Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[Br:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1Br.[O-]P([O-])([O-])=O.[K+].[K+].[K+].N1CCC[C@H]1C(O)=O>CN(C=O)C.O.[Cu]I>[Br:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:6]1[C:7]2[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=2[C:4]2[CH2:3][N:2]([CH3:1])[CH2:15][CH2:14][C:5]1=2
Reactant: Brc1ccccc1Br
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2-c2ccccc2Br)CCN(C)C1

Procedure:
A solution of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (2 g, 9.986 mmol), 1,2-dibromobenzene (1.7 mL, 14.97 mmol), K3PO4 (6.35 g, 29.95 mmol), CuI (189 mg, 0.99 mmol) and L-proline (229 mg, 1.99 mmol) in dry DMF (20 mL) was stirred at 150° C. for 24 h. The reaction mixture was diluted with water (150 mL) and extracted with EtOAc (250 mL). The organic layer was washed with water (10×100 mL), dried over anhydrous sodium sulfate and evaporated to afford crude material, which was purified by column chromatography using neutral alumina and 3% EtOAc-hexane, to yield 5-(2-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:31]>ClCCl>[Br:31][CH2:5][C:4]1[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=1[O:2][CH3:1]
Reactant: COc1ccccc1CO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccccc1CBr
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.6 %

Procedure:
To a 100-mL round-bottomed flask was added 2-methoxybenzyl alcohol (1.33 mL, 9.99 mmol, Aldrich, St. Louis, Mo.), triphenylphosphine (2.62 g, 9.99 mmol, Aldrich, St. Louis, Mo.) and carbon tetrabromide (0.969 mL, 9.99 mmol, Aldrich, St. Louis, Mo.) in dichloromethane (20 mL). The reaction mixture was stirred at room temperature for 4 h and then the solvent was removed in vacuo and the residue was purified by silica gel chromatography, eluting with 10% EtOAc in hexanes to give 1-(bromomethyl)-2-methoxybenzene (1.78 g) as a white solid.
Reaction SMILES: Br[C:2]1[C:3]2[NH:7][C:6]([C:8](C3C=C(C(C)(C)C)C=C(C(C)(C)C)C=3)=[C:9]3[N:40]=[C:12]([C:13](Br)=[C:14]4[NH:38][C:17](=[C:18](C5C=C(C(C)(C)C)C=C(C(C)(C)C)C=5)[C:19]5[CH:20]=[CH:21][C:22]=1[N:23]=5)[CH:16]=[CH:15]4)[CH:11]=[CH:10]3)=[CH:5][CH:4]=2.C1C=C2C=CC(O)=C(C3C4C(=CC=CC=4)C=CC=3O)C2=CC=1.C1C=CC(P(C2C(OC3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=CC=3)=CC=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C>[C:3]12[CH:2]=[C:22]3[N:23]=[C:19]([CH:20]=[CH:21]3)[CH:18]=[C:17]3[NH:38][C:14]([CH:15]=[CH:16]3)=[CH:13][C:12]3=[N:40][C:9]([CH:10]=[CH:11]3)=[CH:8][C:6]([NH:7]1)=[CH:5][CH:4]=2
Reactant: CC(C)(C)c1cc(-c2c3nc(c(Br)c4ccc([nH]4)c(-c4cc(C(C)(C)C)cc(C(C)(C)C)c4)c4nc(c(Br)c5ccc2[nH]5)C=C4)C=C3)cc(C(C)(C)C)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C1=Cc2cc3ccc(cc4nc(cc5ccc(cc1n2)[nH]5)C=C4)[nH]3

Procedure:
The general procedure was used to couple 5,15-dibromo-10,20-di(3,5-di-tert-butylphenyl)porphyrin (0.043 g, 0.05 mmol) with R-(+)-1,1′-bi-2-naphthol (0.167 g, 0.58 mmol), using Pd2(dba)3 (0.0046 g, 0.005 mmol) and DPEphos (0.0107 g, 0.02 mmol) in the presence of Cs2CO3 (0.0652 g, 0.2 mmol). The reaction was conducted in toluene (5 mL) at 100° C. for 20 h. The title compound was isolated by flash column chromatography (silica gel, ethyl acetate:hexanes (v/v)=1:5) as purple solids (0.022 g, 35%). 1H NMR (300 MHz, CDCl3): δ 9.21 (d, J=4.8 Hz, 4H), 8.77 (d, J=4.8 Hz, 4H), 7.37-8.05 (m, 26H), 7.07 (d, J=16.2 Hz, 2H), 6.49 (d, J=9.6 Hz, 2H), 5.66 (s, 2H), 1.51 (m, 36H), −2.45 (s, 2H). 13C NMR (75 MHz, CDCl3): δ 161.2, 151.9, 149.0, 140.0, 134.4, 133.9, 131.7, 130.8, 130.3, 129.7, 129.6, 128.9, 128.6, 128.4, 127.9, 127.4, 127.0, 125.2, 125.0, 123.7, 121.3, 117.8, 117.2, 114.5, 35.0, 31.7. UV-vis (CHCl3, λmax, nm): 425, 521, 558, 598, 655. HRMS-MALDI ([M+H]+): calcd for C88H79N4O4, 1255.6096, found 1255.6045 with an isotope distribution pattern that is the same as calculated one.
Reaction SMILES: O=[C:2]1[CH:9]2[CH2:10][C:5]3([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:6][CH:7]([CH2:11][CH:3]1[CH2:4]3)[CH2:8]2.[NH2:20][OH:21].Cl.[OH-].[Na+]>CCO.O>[OH:21][N:20]=[C:2]1[CH:9]2[CH2:10][C:5]3([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:6][CH:7]([CH2:11][CH:3]1[CH2:4]3)[CH2:8]2
Reactant: NO
Reactant: CC(C)(C)OC(=O)NC12CC3CC(C1)C(=O)C(C3)C2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)NC12CC3CC(C1)C(=NO)C(C3)C2
Temperature: 80 °C
Yield: 90 %

Procedure:
The mixture of ketone 1C (3 0 mmol), NH2OH—HCl (5 mmol), and NaOH (5 mmol) was diluted with EtOH (5 mL) and H2O (1 mL) and the reaction mixture was heated at 80° C. for 16 h. Upon cooling, the reaction mixture was extracted with DCM (10 mL×3) and the combined organic layers were dried (Na2SO4) and concentrated to provide oxime 14A in 90% yield as a solid. The material was used in the next step without further purification. Data: LC/MS (ESR) m/z 281 [M+1]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([OH:18])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[CH2:20][CH:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=2)[CH2:23][CH2:22]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH2:20][CH:21]3[CH2:22][CH2:23][N:24]([C:27]4[CH:28]=[CH:29][N:30]=[CH:31][CH:32]=4)[CH2:25][CH2:26]3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(O)ccc2C1
Reactant: OCC1CCN(c2ccncc2)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2cc(OCC3CCN(c4ccncc4)CC3)ccc2C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 73.6 %

Procedure:
To a solution of 6-hydroxy-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid tert-Butyl Ester (320 mg) and 4-hydroxymethyl-1-(pyridin-4-yl)piperidine (247 mg) in a mixture of tetrahydrofuran (15 ml) and methylene chloride (5 ml) were successively added triphenylphosphine (370 mg) and diisopropyl azodicarboxylate (0.28 ml), and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, the solvent was evaporated and the obtained residue was purified by silica gel column chromatography (hexane:acetone=3:2-1:1, 1% triethylamine) and dried under reduced pressure to give the title compound (400 mg).
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[CH:19][N:18]=[C:17]2[N:26]1[CH2:31][CH2:30][CH:29]([CH:32]([OH:34])[CH3:33])[CH2:28][CH2:27]1>ClCCl>[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[CH:19][N:18]=[C:17]2[N:26]1[CH2:31][CH2:30][CH:29]([C:32](=[O:34])[CH3:33])[CH2:28][CH2:27]1
Reactant: COc1cc2ncnc(N3CCC(C(C)O)CC3)c2cc1OC
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COc1cc2ncnc(N3CCC(C(C)=O)CC3)c2cc1OC
Reaction time: 24 h

Procedure:
Pyridinium chlorochromate (6.2 g) was added at room temperature to a stirred solution of 6,7-dimethoxy-4-[4-(1-hydroxyethyl)piperid-1-yl]quinazoline (7.60 g) in dichloromethane (150 cm3) and the mixture was stirred for 24 hours. The mixture was filtered through "Avicel" (Trademark) and the solution was washed with 2M sodium hydroxide (3×50 cm3). The dried (MgSO4) organic phase was evaporated and the residue chromatographed on silica ("Merck" 60.9385) eluting with chloroform to give a solid which was recrystallized from ethyl acetate to afford 6,7-dimethoxy-4-[4-(1-oxoethyl)piperid-1-yl]quinazoline, m.p. 116°-117° (3.05 g).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:14])=O>>[Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([Cl:14])=[O:5]
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ccc(Cl)nc1Cl

Procedure:
A solution of commercially available (Aldrich) 2,6-dichloro-nicotinic acid (2.0 g, 10.4 mmol) in thionyl chloride (10 mL) was heated to 80° C. for 2 h. After cooling, the solution was concentrated in vacuo to give 2,6-dichloro-nicotinoyl chloride as yellow oil which was carried on to the next step without further purification. This transformation can also be accomplished using oxalyl chloride with catalytic DMF in place of thionyl chloride.
Reaction SMILES: [C:1]([C:3]1[C:4]([Br:16])=[C:5]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])[C:6]([Br:10])=[CH:7][C:8]=1[Br:9])#[N:2].S(=O)(=O)(O)[OH:18]>>[C:1]([C:3]1[C:4]([Br:16])=[C:5]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])[C:6]([Br:10])=[CH:7][C:8]=1[Br:9])(=[O:18])[NH2:2]
Reactant: N#Cc1c(Br)cc(Br)c(CCC(=O)O)c1Br
Reactant: O=S(=O)(O)O
Product: NC(=O)c1c(Br)cc(Br)c(CCC(=O)O)c1Br
Temperature: 60 °C
Reaction time: 2 h

Procedure:
13 g of 3-(3-cyano-2,4,6-tribromophenyl)propionic acid is suspended in 50 ml of concentrated sulfuric acid and heated initially to 60° C. for 30 minutes and thereafter to 95° C. for 2 hours. The solution is then poured on 300 g of ice and agitated for 3 hours in an ice bath. The thus-precipitated product is vacuum-filtered, washed with ice water, and dried at 50° C. under vacuum. Yield: 14 g of 3-(3-carbamoyl-2,4,6-tribromophenyl)propionic acid with 90% of theory, mp 197° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[C:9](=O)[CH2:8][CH2:7][CH2:6][C:5]2=1.[F:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:21][C:20]3[CH:22]=[CH:23][C:17]([F:16])=[CH:18][CH:19]=3)[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: O=C1CCCc2c1[nH]c1ccc(Cl)cc21
Reactant: Nc1ccc(F)cc1
Product: Fc1ccc(NC2CCCc3c2[nH]c2ccc(Cl)cc32)cc1

Procedure:
6-Chloro-N-(4-fluorophenyl)-2,3,4,9-tetrahydro-1H-carbazol-1-amine was prepared from 6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-one and 4-fluoroaniline in a similar manner as described in Example 13 to give 63 mg (43% yield) of a yellow solid. 1H-NMR (CDCl3): δ 8.03 (s, 1H), 7.46 (m, 1H), 7.23-7.05 (m, 2H), 6.95 (m, 2H), 6.66 (m, 2H), 4.72 (s, 1H), 3.70 (s, 1H), 2.70 (m, 2H), 2.21 (m, 1H), 2.01 (m, 1H), 1.93-1.71 (m, 2H); MS m/z 313 (M−1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13](Br)=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[OH:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>O.O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:23]2[CH:22]=[CH:21][CH:20]=[C:19]([OH:18])[CH:24]=2)=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCc1ccc(Br)cc1
Reactant: OB(O)c1cccc(O)c1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCCc1ccc(-c2cccc(O)c2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of [2-(4-bromo-phenyl)-ethyl]-carbamic acid tert-butyl ester (500 mg), 3-hydroxybenzeneboronic acid (296 mg), sodium carbonate (265 mg), palladium (II) acetate (7 mg) and tricyclohexylphosphine (10 mg) in water (3 ml) and dioxane (12 ml) is kept at 90° C. under micro wave conditions for 180 min. The mixture is cooled down to rt and is filtered through an EXTUBE extraction column (Varian) with EtOAc (200 ml). The filtrate is evaporated and the resulting crude product is purified on silica (150 g) with cyclohexane/EtOAc 5/1 to afford pure [2-(3′-hydroxy-biphenyl-4-yl)-ethyl]-carbamic acid tert-butyl ester.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[N:27](C(OCC)C)[N:26]=[N:25][N:24]=3)=[CH:13][CH:12]=2)[C:8]([C:33]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([CH2:41][N:42]([CH2:45][CH3:46])[CH2:43][CH3:44])[N:36]=2)=[O:34])=[C:7]([Cl:47])[N:6]=1)[CH2:2][CH2:3][CH3:4].Cl.[OH-].[Na+]>O1CCCC1>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:27][N:26]=[N:25][N:24]=3)=[CH:13][CH:12]=2)[C:8]([C:33]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([CH2:41][N:42]([CH2:43][CH3:44])[CH2:45][CH3:46])[N:36]=2)=[O:34])=[C:7]([Cl:47])[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(C(=O)c2cccc(CN(CC)CC)n2)n1Cc1ccc(-c2ccccc2-c2nnnn2C(C)OCC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCc1nc(Cl)c(C(=O)c2cccc(CN(CC)CC)n2)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 85.7 %

Procedure:
21 mg (0.032 mmole) of the compound obtained in step 1 was dissolved in 0.5 ml of tetrahydrofuran and to the resulting solution was added 0.3 ml of aqueous 1N HCl solution. The resultant was stirred for 5 hours at room temperature, neutralized with aqueous 1N NaOH solution, concentrated under reduced pressure and purified with silica gel column chromatography to obtain 16 mg of the title compound (yield 85.8%).
Reaction SMILES: [CH3:1][C:2]1[C:10]([C:11](=[O:18])[C:12]2[CH2:17][CH2:16][CH2:15][NH:14][CH:13]=2)=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[H-].[Na+].[CH2:21](Cl)[CH3:22]>CN(C)C=O>[CH3:1][C:2]1[C:10]([C:11](=[O:18])[C:12]2[CH2:17][CH2:16][CH2:15][N:14]([CH2:21][CH3:22])[CH:13]=2)=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1
Reactant: CCCl
Reactant: Cc1nn2ccccc2c1C(=O)C1=CNCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN1C=C(C(=O)c2c(C)nn3ccccc23)CCC1

Procedure:
One g of 2-methyl-3-(1,4,5,6-tetrahydronicotinoyl)pyrazolo[1,5-a]pyridine was dissolved in 20 ml of dimethyl-formamide and 0.3 g of sodium hydride (55%) was added whilst stirring to the mixture. The mixture was stirred at room temperature for 1 hour, and then 1 g of ethylchloride was added and stirred at 60° C. for 2 hours. After removal of solvent in vacuo, the residue was chromatographed over SiO2 employing CH2Cl2 --ethyl acetate--methanol (8:1.5:0.5) mixture as eluent. The eluate was evaporated to dryness in vacuo and the residue was recrystallized from benzene-hexane to afford the title compound in yield of 0.8 g (72%), mp. 104°-105° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:20]=[C:19]2[C:15]([C:16]([NH2:21])=[N:17][NH:18]2)=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1>N1C=CC=CC=1>[CH2:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:20]=[C:19]2[C:15]([C:16]([NH:21][C:27](=[O:28])[C:26]3[CH:30]=[CH:31][C:23]([Br:22])=[CH:24][CH:25]=3)=[N:17][NH:18]2)=[CH:14][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1n[nH]c2cc(OCCOCc3ccccc3)ccc12
Reactant: O=C(Cl)c1ccc(Br)cc1
Solvent: c1ccncc1
Product: O=C(Nc1n[nH]c2cc(OCCOCc3ccccc3)ccc12)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.9 %

Procedure:
To a stirred solution of 6-(2-benzyloxy-ethoxy)-1H-indazol-3-ylamine (3.0 g, 10.6 mmol) in 30 ml of dry pyridine, at 0° C., under argon atmosphere, was added portionwise 4-bromo-benzoyl chloride (2.32 g, 10.6 mmol). The reaction mixture was allowed to warm to r.t. under stirring overnight then evaporated to dryness. The residue was treated with 50 ml of MeOH and 25 ml of 2N NaOH and stirred at r.t. for 1 h. The mixture was concentrated to ca. 10 ml by rotary evaporation, diluted with 200 ml of water, stirred for 15 min at r.t. and the suspended solid filtered and washed with water. After drying under vacuum, the crude solid was purified by chromatography (Biotage SP1 Flash Purification system) on a silica gel cartridge (Biotage SNAP 100 g) using DCM as eluant A and DCM/MeOH 9:1 as eluant B. Elution with a gradient from A/B 100:0 to 70:30 over 25 CV gave a pink solid that was triturated with EtOAc (50 ml), filtered, washed with EtOAc and dried affording 3.01 g (yield: 61%) of the title compound as a whitish solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([N:14]3[C:19](=[O:20])[C:18]([CH2:21][C:22]4[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=4)=[N:17][C:16]4[CH:28]=[CH:29][CH:30]=[N:31][C:15]3=4)[CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.[C:32]1(=[O:42])[O:37][C:35](=[O:36])[C:34]2=[CH:38][CH:39]=[CH:40][CH:41]=[C:33]12>O1CCOCC1.O>[C:35]([C:34]1[CH:38]=[CH:39][CH:40]=[CH:41][C:33]=1[C:32]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([N:14]3[C:19](=[O:20])[C:18]([CH2:21][C:22]4[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=4)=[N:17][C:16]4[CH:28]=[CH:29][CH:30]=[N:31][C:15]3=4)[CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1)=[O:42])([OH:37])=[O:36]
Reactant: Nc1cccc(-c2cccc(-n3c(=O)c(Cc4cccnc4)nc4cccnc43)c2)c1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1ccccc1C(=O)Nc1cccc(-c2cccc(-n3c(=O)c(Cc4cccnc4)nc4cccnc43)c2)c1
Yield: 80.6 %

Procedure:
A solution of 4-[3-(3-aminophenyl)phenyl]-2-(3-pyridylmethyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (100 mg) and phthalic anhydride (48 mg) in dioxane (3 ml) was stirred overnight at room temperature. The reaction mixture was diluted with water, and precipitated crystals were collected to give 4-[3-[3-(2-carboxybenzoylamino)phenyl]phenyl]-2-(3-pyridylmethyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (110 mg).
Reaction SMILES: Cl.[F:2][C:3]([F:17])([F:16])[CH2:4][CH2:5][O:6][C:7]1[N:12]=[CH:11][C:10]([CH:13]([NH2:15])[CH3:14])=[CH:9][CH:8]=1.[NH2:18][C:19]1[N:24]=[C:23]([C:25](O)=[O:26])[CH:22]=[CH:21][N:20]=1>>[NH2:18][C:19]1[N:24]=[C:23]([C:25]([NH:15][CH:13]([C:10]2[CH:11]=[N:12][C:7]([O:6][CH2:5][CH2:4][C:3]([F:2])([F:16])[F:17])=[CH:8][CH:9]=2)[CH3:14])=[O:26])[CH:22]=[CH:21][N:20]=1
Reactant: Nc1nccc(C(=O)O)n1
Reactant: CC(N)c1ccc(OCCC(F)(F)F)nc1
Agent: Cl
Product: CC(NC(=O)c1ccnc(N)n1)c1ccc(OCCC(F)(F)F)nc1
Yield: 64 %

Procedure:
The title compound is prepared in 64% yield (100 mg, a white solid) from 1-(6-(3,3,3-trifluoropropoxy)pyridin-3-yl)ethanamine hydrochloride (120 mg, 0.4 mmol, Amine-21, single enantiomer) and 2-aminopyrimidine-4-carboxylic acid (62 mg, 0.4 mmol) by the similar manner in Step-1 of Example 8.
Reaction SMILES: [CH3:1][C:2]1([CH2:14][OH:15])[O:7][C:6]2=[N:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][N:5]2[CH2:4][CH2:3]1.[I:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20]Br.[H-].[Na+]>>[I:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20][O:15][CH2:14][C:2]1([CH3:1])[O:7][C:6]2=[N:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][N:5]2[CH2:4][CH2:3]1
Reactant: CC1(CO)CCn2cc([N+](=O)[O-])nc2O1
Reactant: BrCc1cccc(I)c1
Agent: [H-]
Agent: [Na+]
Product: CC1(COCc2cccc(I)c2)CCn2cc([N+](=O)[O-])nc2O1
Yield: 69 %

Procedure:
Alkylation of oxazine alcohol 149 (see Example 2OO) with 3-iodobenzyl bromide (1.6 equiv.) and NaH (1.8 equiv.) as in Example 2UU above for 3.5 h, followed by chromatography of the product on silica gel, eluting with CH2Cl2 (foreruns) and then with 0-2% EtOAc/CH2Cl2, gave 7-{[(3-iodobenzyl)oxy]methyl}-7-methyl-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (155) (69%) as a cream solid: mp (CH2Cl2/pentane) 122-125° C. (dec); 1H NMR (CDCl3) δ 7.63 (br d, J=7.9 Hz, 1H), 7.58 (m, 1H), 7.40 (s, 1H), 7.19 (br d, J=7.7 Hz, 1H), 7.06 (t, J=7.7 Hz, 1H), 4.49 (s, 2H), 4.11 (ddd, J=12.4, 7.3, 5.8 Hz, 1H), 4.01 (ddd, J=12.5, 6.7, 6.0 Hz, 1H), 3.63 (d, J=10.2 Hz, 1H), 3.60 (d, J=10.2 Hz, 1H), 2.37 (ddd, J=14.4, 6.7, 6.0 Hz, 1H), 2.12 (ddd, J=14.4, 7.3, 6.0 Hz, 1H), 1.47 (s, 3H). Anal. (C15H16IN3O4) C, H, N.
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:13][C:12]([C:14]2[N:15]=[CH:16][N:17]([C:19]3[CH:24]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=4)[CH:22]=[C:21]([C:35]([F:38])([F:37])[F:36])[N:20]=3)[CH:18]=2)=[N:11][C:10]=1[CH3:39])(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>>[CH3:39][C:10]1[N:11]=[C:12]([C:14]2[N:15]=[CH:16][N:17]([C:19]3[CH:24]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=4)[CH:22]=[C:21]([C:35]([F:37])([F:36])[F:38])[N:20]=3)[CH:18]=2)[S:13][C:9]=1[S:6]([NH2:5])(=[O:8])=[O:7]
Reactant: Cc1nc(-c2cn(-c3cc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)cn2)sc1S(=O)(=O)NC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(-c2cn(-c3cc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)cn2)sc1S(N)(=O)=O
Temperature: 23 °C
Reaction time: 16 h
Yield: 51.7 %

Procedure:
To 4-methyl-2-{1-[6-trifluoromethyl-4-(4-trifluoromethyl-phenyl)-pyridin-2-yl]-1H-imidazol-4-yl}-thiazole-5-sulfonic acid tert-butylamide (example 300) (0.150 g, 0.254 mmol) was added TFA (5 mL) and the reaction mixture was stirred at 23° C. for 16 h. The mixture was evaporated to dryness and partitioned between TBME and saturated NaHCO3 solution, the organic layer was dried over Na2SO4. Removal of the solvent in vacuum left a crude product which was triturated with diethyl ether to give the title compound as a white solid (0.070 g, 51%). MS (ISP) 534.2 [(M+H)+]; mp 170° C. (dec.).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[N+:22]([O-])=O)[CH:9]=[CH:10][CH:11]=1)[CH3:2]>C1COCC1.[Ni]>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:20])([F:19])[F:21])=[CH:14][C:13]=2[NH2:22])[CH:9]=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cccc(-c2ccc(C(F)(F)F)cc2[N+](=O)[O-])c1
Agent: [Ni]
Solvent: C1CCOC1
Product: CCOC(=O)Cc1cccc(-c2ccc(C(F)(F)F)cc2N)c1
Reaction time: 4.5 h
Yield: 59.8 %

Procedure:
2′-Nitro-4′-(trifluoromethyl)-[1,1′-biphenyl]-3-acetic acid ethyl ester (107 mg, 0.30 mmol) in THF (6 mL) was treated with about 150 mg of Raney® nickel (50 wt % in H2O). The reaction was shaken on a Parr apparatus under 50 psi of H2. After 4.5 h, another 200 mg of Raney® nickel was added and the reaction was shaken an additional 2 h under 50 psi H2. The reaction mixture was filtered through Celite®, concentrated in vacuo and purified via column chromatography to afford 2′-amino-4′-(trifluoromethyl)-[1,1′-biphenyl]-3-acetic acid ethyl ester (58 mg, 59% yield). MS (ESI) m/z: 324.2 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[C:15]([I:16])=[N:14][NH:13][C:8]=2[N:9]=[C:10]([Cl:12])[CH:11]=1)=[O:5])[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:29]1[CH:34]=[CH:33][CH2:32][CH2:31][CH2:30]1>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[C:15]([I:16])=[N:14][N:13]([CH:30]3[CH2:31][CH2:32][CH2:33][CH2:34][O:29]3)[C:8]=2[N:9]=[C:10]([Cl:12])[CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(Cl)nc2[nH]nc(I)c12
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cc(Cl)nc2c1c(I)nn2C1CCCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.2 %

Procedure:
To a solution of 6-chloro-3-iodo-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid ethyl ester (14 g, 39.8 mmol) and p-toluenesulfonic acid monohydrate (0.75 g, 3.9 mmol) in anhydrous chloroform (200 ml) at 0° C. was added dropwise 3,4-dihydro-2H-pyran (5.45 ml, 59.7 mmol). The reaction mixture was allowed to warm to room temperature, stirred overnight and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography using a stepwise gradient of ethyl acetate (0-20%) in cyclohexane to afford the title compound as a yellow solid (9.4 g, 54%). LC/MS (Method LC8): Rt=2.08 min; m/z=351 [M+H-THP]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH3:10])=[N:7][C:6]=2[CH:11]=1.CO[CH:14]1[CH2:18][CH2:17][CH:16](OC)O1.C(O)(=O)C>C(Cl)Cl>[N:1]1([C:2]2[CH:3]=[CH:4][C:5]3[O:9][C:8]([CH3:10])=[N:7][C:6]=3[CH:11]=2)[CH:14]=[CH:18][CH:17]=[CH:16]1
Reactant: COC1CCC(OC)O1
Reactant: Cc1nc2cc(N)ccc2o1
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1nc2cc(-n3cccc3)ccc2o1
Yield: 40 %

Procedure:
5-Amino-2-methylbenzoxazole (30.0 g, 0,203 mol) and 2,5-dimethoxytetrahydrofuran (30.0 g, 0.227 mol) were combined with 90 mL of acetic acid and the solution was heated at reflux for 1 hr. The mixture was evaporated to a red slurry and mixed with hexane to give a dark solid. The solid was dissolved in methylene chloride and extracted with basic water. The organic phase was removed, dried, and evaporated to a brown solid. Recrystallization from hexane/heptane afforded 18 g (45% yield) of product, m.p. 115°-121° C.