 5% acetone/hexane to give the title compound. 1H NMR (CDCl3, 500 MHz): δ 5.85 (s, 1H); 2.56 (m, 4H); 2.43 (t, J=5.6 Hz, 2H); 2.28 (t, J=5.6 Hz, 2H); 1.08 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[C:28]1([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:33]=[CH:32][CH:31]=[C:30](B(O)O)[CH:29]=1>>[C:28]1([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:33]=[CH:32][CH:31]=[C:30]([N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=3)[C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7]2)[CH:29]=1
Reactant: OB(O)c1cccc(-c2ccccc2)c1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccccc21
Product: O=C1OC2(CCN(C(=O)c3cn(-c4cccc(-c5ccccc5)c4)c4cc(Cl)ccc34)CC2)c2ccccc21

Procedure:
Following the general procedure VI as described above, the arylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 16) with commercially available 3-biphenylboronic acid gave the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([C:9]2[CH:22]=[CH:21][C:12]([C:13]([NH:15][CH2:16][CH2:17][CH2:18][O:19][CH3:20])=[O:14])=[CH:11][N:10]=2)[C:6]=1[O:7]C.[CH2:23]([O:25][C:26]1[CH:31]=[C:30](B(O)O)[CH:29]=[CH:28][N:27]=1)[CH3:24]>>[CH2:23]([O:25][C:26]1[CH:31]=[C:30]([C:2]2[CH:3]=[N:4][N:5]([C:9]3[CH:22]=[CH:21][C:12]([C:13]([NH:15][CH2:16][CH2:17][CH2:18][O:19][CH3:20])=[O:14])=[CH:11][N:10]=3)[C:6]=2[OH:7])[CH:29]=[CH:28][N:27]=1)[CH3:24]
Reactant: COCCCNC(=O)c1ccc(-n2ncc(Br)c2OC)nc1
Reactant: CCOc1cc(B(O)O)ccn1
Product: CCOc1cc(-c2cnn(-c3ccc(C(=O)NCCCOC)cn3)c2O)ccn1

Procedure:
The title compound was prepared in a manner similar to Example 213 using 6-(4-bromo-5-methoxy-1H-pyrazol-1-yl)-N-(3-methoxypropyl)nicotinamide and (2-ethoxypyridin-4-yl)boronic acid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.25 (t, J=7.1 Hz, 3H) 1.71 (quin, J=6.7 Hz, 2H) 3.18 (s, 3H) 3.21-3.29 (m, 2H) 3.32 (t, J=6.3 Hz, 2H) 4.22 (q, J=7.1 Hz, 2H) 7.31 (s, 1H) 7.40 (d, J=5.3 Hz, 1H) 7.94 (d, J=5.6 Hz, 1H) 8.26-8.34 (m, 1H) 8.34-8.42 (m, 1H) 8.47 (br. s., 1H) 8.61 (t, J=5.6 Hz, 1H) 8.82 (d, J=1.5 Hz, 1H) 13.42 (br. s., 1H). MS m/z 398 [M+H]+.
Reaction SMILES: Br[N:2]1C(=O)CC[C:3]1=O.[Cl:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH2:19][C:20]([OH:22])=[O:21])[C:14]([CH3:23])=[C:13]2[C:24]1[C:33]2[C:28](=[CH:29][C:30]([Cl:34])=[CH:31][CH:32]=2)[N:27]=[CH:26][CH:25]=1.CN.C1COCC1>CN1C(=O)CCC1.ClCCl>[Cl:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH2:19][C:20]([OH:22])=[O:21])[C:14]([CH2:23][NH:2][CH3:3])=[C:13]2[C:24]1[C:33]2[C:28](=[CH:29][C:30]([Cl:34])=[CH:31][CH:32]=2)[N:27]=[CH:26][CH:25]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c(-c2ccnc3cc(Cl)ccc23)c2cc(Cl)ccc2n1CC(=O)O
Agent: CN
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: CNCc1c(-c2ccnc3cc(Cl)ccc23)c2cc(Cl)ccc2n1CC(=O)O
Reaction time: 1 h

Procedure:
1-Bromo-2,5-pyrrolidinedione (125 mg) was added to a solution of the product from Example 27 step b) (250 mg) in NMP (0.5 ml) and dichloromethane (5 ml), and the solution stirred for 30 min. 2M methylamine/THF (3.25 ml) was then added and the solution stirred for 1 hour. The mixture was diluted with dichloromethane (20 ml), washed with saturated aqueous sodium bicarbonate and water. The organic layer was dried (MgSO4), filtered, evaporated in vacuo and the residue purified by reverse phase HPLC. After evaporation in vacuo the oily residue was treated with ether to give a solid, filtered off and dried to yield the title compound as a white solid (60 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[CH:13][C:14]#[N:15])[CH2:9][N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[C:6]=2[CH:23]=1.S(=O)(=O)(O)[OH:25].[OH-].[Na+]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[CH:13][C:14](=[O:25])[NH2:15])[CH2:9][N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[C:6]=2[CH:23]=1
Reactant: O=S(=O)(O)O
Reactant: CN1C(=CC#N)CN=C(c2ccccc2Cl)c2cc(Cl)ccc21
Agent: [Na+]
Agent: [OH-]
Product: CN1C(=CC(N)=O)CN=C(c2ccccc2Cl)c2cc(Cl)ccc21
Temperature: 50 °C

Procedure:
5.4 g of 7-chloro-1-methyl-2-cyanomethylene-5-(2'-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine are introduced portion-wise into 26 ml of concentrated sulfuric acid and are dissolved therein while the mixture is slowly heated-up to a temperature of 50° C. The solution is kept at a temperature of 50° C. for 1 more hour. For working-up after cooling the solution is poured onto ice, the sulfuric acid is neutralized with diluted sodiumhydroxide solution and the raw product is extracted with methylenechloride. The organic phase is separated, washed with water to neutral reaction and dried over sodium sulfate. After filtration and evaporation of the solvent under vacuum, a residue is obtained and is crystallized by trituration with ether. After re-crystallization from ethanol, 7-chloro-1-methyl-2-carbamoylmethylene-5-(2'-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine, having a melting point of 212° to 217° C., is obtained.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][NH:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1)=[O:8])C.Cl.[OH-].[Na+]>CO.O>[F:19][C:16]([F:17])([F:18])[C:13]1[CH:12]=[CH:11][C:10]([N:9]2[CH:4]=[CH:5][NH:6][C:7]2=[O:8])=[CH:15][CH:14]=1
Reactant: CCOC(CNC(=O)Nc1ccc(C(F)(F)F)cc1)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=c1[nH]ccn1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 74.4 %

Procedure:
1-(2,2-Diethoxyethyl)-3-(4-trifluoromethylphenyl)urea (9.2 g, 28.7 mmol) was dissolved in a mixture of 113 ml of methanol and 57 ml of water. To the reaction solution was added 67.5 ml of 0.48N hydrochloric acid and the mixture was stirred for 48 hours at room temperature. To the reaction solution was added 1N sodium hydroxide to adjust pH to 7, followed by being concentrated under reduced pressure. The residue was extracted with ethyl acetate (100 ml×4). The extracts were combined, washed with water and saturated aqueous solution of sodium chloride successively, dried over magnesium sulfate and distilled off. The crystals thus separated out were recystallized from ethyl acetate-isopropylether to give 4.87 g of 1-(4-trifluoromethylphenyl)-2(1H,3H)-imidazolone (74%) as colorless prisms.
Reaction SMILES: Br.Br[CH2:3][C:4]([C:6]12[CH2:13][N:10]([CH2:11][CH2:12]1)[CH2:9][CH2:8][CH2:7]2)=[O:5].[N-:14]=[N+:15]=[N-:16].[Na+]>CN(C)C=O>[N:14]([CH2:3][C:4]([C:6]12[CH2:13][N:10]([CH2:11][CH2:12]1)[CH2:9][CH2:8][CH2:7]2)=[O:5])=[N+:15]=[N-:16]
Reactant: O=C(CBr)C12CCCN(CC1)C2
Reactant: [N-]=[N+]=[N-]
Agent: Br
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCC(=O)C12CCCN(CC1)C2
Temperature: 25 °C
Reaction time: 21 h

Procedure:
A solution of 5-(α-bromoacetyl)-1-azabicyclo[3.2.1]octane hydrobromide (D27) (1.8 g; 5.8 mmole) in dry N,N-dimethylformamide (25 ml) was treated with sodium azide (0.41 g; 6.3 mmole) and stirred in the dark at room temperature for 21 h. The reaction mixture was concentrated in vacuo and the residue was treated with a saturated potassium carbonate solution (25 ml) and extracted into chloroform (4×25 ml). The dried (sodium sulphate) organic layers were concentrated in vacuo to give the title compound (D28) as an orange oil (0.75 g; 67%) which was used in the next stage without purification.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[NH2:23][C:24]([CH3:30])([CH3:29])[CH2:25][C:26]([OH:28])=[O:27].C[O-].[Na+].Cl>CN(C=O)C.O>[OH:15][C:14]1[C:13]2[C:8](=[CH:9][C:10]([O:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:11][CH:12]=2)[CH:7]=[N:6][C:5]=1[C:3]([NH:23][C:24]([CH3:30])([CH3:29])[CH2:25][C:26]([OH:28])=[O:27])=[O:4]
Reactant: COC(=O)c1ncc2cc(Oc3ccccc3)ccc2c1O
Reactant: CC(C)(N)CC(=O)O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(CC(=O)O)NC(=O)c1ncc2cc(Oc3ccccc3)ccc2c1O
Yield: 32.4 %

Procedure:
To a mixture of 4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (100 mg, 0.34 mmol) and 3-amino-3-methyl-butyric acid (Oakwood) (199 mg, 1.7 mmol) in DMF (3 mL) was added sodium methoxide solid (73 mg, 1.36 mmoL). The mixture was gently refluxed for 2 h. After cooled, it was diluted with water (100 mL) and acidified by 1 N HCl aqueous solution to pH=3-4. Precipitate was collected and dried in vacuo. The crude product was purified by silica gel chromatography, eluting with 20%-100% EtOAc-hexanes, to provide the title compound (42 mg, 0.11 mmol) in 33% yield. LC-MS ESI−: 379.04 (M−1)−.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([NH:13]C(=O)OC(C)(C)C)[CH:9]=[CH:10][C:11]=1[CH3:12].[OH-].[Na+]>Cl>[CH3:1][N:2]([CH3:21])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:9]=[CH:10][C:11]=1[CH3:12])[NH2:13]
Reactant: Cc1ccc(NC(=O)OC(C)(C)C)cc1OCCN(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc(N)cc1OCCN(C)C
Temperature: 25 °C
Yield: 89.6 %

Procedure:
A solution of 8 (1.15 g) in 6N HCl (10 mL) was heated at 60° C. for 4 hours. After cooling to room temperature, the solution was neutralized with 6N NaOH solution. The aqueous mixture was extracted with EtOAc (2×30 mL), the combined organic layers were washed with brine (1×50 mL) and dried over MgSO4. The solids were filtered, and the filtrate was concentrated under reduced pressure to give the desired product as an oil (0.68 g).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH:13]=[CH2:14])=[CH:8][C:7]=1[O:15][CH3:16])[CH:2]1[O:4][CH2:3]1.C([O-])([O-])=[O:18].[Na+].[Na+]>O>[CH2:12]([C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:1][CH:2]([OH:4])[CH2:3][OH:18])=[C:7]([O:15][CH3:16])[CH:8]=1)[CH:13]=[CH2:14]
Reactant: O=C([O-])[O-]
Reactant: C=CCc1ccc(OCC2CO2)c(OC)c1
Agent: [Na+]
Solvent: O
Product: C=CCc1ccc(OCC(O)CO)c(OC)c1
Temperature: 80 °C
Yield: 97 %

Procedure:
A 3,000 mL, 3-necked, round-bottom flask was equipped with a mechanical stirrer, a reflux condenser and a 250 mL addition funnel. The flask was charged with H2O (1,500 mL) and 70% HClO4 (1 mL) and heated to ca. 80° C. while stirring vigorously (ca. 750 rpm). 4-Allyl-2-methoxyphenyl glycidyl ether was placed in the addition funnel and was added dropwise to the reaction mixture over a 4-5 hour period. The reaction mixture was stirred for 48 hours at ca. 80° C. The mixture was then allowed to cool and was neutralized with 5% Na2CO3. The phases were separated and the aqueous phase extracted with CH2Cl2 (1,500 mL). The CH2Cl2 and H2 were removed from the 3-(4-allyl-2-methoxyphenoxy)-1,2-propanediol, i.e., ##STR23## by evaporation in vacuo to yield a pale amber oil (355 g, 97%) which crystallized on standing; mp 77°-79° C. (recrystallized from benzend).
Reaction SMILES: [F:1][C:2]1[C:3]2[N:4]([C:10](=[S:13])[NH:11][N:12]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C[O-].[Na+]>CO.O>[F:1][C:2]1[C:3]2[N:12]([NH:11][C:10](=[S:13])[N:4]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COc1ncc(F)c2n[nH]c(=S)n12
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ncc(F)c2nc(=S)[nH]n12
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
A mixture of 10.01 g (0.050 mol) of 8-fluoro-5-methoxy-1,2,4-triazolo[4,3-c]pyrimidine-3(2H)-thione in 8.6 g of methanol was prepared and cooled with an ice water bath. Sodium methoxide in methanol (32.4 g of 25 percent, 0.15 mol) was added under nitrogen with stirring and cooling. After 2.5 hours, 25.6 mL of ice cold 6.25N aqueous hydrochloric acid was added with stirring to the thick slurry obtained. The resulting mixture was diluted with a little water and the solids were recovered by vacuum filtration and dried under reduced pressure to obtain 8.26 g (83 percent of theory) of the title compound as a colorless powder. The compound melts at 155°-160° C. and then resolidifies and does not remelt up to 230° C.
Reaction SMILES: C(C1C=CC(C(NC2C=CC(C3C=C4C(CN([C@@H](C(C)C)C(O)=O)C4=O)=CC=3)=NC=2)=O)=CC=1)(C)(C)C.[CH2:37]([O:41][C:42]1[CH:74]=[CH:73][C:45]([C:46]([NH:48][C:49]2[CH:50]=[CH:51][C:52]([C:55]3[CH:63]=[C:62]4[C:58]([CH2:59][N:60]([C@@H:65]([CH:70]([CH3:72])[CH3:71])[C:66]([O:68]C)=[O:67])[C:61]4=[O:64])=[CH:57][CH:56]=3)=[N:53][CH:54]=2)=[O:47])=[CH:44][CH:43]=1)[CH2:38][CH2:39][CH3:40]>>[CH2:37]([O:41][C:42]1[CH:74]=[CH:73][C:45]([C:46]([NH:48][C:49]2[CH:50]=[CH:51][C:52]([C:55]3[CH:63]=[C:62]4[C:58]([CH2:59][N:60]([C@@H:65]([CH:70]([CH3:71])[CH3:72])[C:66]([OH:68])=[O:67])[C:61]4=[O:64])=[CH:57][CH:56]=3)=[N:53][CH:54]=2)=[O:47])=[CH:44][CH:43]=1)[CH2:38][CH2:39][CH3:40]
Reactant: CCCCOc1ccc(C(=O)Nc2ccc(-c3ccc4c(c3)C(=O)N([C@H](C(=O)OC)C(C)C)C4)nc2)cc1
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(C(C)(C)C)cc4)cn3)cc2C1=O
Product: CCCCOc1ccc(C(=O)Nc2ccc(-c3ccc4c(c3)C(=O)N([C@H](C(=O)O)C(C)C)C4)nc2)cc1
Yield: 78 %

Procedure:
The compound of example 412 was prepared analogous to the compound of example 404 by hydrolysis of the compound of example 411.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][CH:3]=1.[N:8]([O:10]CCC(C)C)=[O:9]>>[NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9]
Reactant: Cn1nccc1N
Reactant: CC(C)CCON=O
Product: Cn1ncc([N+](=O)[O-])c1N

Procedure:
Total yields of up to 46 percent are obtained when the 5-amino-1-methylpyrazole is converted with isoamyl nitrite to produce 5-amino-1-methyl-4-nitropyrazole and reduced with zinc(II)chloride to give 4,5-diamino-1-methylpyrazole according to H. Dorn, et al., Liebigs Ann. Chem. 717, p. 118 (1968).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][C:3]=1[O:14][CH3:15].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.Cl[CH2:28][C:29]1[N:30]=[C:31]([C:35]2[O:36][CH:37]=[CH:38][CH:39]=2)[O:32][C:33]=1[CH3:34]>O>[CH2:12]([O:11][C:9](=[O:10])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([O:1][CH2:28][C:29]2[N:30]=[C:31]([C:35]3[O:36][CH:37]=[CH:38][CH:39]=3)[O:32][C:33]=2[CH3:34])=[C:3]([O:14][CH3:15])[CH:4]=1)[CH3:13]
Reactant: CCOC(=O)Cc1ccc(O)c(OC)c1
Reactant: Cc1oc(-c2ccco2)nc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1

Procedure:
To a mixture of ethyl (4-hydroxy-3-methoxyphenyl)acetate (7.00 g), potassium carbonate (5.43 g) and N,N-dimethylformamide (100 mL) was added 4-chloromethyl-2-(2-furyl)-5-methyl-1,3-oxazole (7.77 g) with stirring, and the mixture was stirred overnight at 80° C. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with distilled water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give ethyl(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxyphenyl)acetate from a fraction eluted with ethyl acetate-hexane (1:4, v/v). Recrystallization from ethyl acetate-hexane gave white crystal (8.22 g, yield 56%) melting point: 106-107° C.