Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[S:8][CH:9]=[C:10]([CH2:12][O:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20]O)=[CH:16][N:15]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:24])=O>>[Cl:24][CH2:20][C:17]1[CH:18]=[CH:19][C:14]([O:13][CH2:12][C:10]2[N:11]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[S:8][CH:9]=2)=[N:15][CH:16]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc(OCc2csc(-c3ccccc3)n2)nc1
Product: ClCc1ccc(OCc2csc(-c3ccccc3)n2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
A mixture of 2-(2-phenyl-4-thiazolylmethoxy)-5-pyridylmethanol (2.98 g) and thionyl chloride (15 ml) was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure and saturated aqueous sodium hydrogen carbonate was added to the residue. The mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and 5-chloromethyl-2-(2-phenyl-4-thiazolylmethoxy)pyridine (2.40 g, yield 76%) was obtained as colorless crystals from a fraction eluted with ethyl acetate. The crystals were recrystallized from tetrahydrofuran-hexane. melting point: 117–118° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1.[N:17]([O-])=[O:18].[Na+]>C(O)(=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:17][OH:18])[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: O=N[O-]
Reactant: O=C(Cc1ccc(F)cc1)c1ccncc1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C(C(=NO)c1ccc(F)cc1)c1ccncc1

Procedure:
2-(4-Fluorophenyl)-1-pyridin-4-ylethanone (0.04 mol/8.6 g) (prepared as described in example 20, steps (a) and (b)) was dissolved in 80 ml of glacial acetic acid. NaNO2 (0.04 mol/2.76 g), dissolved in the smallest amount of H2O possible, was then added dropwise with ice-cooling and stirring. The mixture was then stirred at 0° C. for another 2 h. 500 ml of H2O were then added, and the mixture was stirred at room temperature for another 1 h. The title compound precipitated as a white powder. The precipitate was filtered off, washed with H2O and dried over P2O5 under reduced pressure. Yield: 5.9 g (60%)
Reaction SMILES: Br.Br[CH2:3][C:4]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)=O.Br.[C:13]([O:17][C:18](=[O:24])[CH2:19][S:20][C:21](=[NH:23])[NH2:22])([CH3:16])([CH3:15])[CH3:14].C(N(C(C)C)CC)(C)C>C(#N)C>[C:13]([O:17][C:18](=[O:24])[CH2:19][S:20][C:21]1[NH:23][CH:3]=[C:4]([C:6]2[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=2)[N:22]=1)([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)CSC(=N)N
Reactant: O=C(CBr)c1cccnc1
Agent: Br
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CSc1nc(-c2cccnc2)c[nH]1

Procedure:
150 mg (0.534 mmol) 2-Bromo-1-(pyridin-3-yl)-ethanone hydrobromide, 144.8 mg (0.534 mmol) of carbamimidoylsulfanyl-acetic acid tert-butyl ester hydrobromide and 207 mg (1.6 mmol) of diisopropylethylamine in 5 ml of acetonitrile were stirred at room temperature for 3 h. After evaporation, water and dichloromethane were added, the organic phase was separated, washed with water, dried, evaporated, and the product was purified by RP18 chromatography. Yield: 34 mg.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([NH2:11])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20]1[CH:21]=[C:22]([CH2:26][C:27]([O:29][CH3:30])=[O:28])[CH:23]=[CH:24][CH:25]=1>CN(C=O)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][C:27]([O:29][CH3:30])=[O:28])[CH:21]=2)=[C:4]([NH2:11])[N:3]=1
Reactant: Nc1nc(Cl)nc2nc[nH]c12
Reactant: COC(=O)Cc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)Cc1cccc(Cn2cnc3c(N)nc(Cl)nc32)c1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 64.1 %

Procedure:
2-Chloroadenine (1.70 g, 10.0 mmol) and potassium carbonate (9.67 g, 70.0 mmol) were added to DMF (35 ml) and the mixture was stirred at 60° C. for 1.5 hours. After cooling to room temperature, methyl 3-bromomethylphenylacetate (3.16 g, 13.0 mmol) was added thereto and the mixture was stirred at room temperature for 1.5 hours. After removing the solvent, thereto was added chloroform (50 ml) and the resulting solid was washed with water to give the captioned compound (2.13 g, 6.41 mmol, yield: 64%) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C>CCO>[Cl:1][C:2]1[N:7]=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: Nc1ccccc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Clc1nccc(Nc2ccccc2)n1

Procedure:
2,4-Dichloropyrimidine (3.75 g, 25 mmol) was dissolved in EtOH (12 ml) and treated with aniline (2.27 ml, 25 mmol) and triethylamine (3.82 ml, 27.2 mmol). The reaction mixture was heated to reflux for 6 hours, partitioned between EtOAc and water. The organic phase was washed with 1M HCl, dried over MgSO4 and evaporated to obtain a cream coloured solid. This material was purified by chromatography (25–50% EtOAc in isohexane) to give the title product as an off white solid. NMR (300 MHz) 6.73 (d, 1H), 7.08 (t, 1H), 7.35 (t, 2H), 7.57 (d, 2H), 8.12 (d, 1H), 9.95 (brs, 1H); m/z: (ES+) 206 (MH+).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1>>[N:14]1[CH:15]=[CH:16][CH:17]=[C:12]([NH:11][C:2]2[N:10]=[CH:9][CH:8]=[CH:7][C:3]=2[CH:4]=[O:6])[CH:13]=1
Reactant: Nc1cccnc1
Reactant: O=C(O)c1cccnc1Cl
Product: O=Cc1cccnc1Nc1cccnc1

Procedure:
The procedure of Synthetic Example 1 or partly modified processes thereof were repeated using 2-chloronicotinic acid and 3-aminopyridine to obtain 2-(pyridin-3-ylamino)nicotinaldehyde.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[NH:6][C:5]2([CH3:13])[CH3:12].Cl[C:15]1[N:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:18]=[N:17][N:16]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:12][C:5]1([CH3:13])[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([O:1][C:15]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:18]=[N:17][N:16]=3)[CH:3]=2)[C:7](=[O:11])[NH:6]1
Reactant: Clc1nnnn1-c1ccccc1
Reactant: CC1(C)NC(=O)c2ccc(O)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)NC(=O)c2ccc(Oc3nnnn3-c3ccccc3)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
A solution of lactam 62 (1.77 g, 10.0 mmol) and 5-chloro-1phenyl-1H-tetrazole (2.17 g, 12.0 mmol) in dry DMF (50 mL) is treated with solid K2CO3 (2.07 g, 15.0 mmol). The mixture is stirred overnight at rt, then poured into water and extracted with EtOAc (2×). The organic phase is washed with water (3×) and brine (2×), then dried (MgSO4), filtered, and evaporated. The residue is crystallized from CH2Cl2 to give a white solid, mp 202-204° C. The material weighs 3.10 g (97% yield) . 1H NMR (CDCl3) 7.90 (d, 1, J=8.3), 7.80 (m, 2), 7.60-7.55 (m, 4), 7.50-7.45 (m, 1), 6.78 (s, 1), 1.59 (s, 6); 13C NMR (CDCl3) 168.45, 158.80, 156.15, 155.27, 132.83, 129.81, 128.77, 125.78, 122.33, 119.44, 112.11, 59.14, 53.39, 27.59; MS (MW=321.3, EI, eE=70 eV) m/z 321 (M+), 306, 293, 278, 261, 250, 236, 222, 208, 187, 176, 161 (base peak), 145, 133, 117, 103, 91, 77, 65, 42.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:10]([C:14]([OH:16])=[O:15])=[CH:11][S:12][CH:13]=2)=[CH:4][CH:3]=1.[C:17](=O)([O-])O.[Na+].IC.CN(C)C=O>O>[CH3:17][O:15][C:14]([C:10]1[C:9]([S:8][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[CH:13][S:12][CH:11]=1)=[O:16]
Reactant: O=C(O)c1cscc1Sc1ccc(Cl)cc1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cscc1Sc1ccc(Cl)cc1
Temperature: 25 °C
Yield: 95.1 %

Procedure:
A mixture of 4-(4-chlorophenylsulfanyl)thiophene-3-carboxylic acid (1.0 g), sodium hydrogen carbonate (1.6 g), iodomethane (2.3 mL) and N,N-dimethylformamide (10 mL) was stirred was stirred at 40° C. for 5 hours. The mixture was cooled to room temperature, diluted with water (100 mL) and the aqueous phase extracted with ethyl acetate. The combined organic extract was dried over magnesium sulfate and concentrated under reduced pressure to afford the title compound as a yellow oil (1.0 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([OH:13])[CH2:10][CH:9]1[C:14]([O:16][CH2:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][CH:21]=1)=[O:19])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:27][C:28]([F:36])(S(F)(=O)=O)C(O)=O>CC#N.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][CH:28]([F:36])[F:27])[CH2:10][CH:9]1[C:14]([O:16][CH2:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][CH:21]=1)=[O:19])=[O:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)C(F)(F)S(=O)(=O)F
Reactant: CC(C)(C)OC(=O)N1CC(O)CC1C(=O)OCC(=O)c1ccc(Br)cc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC(OC(F)F)CC1C(=O)OCC(=O)c1ccc(Br)cc1
Temperature: 45 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
To 4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 2-[2-(4-bromo-phenyl)-2-oxo-ethyl]ester 1-tert-butyl ester (500 mg) and Cu(I)I (45 mg) in MeCN (8 mL) at 45° C. was added 242 μl of difluoro-fluorosulfonyl-acetic acid in 2 mL of MeCN dropwise for 60 min. The reaction mixture was stirred at 45° C. for 60 min. and evaporated under reduced pressure, and resulting residue was taken up in ethyl acetate (100 mL). The organic phase was washed with brine (1×100 mL) and dried over sodium sulfate. After the solvent was removed, the resulting oil was subjected to silica gel chromatography using effluent of 10-50% ethyl acetate and hexanes. The fractions containing product were combined and the solvent was removed under reduced pressure to provide 4-Difluoromethoxy-pyrrolidine-1,2-dicarboxylic acid 2-[2-(4-bromo-phenyl)-2-oxo-ethyl]ester 1-tert-butyl ester (339 mg, 61%) as a clear oil.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][OH:15])=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O.CCOCC>C(Cl)Cl>[C:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][CH2:13][CH:14]=[O:15])=[CH:10][CH:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)Oc1ccc(CCCO)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)Oc1ccc(CCC=O)cc1
Reaction time: 1.5 h

Procedure:
To a solution of 3-(4-tert-butoxyphenyl)-propan-1-ol S4 (2.39 g, 11.5 mmol) in anhydrous CH2Cl2 (115 mL) under N2 was added PCC (3.73 g, 17.3 mmol). The reaction flask was fitted with a reflux condenser, and the reaction mixture was stirred under N2 for 90 min. Anhydrous Et2O (120 mL) was added to the reaction mixture, and a brown solid precipitated out. The resulting slurry was filtered through a pad of silica gel to remove the solid. The brown gum left in the reaction flask washed with Et2O (3×50 mL). The combined filtrate was concentrated to give a yellow oil (1.54 g, 65% crude yield) that was carried on to the next step without further purification. TLC Rf=0.50 (Hex/EtOAc, v/v, 7:3). 1H NMR (300 MHz, CDCl3): 9.82 (t, J=1.5 Hz, 1H), 7.08 (m, 2H), 6.91 (m, 2H), 2.92 (t, J=7.5 Hz, 2H), 2.77 (t, J=7.5 Hz, 2H), 1.32 (s, 9H), FIG. 71. 13C NMR (75 MHz, CDCl3): 201.9, 154.0, 135.3, 128.8, 124.5, 45.6, 29.0, 27.7, FIG. 72. TOF-MS-ESI: [2M+Na]+ calculated 435.55 found 435.6.
Reaction SMILES: [C:1]([C:3]([OH:29])([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=1[Cl:28])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][N:14]([CH2:18][CH2:19][CH3:20])[CH2:15][CH2:16][CH3:17])=[CH:6][CH:5]=1)#[CH:2].[H][H]>[Pd].C1C=CC=CC=1>[CH2:1]([C:3]([OH:29])([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=1[Cl:28])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][N:14]([CH2:18][CH2:19][CH3:20])[CH2:15][CH2:16][CH3:17])=[CH:6][CH:5]=1)[CH3:2]
Reactant: C#CC(O)(c1ccc(OCCCN(CCC)CCC)cc1)c1ccc(Cl)cc1Cl
Reactant: [H][H]
Agent: [Pd]
Solvent: c1ccccc1
Product: CCCN(CCC)CCCOc1ccc(C(O)(CC)c2ccc(Cl)cc2Cl)cc1

Procedure:
21.7 g. of α-ethinyl-α-(2,4-dichlorophenyl)-4-[3-(dipropylamino)-propoxy]-benzylalcohol are dissolved in 210 ml. of benzene, and the solution is hydrogenated in the presence of 1.1 g. of a 10% palladium-on-charcoal catalyst. When the uptake of the calculated amount of hydrogen is complete (about 3 hours), catalyst is filtered off and benzene is distilled off. The crude product weighing 21 g. is distilled in vacuo, to yield a product boiling at 194° to 196° C./6.6 Pa.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][CH2:8][OH:9])[N:5]=[CH:4][C:3]=1[N:10]=O.[H][H]>>[NH2:10][C:3]1[CH:4]=[N:5][N:6]([CH2:7][CH2:8][OH:9])[C:2]=1[NH2:1]
Reactant: Nc1c(N=O)cnn1CCO
Reactant: [H][H]
Product: Nc1cnn(CCO)c1N

Procedure:
contacting the alkanol solution of (IV) from step (vii) with hydrogen in the presence of an insoluble hydrogenation catalyst under hydrogenation conditions of temperature and pressure to produce a product solution of 4,5-diamino-1-(2′-hydroxyethyl)pyrazole in an alkanol; and
Reaction SMILES: [NH2:1][C:2]1[C:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[C:9]=2[Cl:15])=[C:5]([OH:16])[N:4]([CH3:17])[N:3]=1.O=[C:19]([C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1)[CH2:20][C:21](OCC)=[O:22]>C(O)(=O)C>[Cl:15][C:9]1[C:10]([Cl:14])=[CH:11][CH:12]=[CH:13][C:8]=1[CH2:7][C:6]1[C:5](=[O:16])[N:4]([CH3:17])[N:3]2[C:21]([OH:22])=[CH:20][C:19]([C:26]3[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=3)=[N:1][C:2]=12
Reactant: CCOC(=O)CC(=O)c1ccncc1
Reactant: Cn1nc(N)c(Cc2cccc(Cl)c2Cl)c1O
Solvent: CC(=O)O
Product: Cn1c(=O)c(Cc2cccc(Cl)c2Cl)c2nc(-c3ccncc3)cc(O)n21
Yield: 40.7 %

Procedure:
A mixture of 3-amino-4-(2,3-dichlorobenzyl)-1-methyl-1H-pyrazol-5-ol (150 mg, 0.551 mmol) and ethyl 3-oxo-3-(pyridin-4-yl)propanoate (128 mg, 0.662 mmol) in acetic acid (10 mL), was stirred under reflux for 6 h. The reaction mixture was cooled, concentrated. The resulting residue was purified by silica gel chromatography eluted with DCM:MeOH=10:1 to provide the titled compound (90 mg, 41%), as a white solid; LC/MS: MS (ES+) m/e 401 (MH+); 1H NMR (300 MHz, DMSO-d6) δ ppm 3.55 (s, 3H), 3.82 (s, 2H), 6.07 (s, 1H), 7.12 (dd, J=1.2, 7.8 Hz, 1H), 7.26 (t, J=7.8 Hz, 1H), 7.50 (dd, J=1.2, 7.8 Hz, 1H), 7.71 (dd, J=1.8, 4.8 Hz, 2H), 7.76 (dd, J=1.8, 4.8 Hz, 1H), 11.94 (s, 1H).
Reaction SMILES: CO[C:3]([C:5]1[S:6][C:7]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[CH:8][C:9]=1[N:10]=[CH:11][N:12]([CH3:14])C)=[O:4].[CH3:22][N:23]1[CH2:28][CH2:27][CH:26]([CH2:29][O:30][C:31]2[CH:32]=[C:33](CN)[CH:34]=[CH:35][CH:36]=2)[CH2:25][CH2:24]1>CO>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([C:7]2[S:6][C:5]3[C:3](=[O:4])[N:12]([CH2:14][C:35]4[CH:34]=[CH:33][CH:32]=[C:31]([O:30][CH2:29][CH:26]5[CH2:25][CH2:24][N:23]([CH3:22])[CH2:28][CH2:27]5)[CH:36]=4)[CH:11]=[N:10][C:9]=3[CH:8]=2)=[CH:20][CH:19]=1
Reactant: COC(=O)c1sc(-c2ccc(Cl)cc2)cc1N=CN(C)C
Reactant: CN1CCC(COc2cccc(CN)c2)CC1
Solvent: CO
Product: CN1CCC(COc2cccc(Cn3cnc4cc(-c5ccc(Cl)cc5)sc4c3=O)c2)CC1

Procedure:
5-(4-Chloro-phenyl)-3-(dimethylamino-methyleneamino)-thiophene-2-carboxylic acid methyl ester (0.165 g, 0.51 mmol) and 1-{3-[(1-methylpiperidin-4-yl)methoxy]phenyl}-methanamine (0.100 g, 0.43 mmol) in MeOH (2 mL) was heated by microwave at 120° C. in 20 minutes, cooled, the formed precipitate filtered off and washed with MeOH to give the title compound as a white solid. Yield: 0.075 g (31%). 1H NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 7.58-7.63 (m, 2H), 7.45 (s, 1H), 7.38-7.43 (m, 2H), 7.22 (m, 1H), 6.79-6.91 (m, 3H), 5.17 (s, 2H), 3.76 (d, 2H, J=6.4 Hz), 2.82-2.89 (m, 2H), 2.25 (s, 3H), 1.87-1.96 (m, 2H), 1.76-1.83 (m, 2H), 1.68-1.76 (m, 1H), 1.32-1.44 (m, 2H).
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]2[CH:27]=[C:28]([C:40]3[CH:45]=[CH:44][CH:43]=[C:42]([F:46])[CH:41]=3)[CH:29]=[C:30](C(N3CCNCC3)=O)[CH:31]=2)=[CH:17][CH:16]=[CH:15][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])([OH:3])=[O:2].C(OC(CCC1C(OCCCC(OCC)=O)=CC=CC=1CCCCCCOC1C=C(C(O)=O)C=C(C2C=CC=C(F)C=2)C=1)=O)C.C(O[C:97]([N:99]1[CH2:105][CH2:104][CH2:103][NH:102][CH2:101][CH2:100]1)=[O:98])(C)(C)C>>[C:1]([CH2:4][CH2:5][C:6]1[C:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]2[CH:27]=[C:28]([C:40]3[CH:45]=[CH:44][CH:43]=[C:42]([F:46])[CH:41]=3)[CH:29]=[C:30]([C:97]([N:99]3[CH2:105][CH2:104][CH2:103][NH:102][CH2:101][CH2:100]3)=[O:98])[CH:31]=2)=[CH:17][CH:16]=[CH:15][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])([OH:3])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: O=C(O)CCCOc1cccc(CCCCCCOc2cc(C(=O)N3CCNCC3)cc(-c3cccc(F)c3)c2)c1CCC(=O)O
Agent: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(=O)O)cc(-c3cccc(F)c3)c2)c1CCC(=O)OCC
Product: O=C(O)CCCOc1cccc(CCCCCCOc2cc(C(=O)N3CCCNCC3)cc(-c3cccc(F)c3)c2)c1CCC(=O)O

Procedure:
The title compound was prepared by the same method as 4-(2-(2-carboxy-ethyl)-3-{6-[3′-fluoro-5-(piperazine-1-carbonyl)-biphenyl-3-yloxy]-hexyl}-phenoxy)-butyric acid starting from 5-{6-[2-(2-ethoxycarbonyl-ethyl)-3-(3-ethoxycarbonyl-propoxy)-phenyl]-hexyloxy}-3′-fluoro-biphenyl-3-carboxylic acid and [1,4]diazepane-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:11])=[N:4][C:5]([Cl:10])=[N:6][C:7]=1[CH2:8]Cl.[CH3:12][O-:13].[Na+]>CO>[Br:1][C:2]1[C:3]([Cl:11])=[N:4][C:5]([Cl:10])=[N:6][C:7]=1[CH2:8][O:13][CH3:12]
Reactant: ClCc1nc(Cl)nc(Cl)c1Br
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COCc1nc(Cl)nc(Cl)c1Br
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80.6 %

Procedure:
To a solution of 5-bromo-2,4-dichloro-6-(chloromethyl)pyrimidine (600 mg, 2.19 mmol) in anhydrous MeOH (15 mL) at 0° C. was added NaOMe (25% wt in MeOH, 521 mg, 2.41 mmol). The mixture was stirred at 0° C. for 30 min and then allow warm to room temperature and stirred overnight. After this time the reaction mixture was concentrated in vacuo. The residue was purified using ISCO chromatography (24 g silica gel, 0-1.5% EtOAc in hexanes in 40 min) to give the title compound (480 mg, 81%) as a white solid. 1H NMR (DMSO, 300 MHz) δ 4.77 (s, 2H), 4.04 (s, 3H).
Reaction SMILES: CN(C)C=O.[OH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[CH:10]2.C(=O)([O-])[O-].[K+].[K+].[CH2:22]([O:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[N:45]([CH2:46][O:47][CH2:48][CH2:49][Si:50]([CH3:53])([CH3:52])[CH3:51])[C:39]3[N:40]=[CH:41][N:42]=[C:43](Cl)[C:38]=3[CH:37]=2)=[CH:32][CH:31]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O>[CH2:22]([O:29][C:30]1[CH:31]=[CH:32][C:33]([C:36]2[N:45]([CH2:46][O:47][CH2:48][CH2:49][Si:50]([CH3:53])([CH3:52])[CH3:51])[C:39]3[N:40]=[CH:41][N:42]=[C:43]([O:6][C:7]4[CH:8]=[C:9]5[C:13](=[CH:14][CH:15]=4)[NH:12][CH:11]=[CH:10]5)[C:38]=3[CH:37]=2)=[CH:34][CH:35]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: Oc1ccc2[nH]ccc2c1
Reactant: C[Si](C)(C)CCOCn1c(-c2ccc(OCc3ccccc3)cc2)cc2c(Cl)ncnc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C[Si](C)(C)CCOCn1c(-c2ccc(OCc3ccccc3)cc2)cc2c(Oc3ccc4[nH]ccc4c3)ncnc21
Reaction time: 4 h
Yield: 39.2 %

Procedure:
After adding 1.9 ml of dimethylformamide, 180 mg of 5-hydroxyindole and 112 mg of potassium carbonate to 190 mg of 6-(4-benzyloxyphenyl)-4-chloro-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine, the mixture was stirred at 135–140° C. for 4 hours. After returning it to room temperature, water was added, and liquid separation and extraction were performed with an ethyl acetate:tetrahydrofuran (5:1) mixed solvent. The organic layer was concentrated and subjected to NH silica gel column chromatography (hexane-ethyl acetate) to obtain 90 mg of the title compound.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[C:9]3[N:17]=[C:16]([C:18]4[CH:19]=[C:20]([NH2:24])[CH:21]=[N:22][CH:23]=4)[CH:15]=[CH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH2:3][CH2:2]1.[Br:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[C:28]([F:36])[CH:27]=1>N1C=CC=CC=1.C(Cl)Cl>[Br:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH:24][C:20]2[CH:21]=[N:22][CH:23]=[C:18]([C:16]3[CH:15]=[CH:14][C:10]4[N:11]=[CH:12][N:13]=[C:8]([O:7][CH:4]5[CH2:5][CH2:6][O:1][CH2:2][CH2:3]5)[C:9]=4[N:17]=3)[CH:19]=2)(=[O:33])=[O:34])=[C:28]([F:36])[CH:27]=1
Reactant: Nc1cncc(-c2ccc3ncnc(OC4CCOCC4)c3n2)c1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1F
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cncc(-c2ccc3ncnc(OC4CCOCC4)c3n2)c1)c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.2 %

Procedure:
To a solution of 5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-amine (Intermediate 12) (0.050 g, 0.155 mmol) in pyridine (0.773 ml) was slowly added 4-bromo-2-fluorobenzene-1-sulfonyl chloride (0.051 g, 0.186 mmol) at 0° C. After stirred for 1 hour at room temperature, the reaction mixture was diluted with DCM and quenched with 1 N. aq HCl. The combined organic layers were washed brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was recrystallized from EtOAc-Hexane to give 4-bromo-2-fluoro-N-(5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)benzene-sulfonamide (0.028 g, 32%) as a purple solid. 1H-NMR (CDCl3, Varian 400 MHz) δ 2.03-2.11 (2H, m), 2.23-2.28 (2H, m), 3.70-3.75 (2H, m), 4.10-4.16 (2H, m), 5.66-5.71 (1H, m), 7.38-7.41 (2H, m), 7.79-7.83 (1H, m), 8.25 (1H, d, J=8.8 Hz), 8.40 (1H, d, J=8.8 Hz), 8.72 (1H, s), 8.85 (1H, s), 9.20 (1H, m). m/z=562.1 [M+1]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]3[N:10]([CH2:11][CH2:12][C:13]4[CH:29]=[CH:28][CH:27]=[CH:26][C:14]=4[CH:15]3[O:18][CH:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)[C:9]=2[CH3:30])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[C:37]([O:41][C:42]([N:44]1[CH2:49][CH:48]=[C:47](B2OC(C)(C)C(C)(C)O2)[CH2:46][CH2:45]1)=[O:43])([CH3:40])([CH3:39])[CH3:38].N>O1CCOCC1.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].O>[C:37]([O:41][C:42]([N:44]1[CH2:45][CH:46]=[C:47]([C:2]2[CH:3]=[CH:4][C:5]([C:8]3[N:17]=[C:16]4[N:10]([CH2:11][CH2:12][C:13]5[CH:29]=[CH:28][CH:27]=[CH:26][C:14]=5[CH:15]4[O:18][CH:19]4[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]4)[C:9]=3[CH3:30])=[CH:6][CH:7]=2)[CH2:48][CH2:49]1)=[O:43])([CH3:40])([CH3:38])[CH3:39]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Cc1c(-c2ccc(Br)cc2)nc2n1CCc1ccccc1C2OC1CCN(C)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: N
Solvent: O
Solvent: C1COCCO1
Product: Cc1c(-c2ccc(C3=CCN(C(=O)OC(C)(C)C)CC3)cc2)nc2n1CCc1ccccc1C2OC1CCN(C)CC1
Temperature: 100 °C

Procedure:
To a solution of compound 2-(4-bromophenyl)-1-methyl-4-(1-methylpiperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene (example 122A) (100 mg, 0.214 mmoles) in 1,4-dioxane (1 mL) in a screw-capped vial under argon are added K2CO3 (89 mg, 0.642 mmole), PdCl2(dppf)2 (6 mg, 10.7 μmole), water (0.2 mL) and 4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (99 mg, 0.321 mmole). The reaction mixture is heated at 100° C. overnight. Water is added to the reaction mixture and pH adjusted to 9-10 by adding concentrated ammonia solution. The aqueous phase is extracted three times with CH2Cl2. The organic phase is dried over magnesium sulphate, filtered and the solvent is removed under reduced pressure. The residue is pre-purified by silica gel chromatography using (CH2Cl2:MeOH:NH4OH) with a gradient from (98:2:0.2) to (96.5:3.5:0.35). The residue is purified by preparative TLC over silica gel using (CH2Cl2:MeOH:NH4OH) with a gradient from (9:1:1) to afford 4-{4-[1-methyl-4-(1-methyl-piperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulen-2-yl]-phenyl}-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester melting at 171° C.