Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([C:21]([O:23]C)=[O:22])[CH:7]=[C:8]2[C:13]=1[O:12][C:11]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[CH:10][C:9]2=[O:20].C1COCC1.Cl>CO.O>[Br:3][C:4]1[CH:5]=[C:6]([C:21]([OH:23])=[O:22])[CH:7]=[C:8]2[C:13]=1[O:12][C:11]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[CH:10][C:9]2=[O:20]
Reactant: COC(=O)c1cc(Br)c2oc(N3CCOCC3)cc(=O)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc(Br)c2oc(N3CCOCC3)cc(=O)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
Sodium hydroxide (32.6 mL, 65.19 mmol) was added to a stirred suspension of methyl 8-bromo-2-morpholino-4-oxo-4H-chromene-6-carboxylate (8 g, 21.73 mmol) dissolved in MeOH (42 mL) and THF (21 mL) at 0° C. The resulting suspension was stirred at room temperature for 1 h. MeOH (60 mL), THF (10 mL) and water (10 mL) were then added to help stirring. Upon completion, the reaction was cooled to 0° C. and HCl 2N was added to the suspension until pH 2. The solid was collected by filtration, washed with water, AcOEt, diethyl ether and dried with P205 under vacuum at 50° C. to give 8-bromo-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (7.0 g, 91%). Mass Spectrum: m/z [M+H]+=354.
Reaction SMILES: [CH2:1]1[C:6]2[NH:7][C:8]3[C:13]([C:14](=[O:15])[C:5]=2[CH2:4][C:3]2[NH:16][C:17]4[C:22]([C:23](=[O:24])[C:2]1=2)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:12][CH:11]=[CH:10][CH:9]=3.CO.[OH-].[Na+].OO>[Cl-].C([N+](CCCC)(CCCC)CCCC)C1C=CC=CC=1.C1C2C(=O)C3C(=CC=CC=3)C(=O)C=2C=CC=1.O>[CH:20]1[CH:21]=[C:22]2[C:23]([C:2]3[C:3]([NH:16][C:17]2=[CH:18][CH:19]=1)=[CH:4][C:5]1[C:14]([C:13]2[C:8]([NH:7][C:6]=1[CH:1]=3)=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:15])=[O:24]
Reactant: O=c1c2c([nH]c3ccccc13)Cc1c([nH]c3ccccc3c1=O)C2
Agent: CCCC[N+](CCCC)(CCCC)Cc1ccccc1
Agent: O=C1c2ccccc2C(=O)c2ccccc21
Agent: OO
Solvent: O
Solvent: CO
Product: O=c1c2ccccc2[nH]c2cc3c(=O)c4ccccc4[nH]c3cc12
Temperature: 37.5 °C
Reaction time: 0.08 h
Yield: 97.9 %

Procedure:
A one liter flask equipped with a thermometer, stirrer and condenser was charged with 40 grams 6,13-dihydroquinacridone, 250 ml methanol, 52.8 grams 50% aqueous sodium hydroxide and 3.0 grams 50% aqueous benzyl tributyl ammonium chloride. The mixture was stirred under a slow flow of nitrogen at 30 to 45° C. for five minutes, heated to 50 to 55° C. and stirred at 50 to 55° C. for one hour. 0.8 grams of the pigment additive toluene sulfonic acid methyl quinacridone in accordance with the teachings in pending application Ser. No. 60/118,405, was added, followed by the addition of 0.5 grams anthraquinone mono sulfonic acid sodium salt as catalyst, and the reaction mixture was heated to reflux. 73 grams of an aqueous 17% hydrogen peroxide solution were added into the reaction mixture with a peristaltic pump at a setting of 0.3 ml/minute maintaining reflux under a slow nitrogen flow. The resulting reddish suspension was further stirred for 10 minutes at reflux then diluted with 100 ml cold water and filtered. The presscake was washed with hot water then dried, yielding 38.9 grams red quinacridone.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:17]=[C:16]([CH2:18][OH:19])[CH:15]=[C:7]([C:8]([N:10]([CH3:14])[CH2:11][CH2:12][CH3:13])=[O:9])[CH:6]=1)[CH3:2].[H-].[Na+].I[CH3:24]>C1COCC1>[CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:17]=[C:16]([CH2:18][O:19][CH3:24])[CH:15]=[C:7]([C:8]([N:10]([CH3:14])[CH2:11][CH2:12][CH3:13])=[O:9])[CH:6]=1)[CH3:2]
Reactant: CI
Reactant: CCCN(C)C(=O)c1cc(CO)cc(C(=O)OCC)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCN(C)C(=O)c1cc(COC)cc(C(=O)OCC)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Stir 5-hydroxymethyl-N-methyl-N-propyl-isophthalamic acid ethyl ester (1.1 g, 3.9 mmol) in THF (20 mL). Add sodium hydride (0.78 g, 60% in mineral oil) and iodomethane (729 μL, 11.7 mmol). Stir at room temperature for 3 h. Concentrate to give the title product which is used directly in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([CH3:23])[N:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:12][C:11]=2[Cl:22])[C:6]=1[CH:7]=[O:8].[BH4-].[Na+].O>C(O)C>[Cl:1][C:2]1[N:3]=[C:4]([CH3:23])[N:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:12][C:11]=2[Cl:22])[C:6]=1[CH2:7][OH:8]
Reactant: CCCCCOc1ccc(Cn2c(C)nc(Cl)c2C=O)c(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCCCOc1ccc(Cn2c(C)nc(Cl)c2CO)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.4 %

Procedure:
4-Chloro-1-(2-chloro-4-(1-pentyloxy)benzyl)-2-methyl-1H-imidazole-5-carbaldehyde (1.05 g) was dissolved in ethanol (10 ml), and sodium borohydride (168 mg) was added under ice-cooling. The mixture was stirred at room temperature for 3 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. To the residue was added hexane (10 ml) and the precipitated crystals were collected by filtration and dried by heating under reduced pressure to give 4-chloro-1-(2-chloro-4-(1-pentyloxy)benzyl)-5-hydroxymethyl-2-methyl-1H-imidazole (786 mg) as colorless crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([CH2:8][CH2:9]Br)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:13][NH:14][CH2:15][CH2:16][OH:17]>C1(C)C(C)=CC=CC=1>[CH3:13][N:14]([CH2:15][CH2:16][OH:17])[CH2:9][CH2:8][C:7]1[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Reactant: CNCCO
Solvent: Cc1ccccc1C
Product: CN(CCO)CCc1ccc([N+](=O)[O-])cc1
Yield: 90.1 %

Procedure:
A mixture of 4-nitrophenethyl bromide (11.5 g) and N-methylethanolamine (8.25 g) in xylene (100 ml) was stirred at reflux for 16 hours. After evaporation, the residue was partitioned between 5% aqueous sodium bicarbonate and methylene chloride. The organic liquors were washed with saturated aqueous brine, dried (MgSO4), filtered and evaporated to give an orange oil (10.1 g). Chromatography on silica ("Kieselgel 60"--Trade Mark) eluting with ethyl acetate followed by collection and evaporation of suitable fractions gave the title compound as a yellow oil, (7.5 g).
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[NH:25][C:24](=[O:26])[O:23][N:22]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:27][CH2:28][CH3:29])[N:5]2[N:30]=[CH:31][N:32]=[C:4]2[N:3]1[CH2:33][C:34]([O:36]C(C)(C)C)=[O:35].FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[NH:25][C:24](=[O:26])[O:23][N:22]=3)=[CH:13][CH:14]=2)=[C:6]([CH2:27][CH2:28][CH3:29])[N:5]2[N:30]=[CH:31][N:32]=[C:4]2[N:3]1[CH2:33][C:34]([OH:36])=[O:35]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(CC(=O)OC(C)(C)C)c2ncnn12
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(CC(=O)O)c2ncnn12
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.5 %

Procedure:
A mixture of tert-butyl [5-oxo-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl]acetate (0.58 g) and trifluoroacetic acid (10 mL) was stirred at room temperature for 2 hr. The reaction mixture was diluted with toluene (10 mL), and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.19 g, 36%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=3)[CH2:11][CH2:10]2)[CH:3]=1.C(O)C.C(N(CC)CC)C>C(OCC)(=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]3[CH:17]=[CH:18][C:19]([NH2:22])=[CH:20][CH:21]=3)[CH2:11][CH2:10]2)[CH:3]=1
Reactant: Cc1cc(C)nc(N2CCCN(c3ccc([N+](=O)[O-])cc3)CC2)c1
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1cc(C)nc(N2CCCN(c3ccc(N)cc3)CC2)c1
Temperature: 25 °C
Yield: 99.6 %

Procedure:
To a solution of 1-(4,6-dimethyl-pyridin-2-yl)-4-(4-nitro-phenyl)-[1,4]diazepane (940 mg, 2.88 mmol) in ethyl acetate (25 mL) was added stannous chloride (3.90 g, 17.3 mmol) and ethanol (5 mL). The reaction mixture was heated to reflux for 15 hours then cooled to room temperature, basified with triethylamine and filtered. The filtrate was concentrated under reduced pressure to afford 4-[4-(4,6-dimethyl-pyridin-2-yl)-[1,4]diazepan-1-yl]-phenylamine (850 mg, 99%) as a brown solid.
Reaction SMILES: [F:1][C:2]1([F:44])[CH2:7][C@H:6]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([S:16]([N:19](CC3C=CC(OC)=CC=3OC)[C:20]3[CH:25]=[CH:24][N:23]=[CH:22][N:21]=3)(=[O:18])=[O:17])=[C:11]([F:37])[CH:10]=2)[C@@H:5]([C:38]2[N:42]([CH3:43])[N:41]=[CH:40][CH:39]=2)[CH2:4][CH2:3]1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:44][C:2]1([F:1])[CH2:7][C@H:6]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([S:16]([NH:19][C:20]3[CH:25]=[CH:24][N:23]=[CH:22][N:21]=3)(=[O:17])=[O:18])=[C:11]([F:37])[CH:10]=2)[C@@H:5]([C:38]2[N:42]([CH3:43])[N:41]=[CH:40][CH:39]=2)[CH2:4][CH2:3]1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(F)c(O[C@H]3CC(F)(F)CC[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nccc1[C@H]1CCC(F)(F)C[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2ccncn2)cc1F
Yield: 94.4 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the 4-{[(1S*,2R*)-5,5-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(2,4-dimethoxybenzyl)-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide (212 mg, 0.334 mmol) prepared in Example 47c, triethylsilane (0.30 mL), trifluoroacetic acid (3.0 mL) and dichloromethane (3.0 mL), to yield the title compound (153 mg, 95%) as a colorless solid.
Reaction SMILES: [Na].[C:2]1(=[O:8])[NH:7][CH2:6][CH2:5][CH2:4][CH2:3]1.Br[C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:25]=[C:24]3[N:18]([CH2:19][CH2:20][C:21]4[CH:37]=[CH:36][CH:35]=[CH:34][C:22]=4[CH:23]3[O:26][CH:27]3[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]3)[C:17]=2[CH3:38])=[CH:12][CH:11]=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>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].C1(C)C=CC=CC=1.CO>[CH3:38][C:17]1[N:18]2[C:24]([CH:23]([O:26][CH:27]3[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]3)[C:22]3[CH:34]=[CH:35][CH:36]=[CH:37][C:21]=3[CH2:20][CH2:19]2)=[N:25][C:16]=1[C:13]1[CH:14]=[CH:15][C:10]([N:7]2[CH2:6][CH2:5][CH2:4][CH2:3][C:2]2=[O:8])=[CH:11][CH:12]=1
Reactant: O=C1CCCCN1
Reactant: Cc1c(-c2ccc(Br)cc2)nc2n1CCc1ccccc1C2OC1CCN(C)CC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CO
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccc(N3CCCCC3=O)cc2)nc2n1CCc1ccccc1C2OC1CCN(C)CC1
Temperature: 110 °C
Reaction time: 0.17 h

Procedure:
In a screw-capped vial are added MeOH (3.5 mL) and sodium metal (2 mg). After 10 min, valerolactam (16 mg, 0.16 mmole) is added. The solvent is removed under reduced pressure. To the residual solid are added 2-(4-bromophenyl)-1-methyl-4-(1-methylpiperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene (example 122A) (50 mg, 0.107 mmole), Pd(dba)2 (4.9 mg, 5.3 μmole), Xantphos (6.2 mg, 10.6 μmole), toluene (0.7 mL). The flask is evacuated and filled with argon and the reaction mixture is heated at 110° C. overnight. Water is added and pH adjusted to 10 with a few drops of 1N NaOH. The aqueous phase is extracted three times with CH2Cl2. The organic phase is dried over magnesium sulphate, filtered and the solvent is removed under reduced pressure. The residue is purified by silica gel chromatography using (CH2Cl2:MeOH:NH4OH) with a gradient from (100:0:0) to (96.5:3.5:0.35) to give 1-{4-[1-methyl-4-(1-methylpiperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulen-2-yl]-phenyl}-piperidin-2-one.
Reaction SMILES: C[C:2]1(C)[O:9][C:7](=[O:8])[CH2:6][C:4](=[O:5])O1.N1C=[CH:15][CH:14]=[CH:13][CH:12]=1.C(Cl)(=O)CCC=C>ClCCl>[O:5]=[C:4]([CH2:15][CH2:14][CH:13]=[CH2:12])[CH2:6][C:7]([O:9][CH3:2])=[O:8]
Reactant: c1ccncc1
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: C=CCCC(=O)Cl
Solvent: ClCCl
Product: C=CCCC(=O)CC(=O)OC
Temperature: 25 °C
Reaction time: 10 h
Yield: 40 %

Procedure:
To a solution of Meldrum's acid (22.0 g) and pyridine (25.0 ml) in dichloromethane (100 ml) was added dropwise pent-4-enoyl chloride (18.5 ml) under ice-cooling. The reaction mixture was stirred at room temperature for 10 hr, and washed with water and 1M hydrochloric acid. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was dissolved in methanol (150 ml), and the mixture was stirred with heating under reflux for 8 hr. After cooling the reaction mixture to room temperature, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column (hexane/ethyl acetate=10/1 to hexane/ethyl acetate=5/1) to give the title compound as a pale-yellow liquid (4.57 g, 40%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)O.P(Br)(Br)[Br:17].O>C(OCC)C>[Br:17][CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1]
Reactant: BrP(Br)Br
Reactant: Cc1ccccc1C(O)c1ccccc1
Solvent: CCOCC
Solvent: O
Product: Cc1ccccc1C(Br)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 133.9 %

Procedure:
To a solution of 28.1 g (140 mmol) of 5 in 150 mL of dry diethyl ether, 25.6 g (8.89 mL, 94.4 mmol) of PBr3 was added at −10° C. The resulting mixture was stirred for 12 hr at room temperature and then added to 450 mL of cold water. The organic layer was separated, and the aqueous layer was extracted with 2×150 mL of water. The combined organic extracts were washed with aqueous NaHCO3, dried over Na2SO4, and then evaporated to dryness. This procedure gave 33.0 g (89%) of the title product.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:9])=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[CH:10](=O)/[CH:11]=[CH:12]/[CH3:13].[OH-].[NH4+]>Cl>[CH3:13][C:12]1[CH:11]=[CH:10][C:7]2[C:2](=[C:3]([CH3:9])[C:4]([OH:8])=[CH:5][CH:6]=2)[N:1]=1
Reactant: Cc1c(N)cccc1O
Reactant: C/C=C/C=O
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Product: Cc1ccc2ccc(O)c(C)c2n1
Yield: 126.7 %

Procedure:
To 3-amino-2-methylphenol (5.0 g, 41 mmol) in refluxing 6N HCl (100 mL) was added dropwise (E)-but-2-enal (5.7 g, 81 mmol) and the reaction was heated to reflux for 2 hours. After cooling, the reaction was neutralized with ammonium hydroxide and extracted with DCM. The combined organic phases were dried over MgSO4, filtered and concentrated under reduced pressure to yield 2,8-dimethylquinolin-7-ol (9.0 g, 51% yield) as a brown solid.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][C:9](Br)=[CH:8]2)(=O)C.[CH3:16][N:17]1[CH:21]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:19]=[N:18]1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.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>[CH3:16][N:17]1[CH:21]=[C:20]([C:9]2[CH:10]=[N:11][C:12]3[C:7]([CH:8]=2)=[CH:6][C:5]([OH:4])=[CH:14][CH:13]=3)[CH:19]=[N:18]1
Reactant: CC(=O)Oc1ccc2ncc(Br)cc2c1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
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: [Na+]
Solvent: CN(C)C=O
Product: Cn1cc(-c2cnc3ccc(O)cc3c2)cn1
Temperature: 90 °C
Yield: 72.2 %

Procedure:
A mixture of Intermediate A (1.8 g, 6.76 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.548 g, 7.44 mmol), Na2CO3 (2.151 g, 20.29 mmol) and Pd(PPh3)4 (0.782 g, 0.676 mmol) in DMF (10 ml) was bubbled with argon for 10 min. Then the mixture was heated at 90° C. for 5 h. After being cooled to rt, the mixture was diluted with EtOAc (40 ml), washed with water and brine, dried over Na2SO4, filtered and concentrated. The residue was recrystallized from EtOAc to afford the title compound as pale gray solid (1.1 g, 65% yield). 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.97 (s, 1H), 8.91 (s, 1H), 8.33 (s, 1H), 8.23 (d, 2H), 8.00 (s, 1H), 7.80 (d, 1H), 7.22 (dd, 1H), 7.00 (d, 1H), 3.90 (s, 3H). LCMS (method B): [M+H]+=226, tR=1.41 min.
Reaction SMILES: Br.[C:2]1([C:8]2[N:9]=[C:10]3[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=[CH:12][N:11]3[CH:21]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O.[OH-].[Na+].CN([CH:32]=[O:33])C>>[CH:32]([C:21]1[N:11]2[CH:12]=[CH:13][CH:14]=[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:10]2=[N:9][C:8]=1[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:33]
Reactant: CN(C)C=O
Reactant: CCOC(=O)c1cccn2cc(-c3ccccc3)nc12
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cccn2c(C=O)c(-c3ccccc3)nc12
Temperature: 0 °C
Yield: 85.5 %

Procedure:
To a solution of ethyl 2-phenyl-imidazo[1,2-a]-pyridine-8-carboxylate hydrogen bromide (14.7 g, 4 m mol) in DMF (8 ml) was dropwise added phosphorus oxychloride (2 ml) keeping the inner temperature to below 15° C. Then, the mixture was allowed to react at room temperature for 30 minutes and at 70° C. for 2 hours. After completion of the reaction, the reaction mixture was cooled, poured into ice water and adjusted to pH 7 by adding 20% sodium hydroxide. The precipitated crystals were collected by filtration and recrystallized from ethanol to obtain the object compound (1.0 g, yield 85.5%) as colorless crystals. m.p. 139° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[F:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[OH:23].C(=O)([O-])[O-].[K+].[K+].O>CN1C(=O)CCC1>[CH3:10][O:9][C:7](=[O:8])[C:6]1[CH:11]=[C:2]([O:23][C:17]2[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:16]=2[F:15])[CH:3]=[CH:4][C:5]=1[N+:12]([O-:14])=[O:13]
Reactant: COC(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: Oc1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: COC(=O)c1cc(Oc2ccc(F)cc2F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 63.5 %

Procedure:
Methyl 5-chloro-2-nitrobenzoate (73 g, 0.34 mol), 2,4-difluorophenol (51.1 g, 0.39 mol) and potassium carbonate (73 g, 0.53 mol) in NMP (200 mL) were stirred at 160° C. for 2 h. The reaction mixture was cooled to room temperature poured into water (250 mL) and extracted into EtOAc (2×100 mL). The organic layer was washed several times with water, dried over sodium sulfate, concentrated in vacuo, and the residue was purified by flash chromatography eluting with hexane: EtOAc (95:5) to yield 66.8 g of 5-(2,4-difluoro-phenoxy)-2-nitro-benzoic acid methyl ester (1A).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH2:15][O:16][CH2:17][CH2:18][OH:19])[C:13]([CH3:20])=[N:12][C:11]=2[CH:21]([CH3:23])[CH3:22])[CH:5]=[C:6]([CH3:8])[CH:7]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1.[CH3:43][O:44][C:45]1(OC)[CH2:49][CH2:48][CH2:47][CH2:46]1>C(Cl)Cl.C(N(CC)CC)C>[CH3:8][C:6]1[CH:5]=[C:4]([S:9][C:10]2[N:14]([CH2:15][O:16][CH2:17][CH2:18][O:19][C:45]3([O:44][CH3:43])[CH2:49][CH2:48][CH2:47][CH2:46]3)[C:13]([CH3:20])=[N:12][C:11]=2[CH:21]([CH3:23])[CH3:22])[CH:3]=[C:2]([CH3:1])[CH:7]=1
Reactant: Cc1cc(C)cc(Sc2c(C(C)C)nc(C)n2COCCO)c1
Reactant: COC1(OC)CCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: O
Product: COC1(OCCOCn2c(C)nc(C(C)C)c2Sc2cc(C)cc(C)c2)CCCC1
Reaction time: 3 h
Yield: 73.2 %

Procedure:
A solution of 5-(3,5-dimethylphenylthio)-4-isopropyl-1-(2-hydroxyethoxymethyl)-2-methyl-1H-imidazole (1) (301 mg, 0.9 mmol) prepared in accordance with the method as described in WO 96/10019 and p-toluenesulfonic acid hydrate (180 mg, 0.945 mmol) in a mixture of methylene chloride (5 mL) - toluene (1 mL) was concentrated under reduced pressure. The obtained residue was dissolved in methylene chloride (9 mL), to which was added 1,1-dimethoxycyclopentane (1.17 g, 9.00 mmol), and the mixture was stirred for 3 hours. Triethylamine (0.19 mL) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The residue was purified by chromatography on an alumina column (eluate: hexane - ethyl acetate (2:1)) to give the compound 2 (285 mg, 73 %) as oil. Rf 0.45 (Al2O3 60, Type E, 2:1 hexane -EtOAc).
Reaction SMILES: [C:1]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:28])[O:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][N:18]([CH3:27])[C:19](=[O:26])[CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=O)[CH2:12][CH2:11]1.[NH2:35][C:36]1[CH:48]=[CH:47][C:39]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])=[C:38]([CH3:49])[CH:37]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[BH4-].[Na+]>C(Cl)Cl.C(O)(=O)C>[C:1]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([O:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][N:18]([CH3:27])[C:19](=[O:26])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][NH:35][C:36]2[CH:48]=[CH:47][C:39]([C:40]([O:42][C:43]([CH3:44])([CH3:45])[CH3:46])=[O:41])=[C:38]([CH3:49])[CH:37]=2)[CH2:12][CH2:11]1)=[O:28]
Reactant: Cc1cc(N)ccc1C(=O)OC(C)(C)C
Reactant: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1cc(NCCCCCC(=O)N(C)CCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)ccc1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.1 %

Procedure:
The compound (135 mg, 0.289 mmol) obtained in Example 4g and the compound (103 mg, 0.473 mmol) obtained in Example 18a were dissolved in methylene chloride (4 mL), acetic acid (73 μL) and sodium triacetoxyborohydride (137 mg, 0.645 mmol) were added, and the mixture was stirred overnight at room temperature. Sodium borohydride (16 mg, 0.430 mmol) was added, and the mixture was stirred at room temperature for 20 minutes. The solvent was evaporated under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=1:1→1:2, v/v) to give the title compound (114 mg; yield, 40%) as a white solid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)Br.[Cl:25][C:26]1[CH:31]=[C:30](CO)[CH:29]=[CH:28][N:27]=1>C(Cl)Cl>[Br:24][CH2:20][C:30]1[CH:29]=[CH:28][N:27]=[C:26]([Cl:25])[CH:31]=1
Reactant: OCc1ccnc(Cl)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Clc1cc(CBr)ccn1
Yield: 73 %

Procedure:
Triphenylphosphine (19 g, 71 mmol) and carbon tetrabromide (29 g, 88 mmol) were added to a solution of 2-chloropyridine-4-methanol (8.5 g, 59 mmol, Reference compound No. 7-1) in methylen chloride (250 mL), then the mixture was stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure, and then the resulting residue was purified by silica gel column chromatography to give 4-bromomethyl-2-chloropyridine. Immediately, 2-mercaptonicotinic acid (9.1 g, 59 mmol) was added to a solution of this bromo intermediate in N,N-dimethylformamide (100 mL) under ice-cooling, then triethylamine (25 mL, 180 mmol) was added dropwise thereto. The reaction mixture was stirred at room temperature for 15 hours, then diethyl ether (100 mL) and water (600 mL) were added thereto, and the organic layer and the aqueous layer were separated. The aqueous layer was adjusted to pH 6 with 2N hydrochloric acid, the precipitated solid was filtered off. The solid was washed with water and diethyl ether, and dried at 50° C. under reduced pressure to give 12 g of the title reference compound as a yellow solid. (Yield 73%)