Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[CH:13]=[C:12]([C:15]4[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=4)[CH:11]=[C:10]([C:22]([O:24][CH3:25])=[O:23])[C:9]=3[CH:8]=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:27][CH2:28][CH2:29][OH:30].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH:1]1([N:6]2[C:14]3[CH:13]=[C:12]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH2:27][CH2:28][CH2:29][OH:30])=[CH:17][CH:16]=4)[CH:11]=[C:10]([C:22]([O:24][CH3:25])=[O:23])[C:9]=3[CH:8]=[N:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: OCCCBr
Reactant: COC(=O)c1cc(-c2ccc(O)cc2)cc2c1cnn2C1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(-c2ccc(OCCCO)cc2)cc2c1cnn2C1CCCC1
Temperature: 100 °C
Yield: 68.5 %

Procedure:
To a stirred solution of methyl 1-cyclopentyl-6-(4-hydroxyphenyl)-1H-indazole-4-carboxylate (0.5 g, 1.48 mmol) in DMF (15 mL), 3-bromopropane-1-ol (0.616 g, 4.46 mmol) and K2CO3 (0.306 g, 2.23 mmol) were added, resulting reaction mass was heated at 100° C. for 4 h. On completion, water was added to reaction mass and extracted with ethyl acetate. Combined organic layers were dried and concentrated under reduced pressure giving crude material which was purified by column chromatography over silica gel (60-120 mesh size) to afford methyl 1-cyclopentyl-6-(4-(3-hydroxypropoxy)phenyl)-1H-indazole-4-carboxylate (0.4 g, 68.2%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5](=[CH:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[O:22][CH3:23])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]>C(O)C.[Ni]>[CH2:9]([O:8][C:6](=[O:7])[CH:5]([CH2:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[O:22][CH3:23])[C:4]([O:3][CH2:1][CH3:2])=[O:24])[CH3:10]
Reactant: CCOC(=O)C(=Cc1c(OC)ccc2ccccc12)C(=O)OCC
Agent: [Ni]
Solvent: CCO
Product: CCOC(=O)C(Cc1c(OC)ccc2ccccc12)C(=O)OCC
Reaction time: 4 h

Procedure:
After being solubilised in ethanol (510 ml), the unsaturated compound obtained in Step A (10 g, 3.05.10−2 mol) is hydrogenated in the presence of Raney nickel at ambient temperature with vigorous stirring. The reaction is monitored by TLC and GPC after 4 hours' hydrogenation. After it has been established that the starting material has disappeared, the catalyst is filtered off over Celite and the ethanol is evaporated off under reduced pressure. The title product is obtained in the form of a colourless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:12][CH2:13][CH2:14][CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[N:5]2[C:10]=1[C:9]([NH2:11])=[N:8][CH:7]=[N:6]2.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:37]=[C:38]([O:40][CH3:41])[CH:39]=1)[CH2:26][O:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:37]=[C:38]([O:40][CH3:41])[CH:39]=1)[CH2:26][O:27][C:28]1[CH:33]=[C:32]([C:2]2[CH:3]=[C:4]([CH2:12][CH2:13][CH2:14][CH2:15][N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[N:5]3[C:10]=2[C:9]([NH2:11])=[N:8][CH:7]=[N:6]3)[CH:31]=[CH:30][CH:29]=1
Reactant: Nc1ncnn2c(CCCCN3CCCC3)cc(Br)c12
Reactant: COc1cc(COc2cccc(B(O)O)c2)cc(OC)c1
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: COCCOC
Product: COc1cc(COc2cccc(-c3cc(CCCCN4CCCC4)n4ncnc(N)c34)c2)cc(OC)c1
Temperature: 80 °C
Yield: 27.5 %

Procedure:
To a stirred solution of 5-bromo-7-(4-pyrrolidin-1-ylbutyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (70 mg, 0.21 mmol), 3-(3,5-dimethoxybenzyloxy)phenyl boronic acid (179 mg, 0.62 mmol), and tetrakis(triphenylphosphine)palladium(0) (23 mg, 0.021 mmol) in degassed DME (1.5 mL) was added aqueous Na2CO3 solution (2 M, 310 μL). The reaction was heated (80° C.) for 17 h and then cooled to rt. The mixture was partitioned between ethyl acetate (25 mL) and water (25 mL). The layers were separated and the organic phase was washed dried (Na2SO4) and concentrated to dryness. The residue was purified by preparative HPLC using a gradient elution from 20% to 70% acetonitrile followed by preparative TLC eluting with 9:1 ethyl acetate/methanol (with 1% concentrated ammonium hydroxide) to obtain 29 mg (28%) of the desired product. 1H NMR (300 MHz, DMSO-d6) δ 7.88 (s, 1 H), 7.36 (t, 1 H), 7.07-7.04 (m, 1 H), 7.03-6.96 (m, 2 H), 6.60 (d, 2 H), 6.55 (s, 1 H), 6.43 (t, 1 H), 5.07 (s, 2 H), 3.73 (s, s H), 2.88 (t, 2 h), 2.56-2.48 (m, 6 H), 1.78-1.65 (m, 6 H), 1.60-1.49 (m, 2 H); ES-MS m/z 502.2 [M+H]+, HPLC RT (min) 2.27.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:4]([NH:17][C:18]2[CH:31]=[C:21]3[CH2:22][N:23]([CH2:26][C:27]([F:30])([F:29])[F:28])[CH2:24][CH2:25][N:20]3[N:19]=2)[C:3]1=[O:32].[C:33]([C:37]1[CH:38]=[C:39]2[C:44](=[C:45]([F:47])[CH:46]=1)[C:43](=[O:48])[N:42]([C:49]1[N:56]=[CH:55][CH:54]=[C:53](Cl)[C:50]=1[CH:51]=[O:52])[N:41]=[CH:40]2)([CH3:36])([CH3:35])[CH3:34].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C.O>[C:33]([C:37]1[CH:38]=[C:39]2[C:44](=[C:45]([F:47])[CH:46]=1)[C:43](=[O:48])[N:42]([C:49]1[N:56]=[CH:55][CH:54]=[C:53]([C:6]3[CH:5]=[C:4]([NH:17][C:18]4[CH:31]=[C:21]5[CH2:22][N:23]([CH2:26][C:27]([F:29])([F:28])[F:30])[CH2:24][CH2:25][N:20]5[N:19]=4)[C:3](=[O:32])[N:2]([CH3:1])[CH:7]=3)[C:50]=1[CH:51]=[O:52])[N:41]=[CH:40]2)([CH3:36])([CH3:34])[CH3:35]
Reactant: CC(C)(C)c1cc(F)c2c(=O)n(-c3nccc(Cl)c3C=O)ncc2c1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cc(Nc2cc3n(n2)CCN(CC(F)(F)F)C3)c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: Cn1cc(-c2ccnc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2C=O)cc(Nc2cc3n(n2)CCN(CC(F)(F)F)C3)c1=O
Temperature: 100 °C
Yield: 44.7 %

Procedure:
A 25-mL round-bottomed flask equipped with a reflux condenser was charged with 134d (200 mg, 0.44 mmol), 2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-4-chloronicotinaldehyde 103b (159 mg, 0.44 mmol), K3PO4 (186 mg, 0.88 mmol), sodium acetate (72 mg, 0.88 mmol), 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium(II) (16 mg, 0.022 mmol), and acetonitrile/water (8/0.2 mL). After three cycles of vacuum/N2 flush, the mixture was heated at 100° C. for 1 h under N2 protection. Analysis of the reaction mixture by LCMS showed complete conversion to the desired product. The reaction mixture was cooled to room temperature and diluted with dichloromethane (30 mL) and water (15 mL). The water layer was separated and extracted with dichloromethane (2×15 mL). The combined organic extract was dried over Na2SO4, filtered, and concentrated under reduced pressure. The dark residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (80/1 to 30/1) to afford 134e (128 mg, 45%) as a yellow solid. MS-ESI: [M+H]+ 651.3
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.Br.Br[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1>>[N:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][N:13]1[CH:14]=[C:10]([C:9]#[C:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=2)[N:11]=[C:12]1[CH3:15]
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)c[nH]1
Reactant: BrCc1ccccn1
Agent: Br
Product: Cc1nc(C#Cc2ccnc(Cl)c2)cn1Cc1ccccn1

Procedure:
The title compound, MS: m/e=309.2 (M+H+), was prepared in accordance with the general method of example 1 from 2-chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 2-(bromomethyl)pyridine hydrobromide.
Reaction SMILES: [CH:1]([N:4]([CH:8]([CH3:10])[CH3:9])[CH2:5][CH2:6][NH2:7])([CH3:3])[CH3:2].C(N(CC)CCN[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH:28]=[O:29])=[O:18])C>C(Cl)(Cl)Cl>[CH:1]([N:4]([CH:8]([CH3:10])[CH3:9])[CH2:5][CH2:6][NH:7][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH:28]=[O:29])=[O:18])([CH3:3])[CH3:2]
Reactant: CC(C)N(CCN)C(C)C
Reactant: CCCCCCCCCCCCCCCCCCN(C=O)c1ccccc1COC(=O)NCCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCN(C=O)c1ccccc1COC(=O)NCCN(C(C)C)C(C)C
Temperature: 70 °C
Reaction time: 2 h
Yield: 52.6 %

Procedure:
N,N-Diisopropylethylenediamine (0.79 g) was added to the intermediate (a) (2.62g) obtained in Example 28. After being stirred for 2 hours at 70° C., the reaction mixture, with chloroform added thereto, was washed with 1N sodium hydroxide aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and then filtrated. The solvent was evaporated out and the residue was purified by silica gel column chromatography (silica gel 85 g, chloroform:methanol=100:1), thereby yielding 1.45 g of the aimed compound as white solid.
Reaction SMILES: [CH2:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:22][CH3:23])=[C:10](/[C:13](/[CH3:21])=[C:14](/[F:20])\[C:15](OCC)=[O:16])[CH:11]=2)[O:6][C:5]([CH3:25])([CH3:24])[CH:4]=1)[CH3:2].[H-].C([Al+]CC(C)C)C(C)C>C1COCC1>[CH2:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:22][CH3:23])=[C:10](/[C:13](/[CH3:21])=[C:14](/[F:20])\[CH2:15][OH:16])[CH:11]=2)[O:6][C:5]([CH3:24])([CH3:25])[CH:4]=1)[CH3:2]
Reactant: CCOC(=O)/C(F)=C(/C)c1cc2c(cc1OC)OC(C)(C)C=C2CC
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: CCC1=CC(C)(C)Oc2cc(OC)c(/C(C)=C(/F)CO)cc21
Temperature: -78 °C
Reaction time: 4 h

Procedure:
To a solution of ethyl (2E)-3-(4-ethyl-7-methoxy-2,2-dimethyl-2H-chromen-6-yl)-2-fluoro-but-2-enoate (Compound 68, 349 mg, 0.96 mmol) in THF (15 mL) under argon at 0° C. was added diisobutylaluminum hydride (1.0 M in hexanes, 2.9 mL, 2.9 mmol). The resulting mixture was stirred at −78° C. for 4 h. The reaction was quenched slowly with saturated NH4Cl, celite, and diluted with diethyl ether. The resulting mixture was stirred at 25° C. for 1 h. The product was filtered through a pad of celite. The solution was dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 1:4 ethyl acetate/hexane) to yield the title compound as a yellow solid.
Reaction SMILES: C[O:2][C:3](=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:10]=1.O.[OH-].[Na+]>CO>[C:15]1([C:11]2[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=2)[O:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:21])=[O:2])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)CCCCOc1cccc(-c2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CCCCOc1cccc(-c2ccccc2)c1
Reaction time: 3.5 h
Yield: 89.5 %

Procedure:
To a solution in methanol (7.5 mL) of 5-(3-phenylphenoxy)pentanoic acid methyl ester (1.42 g, 5.0 mmol), prepared as in step 1, was added water (3.75 mL) and aqueous 4N sodium hydroxide (3.75 mL). The reaction mixture was stirred for 3.5 hours and then was concentrated in vacuo. The residue was partitioned between water and ethyl ether. The aqueous phase was taken to pH 2 with concentrated HCl and extracted twice with ethyl acetate. The combined ethyl acetate extracts were dried over Na2SO4, filtered, and concentrated in vacuo to give a white solid. Trituration of the solid with 1:1 ethyl ether-hexanes gave 5-(3-phenylphenoxy)pentanoic acid (1.21 g) as a white powder.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[F:21][C:22]([F:37])([F:36])[C:23]1[CH:24]=[C:25]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[C:26](Cl)=[O:27]>>[F:21][C:22]([F:36])([F:37])[C:23]1[CH:24]=[C:25]([CH:29]=[C:30]([C:32]([F:35])([F:33])[F:34])[CH:31]=1)[C:26]([N:20]=[C:16]([N:7]1[CH2:6][C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=2[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[CH2:8]1)[O:17][CH2:18][CH3:19])=[O:27]
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: CCOC(=NC(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate and 3,5-bis-(trifluoromethyl)benzoyl chloride, there is obtained ethyl N-[3,5-bis-(trifluoromethyl)-benzoyl]-5,7-dihydro-6H-dibenz[c,e]azepine-6 -carboximidate, m.p. 129°-130° C.;
Reaction SMILES: [C:1]([CH2:3][CH2:4][S:5][C:6]1[CH:11]=[C:10]([NH2:12])[C:9]([S:13][CH2:14][CH2:15][C:16]#[N:17])=[CH:8][C:7]=1[NH2:18])#[N:2].[N+:19]([C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1)([O-:21])=[O:20].O>CN1C(=O)CCC1>[C:1]([CH2:3][CH2:4][S:5][C:6]1[CH:11]=[C:10]([NH2:12])[C:9]([S:13][CH2:14][CH2:15][C:16]#[N:17])=[CH:8][C:7]=1[NH:18][C:26](=[O:27])[C:25]1[CH:24]=[CH:23][C:22]([N+:19]([O-:21])=[O:20])=[CH:30][CH:29]=1)#[N:2]
Reactant: N#CCCSc1cc(N)c(SCCC#N)cc1N
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: O
Solvent: CN1CCCC1=O
Product: N#CCCSc1cc(NC(=O)c2ccc([N+](=O)[O-])cc2)c(SCCC#N)cc1N
Reaction time: 0.17 h
Yield: 61.3 %

Procedure:
2,5-Bis[(cyanoethyl)thio]-1,4-phenylenediamine (13.9 g, 50 mmol) was dissolved in 90 mL of NMP in a 250 mL 3-necked round-bottom flask under nitrogen purge. The resultant clear red solution was cooled to 0˜5° C. in an ice bath, followed by addition of freshly distilled triethylamine (TEA) by syringe. After stirring for 10 minutes, a mixture of 4-nitrobenzoyl chloride (10.2 g, 55 mmol) and 90 mL of NMP was added into the stirred red solution drop by drop over a period of 0.5 h. The resultant solution was stirred at 0˜5° C. for 2 h and at room temperature for 1 h, followed by addition of 800 mL of water with stirring. The resultant yellow precipitate was collected by filtration, followed by washing with 800 mL of deionized water twice and 300 mL of methanol once. The obtained product was extracted with methanol using a Soxhlet extractor for 24 h. A yellow solution was collected and evaporated, followed by drying at 60° C. under vacuum overnight, giving the title compound as a red powder (13.1 g, yield 61%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]3[O:26][CH2:27][O:28][C:22]=3[CH:21]=2)[C:11]2[C:16]([CH3:17])=[CH:15][S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]4[O:26][CH2:27][O:28][C:22]=4[CH:21]=3)[C:11]3[C:16]([CH3:17])=[CH:15][S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1ncc[nH]1
Reactant: Cc1csc2nc(Cl)nc(NCc3ccc4c(c3)OCO4)c12
Product: Cc1csc2nc(-n3ccnc3C)nc(NCc3ccc4c(c3)OCO4)c12

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2-chloro-5-methyl-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-5-methyl-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:4]=1[C:5]([N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:17])[CH:15]=2)[NH:10][C:9](=[O:18])[C@H:8]1[CH2:19][CH3:20])=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:34][CH3:35]>C(#N)C>[CH3:1][O:2][C:3]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:4]=1[C:5]([N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:17])[CH:15]=2)[N:10]([CH2:34][CH3:35])[C:9](=[O:18])[C@H:8]1[CH2:19][CH3:20])=[O:6]
Reactant: CCI
Reactant: CC[C@@H]1C(=O)Nc2ccc(F)cc2N1C(=O)c1ccc(OC)cc1OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC[C@@H]1C(=O)N(CC)c2ccc(F)cc2N1C(=O)c1ccc(OC)cc1OC
Temperature: 89 °C
Reaction time: 12 h
Yield: 70.9 %

Procedure:
To a stirred solution of (3R)-4-(2,4-dimethoxybenzoyl)-3-ethyl-6-fluoro-3,4-dihydroquinoxalin-2(1H)-one (0.25 g, 0.73 mmol) in acetonitrile (6 mL) under nitrogen was added cesium carbonate (0.24 g, 0.74 mmol) and iodoethane (0.19 mL, 0.37 g, 2.4 mmol). The mixture was stirred at 89° C. in a sealed tube for 12 h. The solvent was evaporated, and the residue was partitioned between water and methylene chloride. The layers were separated, and the organic layer was washed twice with water, dried over magnesium sulfate, concentrated in vacuo, and purified via Biotage Horizon® (SiO2, gradient from 7% EtOAc/hexane to 51% EtOAc/hexane) to yield 0.20 g (71%) of (3R)-4-(2,4-dimethoxybenzoyl)-1,3-diethyl-6-fluoro-3,4-dihydroquinoxalin-2(1H)-one.
Reaction SMILES: N[C@H](C(O)=O)CCC(O)=O.[Cl:11][C:12]1[CH:13]=[CH:14][C:15]2[CH2:21][CH2:20][NH:19][CH2:18][C@H:17]([CH3:22])[C:16]=2[CH:23]=1.[O:24]=[CH:25][C@@H:26]([C@H:28]([C@@H:30]([C@@H:32]([C:34]([O-:36])=[O:35])[OH:33])[OH:31])[OH:29])[OH:27]>O>[O:24]=[CH:25][C@@H:26]([C@H:28]([C@@H:30]([C@@H:32]([C:34]([OH:36])=[O:35])[OH:33])[OH:31])[OH:29])[OH:27].[Cl:11][C:12]1[CH:13]=[CH:14][C:15]2[CH2:21][CH2:20][NH:19][CH2:18][C@H:17]([CH3:22])[C:16]=2[CH:23]=1
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(=O)[O-]
Agent: C[C@H]1CNCCc2ccc(Cl)cc21
Agent: N[C@@H](CCC(=O)O)C(=O)O
Solvent: O
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(=O)O

Procedure:
The solubility of Compound 1 glucuronate in water was determined by UPLC to be 2.5 mg/mL, with a final pH of 6.80.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][CH:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[C:6]=2[CH:21]=1.[CH:22](OCC)(OCC)OCC>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:22]=[N:13][N:12]=[C:10]3[CH2:9][CH:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[C:6]=2[CH:21]=1
Reactant: CCOC(OCC)OCC
Reactant: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2Cl)=CC1
Product: Clc1ccc2c(c1)C(c1ccccc1Cl)=CCc1nncn1-2

Procedure:
In analogy to Example 16(b), by reacting 7-chloro-5-(2-chlorophenyl)-2-hydrazino-3H-1-benzazepine with triethyl orthoformate there is obtained 8-chloro-6-(2-chlorophenyl)-4H-s-triazolo[4,3-a][1]benzazepine of melting point 189°-190°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.[F:9][C:10]1[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[C:11]=1[C:12]([NH:14][C:15]1[S:16][C:17]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)=[C:18](C2C=CC=CN=2)[N:19]=1)=[O:13]>>[F:40][C:36]1[CH:37]=[CH:38][CH:39]=[C:10]([F:9])[C:11]=1[C:12]([NH:14][C:15]1[S:16][C:17]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)=[C:18]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=2)[N:19]=1)=[O:13]
Reactant: Cc1cccc(Br)n1
Reactant: O=C(Nc1nc(-c2ccccn2)c(-c2cccc(C(F)(F)F)c2)s1)c1c(F)cccc1F
Product: Cc1cccc(-c2nc(NC(=O)c3c(F)cccc3F)sc2-c2cccc(C(F)(F)F)c2)n1

Procedure:
Compound 108 was prepared from 22a and 2-bromo-6-methylpyridine as described for the preparation of Compound 107.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[N:12]=[CH:11][N:10]=[C:9]([NH2:13])[CH:8]=2)=[CH:4][CH:3]=1.C1([O:22][C:23](=O)[NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([S:31]([CH3:34])(=[O:33])=[O:32])[CH:26]=2)C=CC=CC=1.C(OCC)(=O)C.O>CS(C)=O.CO>[NH2:13][C:9]1[N:10]=[CH:11][N:12]=[C:7]([O:6][C:5]2[CH:14]=[CH:15][C:2]([NH:1][C:23]([NH:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([S:31]([CH3:34])(=[O:33])=[O:32])[CH:26]=3)=[O:22])=[CH:3][CH:4]=2)[CH:8]=1
Reactant: CS(=O)(=O)c1cccc(NC(=O)Oc2ccccc2)c1
Reactant: Nc1ccc(Oc2cc(N)ncn2)cc1
Solvent: CS(C)=O
Solvent: CO
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1cccc(NC(=O)Nc2ccc(Oc3cc(N)ncn3)cc2)c1
Yield: 42.7 %

Procedure:
6-(4-Aminophenoxy)pyrimidin-4-ylamine (88.9 mg, 0.440 mmol) and (3-methylsulfonylphenyl)carbamic acid phenyl ester (128 mg, 0.440 mmol) were stirred in dimethylsulfoxide (2 ml) at 85° C. for18 hours. The reaction solution was distributed between ethyl acetate and water, the organic layer was washed with 1N aqueous sodium hydroxide, water and saturated brine and dried over anhydrous magnesium sulfate, the drying agent was filtered off and the filtrate was distilled off under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (eluent—ethyl acetate:methanol=30:1), the fraction containing the target substance was concentrated and suspended in ethyl acetate, the suspension was diluted with hexane and the crystals were filtered out, washed with hexane and blow-dried to obtain the title compound (75.0 mg, 0.188 mmol, 43%) as colorless crystals.
Reaction SMILES: [SH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].I[C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=1[OH:20])[C:14]([OH:16])=[O:15].[OH-].[K+]>O.[Cu]>[OH:5][CH2:4][C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[S:1][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=1[OH:20])[C:14]([OH:16])=[O:15]
Reactant: OCc1ccccc1S
Reactant: O=C(O)c1ccc(O)c(I)c1
Agent: [Cu]
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1ccc(O)c(Sc2ccccc2CO)c1

Procedure:
A mixture of 25 gm o-mercaptobenzyl alcohol (0.18 mole), 39.6 gm 3-iodo-4-hydroxy benzoic acid (0.15 mole), 11.43 g copper powder (0.18 mole), 70 cc 40% aqueous potassium hydroxide solution (0.5 mole) and 300 cc water was placed under nitrogen atmosphere and stirred under reflux for 18 hours. After cooling the mixture was diluted with 400 cc of water and extracted twice with 100 cc of ethyl acetate to remove neutral products. The aqueous fraction was filtered and the filtrate acidified with conc. HCl to afford the title compound as an oil which solidified and was filtered. There was obtained 32.8 g of solid product.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[F:5][C:6]1[CH:7]=[C:8]([N:18]2[CH2:22][C@H:21]([CH2:23][NH:24][C:25](=[O:27])[CH3:26])[O:20][C:19]2=[O:28])[CH:9]=[CH:10][C:11]=1[N:12]1[CH2:17][CH:16]2[CH:14]([O:15]2)[CH2:13]1>CC(C)=O.O>[N:1]([CH:16]1[CH:14]([OH:15])[CH2:13][N:12]([C:11]2[CH:10]=[CH:9][C:8]([N:18]3[CH2:22][C@H:21]([CH2:23][NH:24][C:25](=[O:27])[CH3:26])[O:20][C:19]3=[O:28])=[CH:7][C:6]=2[F:5])[CH2:17]1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CC4OC4C3)c(F)c2)C(=O)O1
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CC(O)C(N=[N+]=[N-])C3)c(F)c2)C(=O)O1
Temperature: 55 °C

Procedure:
Sodium azide (42 mg, 0.64 mmol) was added to a solution of N-({(5S)-3-[3-fluoro-4-(6-oxa-3-azabicyclo[3.1.0]hex-3-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide (36 mg, 0.107 mmol, prepared using the general procedure described for Example 40) in 2:1 acetone-H2O (1.0 mL) and the solution heated at 55° C. for 16 hours. The solution was cooled, concentrated to remove acetone, diluted with water and extracted with chloroform. Combined organic extracts were dried (MgSO4), filtered and concentrated to provide the title compound. This material was used directly in the next reaction. MS (m/z): [M+H]+=379
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][C:7]1[O:11][N:10]=[C:9]([C:12]2[N:16]3[N:17]=[C:18]([O:25][CH2:26][C:27]4[N:32]=[CH:31][C:30]([CH2:33][CH2:34][OH:35])=[CH:29][CH:28]=4)[C:19]4[C:24]([C:15]3=[N:14][N:13]=2)=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:8]=1.CCN(CC)CC>C(Cl)Cl>[CH3:6][C:7]1[O:11][N:10]=[C:9]([C:12]2[N:16]3[N:17]=[C:18]([O:25][CH2:26][C:27]4[N:32]=[CH:31][C:30]([CH2:33][CH2:34][O:35][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:29][CH:28]=4)[C:19]4[C:24]([C:15]3=[N:14][N:13]=2)=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:8]=1
Reactant: Cc1cc(-c2nnc3c4ccccc4c(OCc4ccc(CCO)cn4)nn23)no1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(-c2nnc3c4ccccc4c(OCc4ccc(CCOS(C)(=O)=O)cn4)nn23)no1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Methanesulfonyl chloride (96 μl, 1.22 mmol) was added to an ice-cold solution of 2-{6-[3-(5-methylisoxazol-3-yl)-[1,2,4]triazolo[3,4-α]phthalazin-6-yloxymethyl]pyridin-3-yl}ethanol (250 mg, 0.62 mmol) and Et3N (173 μl, 122 mmol) in CH2Cl2 (50 ml) at 0° C. under nitrogen. The resulting mixture was stirred at 0° C. for 1 h, then diluted with CH2Cl2 (50 ml). The resultant solution was washed with H2O (50 ml), HCl (40 ml) and NaHCO3 solution (sat., 40 ml). The colourless solution was dried (MgSO4) and concentrated under reduced pressure. The resultant mesylate was used directly without any further purification.