Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CI.[C:3]1([CH2:9][NH:10][CH2:11][CH2:12][C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([CH2:22][C:23]([NH2:25])=[O:24])[CH:20]=3)[NH:15][CH:14]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:26](N(C(C)C)CC)(C)C>O1CCCC1>[OH2:24].[CH3:26][N:10]([CH2:9][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)[CH2:11][CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([CH2:22][C:23]([NH2:25])=[O:24])[CH:20]=2)[NH:15][CH:14]=1.[CH3:26][N:10]([CH2:11][CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([CH2:22][C:23]([NH2:25])=[O:24])[CH:20]=2)[NH:15][CH:14]=1)[CH2:9][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: NC(=O)Cc1ccc2[nH]cc(CCNCc3ccccc3)c2c1
Reactant: CCN(C(C)C)C(C)C
Solvent: CI
Solvent: C1CCOC1
Product: CN(CCc1c[nH]c2ccc(CC(N)=O)cc12)Cc1ccccc1
Product: O
Temperature: 25 °C
Reaction time: 16 h
Yield: 124 %

Procedure:
A solution of methyl iodide (0.83 g) in tetrahydrofuran (50 ml) was added at room temperature to a solution of 3-[2-[(phenylmethyl)amino]ethyl]-1H-indole-5-acetamide (1.8 g) and diisopropylethylamine (0.76 g) in dry tetrahydrofuran (150 ml). The resulting solution was stirred at room temperature for 16 h and was then evaporated in vacuo to dryness. The residue was partitioned between chloroform (225 ml) and 8% aqueous sodium hydrogen carbonate (250 ml). The organic layer was run off and the aqueous layer extracted with more chloroform (200 ml). The combined organic solutions were dried (Na2SO4), filtered and evaporated to afford a gum (1.6 g) which was purified by column chromatography on silica gel (Merck Type 60, 250 g) eluting with methanol in chloroform (1-10%). The product-bearing fractions afforded the title compound as a pale yellow oil which slowly crystallised on standing 0.4 g m.p. 123°-126° (bubbles above 93°).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([CH2:9][N:10]2[C:22]3[CH:21]=[CH:20][CH:19]=[C:18]([OH:23])[C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][C:15]=3[C:24](OC)=[O:25])[CH:6]=[CH:7][CH:8]=1.Cl.[OH-].[NH4+:32]>C1COCC1.C(OCC)(=O)C>[F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([CH2:9][N:10]2[C:22]3[CH:21]=[CH:20][CH:19]=[C:18]([OH:23])[C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][C:15]=3[C:24](=[O:25])[NH2:32])[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)c1cccc2c1c1c(O)cccc1n2Cc1cccc(C(F)(F)F)c1
Reactant: [NH4+]
Agent: Cl
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: NC(=O)c1cccc2c1c1c(O)cccc1n2Cc1cccc(C(F)(F)F)c1
Yield: 50 %

Procedure:
A solution of the 9-[(3-trifluoromethylphenyl)methyl]-4-hydroxy-5-carbomethoxy carbazole (250 mg, 0.625 mM) in 5 mL THF and 20 mL concentrated aqueous ammonium hydroxide was sonicated for 30 h at 40-50° C. The mixture was diluted with ethyl acetate and acidified to pH 1 with 5 N HCl. The aqueous layer was extracted three times with ethyl acetate. The combined organic extracts were washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with gradient methylene chloride/ethyl acetate) to afford 120 mg (50%) of the 9-[(3-trifluoromethylphenyl)methyl]-4-hydroxy-5-carbamoyl carbazole as a white solid. 1H NMR (DMSO-d6) δ10.5 (s, 1H), 8.8 (br s, 1H), 8.4 (br s, 1H), 7.8 (d, 1H, J=8 Hz), 7.6-7.5 (m, 5H), 7.3 (t, 1H, J=8 Hz), 7.15 (d, 1H, J=8 Hz), 7.1 (d, 1H, J=8 Hz), 6.6 (d, 1H, J=8 Hz), and 5.8 (s, 2H). IR (KBr, cm−1) 3429, 3206, and 1630. MS (ES) m/e 383, 385.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][O:5][CH:6]([C:9]1[CH:10]=[N:11][C:12]([CH3:15])=[N:13][CH:14]=1)[C:7]#[N:8].C(Br)(Br)(Br)[Br:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOCC>C(Cl)Cl>[Br:17][CH2:2][CH2:3][CH2:4][O:5][CH:6]([C:9]1[CH:10]=[N:11][C:12]([CH3:15])=[N:13][CH:14]=1)[C:7]#[N:8]
Reactant: Cc1ncc(C(C#N)OCCCO)cn1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1ncc(C(C#N)OCCCBr)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2-(3-hydroxypropoxy)-2-(2-methylpyrimidin-5-yl)acetonitrile (54 mg, 0.26 mmol) and CBr4 (259 mg, 0.782 mmol) in DCM (3 ml) was cooled at 0° C. Triphenylphosphine (205 mg, 0.782 mmol) in DCM (1 ml) was added dropwise over a period of 5 minutes. The reaction was stirred for 2 hours and then allowed to warm to room temperature. To the mixture was added Et2O (5 mL) and the cloudy solution was filtred through a plug of celite. The resulting solution was concentrated in vacuo and purified by flash chromatography to yield 2-(3-Bromopropoxy)-2-(2-methylpyrimidin-5-yl)acetonitrile.
Reaction SMILES: [NH2:1][C@H:2]1[C:11]([CH3:13])([CH3:12])[C:10]2[CH:9]=[C:8]([C:14]([NH2:16])=[O:15])[CH:7]=[CH:6][C:5]=2[CH2:4][C@@H:3]1[O:17][CH3:18].[CH3:19][C:20]([CH3:30])([CH3:29])[CH2:21][C:22]([NH:24][CH2:25][CH2:26][CH:27]=O)=[O:23].C(O)(C(F)(F)F)=O>>[CH3:19][C:20]([CH3:29])([CH3:30])[CH2:21][C:22]([NH:24][CH2:25][CH2:26][CH2:27][NH:1][C@H:2]1[C:11]([CH3:13])([CH3:12])[C:10]2[CH:9]=[C:8]([C:14]([NH2:16])=[O:15])[CH:7]=[CH:6][C:5]=2[CH2:4][C@@H:3]1[O:17][CH3:18])=[O:23]
Reactant: CO[C@H]1Cc2ccc(C(N)=O)cc2C(C)(C)[C@@H]1N
Reactant: CC(C)(C)CC(=O)NCCC=O
Solvent: O=C(O)C(F)(F)F
Product: CO[C@H]1Cc2ccc(C(N)=O)cc2C(C)(C)[C@@H]1NCCCNC(=O)CC(C)(C)C

Procedure:
Following the process of Example 11(c) using (6S,7S)-7-amino-6-methoxy-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalene-2-carboxylic acid amide and 3,3-dimethyl-N-(3-oxo-propyl)-butyramide the TFA salt of the title compound was prepared. (m/z): [M+H]+ calcd for C23H37N3O3, 404.28; found, 404.4.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:26][O:27][C:28]1[C:29]([CH3:58])=[C:30]([C:49]([O:56][CH3:57])=[C:50]([O:54][CH3:55])[C:51]=1[O:52][CH3:53])[CH2:31][C:32]1[CH:33]=[CH:34][C:35]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[C:36]([CH:40]=1)[C:37](O)=[O:38]>C(Cl)Cl>[CH3:26][O:27][C:28]1[C:29]([CH3:58])=[C:30]([C:49]([O:56][CH3:57])=[C:50]([O:54][CH3:55])[C:51]=1[O:52][CH3:53])[CH2:31][C:32]1[CH:33]=[CH:34][C:35]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[C:36]([CH:40]=1)[C:37]([NH:7][C:6]1[CH:8]=[CH:9][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:38]
Reactant: COc1ccc(N)cc1
Reactant: COc1c(C)c(Cc2ccc(OCc3ccccc3)c(C(=O)O)c2)c(OC)c(OC)c1OC
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(NC(=O)c2cc(Cc3c(C)c(OC)c(OC)c(OC)c3OC)ccc2OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 37.2 %

Procedure:
p-Methoxyaniline (0.250 g, 2.03 mmol), triethylamine (0.206 g, 2.03 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.344 g, 2.03 mmol) were added to a methylene chloride solution (40 ml) of 5-(3,4,5,6-tetramethoxy-2-methylbenzyl)-2-benzyloxybenzoic acid (0.460 g, 1.02 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (ethyl acetate:hexane=1:2) and recrystallized from ether to obtain the titled compound (0.211 g, 0.379 mmol, 37%).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[CH:5]=[N+]=[N-])[CH3:2].C(OC(OCC)CNC(N)=O)C.[Cl:23][CH2:24][C:25](=[O:49])[C@:26]1([OH:48])[C@:43]2([CH3:44])[C@H:29]([C@H:30]3[C@H:40]([C@@H:41]([OH:45])[CH2:42]2)[C@:38]2([CH3:39])[C:33](=[CH:34][C:35](=[O:46])[CH:36]=[CH:37]2)[CH2:32][CH2:31]3)[CH2:28][C@H:27]1[OH:47]>CO>[Cl:23][CH2:24][C:25](=[O:49])[C@:26]1([OH:48])[C@:43]2([CH3:44])[C@H:29]([C@H:30]3[C@H:40]([C@@H:41]([OH:45])[CH2:42]2)[C@:38]2([CH3:39])[C:33](=[CH:34][C:35](=[O:46])[CH:36]=[CH:37]2)[CH2:32][CH2:31]3)[CH2:28][C@H:27]1[O:47][CH2:5][CH:4]([O:8][CH2:9][CH3:10])[O:3][CH2:1][CH3:2]
Reactant: C[C@]12C=CC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1C[C@@H](O)[C@]2(O)C(=O)CCl
Reactant: CCOC(C=[N+]=[N-])OCC
Agent: CCOC(CNC(N)=O)OCC
Solvent: CO
Product: CCOC(CO[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@]2(C)[C@@]1(O)C(=O)CCl)OCC
Temperature: 0 °C

Procedure:
A solution of 2,2-diethoxy-1-diazoethane (prepared from 0.0935 mole of N-2,2-diethoxyethyl urea by the method of W. Kirmse and M. Buschhoff, Chem. Ber., 100, 1491 (1967)) in 300 ml of 3:2 ether-pentane is diluted with 100 ml of methanol and cooled to 0°C. 21-Chloro-11β,16α,17-trihydroxypregna-1,4-diene-3,20-dione, 16,17-cycloborate is added in portions until nitrogen evolution ceases. The solvent is removed in vacuo to yield the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[NH:7][C:8]([C:10]1[S:11][C:12]([S:35][CH3:36])=[C:13]([S:15]([C:18]2[CH:19]=[C:20]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([N+:31]([O-])=O)=[CH:26][C:25]=3[Cl:34])[CH:21]=[CH:22][CH:23]=2)(=[O:17])=[O:16])[CH:14]=1)=[NH:9])([CH3:4])([CH3:3])[CH3:2].CCO.[Cl-].[NH4+]>[Fe].O>[C:1]([O:5][C:6](=[O:37])[NH:7][C:8]([C:10]1[S:11][C:12]([S:35][CH3:36])=[C:13]([S:15]([C:18]2[CH:19]=[C:20]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([NH2:31])=[CH:26][C:25]=3[Cl:34])[CH:21]=[CH:22][CH:23]=2)(=[O:16])=[O:17])[CH:14]=1)=[NH:9])([CH3:3])([CH3:4])[CH3:2]
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cc([N+](=O)[O-])cc2Cl)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cc(N)cc2Cl)c1
Temperature: 50 °C

Procedure:
{[4-(2′-Chloro-6′-methyl-4′-nitro-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (20 mg, 0.034 mmol, Example 134: step a) was dissolved into EtOH (2 mL). To this was added ammonium chloride (18 mg, 0.34 mmol) dissolved into water (4 mL). The reaction was heated to 50° C. and iron (9.6 mg, 0.34 mmol) was added. The reaction was then heated to 80° C. for 12 hours followed by filtration through celite with methanol and EtOAc. The solvents were removed in vacuo resulting in desired product that was used with out further purification or characterization.
Reaction SMILES: [CH3:1]C(OC(/N=N/C(OC(C)C)=O)=O)C.[NH2:15][C:16]1[C:24]2[C:19](=[N:20][C:21](N3CCC(NCC(O)C4C=CC(NS(C)(=O)=O)=CC=4)CC3)=[CH:22][C:23]=2[CH2:25]CC)[S:18][C:17]=1[C:49]([NH2:51])=[O:50].[OH:52][C:53]1[CH:61]=[CH:60][C:56]([C:57]([NH2:59])=[O:58])=[CH:55][CH:54]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[NH2:15][C:16]1[C:24]2[C:19](=[N:20][C:21]([CH3:1])=[CH:22][C:23]=2[CH2:25][O:52][C:53]2[CH:61]=[CH:60][C:56]([C:57](=[O:58])[NH2:59])=[CH:55][CH:54]=2)[S:18][C:17]=1[C:49]([NH2:51])=[O:50]
Reactant: NC(=O)c1ccc(O)cc1
Reactant: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Reactant: CCCc1cc(N2CCC(NCC(O)c3ccc(NS(C)(=O)=O)cc3)CC2)nc2sc(C(N)=O)c(N)c12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(COc2ccc(C(N)=O)cc2)c2c(N)c(C(N)=O)sc2n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
DIAD (23 mg, 0.116 mmol) was added to a solution of 3-amino-4-hydroxymethyl-6-methyl-thieno[2,3-b]pyridine-2-carboxylic acid amide (see Example 12) (25 mg, 0.105 mmol), 4-hydroxy-benzamide (15 mg, 0.116 mmol), and Ph3P (30 mg, 0.116 mmol) in THF (2.5 mL) at 0° C. The mixture was warmed to room temperature and stirred for 24 h. The reaction mixture was concentrated and triturated with 2:1 EtOAc:MeOH giving the title compound (7 mg, 19%) as an orange solid, m.p.>250° C.
Reaction SMILES: O[C:2]([C:4]([F:7])(F)F)=O.[CH3:8][C:9]1[N:14]2[CH:15]=[C:16]([CH2:18][CH2:19][C:20]3[NH:21][CH:22]=[C:23]([C:25]4[S:26][CH:27]=[CH:28][CH:29]=4)[N:24]=3)[N:17]=[C:13]2[N:12]=[C:11]([CH3:30])[CH:10]=1.[H-].[Na+].BrCCF.CO>CN(C=O)C>[F:7][CH2:4][CH2:2][N:21]1[CH:22]=[C:23]([C:25]2[S:26][CH:27]=[CH:28][CH:29]=2)[N:24]=[C:20]1[CH2:19][CH2:18][C:16]1[N:17]=[C:13]2[N:12]=[C:11]([CH3:30])[CH:10]=[C:9]([CH3:8])[N:14]2[CH:15]=1
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1cc(C)n2cc(CCc3nc(-c4cccs4)c[nH]3)nc2n1
Agent: FCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1cc(C)n2cc(CCc3nc(-c4cccs4)cn3CCF)nc2n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 39 %

Procedure:
To a solution of 5,7-Dimethyl-2-[2-(4-thiophen-2-yl-1H-imidazol-2-yl)-ethyl]-imidazo[1,2-a]pyrimidine TFA salt (10.9 mg, 0.025 mmol) in DMF (6 mL) was added sodium hydride (60% in mineral oil, 7.0 mg, 0.175 mmol), the reaction vessel was capped and stirred at RT for 5 minutes. 1-Bromo-2-fluoroethane (4.76 mg, 0.0375 mmol) was added and the reaction was shaken under an atmosphere of argon for 30 minutes at RT then 30 minutes at 70° C. To the cooled reaction methanol (100 μL) was added and the solution subjected to preparative LC-MS purification to yield the title compound. 39% yield, LC-MS: m/z=370.2 (MH+), tR=0.43 minutes, method A.
Reaction SMILES: [N+:1]([CH2:4][CH2:5][C:6](Cl)=[O:7])([O-:3])=[O:2].[CH:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[N+:1]([CH2:4][CH2:5][C:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:7])([O-:3])=[O:2]
Reactant: O=C(Cl)CC[N+](=O)[O-]
Reactant: c1ccccc1
Product: O=C(CC[N+](=O)[O-])c1ccccc1

Procedure:
The title compound was prepared from benzene and 3-nitropropanoyl chloride, according to example 2, affording compound (15) with 78% yield, mp 72-74° C.
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[F:17][C:18]1[CH:23]=[CH:22][C:21]([O:24]C)=[CH:20][CH:19]=1.[Al+3].[Cl-].[Cl-].[Cl-]>ClCCl.CN(C=O)C>[F:17][C:18]1[CH:19]=[CH:20][C:21]([OH:24])=[C:22]([C:8](=[O:10])[CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:23]=1
Reactant: COc1ccc(F)cc1
Reactant: O=C(O)Cc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cc1ccccc1)c1cc(F)ccc1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
Phenylacetic acid (8.09 g, 59.46 mmoles) was dissolved in 15 ml dichloromethane. To this mixture, oxalylchloride (5.2 ml, 59.46 mmoles) and DMF (3 drops) were added at 0° C. and stirred for 30 min. The solvent was evaporated and dissolved in 15 ml dichloromethane. To this mixture, 4-fluoroanisole (5.0 g, 39.64 mmoles) was added and cooled to 0° C. At 0° C. AlCl3 (7.92 g, 59.46 mmoles) was added and the reaction mixture was warmed to RT and stirred for 12 h. The reaction mixture was quenched by the addition of 2N HCl, extracted with ethyl acetate, dried over sodium sulphate and concentrated. The crude product was purified by column chromatography with ethyl acetate:petroleum ether to afford the title compound as off-white solid (5.1 g, 56% yield. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 11.43(s,1H), 7.77(dd, J=9.5,3.2Hz, 1H), 7.42(dt, J=8.7,3.2Hz, 1H), 7.33(t, J=7.3Hz, 2H), 7.26(m, 3H), 7.01(q, J=4.6 Hz, 1H),4.42(s, 2H).
Reaction SMILES: O[CH:2]=[C:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:4]#[N:5].CC(O)=O.[NH:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)[NH2:17]>CCO>[C:6]1([C:3]2[CH:2]=[N:17][N:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[C:4]=2[NH2:5])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NNc1ccccn1
Reactant: N#CC(=CO)c1ccccc1
Solvent: CC(=O)O
Solvent: CCO
Product: Nc1c(-c2ccccc2)cnn1-c1ccccn1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
To a solution of 3-hydroxy-2-phenylacrylonitrile (3.4 mmol) in EtOH (6.8 mL) is added AcOH (0.66 mL) and 2-hydrazinopyridine (6.8 mmol) at room temperature. After stirred at 80° C. for 5 h, the reaction mixture is cooling and concentrated in vacuo. The residue is diluted with H2O and extracted with AcOEt. The organic extracts are washed with brine, dried over Na2SO4 and concentrated in vacuo. The resulting residue is triturated with ether to give the title compound; 1H NMR (CDCl3) δ 6.27 (br, 2H), 7.11-7.14 (m, 1H), 7.21-7.25 (m, 1H), 7.40-7.48 (m, 4H), 7.65 (s, 1H), 7.79-7.84 (m, 1H), 8.02 (d, 1H), 8.35-8.37 (m, 1H).
Reaction SMILES: C(O)C.[F:4][C:5]1[CH:28]=[CH:27][C:8]([NH:9][C:10]2[CH:19]=[C:18]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:17]=[CH:16][C:11]=2[C:12]([O:14]C)=[O:13])=[CH:7][CH:6]=1.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(OCC)(=O)C>[F:4][C:5]1[CH:28]=[CH:27][C:8]([NH:9][C:10]2[CH:19]=[C:18]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:17]=[CH:16][C:11]=2[C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1
Reactant: COC(=O)c1ccc(Oc2ccccc2)cc1Nc1ccc(F)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C(O)c1ccc(Oc2ccccc2)cc1Nc1ccc(F)cc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 29 %

Procedure:
To a suspension of ethanol 3.0 mL of methyl 2-(4-fluoroanilino)-4-phenoxybenzoate 36 mg was added 10% sodium hydroxide aqueous solution 1.0 mL at room temperature, and it was stirred at 60° C. for 1 hour and 30 minutes. After the reaction mixture was cooled to room temperature,10% sodium hydroxide aqueous solution 1.0 mL was added, and it was heated and refluxed for 30 minutes. After the reaction mixture was cooled to room temperature,10% citric acid aqueous solution and ethyl acetate were added to it. The organic layer was separated and collected,dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. Diisopropyl ether and hexane were added to the obtained residue, and insoluble matter was filtrated. The solvent of filtrate was removed under reduced pressure, hexane was added to the residue, and solid matter was filtrated to give 2-(4-fluoroanilino)-4-phenoxybenzoic acid 10 mg of white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.C(Cl)(=O)C(Cl)=O.[F:18][C:19]1[CH:24]=[CH:23][C:22]([O:25]C)=[CH:21][CH:20]=1.[Al+3].[Cl-].[Cl-].[Cl-]>ClCCl.CN(C=O)C>[F:18][C:19]1[CH:20]=[CH:21][C:22]([OH:25])=[C:23]([C:9](=[O:11])[CH2:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[CH:24]=1
Reactant: COc1ccc(F)cc1
Reactant: O=C(O)Cc1cccc(F)c1
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cc1cccc(F)c1)c1cc(F)ccc1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
3-Fluorophenylacetic acid (7.33 g, 47.56 mmoles) was dissolved in 25 ml dichloromethane. To this mixture, oxalylchloride (7.54 g, 59.46 mmoles) and DMF (3 drops) were added at 0° C. and stirred for 30 min. The solvent was evaporated and dissolved in 25 ml dichloromethane. To this mixture, 4-fluoroanisole (5.00 g, 39.64 mmoles) was added and cooled to 0° C. At 0° C. AlCl3 (7.95 g, 59.46 mmoles) was added and the reaction mixture was warmed to RT and stirred for 12 h. The reaction mixture was quenched by the addition of 2N HCl, extracted with ethyl acetate, dried over sodium sulphate and concentrated. The crude product was purified by column chromatography with ethyl acetate:petroleum ether to afford the title compound as colourless solid (4.5 g, 45% yield. 1H-NMR (δ ppm, DMSO-D6, 400 MHz): δ 11.34 (s, 1H), 7.75 (dd, J=9.4, 3.1 Hz, 1H), 7.42 (m, 2H), 7.12 (m, 3H), 7.05 (dd, J=9.0, 4.5 Hz, 1H), 4.47 (s, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH2:20][CH2:21]OS(C)(=O)=O)[CH:18]=2)[NH:13][C:12]=1[CH3:27])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>O1CCOCC1>[CH2:1]([O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH2:20][CH2:21][N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[CH:18]=2)[NH:13][C:12]=1[CH3:27])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1[nH]c2ccc(CCOS(C)(=O)=O)cc2c1C(=O)OCc1ccccc1
Reactant: C1CCNCC1
Solvent: C1COCCO1
Product: Cc1[nH]c2ccc(CCN3CCCCC3)cc2c1C(=O)OCc1ccccc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
To a solution of 5-(2-methanesulfonyloxy-ethyl)-2-methyl-1H-indole-3-carboxylic acid benzyl ester (450 mg, 1.16 mmol, Example 56, Step D) in dioxane (10 mL) was added piperidine (1.1 mL, 11.6 mmol). The mixture was stirred at 80° C. for 2 hours and then partitioned between methylene chloride and water. The organic phase was washed with water and brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo to give a solid residue, which was recrystallized from ethyl acetate and diethyl ether to give 275 mg (63%) of the desired product as a white solid: mp 159-161° C.; MS(APCI+): m/z 377.1 (MH+); Anal. Calcd for C24H28N2O2.1.04H2O: C, 72.93; H, 7.67; N, 7.09. Found: C, 72.54; H, 7.31; N, 7.04.
Reaction SMILES: [N:1]([CH:4]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5]1)=[N+]=[N-]>CO.[Pd]>[N:11]1[CH:12]=[CH:13][CH:14]=[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]([NH2:1])[C:10]=12
Reactant: [N-]=[N+]=NC1CCCCc2cccnc21
Agent: [Pd]
Solvent: CO
Product: NC1CCCCc2cccnc21
Yield: 88 %

Procedure:
To a solution of the azide (23.18 g, 0.123 mol) in methanol (150 mL) was added Palladium, 10 wt. % on activated carbon (1.95 g) and the resultant mixture was hydrogenated at 40 psi on a Parr shaker. The mixture was vacuum filtered through celite and the cake was washed with methanol. The solvent was removed from the filtrate under reduced pressure and the oil obtained was distilled (Kugelrohr, bp 105-140° C.@0.2 Torr) to provide 17.56 g (88%) of 6,7,8,9-Tetrahydro-5H-cyclohepta[b]pyridin-9-ylamine as a pale yellow oil. 1H NMR (CDCl3) δ 1.23-1.37 (m, 1H), 1.43-1.57 (m, 1H), 1.78-2.10 (m, 6H) including 2.04 (s, 2H), 2.71-2.85 (m, 2H), 4.19 (dd, 1H, J=10.0, 1.5), 7.05 (dd, 1H, J=7.4, 4.9 Hz), 7.36 (d, 1H, J=5.9 Hz), 8.38 (d 1H, J=4.9 Hz).
Reaction SMILES: C(O)C.C(O[CH:7]=[C:8]([C:14]([CH3:16])=O)[C:9]([O:11]CC)=[O:10])C.Cl.[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][NH2:26])=[CH:21][CH:20]=1.[OH-].[Na+]>O>[CH3:16][C:14]1[N:25]([C:22]2[CH:23]=[CH:24][C:19]([CH3:18])=[CH:20][CH:21]=2)[N:26]=[CH:7][C:8]=1[C:9]([OH:11])=[O:10]
Reactant: Cc1ccc(NN)cc1
Reactant: CCOC=C(C(C)=O)C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1ccc(-n2ncc(C(=O)O)c2C)cc1
Yield: 57.7 %

Procedure:
To an ethanol (70 ml) and water (70 ml) solution of ethyl 2-(ethoxymethylene)acetoacetate (16.67 g) prepared according to a method described in J. Chem. Soc. Perkin trans. I, 1875 (1988), was added 4-methylphenylhydrazine hydrochloride (14.2 g) and the mixture was stirred at reflux temperature for 7.5 hours. Sodium hydroxide (8.5 g) was added and the mixture was further stirred at reflux temperature for an hour. After completion of the reaction, the solvent was evaporated, diluted hydrochloric acid was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was washed with n-hexane to give the titled compound (11.17 g).
Reaction SMILES: C([O:9][C:10]1[C:11]([C:31]([O:33][CH3:34])=[O:32])=[N:12][C:13]([C:17]2([CH3:30])[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20][CH2:19][NH:18]2)=[N:14][C:15]=1[OH:16])(=O)C1C=CC=CC=1.[BH3-][C:36]#N.[Na+].C(O[Na])(C)=O.C=O>CO>[C:26]([O:25][C:23]([N:21]1[CH2:20][CH2:19][N:18]([CH3:36])[C:17]([C:13]2[N:12]=[C:11]([C:31]([O:33][CH3:34])=[O:32])[C:10]([OH:9])=[C:15]([OH:16])[N:14]=2)([CH3:30])[CH2:22]1)=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: [BH3-]C#N
Reactant: COC(=O)c1nc(C2(C)CN(C(=O)OC(C)(C)C)CCN2)nc(O)c1OC(=O)c1ccccc1
Agent: C=O
Agent: CC(=O)O[Na]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1nc(C2(C)CN(C(=O)OC(C)(C)C)CCN2C)nc(O)c1O
Temperature: 25 °C

Procedure:
Crude material methyl 5-(benzoyloxy)-2-[4-(tert-butoxycarbonyl)-2-methylpiperazin-2-yl]-6-hydroxypyrimidine-4-carboxylate (C-44) obtained in step 1 was dissolved in MeOH, and NaCNBH3 (2.8 eq), AcONa (3.2 eq) and HCHO (37% in H2O, 4 eq) were added. The reaction mixture was stirred at room temperature. After 30′, the solvent was evaporated and the crude solid (C-45) obtained washed with Et2O.