Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[C:18]([C:29]([NH2:31])=[O:30])[CH:19]=[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:21]=3)[NH:16][CH:15]=2)[CH2:10][CH2:9]1)(=[O:7])=[O:6].[CH3:32][O:33][C:34]1[CH:35]=[C:36]([OH:40])[CH:37]=[CH:38][CH:39]=1.C([O-])([O-])=O.[K+].[K+]>[I-].[Na+]>[CH3:32][O:33][C:34]1[CH:35]=[C:36]([O:40][CH2:2][CH2:3][CH2:4][S:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[C:22]4[C:17](=[C:18]([C:29]([NH2:31])=[O:30])[CH:19]=[C:20]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[CH:21]=4)[NH:16][CH:15]=3)[CH2:10][CH2:9]2)(=[O:7])=[O:6])[CH:37]=[CH:38][CH:39]=1
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)c[nH]c12
Reactant: COc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: COc1cccc(OCCCS(=O)(=O)N2CCC(c3c[nH]c4c(C(N)=O)cc(-c5ccccc5)cc34)CC2)c1
Yield: 42 %

Procedure:
Following the general procedure of example 159, 3-{1-[(3-chloropropyl)sulfonyl]-4-piperidinyl}-5-phenyl-1H-indole-7-carboxamide (40.0 mg, 0.087 mmol), 3-methyloxyphenol (124 mg, 0.87 mmol), K2CO3 (35.0 mg, 0.35 mmol) and sodium iodide (0.5 mg) were reacted to give the title compound (20.0 mg, 42%).
Reaction SMILES: C([Li])CCC.CCCCCC.CN(CCN(C)C)C.[CH3:20][C:21]1[S:25][C:24]2[C:26](=O)[CH2:27][CH2:28][C:23]=2[CH:22]=1.[CH2:30]([N:32]1[C:41]2[C:36](=[CH:37][C:38]([CH:42]([CH3:44])[CH3:43])=[CH:39][CH:40]=2)[C:35](=[O:45])C=C1C1OC=CC=1)[CH3:31]>C1COCC1.[Cl-].[NH4+]>[CH2:30]([N:32]1[C:41]2[C:36](=[CH:37][C:38]([CH:42]([CH3:44])[CH3:43])=[CH:39][CH:40]=2)[C:35](=[O:45])[C:27]2[CH2:28][C:23]3[CH:22]=[C:21]([CH3:20])[S:25][C:24]=3[C:26]1=2)[CH3:31]
Reactant: Cc1cc2c(s1)C(=O)CC2
Reactant: CCn1c(-c2ccco2)cc(=O)c2cc(C(C)C)ccc21
Agent: CN(C)CCN(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCn1c2c(c(=O)c3cc(C(C)C)ccc31)Cc1cc(C)sc1-2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 1.53M solution of n-butyl lithium in hexane (0.47 mL, 0.72 mmol) were added under argon atmosphere TMEDA (0.11 mL, 0.72 mmol) at room temperature and then 2-methyl-4,5-dihydro-6H-cyclopenta[b]thiophen-6-one (0.11 g, 0.72 mmol) in anhydrous THF dropwise with ice cooling and stirring. The reaction mixture was stirred at room temperature for 1 hour and ice-cooled again. To this was added dropwise a solution of 1-ethyl-6-isopropylisatoic anhydride (Example 6, step 1) (0.11 g, 0.48 mmol) in anhydrous THF. The reaction mixture was stirred at room temperature for 2 hours and diluted with saturated aqueous solution of ammonium chloride. The organic layer was concentrated to dryness and the residue was dissolved in ethyl acetate. This solution was washed with saturated sodium chloride solution, dried with sodium sulfate and evaporated again. The residue was subjected to silica gel-chromatography (chloroform: acetone=9:1) and crystallization from diethyl ether to give the title compound. 1H-NMR (CDCl3) δ 1.33 (6H, d, CH(CH3)2), 1.58 (3H, t, CH2CH3), 2.64 (3H, s, CH3), 3.10 (1H, septet, CH), 3,78 (2H, s, H-4), 4,49 (2H, q, NCH2), 6.97 (1H, s, H-3), 7.49 (1H, d, H-9), 7.56 (1H, dd, H-8), 8.45 (1H, d, H-6)
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]([NH:5][C@@H:6]([CH3:32])[C@H:7]([O:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]([C:24]1[CH:29]=[CH:28][C:27]([CH2:30]O)=[CH:26][CH:25]=1)[N:19]=[CH:18]2)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].[CH2:35]([N:37](CC)[CH2:38]C)C.CS(Cl)(=O)=O.CNC>[Cl-].[Na+].O.ClCCl>[CH3:35][N:37]([CH2:30][C:27]1[CH:26]=[CH:25][C:24]([N:20]2[C:21]3[C:17](=[CH:16][C:15]([O:14][C@H:7]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[C@@H:6]([NH:5][C:3](=[O:4])[C:2]([F:34])([F:33])[F:1])[CH3:32])=[CH:23][CH:22]=3)[CH:18]=[N:19]2)=[CH:29][CH:28]=1)[CH3:38]
Reactant: CCN(CC)CC
Reactant: C[C@H](NC(=O)C(F)(F)F)[C@H](Oc1ccc2c(cnn2-c2ccc(CO)cc2)c1)c1ccccc1
Agent: CNC
Agent: CS(=O)(=O)Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: C[C@H](NC(=O)C(F)(F)F)[C@H](Oc1ccc2c(cnn2-c2ccc(CN(C)C)cc2)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a stirred, ice-cooled suspension of 2,2,2-trifluoro-N-((1R,2S)-1-(1-(4-(hydroxymethyl)phenyl)-1H-indazol-5-yloxy)-1-phenylpropan-2-yl)acetamide (141, 118 mg, 0.25 mmol) and triethylamine (0.35 mL, 2.5 mmol) was added methanesulfonyl chloride (140 μL, 1.8 mmol). After stirring for 50 min at 0° C. brine and dichloromethane (10 mL) were added. The mixture was washed with aqueous KHSO4 (1M) and sat. aqueous NaHCO3. To the organic phase was added dimethylamine (0.75 mL, 11.3 mmol). The mixture was stirred at ambient temperature for 40 min and was then evaporated. Preparative HPLC (Kromasil C-18, 2.5×20 cm, 30-90% CH3CN in water/40 min (0.1% TfA) afforded slightly impure title compound as a TfA-salt. The material was dissolved in MeOH and absorbed on a plug of acidic ion exchange resin (SCX, 5 g, pre-washed with MeOH). Eluting subsequently with MeOH and methanolic ammonia (2M) gave somewhat impure title compound. Purification by preparative HPLC on an XBridge C-18 column using a gradient of 50-90% acetonitrile in water containing 0.1% aqueous ammonia (28%). afforded pure N-((1R,2S)-1-(1-(4-((dimethylamino)methyl)phenyl)-1H-indazol-5-yloxy)-1-phenylpropan-2-yl)-2,2,2-trifluoroacetamide (77 mg, 61%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:33]=[CH:32][C:7]2[N:8]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27](O)=[O:28])=[CH:23][C:22]=3[O:30][CH3:31])(=[O:20])=[O:19])[C:9](=[O:17])[N:10]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[C:6]=2[CH:5]=1)[CH3:2].[NH2:34][C:35]([CH3:39])([CH3:38])[CH2:36][OH:37].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH:11]1([N:10]2[C:6]3[CH:5]=[C:4]([O:3][CH2:1][CH3:2])[CH:33]=[CH:32][C:7]=3[N:8]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27](=[O:28])[NH:34][C:35]([CH3:39])([CH3:38])[CH2:36][OH:37])=[CH:23][C:22]=3[O:30][CH3:31])(=[O:19])=[O:20])[C:9]2=[O:17])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CC(C)(N)CO
Reactant: CCOc1ccc2c(c1)n(C1CCCCC1)c(=O)n2S(=O)(=O)c1ccc(C(=O)O)cc1OC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1ccc2c(c1)n(C1CCCCC1)c(=O)n2S(=O)(=O)c1ccc(C(=O)NC(C)(C)CO)cc1OC
Yield: 20.9 %

Procedure:
This compound is prepared by the procedure described in EXAMPLE 100 starting from 0.5 g of the compound obtained in EXAMPLE 13, 0.5 g of 2-amino-2- methylpropan-1-ol, 0.6 g of BOP, 1 ml of DIPEA and 20 ml of DCM. It is chromatographed on silica using a DCM/MeOH mixture (99/1; v/v) as the eluent to give 0.12 g of the expected product in the form of white crystals. M.p.=218° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[N:14]([CH3:31])[C:15]([C:24]3[CH:29]=[CH:28][N:27]=[C:26]([NH2:30])[N:25]=3)=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[CH:18]=3)[C:10]=2[C:9]1=[O:32])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:33]([C:36]1[CH:41]=[CH:40][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:38][CH:37]=1)=[C:34]=[O:35]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[N:14]([CH3:31])[C:15]([C:24]3[CH:29]=[CH:28][N:27]=[C:26]([NH2:30])[N:25]=3)=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:34]([NH:33][C:36]4[CH:37]=[CH:38][C:39]([C:42]([F:43])([F:44])[F:45])=[CH:40][CH:41]=4)=[O:35])[CH:18]=3)[C:10]=2[C:9]1=[O:32])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1c2c(c(-c3cccc(N)c3)c1-c1ccnc(N)n1)C(=O)N(C(=O)OC(C)(C)C)CC2
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Product: Cn1c2c(c(-c3cccc(NC(=O)Nc4ccc(C(F)(F)F)cc4)c3)c1-c1ccnc(N)n1)C(=O)N(C(=O)OC(C)(C)C)CC2
Yield: 61.2 %

Procedure:
To a solution of 3-(3-amino-phenyl)-2-(2-amino-pyrimidin-4-yl)-1-methyl-4-oxo-1,4,6,7-tetrahydro-pyrrolo[3,2-c]pyridine-5-carboxylic acid tert-butyl ester (40 mg, 0.092 mmol) (prepared as described in Example 1) in dichloromethane (1 mL), 1-isocyanato-4-trifluoromethyl-benzene (0.014 mL, 0.101 mmol) was added. The mixture was stirred until disappearance of the starting material. The solvent was evaporated and the residued was suspended in diethylether and filtered to give 35 mg of 2-(2-Amino-pyrimidin-4-yl)-1-methyl-4-oxo-3-{3-[3-(4-trifluoromethyl-phenyl)-ureido]-phenyl}-1,4,6,7-tetrahydro-pyrrolo[3,2-c]pyridine-5-carboxylic acid tert-butyl ester. (y: 61%)
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[C:7]([CH3:12])([CH3:11])[C:8]([OH:10])=[O:9])([CH3:4])([CH3:3])[CH3:2].ClCCl.[CH:17]1(O)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.CC(OC)(C)C>[CH:17]1([O:9][C:8](=[O:10])[C:7]([CH3:12])([CH3:11])[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:13])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)C(C)(C)C(=O)O
Reactant: OC1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: COC(C)(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C(C)(C)C(=O)OC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 2,2-dimethylmalonic acid mono-t-butyl ester [CAS No. 143688-40-8] (800 mg), DMAP (104 mg), and dichloromethane (8 mL), cyclohexanol (0.494 mL) and WSC (976 mg) were sequentially added at 0° C. The resulting mixture was stirred overnight at room temperature, and TBME (50 mL) was added thereto. The resulting mixture was sequentially washed with water (30 mL) and saturated aqueous sodium chloride solution (30 mL), and dried over anhydrous magnesium sulfate. The resulting mixture was filtered, and the filtrate obtained was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (mixed solvent of heptane-ethyl acetate) to obtain the captioned compound (817 mg).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1)=[O:6].O.Cl>C1COCC1>[CH3:20][O:19][C:16]1[CH:15]=[CH:14][C:13]([C:10]2[CH:11]=[CH:12][C:7]([C:5]([OH:6])=[O:4])=[CH:8][CH:9]=2)=[CH:18][CH:17]=1
Reactant: COC(=O)c1ccc(-c2ccc(OC)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-c2ccc(C(=O)O)cc2)cc1
Yield: 98.3 %

Procedure:
1 N NaOH (148.5 mL, 148.5 mmol) was added under nitrogen to a solution of 4′-methoxy-biphenyl-4-carboxylic acid methyl ester (12.0 g, 49.5 mmol), prepared in the previous step, in 1 L of THF plus 250 mL of water at room temperature. After the addition the reaction was refluxed for 16.5 h (overnight). After cooling to approximately room temperature the reaction was acidified by the addition of 1 N HCl and then concentrated under reduced pressure. The solid that formed was collected by filtration and dried under reduced pressure to give 4′-methoxy-biphenyl-4-carboxylic acid (11.11 g, 98%) as a white solid, mp 245-250° C.; MS (ESI) m/z 227 [M−H]−. Elemental Analysis for C14H12O3: Calc'd: C, 73.67; H, 5.30; N, 0.00; Found: C, 69.52; H, 5.01; N, 0.04.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][CH2:11][C@H:12]2[O:16]C(C)(C)[O:14][C:13]2=O)[CH:5]=[C:6]([F:8])[CH:7]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)C>CO>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:10][CH2:11][C@@H:12]([OH:16])[C:13]2=[O:14])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CC1(C)OC(=O)[C@@H](CCNc2cc(F)cc(F)c2)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOCC
Solvent: CO
Product: O=C1[C@H](O)CCN1c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.1 %

Procedure:
A stirred solution of (R)-5-(2-(3,5-difluorophenylamino)ethyl)-2,2-dimethyl-1,3-dioxolan-4-one (8.0 g, 29.5 mmol) and p-toluensulfonic acid monohydrate (508 mg, 2.95 mmol) in MeOH (75 mL) under nitrogen was heated to 70° C. for 75 minutes. The reaction mixture was slowly cooled to RT and then continued to stir at RT overnight. The reaction mixture was concentrated under reduced pressure to provide 9.5 g of a brown waxy solid. The solid was dissolved in MeOH (10 mL) and diethyl ether (100 mL) was added. The solution was allowed to stand at RT overnight. The solid was collected, washed with diethyl ether (2×25 mL) and dried under vacuum to provide (R)-1-(3,5-difluorophenyl)-3-hydroxypyrrolidin-2-one as a tan solid (4.09 g, 19.2 mmol, 65%). 1H-NMR (400 MHz, CDCl3) δ 7.35-7.27 (m, 2H), 6.68-6.63 (m, 1H), 4.51 (dd, J=8.3, 9.8 Hz, 1H), 3.85-3.71 (m, 2H), 3.08 (s, 1H), 2.69-2.62 (m, 1H) and 2.19-2.07 (m, 1H) ppm. LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=214.1; tR=0.97 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].[NH2:12][C:13]1[C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:21]2[C:16]([C@H:17]3[CH2:29][CH2:28][O:27][C@H:18]3[CH2:19][O:20]2)=[CH:15][CH:14]=1>C(Cl)Cl.N1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:12][C:13]1[C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:21]2[C:16]([C@H:17]3[CH2:29][CH2:28][O:27][C@H:18]3[CH2:19][O:20]2)=[CH:15][CH:14]=1)(=[O:10])=[O:9]
Reactant: COC(=O)c1c(N)ccc2c1OC[C@@H]1OCC[C@H]21
Reactant: O=S(=O)(Cl)c1ccccc1F
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1c(NS(=O)(=O)c2ccccc2F)ccc2c1OC[C@@H]1OCC[C@H]21
Yield: 66.3 %

Procedure:
2-Fluorobenzenesulfonyl chloride (0.5 g) was added to a solution of methyl cis-(3aRS,9bRS)-7-amino-1,3a,4,9b-tetrahydro-2H-furo[2,3-c]chromene-6-carboxylate (Intermediate 19, 0.53 g) in DCM (10 mL) and pyridine (20 mL) and the resultant mixture was stirred at room temperature for 48 hours. The mixture was evaporated to dryness and the residue was treated with water, extracted with DCM, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-60% to give methyl cis-(3aRS,9bRS)-7-(2-fluorobenzenesulfonylamino)-1,3a,4,9b-tetrahydro-2H-furo[2,3-c]chromene-6-carboxylate (0.574 g) as a pale yellow solid.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[C:20]3[CH:19]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=4)[CH:17]=[C:16]([O:31][CH2:32][C:33]([O:35]C)=[O:34])[C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][C:13]=3[C:37](=[O:39])[NH2:38])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl>C(O)C>[C:1]1([CH2:7][N:8]2[C:20]3[CH:19]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=4)[CH:17]=[C:16]([O:31][CH2:32][C:33]([OH:35])=[O:34])[C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][C:13]=3[C:37](=[O:39])[NH2:38])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)COc1cc(-c2ccc(C(F)(F)F)cc2)cc2c1c1c(C(N)=O)cccc1n2Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NC(=O)c1cccc2c1c1c(OCC(=O)O)cc(-c3ccc(C(F)(F)F)cc3)cc1n2Cc1ccccc1
Reaction time: 0.5 h
Yield: 74.2 %

Procedure:
A solution of the {9-[(phenyl)methyl]-2-(4-trifluoromethylphenyl)-5-carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester (101 mg, 0.19 mM) and 0.95 mL (1.9 mM) of 2 N NaOH in 9.5 mL of ethanol was stirred for 30 minutes at 25° C. The reaction was acidified with 1N HCl to pH=2. After stirring 30 minutes, the resultant white precipitate was collected by filtration, washed with water, then dried in vacuo to afford 73 mg (75%) {9-[(phenyl)methyl]-2-(4-trifluoromethylphenyl)-5-carbamoylcarbazol-4-yl}oxyacetic acid. 1H NMR (DMSO-d6) δ 11.0 (bs, 1H), 8.0 (d, J=8 Hz, 2H), 7.85 (d, J=8 Hz, 2H), 7.8 (bs, 1H), 7.7 (s, 1H), 7.65 (d, J=8 Hz, 1H), 7.4 (m, 2H), 7.3-7.1 (m, 6H), 7.0 (s, 1H), 5.8 (s, 2H), 5.0 (s, 2H). MS (ES) m/e 502, 519.
Reaction SMILES: OC1C=CC(/C=C/[CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)=CC=1OC.[F:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH2:40]CBr)=[CH:35][CH:34]=1>>[F:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[CH:19][C:20]([O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:35][CH:34]=1
Reactant: Fc1ccc(OCCBr)cc1
Reactant: COc1cc(/C=C/CN2CCC(c3ccc(Oc4ccccc4)cc3)CC2)ccc1O
Product: Fc1ccc(OCCN2CCC(c3ccc(Oc4ccccc4)cc3)CC2)cc1

Procedure:
The same procedure was followed as in Example 11 using the compound (9) synthesized in Example 2 and 2-(4-fluorophenyl)oxyethyl bromide to produce the above.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:9]([C:13]([F:16])([F:15])[F:14])[O:10]2)=[CH:5][C:4]=1[Cl:22].[N-:23]=[N+:24]=[N-:25].[Na+]>CN(C=O)C>[N:23]([CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:9]([C:13]([F:16])([F:15])[F:14])[O:10]2)=[CH:5][C:4]=1[Cl:22])=[N+:24]=[N-:25]
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(CBr)cc2OC1C(F)(F)F
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1=Cc2cc(Cl)c(CN=[N+]=[N-])cc2OC1C(F)(F)F
Temperature: 50 °C

Procedure:
The ester from step 3 (2.2 g, 5.5 mmole) and sodium azide (1.79 g, 27.5 mmole) were dissolved in DMF (15 mL). The mixture was heated at 50° C. under nitrogen for overnight. The solid was filtered off and washed with EtOAc. The organic layer was washed with water and dried over MgSO4. After concentrated the ester was of suitable purity to use without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.[Br:8][C:9]1[CH:10]=[CH:11][C:12]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)=[C:13]([CH:17]=1)[C:14](O)=[O:15].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C)C=O.O>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)=[C:13]([CH:17]=1)[C:14]([NH:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)=[O:15]
Reactant: Nc1cccnc1
Reactant: O=C(O)c1cc(Br)ccc1OCc1cccc(F)c1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1cccnc1)c1cc(Br)ccc1OCc1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Neat pyridin-3-amine (116 mg, 1.23 mmol) was added in one charge to a stirred suspension of 5-bromo-2-{[(3-fluorophenyl)methyl]oxy}benzoic acid (may be prepared as described in Description 83; 200 mg, 0.62 mmol), EDC (354 mg, 1.85 mmol), HOBT (283 mg, 1.85 mmol) and triethylamine (0.26 ml, 1.85 mmol) in N,N-dimethylformamide (6 ml) in air at room temperature. The reaction mixture was stirred at 25° C. overnight. Water (25 ml) was added, and the mixture was extracted with ethyl acetate (20 ml×3). The organic phase was washed with saturated brine (10 ml), water (25 ml), dried over sodium sulfate, and evaporated in vacuo. The residue was purified with Prep-TLC (elute: dichloromethane:methanol=25:1) to obtain crude product which was washed with methanol (4 ml) to yield the title compound as a white solid. 33 mg.
Reaction SMILES: [OH:1][C:2]([C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[CH:36]=[C:35]([NH:40][C:41](=[O:43])[CH3:42])[CH:34]=[CH:33]2)([C:6]1[N:7]=[CH:8][N:9](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4].Cl.N1C=CC=CC=1.C(=O)([O-])O.[Na+]>CO>[OH:1][C:2]([C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[CH:36]=[C:35]([NH:40][C:41](=[O:43])[CH3:42])[CH:34]=[CH:33]2)([C:6]1[N:7]=[CH:8][NH:9][CH:10]=1)[CH:3]([CH3:5])[CH3:4]
Reactant: CC(=O)Nc1ccc2cc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)ccc2c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CO
Product: CC(=O)Nc1ccc2cc(C(O)(c3c[nH]cn3)C(C)C)ccc2c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
N-{6-[1-Hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]naphthalen-2-yl}acetamide (11.5 g) and pyridine hydrochloride (390 mg) were dissolved in methanol (8 ml) and the mixture was stirred at 60° C. for 2 h. After allowing to cool, the mixture was neutralized with saturated aqueous sodium hydrogen carbonate. The solvent was evaporated and the residue was collected by filtration and washed with ethanol. The filtrate was concentrated and the obtained residue was purified by silica gel column chromatography (eluate, dichloromethane:methanol =30:1→10:1) and recrystallized from ethyl acetate to give the title compound (5.52 g) as a pale-red powder.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C@@H:8]([NH:12][C:13](=O)[C@H:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=3)[OH:15])[CH2:9]2)=[CH:4][CH:3]=1.B.CSC.B#B.B.CSC>O1CCCC1.CO>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C@@H:8]([NH:12][CH2:13][C@H:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=3)[OH:15])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C(N[C@@H]1CCc2ccc(O)cc2C1)[C@@H](O)c1cccc(Cl)c1
Agent: B
Agent: B#B
Solvent: C1CCOC1
Solvent: CO
Solvent: CSC
Product: Oc1ccc2c(c1)C[C@H](NC[C@@H](O)c1cccc(Cl)c1)CC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3 g of N-[(2R)-7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl]-(S)-3-chloromandelamide, SR 58588, PREPARATION VI, in 40 ml of anhydrous tetrahydrofuran, heated with reflux under nitrogen stream, there is added 2.7 ml of a 10M solution of borane-methylsulfide (reagent which generates diborane consisting of a complex of borane and dimethylsulfide) in 20 ml of tetrahydrofuran, and heated for 4 hours with reflux. To the solution cooled at room temperature, there is added 25 ml of methanol and the reaction mixture is left under stirring at first 30 minutes at room temperature, then, 30 minutes with reflux. After concentration under reduced pressure and filtration, the residue is crystallized twice from isopropanol to give the N-[(2R)-7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl]-(2S)-2-(3-chlorophenyl)-2-hydroxyethanamine, SR 58590; m.p. 186°-188° C.; /alpha/=+76° (methanol, c=0,5%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](Cl)=[N:7][N:6]=[CH:5]2.C(=O)([O-])[O-].[K+].[K+].[CH3:19][N:20]([CH3:24])[CH2:21][CH2:22][NH2:23]>CN(C)C=O.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([NH:23][CH2:22][CH2:21][N:20]([CH3:24])[CH3:19])=[N:7][N:6]=[CH:5]2
Reactant: Clc1nncc2cc(Br)ccc12
Reactant: CN(C)CCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(C)CCNc1nncc2cc(Br)ccc12
Temperature: 80 °C
Reaction time: 16 h

Procedure:
6-Bromo-1-chlorophthalazine (0.22 g, 0.91 mmol) was dissolved in N,N-dimethylformamide (3 mL) and potassium carbonate (0.25 g, 1.81 mmol) and N1,N1-dimethylethane-1,2-diamine (0.20 mL, 1.81 mmol) was added. The reaction mixture was heated to 80° C. for 5 h, cooled to ambient temperature and stirred for 16 h. The reaction mixture was diluted with 20 mL of EtOAc, added to an addition funnel and partitioned with sodium bicarbonate (saturated, aqueous). The organic layer was washed 3x with 20 mL of sodium bicarbonate (saturated, aqueous) and once with aqueous brine, separated, dried over sodium sulfate, and concentrated via rotovap to give crude product. The crude was purified by chromatography to obtain the title compound. Found MS (ES+): 295(M+H)+.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH:7]=O)=[CH:4][CH:3]=1.[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N:16]1[C:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:23]2[C:18]([N:19]([CH3:34])[C:20](=[O:33])[N:21]([CH3:32])[C:22]2=[O:31])=[CH:17]1>C(O)C>[CH3:1][C:2]1[O:6][C:5]([CH:7]2[NH:9][C:10]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:16]3[C:17]2=[C:18]2[N:19]([CH3:34])[C:20](=[O:33])[N:21]([CH3:32])[C:22](=[O:31])[C:23]2=[C:24]3[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(C=O)o1
Reactant: Cn1c(=O)c2c(-c3ccccc3)n(-c3ccccc3N)cc2n(C)c1=O
Solvent: CCO
Product: Cc1ccc(C2Nc3ccccc3-n3c(-c4ccccc4)c4c(=O)n(C)c(=O)n(C)c4c32)o1
Temperature: 170 °C
Yield: 40.1 %

Procedure:
A mixture of 5-methylfuran-2-carbaldehyde (32 mg, 29 μl, 0.29 mmol), compound 6 (101 mg, 0.29 mmol), and ethanol (1 mL) were heated in a microwave reactor at 170° C. for 10 min. A white product was isolated, washed and recrystallized from ethanol to afford 51 mg of 7 (42% yield); m.p.>300° C.; 1H NMR (DMSO-d6): δ 7.41 (broad m, 4H), 6.95 (d, 2H, J=8.42 Hz), 6.90-6.83 (m, 2H), 6.29 (d, 2H, J=2.93 Hz), 6.08 (d, 1H, J=2.19 Hz), 5.80 (d, 1H, J=2.93 Hz), 5.69 (d, 1H, J=2.93 Hz), 3.50 (s, 3H), 3.12 (s, 3H), 2.11 (s, 3H). 13C NMR (DMSO): 159.2, 153.1, 151.9, 151.9, 139.2, 131.5, 129.6, 129.4, 128.8, 126.9, 124.3, 122.8, 120.6, 118.2, 117.6, 111.9, 108.9, 107.1, 105.2, 47.8, 32.3, 28.2, 13.9. HRMS (ES+) (m/z): [M+1]+ calculated for C26H23N4O3, 439.1765. found, 439.1771.