Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[CH2:7][N:8]=[C:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:34][CH2:35][CH:36]=[CH2:37]>C1COCC1>[C:1]([O:5][C:6](=[O:22])[CH:7]([N:8]=[C:9]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH2:37][CH2:36][CH:35]=[CH2:34])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CCCBr
Reactant: CC(C)(C)OC(=O)CN=C(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCCC(N=C(c1ccccc1)c1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.1 %

Procedure:
While under a nitrogen atmosphere a stirred solution of (benzhydrylidene-amino)-acetic acid tert-butyl ester (5 g, 16.9 mmol) in THF (80 mL, 0.2 M) was carefully treated with sodium bis(trimethylsilyl)amide (18.6 mL, 1.0 M, 1.1 equiv) at −78° C. After stirring for 30 min, 4-bromo-but-1-ene (2.1 mL, 20.3 mmol, 1.2 equiv) was slowly added. The cooling bath was removed and the reaction mixture gradually warmed to room temperature and stirred for overnight. The solution was cooled to 0° C. and quenched with water. The resulting solution was diluted with ethyl acetate and washed successively with water and saturated aqueous NaCl, dried over MgSO4, filtered and concentrated. Purification by MPLC (1-25% ethyl acetate in heptane) gave 2-(benzhydrylidene-amino)-hex-5-enoic acid tert-butyl ester as colorless oil (5.6 g, 15.9 mmol, 94%).
Reaction SMILES: [OH-].[Li+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=2)=[C:8]([CH:21]=1)[C:9]([O:11]CC1C=CC=C(OC)C=1)=[O:10]>O.C1COCC1>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=2)=[C:8]([CH:21]=1)[C:9]([OH:11])=[O:10]
Reactant: COc1cccc(COC(=O)c2cc(Br)ccc2OCc2cccc(OC)c2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(COc2ccc(Br)cc2C(=O)O)c1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
A solution of lithium hydroxide (395 mg, 9.40 mmol) in water (20 ml) was added dropwise to a stirred solution of [3-(methyloxy)phenyl]methyl 5-bromo-2-({[3-(methyloxy)phenyl]methyl}oxy)benzoate (may be prepared as described in Description 29; 430 mg, 0.94 mmol) in THF (20 ml) over 1 min. The reaction mixture was stirred at 20° C. for 16 h. The organic phase was evaporated and the aqueous phase (20 ml) was extracted with ethyl acetate (20 ml). The aqueous phase (20 ml) was adjusted to pH 2 with 2M hydrochloric acid (1 ml). The aqueous phase was then extracted with ethyl acetate (3×20 ml). The organic phase was evaporated in vacuo to yield the title compound as a light yellow solid. 275 mg.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[NH2:12][C:13]1[CH:17]=[CH:16][S:15][C:14]=1[C:18]([O:20][CH3:21])=[O:19]>C1C=CC=CC=1>[F:8][C:5]1[CH:6]=[CH:7][C:2]([NH:12][C:13]2[CH:17]=[CH:16][S:15][C:14]=2[C:18]([O:20][CH3:21])=[O:19])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Reactant: COC(=O)c1sccc1N
Solvent: c1ccccc1
Product: COC(=O)c1sccc1Nc1ccc(F)cc1[N+](=O)[O-]

Procedure:
The title compound was prepared using the process of Example 1(a) but with 2,5-difluoronitrobenzene and methyl 3-aminothiophene-2-carboxylate as starting materials, m.p. 172°-175° C. (benzene).
Reaction SMILES: C[O-].[Na+].I.[NH:5]=[C:6]1[N:10]([CH3:11])[CH:9]=[CH:8][S:7]1.[C:12]1([N:18]=[C:19]=[S:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(O)C.C1(C)C=CC=CC=1>[CH3:11][N:10]1[CH:9]=[CH:8][S:7][C:6]1=[N:5][C:19]([NH:18][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[S:20]
Reactant: S=C=Nc1ccccc1
Reactant: Cn1ccsc1=N
Agent: C[O-]
Agent: I
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cn1ccsc1=NC(=S)Nc1ccccc1

Procedure:
Sodium methoxide (5.40 g) was added to a stirred mixture of 2-imino-3-methylthiazoline hydroiodide (24.95 g) in ethanol (100 ml) and the mixture brought to reflux. Phenyl isothiocyanate (16.35 g) in toluene (50 ml) was added over 30 minutes and reflux continued for a further hour then cooled in ice. The solid obtained on filtration and washing with ethanol and water was dried to give the product, mpt 172.5°-173.5°. Recrystallisation from iso-propanol gave analytically pure product, mpt 173.5°-174°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([NH:20][CH2:21][CH2:22][CH2:23][N:24]2[CH2:28][CH2:27][CH2:26][C:25]2=[O:29])=[O:19])=[CH:12][C:11]=1[N+:30]([O-])=O.Cl[Sn]Cl>CCO>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([NH:20][CH2:21][CH2:22][CH2:23][N:24]2[CH2:28][CH2:27][CH2:26][C:25]2=[O:29])=[O:19])=[CH:12][C:11]=1[NH2:30]
Reactant: O=C(/C=C/c1ccc(Sc2ccc(Cl)cc2Cl)c([N+](=O)[O-])c1)NCCCN1CCCC1=O
Agent: Cl[Sn]Cl
Solvent: CCO
Product: Nc1cc(/C=C/C(=O)NCCCN2CCCC2=O)ccc1Sc1ccc(Cl)cc1Cl
Temperature: 25 °C

Procedure:
A mixture of nitro compound (780 mg, 1.58 mmol) from Example 33, SnCl2 (1.50 g, 7.91 mmol) in 25 mL of anhydrous EtOH was refluxed under nitrogen atmosphere for 90 minutes. The reaction was then allowed to cool to room temperature, quenched with sat. NaHCO3, extracted with EtOAc.(2×50 mL). The combined organic layer was washed with water and brine, dried over Na2SO4, condensed in vacuo to give the crude aniline as yellowish brown solid, which was converted to the bromide without purification.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[CH2:6][N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)[CH2:29][CH2:28][N:27]([CH2:30][C:31](O)=[O:32])[C:26]2=[O:34])=[CH:21][CH:20]=1.Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1>[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2([C:35]3[CH:36]=[CH:37][C:38]([F:41])=[CH:39][CH:40]=3)[CH2:29][CH2:28][N:27]([CH2:30][C:31](=[O:32])[N:10]3[CH2:11][CH2:12][N:7]([CH2:6][C:5]4[CH:13]=[CH:14][CH:15]=[C:3]([C:2]([F:1])([F:16])[F:17])[CH:4]=4)[CH2:8][CH2:9]3)[C:26]2=[O:34])=[CH:21][CH:20]=1
Reactant: FC(F)(F)c1cccc(CN2CCNCC2)c1
Reactant: O=C(O)CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O)N1CCN(Cc2cccc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(3-(trifluoromethyl)benzyl)piperazine (0.24 g, 1.00 mmol) in dichloromethane (25 mL) under nitrogen was added 2-(3,3-bis(4-fluorophenyl)-2-oxopyrrolidin-1-yl)acetic acid (Example 58D, 0.33 g, 1.00 mmol) followed by N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.39 g, 2.00 mmol) and N,N-dimethylpyridin-4-amine (0.012 g, 0.10 mmol). The reaction mixture was stirred overnight at room temperature. The reaction was concentrated and the residue was partitioned in ethyl acetate/water (8:2). The organic layer was washed with water followed by brine, dried over magnesium sulfate, filtered, and concentrated. Silica gel chromatography eluting with 3% methanol/dichloromethane gave the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.41-7.59 (m, 4H), 7.27-7.35 (m, 4H), 6.96-7.03 (m, 4H), 4.18 (s, 2H), 3.59-3.63 (m, 2H), 3.53 (s, 2H), 3.51 (t, J=6.6 Hz, 2H), 3.41-3.45 (m, 2H), 2.77 (t, J=6.5 Hz, 2H), 2.40-2.44 (m, 2H), 2.31-2.35 (m, 2H); MS (DCI+) m/z 558 (M+H)+.
Reaction SMILES: [C:1]1([C@H:7]([NH:9][C:10]([N:12]2[C:15](=[O:16])[C@@H:14]([S:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-])=O)[CH:19]=3)[C@H:13]2[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:11])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[Sn](Cl)(Cl)(Cl)Cl>C(OCC)(=O)C>[C:1]1([C@H:7]([NH:9][C:10]([N:12]2[C:15](=[O:16])[C@@H:14]([S:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([NH2:24])[CH:19]=3)[C@H:13]2[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:11])[CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)[C@@H]1[C@H](Sc2cccc([N+](=O)[O-])c2)C(=O)N1C(=O)N[C@H](C)c1ccccc1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H]1[C@H](Sc2cccc(N)c2)C(=O)N1C(=O)N[C@H](C)c1ccccc1
Temperature: 50 °C
Yield: 63.6 %

Procedure:
To a solution of 85b (17 mg, 38 umol) in ethyl acetate (1 mL) at room temperature was added tin chloride monohydrate (2.5 eq.) and the solution was heated to 50° C. After 1 h the solution was concentrated in vacuo. The residue was purified by column chromatography using a gradient of hexane/ethyl acetate 20-100% as eluent to yield 87 (10 mg, 63%). Product MS: 414.1 (M+1).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:9][C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][C:19]=1[I:20])[C:13]([O:15][CH3:16])=[O:14].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH2:1]([O:9][C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][C:19]=1[I:20])[C:13]([O:15][CH3:16])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(I)c(O)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)c1ccc(I)c(OCc2ccccc2)c1
Temperature: 60 °C
Yield: 104.2 %

Procedure:
2.35 mL (19.78 mmol, 1.1 eq) of benzyl bromide are added to a solution of 5.0 g (17.98 mmol, 1 eq) of methyl 3-hydroxy-4-iodobenzoate in 30 ml of methyl ethyl ketone in the presence of 5.0 g (36.18 mmol, 2 eq) of potassium carbonate. The reaction mixture is heated at 60° C. for 5 hours and then hydrolyzed in water and extracted with ethyl acetate. 6.9 g of methyl 3-benzyloxy-4-iodobenzoate are obtained in oil form and are used in the following reaction without further purification.
Reaction SMILES: [Na].[C:2]1([C:8](=[N:17][NH2:18])[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=O)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]1([CH2:25][C:26](OCC)=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)C>[C:19]1([C:25]2[C:26](=[O:27])[NH:18][N:17]=[C:8]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:9]=2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)Cc1ccccc1
Reactant: NN=C(C(=O)c1ccccc1)c1ccccc1
Agent: [Na]
Solvent: CCO
Product: O=c1[nH]nc(-c2ccccc2)c(-c2ccccc2)c1-c1ccccc1
Yield: 30 %

Procedure:
Sodium (11.5 g) was allowed to react with ethanol and then benzilmonohydrazone (120 g) and ethyl phenylacetate (84 g) were added and the reaction mixture heated at reflux for 3 hours. The reaction was quenched in water and the suspension acidified. The resulting precipitate was separated and refluxed with acetonitrile, cooled and separated by filtration to obtain 4,5,6-triphenyl-2H-pyridazin-3-one (30 percent yield), m.p. 290°-292° C.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10](=[O:19])[C:11](=[CH2:18])[CH:12]([O:14][C:15](=[O:17])[CH3:16])[CH3:13].CO[CH2:22][N:23]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:24][Si](C)(C)C>C(Cl)Cl>[CH3:8][O:9][C:10]([C:11]1([CH:12]([O:14][C:15](=[O:17])[CH3:16])[CH3:13])[CH2:18][CH2:22][N:23]([CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:24]1)=[O:19]
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: C=C(C(=O)OC)C(C)OC(C)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C1(C(C)OC(C)=O)CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.9 %

Procedure:
Trifluoroacetic acid (0.5 g, 4.38 mmol) was added to a solution of methyl-3-acetoxy-2-methylenebutyrate (5 g, 29.03 mmol) (1) and N-Methoxymethyl-N-trimethylsilylmethylbenzylamine (6.89 g, 29.03 mmol) (2) in MeCl2 (100 ml) at 0° C., then stirred overnight at room temperature. The solvent was evaporated, and residue extracted with EtOAc (200 ml), NaHCO3 (30 ml and H2O (100 ml). The organic layer was separated, dried (MgSO4), filtered and solvent evaporated yielding an oil which chromatographed on silica gel eluting with 30% v/v (EtOAc/hexanes) yielding product (3) as colorless oil (7.53 g, 85% yield). ESMS MH, 306 (C17H23NO4)
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([CH2:11][C:12]([OH:14])=O)[N:3]1[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1.O=C1C2C(=CC=CC=2)C(CC(O)=O)N1[C:37]1[CH:42]=[CH:41][C:40](Cl)=[CH:39][N:38]=1>>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([N:3]2[CH:4]([CH2:11][C:12]([N:38]3[CH2:39][CH2:40][CH2:41][CH2:42][CH2:37]3)=[O:14])[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:2]2=[O:1])=[CH:16][CH:17]=1
Reactant: O=C(O)CC1c2ccccc2C(=O)N1c1ccc(Cl)cn1
Reactant: COc1ccc(N2C(=O)c3ccccc3C2CC(=O)O)cc1
Product: COc1ccc(N2C(=O)c3ccccc3C2CC(=O)N2CCCCC2)cc1

Procedure:
The above (+) acetic acid ester (B) was worked up in the same manner as (v) to give the following compound:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[NH:5][C:6]1[C:7]2[CH:15]=[C:14](F)[N:13]=[CH:12][C:8]=2[N:9]=[CH:10][N:11]=1.[CH3:20][NH2:21]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[NH:5][C:6]1[C:7]2[CH:15]=[C:14]([NH:21][CH3:20])[N:13]=[CH:12][C:8]=2[N:9]=[CH:10][N:11]=1
Reactant: CN
Reactant: Fc1cc2c(Nc3cccc(Br)c3)ncnc2cn1
Solvent: CCO
Product: CNc1cc2c(Nc3cccc(Br)c3)ncnc2cn1
Yield: 340 %

Procedure:
Treatment of 4-(3-bromoanilino)-6-fluoropyrido[3,4-d]pyrimidine (0.20 g, 0.63 mmol) (see a previous experimental) at 100° C. in a pressure vessel with methylamine in ethanol followed by chromatography on alumina (CH2Cl2/MeOH, 99:1) gives 4-(3-bromoanilino)-6-methylaminopyrido[3,4-d]pyrimidine (0.07 g, 340%). 1H NMR (DMSO) δ 9.69 (1H, s), 8.75 (1H, s), 8.41 (1H, s), 8.21 (1H, brs), 7.93 (1H, brd, J=7.6 Hz), 7.41-7.28 (2H, m), 7.06 (1H, s), 6.82 (1H, q, J=5.0 Hz), 4.95 (3H, d, J=5.0 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1.[C:12](Cl)(=[O:16])[CH:13]([CH3:15])[CH3:14].[Al+3].[Cl-].[Cl-].[Cl-]>ClCCCl>[CH3:1][O:2][C:3]1[C:11]([C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1
Reactant: COc1cc2ccccn2n1
Reactant: CC(C)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COc1nn2ccccc2c1C(=O)C(C)C
Yield: 31.5 %

Procedure:
A mixture of 700 mg (4.7 mmol) of 2-methoxypyrazolo[1,5-a]pyridine, 550 mg of isobutyryl chloride and 300 mg of AlCl3 was stirred in 2 ml of DCE at RT for 5 hours. The reaction was quenched with saturated NH4Cl and extracted with ethyl acetate to yield 1 g of crude product. Purification on an Al2O3 column furnished 323 mg of 1-(2-methoxypyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one. Compound 1055.
Reaction SMILES: [C:1](OCC12CC3CC(CC(O)(C3)C1)C2)(=[O:4])[CH:2]=[CH2:3].[C:18]([C:21]12[CH2:30][CH:25]3[CH2:26][CH:27]([CH2:29][C:23]([OH:31])([CH2:24]3)[CH2:22]1)[CH2:28]2)(=[O:20])[CH3:19]>>[C:18]([C:21]12[CH2:30][CH:25]3[CH2:26][CH:27]([CH2:29][C:23]([O:31][C:1](=[O:4])[CH:2]=[CH2:3])([CH2:24]3)[CH2:22]1)[CH2:28]2)(=[O:20])[CH3:19]
Reactant: CC(=O)C12CC3CC(CC(O)(C3)C1)C2
Reactant: C=CC(=O)OCC12CC3CC(CC(O)(C3)C1)C2
Product: C=CC(=O)OC12CC3CC(C1)CC(C(C)=O)(C3)C2
Yield: 97 %

Procedure:
The reaction was conducted in the same manner as the step of Example 36 (2) except that 1-acetyl-3-hydroxyadamantane was used instead of the 1,3-dicarboxy-5-adamantanol, and, as a result, a 1-acety-3-acryloyloxyadamantane (yield: 97%, white solid) was obtained.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[OH:13])([CH3:3])[CH3:2].F[C:15]1[CH:16]=[CH:17][C:18]([N+:23]([O-:25])=[O:24])=[C:19]([O:21][CH3:22])[CH:20]=1>>[N+:23]([C:18]1[CH:17]=[CH:16][C:15]([O:13][C:5]2[C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=[CH:7][C:6]=2[CH:10]([CH3:12])[CH3:11])=[CH:20][C:19]=1[O:21][CH3:22])([O-:25])=[O:24]
Reactant: CC(C)c1cccc(C(C)C)c1O
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Product: COc1cc(Oc2c(C(C)C)cccc2C(C)C)ccc1[N+](=O)[O-]
Yield: 77.4 %

Procedure:
2,6-Diisopropylphenol (11.6 g) was coupled with 5-fluoro-2-nitroanisole (17.5 g), using the same procedure as described in Example 30(a). After purification on column (silica gel, ethyl acetate/petrolium ether, 1:9), 16.6 g (87%) of 2-nitro-5-(2,6-diisopropyl-phenoxy)anisole was obtained.
Reaction SMILES: C(N(CC)CC)C.[N+:8]([C:11]1[N:12]=[C:13]2[N:18]([CH:19]=1)[CH2:17][CH2:16][C@H:15]([CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[CH:24][CH:23]=1)[O:14]2)([O-:10])=[O:9].[CH3:34][S:35](Cl)(=[O:37])=[O:36].Cl>C(Cl)Cl>[CH3:34][S:35]([N:31]1[CH2:32][CH2:33][N:28]([C:25]2[CH:26]=[CH:27][C:22]([O:21][CH2:20][C@@H:15]3[O:14][C:13]4=[N:12][C:11]([N+:8]([O-:10])=[O:9])=[CH:19][N:18]4[CH2:17][CH2:16]3)=[CH:23][CH:24]=2)[CH2:29][CH2:30]1)(=[O:37])=[O:36]
Reactant: CS(=O)(=O)Cl
Reactant: O=[N+]([O-])c1cn2c(n1)O[C@@H](COc1ccc(N3CCNCC3)cc1)CC2
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCN(c2ccc(OC[C@H]3CCn4cc([N+](=O)[O-])nc4O3)cc2)CC1
Reaction time: 14 h

Procedure:
Triethylamine (0.31 ml) was added to a methylene chloride suspension (6 ml) of (R)-2-nitro-7-(4-piperazin-1-ylphenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (0.40 g). Subsequently, methanesulfonyl chloride (0.09 ml) was added thereto dropwise under ice cooling, and the mixture was stirred for 14 hours while it gradually returned to room temperature. A 0.5 N hydrochloric acid aqueous solution was added to the reaction mixture, followed by extraction with methylene chloride. The organic layer was washed with water and a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and the solvent was then distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (methylene chloride:methanol=90:10) and recrystallized from methylene chloride-methanol to afford the title compound as a beige powder (0.15 g).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=3)[N:16]=[C:15]([C:25]([OH:27])=O)[CH:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.ClC1C=C(N2C(C3C=C(F)C=C(Cl)C=3)=CC(C([N:53]3[CH2:57][C:56](=[O:58])[NH:55][CH2:54]3)=O)=N2)C=CC=1F>>[F:11][C:9]([F:12])([F:10])[C:7]1[CH:6]=[C:5]([C:13]2[N:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=3)[N:16]=[C:15]([C:25]([N:53]3[CH2:57][C:56](=[O:58])[NH:55][CH2:54]3)=[O:27])[CH:14]=2)[CH:4]=[C:3]([C:2]([F:1])([F:28])[F:29])[CH:8]=1
Reactant: O=C(O)c1cc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n(-c2cccc(Cl)c2)n1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3ccc(F)c(Cl)c3)n2)CN1
Product: O=C1CN(C(=O)c2cc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)n(-c3cccc(Cl)c3)n2)CN1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 103A in analogy to the synthesis of the compound of Example 1. 26 mg (72% of theory) of the title compound are obtained.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[CH3:23][NH2:24]>C(Cl)Cl.CCOCC>[CH3:23][NH:24][C:14](=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN
Reactant: O=C(O)CCCCCCCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CNC(=O)CCCCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
To a solution of 8-phenyl octanoic acid (28.6 g, 129.8 mmol, 1 eq) in CH2Cl2 (100 mL) cooled to 0° C. was added oxalyl chloride (17 mL, 195 mmol, 1.5 eq) dropwise via an addition funnel over 30 minutes. Upon the completion of the addition, the ice bath was removed and the reaction was stirred at rt for 2 h. It was then heated at reflux for 30 minutes. The reaction was cooled to rt and concentrated in vacuo to afford a yellow oil. It was added as a solution in Et2O (100 mL) to a solution of condensed methyl amine (˜20 mL) in Et2O (200 mL) at −78° C. Immediately, a white precipitate formed. The cold bath was removed and the reaction was allowed to stir overnight warming to rt under a stream of N2. The residue was washed with Et2O and concentrated to afford N-methyl-8-phenyloctanamide (25.2 g, 83%) as a yellow-white solid. 1H NMR.(CDCl3) δ 7.68-7.10 (m, 5H); 5.42 (bs, 1H); 3.80 (m, 3H); 2.60 (m, 2H); 2.18 (m, 2H); 1.60 (m, 4H); 1.30 (m, 8H).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH2:5][N:6]2[C:14]3[C:9](=[CH:10][C:11]([O:15][CH:16]([F:18])[F:17])=[CH:12][CH:13]=3)[C:8]([C:19]3[N:20]=[C:21]4[C:27]([C:28]([NH:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:26][N:25]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[C:22]4=[N:23][CH:24]=3)=[N:7]2)[CH2:2]1.C=O.[C:45](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[C:31]([NH:30][C:28]([C:27]1[C:21]2[C:22](=[N:23][CH:24]=[C:19]([C:8]3[C:9]4[C:14](=[CH:13][CH:12]=[C:11]([O:15][CH:16]([F:18])[F:17])[CH:10]=4)[N:6]([CH2:5][CH:3]4[CH2:4][N:1]([CH3:45])[CH2:2]4)[N:7]=3)[N:20]=2)[N:25]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[CH:26]=1)=[O:29])([CH3:33])([CH3:34])[CH3:32]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CC4CNC4)c4ccc(OC(F)F)cc34)nc12
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CN1CC(Cn2nc(-c3cnc4c(n3)c(C(=O)NC(C)(C)C)cn4COCC[Si](C)(C)C)c3cc(OC(F)F)ccc32)C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 87.1 %

Procedure:
To a stirred solution of 2-(1-(azetidin-3-ylmethyl)-5-(difluoromethoxy)-1H-indazol-3-yl)-N-tert-butyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (37 mg, 61.7 μmol) in methanol (4 mL), cooled to 0° C. with ice bath, was added aqueous formaldehyde (1 mL, 13.4 mmol), followed by the addition of sodium triacetoxyborohydride (29.4 mg, 139 μmol). The reaction mixture was stirred at room temperature for 15 h then concentrated and purified by chromatography (silica, 4 g Analogix column, 0-10% methanol containing 10% ammonium hydroxide in dichloromethane) to give N-tert-butyl-2-(5-(difluoromethoxy)-1-((1-methylazetidin-3-yl)methyl)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (33 mg, 87%). MS (M+H)+=614.
Reaction SMILES: [CH:1](=[N:8][NH:9][C:10](=O)[C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:24])=O>C1(C)C=CC=CC=1>[CH:1](=[N:8][N:9]=[C:10]([Cl:24])[C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(NN=Cc1ccccc1)c1ccc(C(F)(F)F)cc1
Solvent: Cc1ccccc1
Product: FC(F)(F)c1ccc(C(Cl)=NN=Cc2ccccc2)cc1
Yield: 59 %

Procedure:
A mixture of N′-benzylidene-4-trifluoromethylbenzohydrazide (2.92 g), thionyl chloride (1.09 ml) and toluene (50 ml) was heated under reflux for 1 hr. After cooling, the reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=8:1, volume ratio) and recrystallized from hexane to give N-benzylidene-4-trifluoromethylbenzenecarbohydrazonoyl chloride (1.85 g, yield 59%) as pale-yellow plate crystals. melting point: 95–96° C.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=[N:8][OH:9])[NH2:7])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=1[C:20]1[NH:24][C:23](=[O:25])[N:22]([C:26]2[CH:33]=[CH:32][C:29]([C:30]#N)=[CH:28][CH:27]=2)[N:21]=1>CN(C=O)C.[Cl-].[Cl-].[Zn+2]>[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=1[C:20]1[NH:24][C:23](=[O:25])[N:22]([C:26]2[CH:27]=[CH:28][C:29]([C:30]3[O:9][N:8]=[C:6]([C:5]4[CH:10]=[CH:11][C:2]([F:1])=[CH:3][CH:4]=4)[N:7]=3)=[CH:32][CH:33]=2)[N:21]=1
Reactant: N#Cc1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1
Reactant: NC(=NO)c1ccc(F)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CN(C)C=O
Product: O=c1[nH]c(-c2c(F)cccc2Cl)nn1-c1ccc(-c2nc(-c3ccc(F)cc3)no2)cc1
Temperature: 100 °C
Yield: 17.8 %

Procedure:
To a solution of 4-fluoro-N′-hydroxybenzimidamide (Intermediate-18, 0.073 g, 0.47 mmol) in dry DMF (3 mL) under nitrogen atmosphere was added 4-(3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)benzonitrile (step-4 of Intermediate-17, 0.100 g, 0.31 mmol) and ZnCl2 (0.0087 g, 0.06 mmol). The reaction mass was heated at 100° C. for 8-10 h. The reaction mass was quenched with water, extracted in DCM and column purified to afford 0.025 g of desired product. 1H NMR (DMSO-d6): δ 7.02 (br s, 1H), 7.33 (t, 1H), 7.45-7.54 (m, 2H), 7.61 (d, 1H), 7.70 (m, 1H), 7.83 (t, 1H), 8.09-8.17 (m, 2H), 8.26-8.30 (m, 2H), 12.81 (br s, 1H). MS (m/z): 452.05 [M+H]+.