Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][N:6]=[C:7]([Cl:12])[CH:8]=2)[N:3]=1.C([Li])CCC.[C:18]1(=[O:23])[CH2:22][CH2:21][CH2:20][CH2:19]1>C1(C)C=CC=CC=1>[Cl:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][N:6]=1)[N:3]=[C:2]([C:18]1([OH:23])[CH2:22][CH2:21][CH2:20][CH2:19]1)[CH:11]=[CH:10]2
Reactant: Clc1cc2ccc(Br)nc2cn1
Reactant: O=C1CCCC1
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: OC1(c2ccc3cc(Cl)ncc3n2)CCCC1
Temperature: -78 °C
Reaction time: 6 h

Procedure:
A suspension of 2-bromo-6-chloro-1,7-naphthyridine (300 mg, 1 mmol) in toluene (8 mL) cooled at −78° C. under an atmosphere of nitrogen was treated with n-butyllithium (1.6M solution in hexanes, 2.3 mL, 3.7 mmol) dropwise over 5 minutes. The reaction mixture was stirred at this temperature for 6 hours and then cyclopentanone (0.33 mL, 3.7 mmol) was added slowly as a solution in toluene (1.3 mL). After 15 minutes, the mixture was allowed to warm to room temperature and then quenched with a few drops of saturated aqueous ammonium chloride solution. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (50 mL). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated in vacuo to afford a residue that was purified by flash chromatography (silica, 12 g, ISCO, 0-50% ethyl acetate in heptane) to afford the title compound as an orange, waxy solid (65 mg, 20%), which was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][Cl:16])[C:9](=[O:17])[CH2:8][C:7]=2[CH:18]=1.[CH3:19][NH:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=1>>[ClH:16].[ClH:16].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][N:20]([CH3:19])[CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=3)[C:9](=[O:17])[CH2:8][C:7]=2[CH:18]=1
Reactant: COc1ccc2c(c1)CC(=O)N(CCCCl)CC2
Reactant: CNCCc1ccc(OC)c(OC)c1
Product: COc1ccc2c(c1)CC(=O)N(CCCN(C)CCc1ccc(OC)c(OC)c1)CC2
Product: Cl

Procedure:
This compound was prepared analogous to Example 5(b) by reaction of 1-(8-methoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-chloro-propane with N-methyl-N-[2-(3,4-dimethoxy-phenyl)-ethyl]-amine.
Reaction SMILES: [C:1]([C:3]1[CH:21]=[CH:20][C:6]([N:7]([CH2:18][CH3:19])S(C2C=CC(C)=CC=2)(=O)=O)=[CH:5][CH:4]=1)#[N:2].[N+:22]([O-])([OH:24])=[O:23]>S(=O)(=O)(O)O>[C:1]([C:3]1[CH:21]=[CH:20][C:6]([NH:7][CH2:18][CH3:19])=[C:5]([N+:22]([O-:24])=[O:23])[CH:4]=1)#[N:2]
Reactant: O=[N+]([O-])O
Reactant: CCN(c1ccc(C#N)cc1)S(=O)(=O)c1ccc(C)cc1
Agent: O=S(=O)(O)O
Product: CCNc1ccc(C#N)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 28 %

Procedure:
4′-Cyano-N-ethyl-p-toluenesulfonanilide (6.95 g (23.1 mmol) was dissolved in concentrated sulfuric acid (20.0 ml) under cooling with ice. To this, 97% fuming nitric acid (1.00 ml (23.4 mmol)) was added dropwise and the mixture was stirred for 30 minutes under cooling with ice. The resulting mixture was poured into ice-water, followed by extraction with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography with ethyl acetate-hexane (1:3) as eluent, to give 1.25 g (28%) of 4-cyano-N-ethyl-2-nitroaniline as yellow crystals.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=3)=[C:19]([O:30][CH2:31][CH2:32][O:33][C:34]3[N:39]=[CH:38][C:37]([C:40]([O:42]CC)=[CH2:41])=[CH:36][N:35]=3)[N:18]=[CH:17][N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.C(=O)([O-])O.[Na+]>CC(C)=O>[C:40]([C:37]1[CH:38]=[N:39][C:34]([O:33][CH2:32][CH2:31][O:30][C:19]2[N:18]=[CH:17][N:16]=[C:15]([NH:14][S:11]([C:8]3[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:10][CH:9]=3)(=[O:13])=[O:12])[C:20]=2[O:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=2)=[N:35][CH:36]=1)(=[O:42])[CH3:41]
Reactant: C=C(OCC)c1cnc(OCCOc2ncnc(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)c2Oc2cccc(OC)c2)nc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1cccc(Oc2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCOc2ncc(C(C)=O)cn2)c1
Yield: 87 %

Procedure:
A mixture of 4-tert-butyl-N-[6-{2-(5-(1-ethoxyethenyl)pyrimidin-2-yloxy)ethoxy}-5-(3-methoxyphenoxy)pyrimidin-4-yl]benzenesulfonamide (1.022 g), 10% hydrochloric acid (1 ml) and acetone (20 ml) is reacted at room temperature for four hours. The pH value of the reaction solution is adjusted to pH 6 with aqueous sodium hydrogen carbonate solution, and the mixture is evaporated to remove the solvent. To the residue are added aqueous ammonium chloride solution and ethyl acetate, and the ethyl acetate layer is collected. The ethyl acetate layer is washed, dried, and evaporated to remove the solvent. The residue is purified by silica gel column chromatography (solvent; ethyl acetate/n-hexane=1:1~ethyl acetate), and recrystallized from ethyl acetate/n-hexane to give N-[6-{2-(5-acetylpyrimidin-2-yloxy)ethoxy}-5-(3-methoxyphenoxy)pyrimidin-4-yl]-4-tert-butylbenzenesulfonamide (849 mg).
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].C(N(CC)CC)C.[Cl:13][CH2:14][CH2:15][CH2:16][C:17](Cl)=[O:18]>ClCCl>[Cl:13][CH2:14][CH2:15][CH2:16][C:17]([N:3]([O:4][CH3:5])[CH3:2])=[O:18]
Reactant: CNOC
Reactant: O=C(Cl)CCCCl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)CCCCl
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.1 %

Procedure:
While under argon, a solution of N,O-dimethylhydroxylamine hydrochloride (16.9 g, 0.173 mol) and triethylamine (53 mL, 0.381 mol) in dichloromethane (240 mL) was carefully treated with 4-chlorobutyryl chloride (20 g, 0.19 mol) over 40 minutes. After the addition was complete, the reaction mixture was stirred overnight at room temperature. The solid triethylamine hydrochloride was removed by filtration and the remaining solution was washed successively with aq 2 N HCl (×2), 1M K2CO3 and saturated aqueous sodium chloride. The organic layer was dried over MgSO4, filtered and concentrated to give 4-chloro-N-methoxy-N-methylbutanamide (21.8 g) of crude yellow oil that was used in the next step without further purification. ESI MS found for C6H12ClNO2 m/z [166.0/168.0 (M+1)].
Reaction SMILES: [C:1]12([C:11](Cl)=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.N1C=CC=CC=1.[O:20]=[C:21]1[NH:27][C:26]2[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=2[NH:24][CH2:23][CH:22]1[NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34]>ClCCCl>[O:20]=[C:21]1[NH:27][C:26]2[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=2[N:24]([C:11]([C:1]23[CH2:10][CH:5]4[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]4)[CH2:2]2)[CH2:8]3)=[O:12])[CH2:23][CH:22]1[NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34]
Reactant: CC(C)(C)OC(=O)NC1CNc2ccccc2NC1=O
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Solvent: ClCCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NC1CN(C(=O)C23CC4CC(CC(C4)C2)C3)c2ccccc2NC1=O
Yield: 99.7 %

Procedure:
1-Adamantylcarbonyl chloride (795 mg) and pyridine (0.33 ml) were added to 2-oxo-3-tert-butoxycarbonylamino-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (1 g) in anhydrous 1,2-dichloroethane (20 ml). The mixture was refluxed with heat for one hour. After the reaction mixture was allowed to cool, crystals so precipitated were collected by filtration, to thereby obtain 1.58 g of the titled compound as a white solid (yield: 99.8%).
Reaction SMILES: C([O:3][C:4](=[O:24])[CH2:5][C:6]1[C:11]([CH3:12])=[N:10][N:9]2[C:13]([Cl:16])=[CH:14][CH:15]=[C:8]2[C:7]=1[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)C.[OH-].[Na+].CO>O1CCCC1>[Cl:16][C:13]1[N:9]2[N:10]=[C:11]([CH3:12])[C:6]([CH2:5][C:4]([OH:24])=[O:3])=[C:7]([C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[C:8]2=[CH:15][CH:14]=1
Reactant: CCOC(=O)Cc1c(C)nn2c(Cl)ccc2c1-c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nn2c(Cl)ccc2c(-c2ccc(F)cc2)c1CC(=O)O
Reaction time: 8 h
Yield: 90.7 %

Procedure:
To a solution of ethyl[7-chloro-4-(4-fluorophenyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]acetate (300 mg) in tetrahydrofuran (4 ml) was added 1N sodium hydroxide (1.7 ml), followed by methanol (2 ml). After standing at 20° C. overnight, the mixture was partitioned between 1N hydrochloric acid and ethyl acetate. The organic layer was separated, washed with water and brine, dried over magnesium sulfate, and evaporated. The residue was triturated with ether to give [7-chloro-4-(4-fluorophenyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]acetic acid (250 mg) as an yellow powder.
Reaction SMILES: Br[CH:2]([CH2:4][CH2:5][CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:3].[OH:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1>>[CH3:3][CH:2]([O:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1)[CH2:4][CH2:5][CH2:6][CH:7]([CH3:9])[CH3:8]
Reactant: CC(C)CCCC(C)Br
Reactant: N#Cc1ccc(O)cc1
Product: CC(C)CCCC(C)Oc1ccc(C#N)cc1

Procedure:
2-bromo-6-methyl-heptane was reacted with p-hydroxy-benzonitrile to obtain p-[(1,5-dimethyl-hexyl)-oxy]-benzonitrile (boiling point = 165°-168° C/1.0 mmHg);
Reaction SMILES: [OH:1][C:2]([C:11]1[CH:25]=[CH:24][C:14]2[C:15]3[CH2:16][N:17]([CH3:23])[C:18](=[O:22])[C:19]=3[CH:20]=[CH:21][C:13]=2[CH:12]=1)([C:6]1[N:7]=[CH:8][NH:9][CH:10]=1)[CH:3]([CH3:5])[CH3:4].C(N(CC)CC)C.[CH2:33]([O:36][C:37](Cl)=[O:38])[CH:34]=[CH2:35]>CN(C=O)C.O>[CH2:33]([O:36][C:37]([N:9]1[CH:10]=[C:6]([C:2]([C:11]2[CH:25]=[CH:24][C:14]3[C:15]4[CH2:16][N:17]([CH3:23])[C:18](=[O:22])[C:19]=4[CH:20]=[CH:21][C:13]=3[CH:12]=2)([OH:1])[CH:3]([CH3:5])[CH3:4])[N:7]=[CH:8]1)=[O:38])[CH:34]=[CH2:35]
Reactant: C=CCOC(=O)Cl
Reactant: CC(C)C(O)(c1ccc2c3c(ccc2c1)C(=O)N(C)C3)c1c[nH]cn1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=CCOC(=O)n1cnc(C(O)(c2ccc3c4c(ccc3c2)C(=O)N(C)C4)C(C)C)c1
Temperature: 85 °C
Reaction time: 1.5 h

Procedure:
7-[1-Hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl]-2-methyl-1,2-dihydro-3H-benzo[e]isoindol-3-one (13.8 g) was suspended in DMF (400 ml) and the mixture was heated to 85° C. to give a homogeneous solution. This solution was cooled in an ice bath and triethylamine (8.6 ml) was added. Then allyloxycarbonyl chloride (5.2 ml) was slowly added and the reaction mixture was stirred at room temperature for 1.5 hrs. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The extracted layers were combined, washed three times with water, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography (carrier: silica gel, developing solvent: dichloromethane-methanol=100:1-40:1) to give the title compound (15.9 g) as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([F:21])[CH:20]=1)[CH2:5][S:6][C:7]1[N:12]=[C:11]([C:13]#[N:14])[C:10]([N+:15]([O-])=O)=[CH:9][CH:8]=1.[H][H].C[OH:25]>O=[Pt]=O>[NH2:15][C:10]1[C:11]([C:13]([NH2:14])=[O:25])=[N:12][C:7]([S:6][CH2:5][C:4]2[CH:3]=[C:2]([F:1])[CH:20]=[C:19]([F:21])[CH:18]=2)=[CH:8][CH:9]=1
Reactant: CO
Reactant: N#Cc1nc(SCc2cc(F)cc(F)c2)ccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: O=[Pt]=O
Product: NC(=O)c1nc(SCc2cc(F)cc(F)c2)ccc1N

Procedure:
A mixture of 6-(3,5-difluorobenzylthio)-3-nitropicolinonitrile (0.05 g, 0.163 mmol) and PtO2 (0.739 mg, 3.25 μmol) in 10 ml of MeOH is placed under stirring at atmospheric pressure of hydrogen for 2 hours. The catalyst is filtered, the solution is concentrated and the residue thus obtained is purified by silica gel chromatography (AcOEt/heptane) to yield, after concentration, 0.04 g (83%) of white crystals.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH2:18])=[N:2]1.C(N(CC)CC)C.C[O:27][C:28](=O)[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N+:35]([O-:37])=[O:36])[C:30]=1[CH2:38]Br.O>CN(C=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:18]2[CH2:38][C:30]3[C:29](=[CH:34][CH:33]=[CH:32][C:31]=3[N+:35]([O-:37])=[O:36])[C:28]2=[O:27])=[N:2]1
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1CBr
Reactant: Nc1ccccc1/C=C/c1n[nH]c2ccccc12
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1c2cccc([N+](=O)[O-])c2CN1c1ccccc1/C=C/c1n[nH]c2ccccc12
Temperature: 80 °C
Reaction time: 7 h
Yield: 59.2 %

Procedure:
To a solution of Compound 2 (70 mg, 0.26 mmol) in DMF (1.4 mL), triethylamine (91 μL, 0.68 mmol) and 2-bromomethyl-3-nitrobenzoic acid methyl ester (79 mg, 0.29 mmol) were added, followed by stirring at 80° C. for 7.0 hours under nitrogen atomosphere. The reaction mixture was added with water, extracted with ethyl acetate and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform to chloroform/methanol=90/10) to obtain (E)-2-{2-[2-(1H-indazol-3-yl)vinyl]phenyl}-4-nitro-2,3-dihydroisoindol-1-one (61 mg, 60%).
Reaction SMILES: C(N(CC)CC)C.[OH:8]/[N:9]=[C:10](\[NH2:20])/[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([I:18])=[C:14]([CH3:19])[CH:13]=1.Cl[C:22]([O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:23]>ClCCl>[OH:8]/[N:9]=[C:10](\[NH:20][C:22](=[O:23])[O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)/[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([I:18])=[C:14]([CH3:19])[CH:13]=1
Reactant: Cc1cc(C/C(N)=N/O)ccc1I
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C/C(=N/O)NC(=O)Oc2ccccc2)ccc1I
Temperature: 0 °C
Reaction time: 1 h
Yield: 104.7 %

Procedure:
Triethylamine (0.651 mL, 4.67 mmol) was added to (Z)—N′-hydroxy-2-(4-iodo-3-methylphenyl)acetimidamide (Intermediate 29-3; 1.13 g, 3.90 mmol) in dry dichloromethane (30 mL) at 0° C. The resulting yellow solution was stirred at 0° C. for 1 hour. Phenyl chloroformate (0.598 mL, 4.67 mmol) was added and the reaction mixture stirred at 0° C. for a further 1 hour. The solution was washed sequentially with saturated Na2CO3 (50 mL) and water (50 mL×2). The organic layer was dried over MgSO4, filtered and evaporated to afford (Z)-phenyl 1-(hydroxyimino)-2-(4-iodo-3-methylphenyl)ethylcarbamate (1.675 g, 105%) as crude product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[N+:13]([O-])([OH:15])=[O:14]>C(O)(=O)C>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([N+:13]([O-:15])=[O:14])[CH:6]=1
Reactant: COC(=O)Cc1ccc(O)cc1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: COC(=O)Cc1ccc(O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Methyl-2-(4-hydroxyphenyl)acetate (2.0 g, 12.0 mmol) was dissolved in acetic acid (15 ml) and nitric acid (60-62%, 1.27 g, 12.1 mmol) was added at RT. The reaction mixture was stirred for 30 minutes at RT, poured into ice water (100 ml) and extracted with EA. The organic phase was dried over MgSO4, the solvent removed under a vacuum and the residue purified by means of column chromatography (n-hexane/EA=4:1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:10]=3[C:9]=2[O:19][C:20]2[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28]([NH:30][NH2:31])=[O:29])=[CH:22][CH:21]=2)=[C:4]([CH3:32])[CH:3]=1.[C:33](N1C=CN=C1)(N1C=CN=C1)=[O:34].Cl>C1COCC1.C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:10]=3[C:9]=2[O:19][C:20]2[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28]3[O:29][C:33](=[O:34])[NH:31][N:30]=3)=[CH:22][CH:21]=2)=[C:4]([CH3:32])[CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1ccc2c(Oc3ccc(/C=C/C(=O)NN)cc3)c(-c3ccc(F)cc3C)sc2c1
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc2c(Oc3ccc(/C=C/c4n[nH]c(=O)o4)cc3)c(-c3ccc(F)cc3C)sc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.5 %

Procedure:
To a 30 mL screw cap vial, (E)-3-(4-((2-(4-fluoro-2-methylphenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylohydrazide (38 mg, 0.085 mmol) was dissolved in THF (2 mL). The vial was charged with 1,1′-carbonyldiimidazole (16.49 mg, 0.102 mmol) and the reaction was stirred at room temperature for 1 h. The reaction mixture was acidified with 6 N HCl which caused a precipitate to form. The mixture was diluted with DCM to dissolve the precipitate. The organic phase was collected (phase separator) and concentrated to afford (E)-5-(4-((2-(4-fluoro-2-methylphenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)styryl)-1,3,4-oxadiazol-2(3H)-one (31 mg, 0.065 mmol, 77% yield) as an off white solid which was used without further purification. LC/MS (m/z, M-H): 473.0
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:13](=O)[CH2:14][CH3:15])=[C:6](OS(C)(=O)=O)[CH:7]=1.Cl.[F:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][NH2:26])=[CH:21][CH:20]=1.C([O-])(=O)C.[Na+].CCCCCC>C1(C)C=C(C)C=C(C)C=1>[Br:1][C:2]1[CH:7]=[C:6]2[C:5]([C:13]([CH2:14][CH3:15])=[N:26][N:25]2[C:22]2[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=2)=[CH:4][CH:3]=1
Reactant: NNc1ccc(F)cc1
Reactant: CCC(=O)c1ccc(Br)cc1OS(C)(=O)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1cc(C)cc(C)c1
Solvent: CCCCCC
Product: CCc1nn(-c2ccc(F)cc2)c2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 13 h

Procedure:
Methanesulfonic acid 5-bromo-2-propionyl-phenyl ester, prepared as described in U.S. Ser. No. 09/308,954, filed May 8, 1997 as Attorney Docket No. PC9798, 30 grams (97.66 mmol) was combined with 4-fluorophenyl hydrazine hydrochloride (31.76 g, 175.33 mmol) and sodium acetate (30 g, 364 mmol) in mesitylene (400 mL). The reaction mixture was heated to reflux in a Dean-Stark apparatus for 96 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was diluted with 500 mL of diethyl ether and 600 mL of water. Organic layer was separated and aqueous layer extracted with 500 mL of ethyl acetate. Combined organic extracts were washed with water (2×600 mL), brine (1×200 mL), dried over MgSO4 and concentrated which gave a brown-red oil. Hexane (600 mL) was added to crude reaction product and the mixture boiled in a steam bath for a few minutes. This was followed by cooling still the heterogeneous mixture to room temperature and allowing to stand at room temperature for 12-14 hours. The reaction mixture was filtered, undissolved solid washed with additional hexane and filtrate which contained approximately 80% pure desired product concentrated in vacuo to give brown-yellow solid. Purification of this product on silica gel column and eluting with 15% ethyl acetate/85% hexane gave 14.1 grams of light brown-tan solid. Recrystallization from hexane gave light tan needles. mp=72-73° C.; MS (APCI) m/z 319 (base).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[N:13][C:14]([CH3:18])=[CH:15][CH:16]=3)[N:11]([CH2:19][CH3:20])[C:10](=[O:21])[C:9]=2[CH2:22][CH2:23][C:24]#[N:25])[CH:5]=[CH:6][CH:7]=1.[N-:26]=[N+:27]=[N-:28].[Na+].Cl.C(N(CC)CC)C.Cl>CN1CCCC1=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[N:13][C:14]([CH3:18])=[CH:15][CH:16]=3)[N:11]([CH2:19][CH3:20])[C:10](=[O:21])[C:9]=2[CH2:22][CH2:23][C:24]2[NH:28][N:27]=[N:26][N:25]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CCn1c(=O)c(CCC#N)c(-c2cccc(Cl)c2)c2ccc(C)nc21
Agent: Cl
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CCn1c(=O)c(CCc2nnn[nH]2)c(-c2cccc(Cl)c2)c2ccc(C)nc21
Temperature: 130 °C
Reaction time: 20 h
Yield: 16.5 %

Procedure:
A mixture of 700 mg of 4-(3-chlorophenyl)-3-(2-cyanoethyl)-1-ethyl-7-methyl-1,8-naphthyridin-2-(1H)-one, 388 mg of sodium azide, 411 mg of triethylamine hydrochloride and 10 ml of 1-methylpyrrolidin-2-one were stirred at 130° C. for 20 hours. The reaction mixture was cooled to room temperature, acidified by adding 1M hydrochloric acid and then extracted with ethyl acetate. The organic layer was washed with water and saturated brine and the solvent was evaporated. The residue was purified by a silica gel column chromatography (hexane-ethyl acetate) and then recrystallized from ethyl acetate-diisopropyl ether to obtain 130 mg of 4-(3-chlorophenyl)-1-ethyl-7-methyl-3-[2-(1H-tetrazol-5-yl)ethyl]-1,8-naphthyridin-2(1H)-one as pale yellow crystals.
Reaction SMILES: C(OC([N:11]1[C:51]2[C:46](=[CH:47][C:48]([F:52])=[CH:49][CH:50]=2)[C:13]2([CH2:18][CH2:17][N:16]([C:19]([C@H:21]([NH:32][C:33](=[O:45])[C:34]([NH:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])([CH3:36])[CH3:35])[CH2:22][C:23]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[NH:25][CH:24]=3)=[O:20])[CH2:15][CH2:14]2)[CH2:12]1)=O)C1C=CC=CC=1>[OH-].[OH-].[Pd+2].C(O)C>[F:52][C:48]1[CH:47]=[C:46]2[C:13]3([CH2:18][CH2:17][N:16]([C:19]([C@H:21]([NH:32][C:33](=[O:45])[C:34]([NH:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])([CH3:35])[CH3:36])[CH2:22][C:23]4[C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[NH:25][CH:24]=4)=[O:20])[CH2:15][CH2:14]3)[CH2:12][NH:11][C:51]2=[CH:50][CH:49]=1
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)N1CCC2(CC1)CN(C(=O)OCc1ccccc1)c1ccc(F)cc12
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)NC(C)(C)C(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)N1CCC2(CC1)CNc1ccc(F)cc12
Reaction time: 1 h
Yield: 88.9 %

Procedure:
To a solution of 0.363 g of the intermediate obtained from Step B in 5 mL of of ethanol was added 0.10 g of 20% palladium hydroxide on carbon and hydrogenated under H2 balloon for 1 h. The catalyst was filtered off and washed with more methanol. The filtrate was concentrated to yield 0.262 g of the desired material.
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:31])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][N:25]=2)[C:5]1=[O:30])[CH:2]=C.I([O-])(=O)(=O)=[O:33].[Na+]>O1CCCC1.O.[Os](=O)(=O)(=O)=O>[Cl:16][C:12]1[CH:11]=[C:10]([C@@H:8]2[C@@H:7]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)[N:6]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][N:25]=3)[C:5](=[O:30])[C@:4]([CH2:1][CH:2]=[O:33])([CH3:31])[CH2:9]2)[CH:15]=[CH:14][CH:13]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(c2ccncn2)C1=O
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@]1(CC=O)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(c2ccncn2)C1=O
Reaction time: 0.08 h

Procedure:
To a solution of (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(pyrimidin-4-yl)piperidin-2-one (Example 110, Step B) (60 mg, 0.13 mmol) in a mixture of tetrahydrofuran (2.7 mL) and water (880 μL) was added osmium tetroxide (1.7 mg, 6.6 μmol). After 5 minutes, sodium periodate (89 mg, 0.46 mmol) was added and the reaction mixture was stirred for 14 hours. The reaction mixture was filtered through Celite® (J.T. Baker, Phillipsberg, N.J., diatomaceous earth) and washed with EtOAc and water. The organic layer was washed with sat. aq. NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. Purification of the residue by flash chromatography (0 to 75% EtOAc/hexanes, gradient elution) provided the title compound as a colorless solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N:12]1[CH:16]=[CH:15][CH:14]=[CH:13]1.O=C1O[CH2:21][CH2:20][O:19]1>[I-].C([N+](CC)(CC)CC)C.C(OCC)(=O)C.O1CCCC1>[OH:19][CH2:20][CH2:21][O:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N:12]1[CH:16]=[CH:15][CH:14]=[CH:13]1
Reactant: COC(=O)c1ccc(O)c(-n2cccc2)c1
Reactant: O=C1OCCO1
Agent: CC[N+](CC)(CC)CC
Agent: [I-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(OCCO)c(-n2cccc2)c1
Temperature: 140 °C
Yield: 69.3 %

Procedure:
The mixture of methyl 4-hydroxy-3-(pyrrol-1-yl)benzoate (1.5 g), 2-oxo-1,3-dioxolane (0.61 g) and tetraethylammonium iodide (0.38 g) was heated at 140° C. for 3 hours. The resultant mixture was dissolved in the solution of ethyl acetate and tetrahydrofuran. The solution was washed with water and dried over magnesium sulfate. Evaporation of the solvent gave the residue, which was purified by column chromatography on silica gel eluting with the solution of chloroform and ethyl acetate (9:1, V/V). The eluted fractions containing the desired product were collected and evaporated in vacuo to give methyl 4-(2-hydroxyethoxy)-3-(pyrrol-1-yl)benzoate (1.25 g) as an oil.