Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([NH2:12])[CH2:8][CH2:9][CH2:10][CH3:11].C[O:14][C:15]([C:17]1[N:18]=[CH:19][C:20]([N:23]2[CH2:28][CH2:27][N:26]([C:29](=[O:40])[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:36]([F:39])([F:38])[F:37])[CH2:25][CH2:24]2)=[N:21][CH:22]=1)=O>O>[CH2:7]([NH:12][C:15]([C:17]1[N:18]=[CH:19][C:20]([N:23]2[CH2:24][CH2:25][N:26]([C:29](=[O:40])[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:36]([F:39])([F:38])[F:37])[CH2:27][CH2:28]2)=[N:21][CH:22]=1)=[O:14])[CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: COC(=O)c1cnc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)cn1
Reactant: CCCCCN
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Product: CCCCCNC(=O)c1cnc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)cn1
Temperature: 120 °C
Reaction time: 0.17 h
Yield: 68 %

Procedure:
Potassium tert-butoxide (0.112 g, 1.00 mmol) was added to a premixed mixture of amylamine (2.5 mL) and 4-(2-trifluoromethylbenzoyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic acid methyl ester (0.258 g, 0.65 mmol) in a 5 mL reactor for microwave oven. The reaction mixture was irradiated under stirring for 10 minutes at 120° C. On completion of the raction, the mixture was diluted with water and extracted with dichloromethane. The organic layer was washed sequentially with 10% HCl solution, water and sodium hydroxide solution, then separated and dried with Na2SO4. Removal of the solvent afforded the title compound in 68% yield (0.200 g). 1H NMR (300 MHz, CDCl3) δ 8.85, 7.97, 7.74, 7.63, 7.56, 7.49, 7.36, 4.05-4.00, 3.89-3.82, 3.78-3.73, 3.70-3.61, 3.44-3.40, 3.33-3.31, 2.16, 1.63-1.58, 1.37-0.134.
Reaction SMILES: CN(C)C=O.[C:6]1(=[O:26])[N:10]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[Cl:20])[NH:13][N:12]=2)[C:9](=[O:21])[C:8]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:7]12.Br.Br[CH2:29][CH2:30][CH2:31][N:32]([CH2:35][CH3:36])[CH2:33][CH3:34].C(=O)([O-])[O-].[K+].[K+]>O>[CH2:33]([N:32]([CH2:35][CH3:36])[CH2:31][CH2:30][CH2:29][N:13]1[C:14]2[C:19](=[C:18]([Cl:20])[CH:17]=[CH:16][CH:15]=2)[C:11]([N:10]2[C:9](=[O:21])[C:8]3=[CH:22][CH:23]=[CH:24][CH:25]=[C:7]3[C:6]2=[O:26])=[N:12]1)[CH3:34]
Reactant: O=C1c2ccccc2C(=O)N1c1n[nH]c2cccc(Cl)c12
Reactant: CCN(CC)CCCBr
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)CCCn1nc(N2C(=O)c3ccccc3C2=O)c2c(Cl)cccc21
Temperature: 80 °C
Reaction time: 12 h
Yield: 59 %

Procedure:
To 60 ml of anhydrous N,N-dimethylformamide were added 4.54 g of 3-phthalimido-4-chloroindazole obtained in the same method as described in Example 1, 4.83 g of 3-bromopropyldiethylamine hydrobromide and 6.3 g of anhydrous potassium carbonate, and the mixture was stirred for 12 hours at 80° C. After cooling, the mixture was added with 80 ml of water and extracted with diethyl ether. The diethyl ether layer was extracted three times with 2N hydrochloric acid, and the hydrochloric acid layer was washed with diethyl ether. After the pH of the layer was adjusted to 14 with potassium carbonate, the layer was extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate and chloroform was removed under reduced pressure to give 3.70 g of 1-(3-diethylaminopropyl)-3-phthalimido-4-chloroindazole having the following analytical values in a yield of 59%.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:17]([CH3:18])[C:16]3[C:19](Br)=[C:20]([F:23])[CH:21]=[CH:22][C:15]=3[N:14]=2)[CH3:12])[N:5]=[CH:4][N:3]=1.[C:25]1(B(O)O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:17]([CH3:18])[C:16]3[C:19]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[C:20]([F:23])[CH:21]=[CH:22][C:15]=3[N:14]=2)[CH3:12])[N:5]=[CH:4][N:3]=1
Reactant: OB(O)c1ccccc1
Reactant: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)c(Br)c2n1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)c(-c3ccccc3)c2n1C
Temperature: 140 °C
Yield: 57.6 %

Procedure:
A mixture of 4-amino-6-[(S)-1-(7-bromo-6-fluoro-1-methyl-1H-benzoimidazol-2-yl)ethylamino]pyrimidine-5-carbonitrile, (0.10 g, 0.26 mmol), phenylboronic acid (0.041 g, 0.33 mmol), tetrakis(triphenylphosphine)palladium(0) (0.015 g, 0.013 mmol) and caesium carbonate (0.17 g, 0.51 mmol) in dioxane (3 mL) and water (1.5 mL) was placed in a sealed tube and degassed with nitrogen for 5 min, then heated for 30 minutes at 140° C. by microwave irradiation. The resulting mixture was loaded onto an Isolute® SCX-2 cartridge and washed with MeOH then the product eluted with 2M NH3/MeOH. then concentrated in vacuo. The resulting residue was purified by chromatography (SiO2, 0-7% (2M ammonia in methanol) in DCM) then by preparative HPLC (Phenomenex Gemini 5 μm C18 on a 78 min gradient 20-98% 0.1% HCO2H in acetonitrile/water). The relevant fractions were concentrated to approximately ⅓ volume and partitioned between DCM (3×) and saturated aqueous NaHCO3. The combined DCM extracts were dried (Na2SO4) and concentrated in vacuo to give 424 as a white solid (0.058 g, 58%). LCMS (Method K): RT 3.55 min [M+H]+ 388.0. 1H NMR (DMSO-d6, 400 MHz): δ 8.03 (1H, s), 7.66-7.62 (2H, m), 7.52-7.41 (5H, m), 7.30 (2H, s), 7.13 (1H, m), 5.61 (1H, m), 3.15 (3H, s), 1.57 (3H, d, J=6.72 Hz)
Reaction SMILES: CN(C=O)C.P(Cl)(Cl)([Cl:8])=O.[Br:11][C:12]1[CH:21]=[CH:20][C:15]2[NH:16][C:17](=O)[S:18][C:14]=2[CH:13]=1.C([O-])([O-])=O.[K+].[K+]>O>[Br:11][C:12]1[CH:21]=[CH:20][C:15]2[N:16]=[C:17]([Cl:8])[S:18][C:14]=2[CH:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c2ccc(Br)cc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1nc2ccc(Br)cc2s1
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 95.4 %

Procedure:
DMF (0.807 mL, 10.4 mmol) was added to phosphorous oxychloride (8.10 mL, 86.9 mmol), and the reaction mixture was stirred for 15 min. 6-bromobenzo[d]thiazol-2(3H)-one (2.00 g, 8.69 mmol) was added and the reaction mixture was heated to 100° C. overnight. Upon cooling to rt, the reaction mixture was slowly added to a solution of K2CO3 (75 g) in water (200 mL) while maintaining the temperature below 35° C. Additional K2CO3 was added in order to maintain the pH above 10. Upon complete addition, the mixture was allowed to stir for 1 h. The solid was collected by filtration, washed with water (2×25 mL), and air dried. Further drying in a vacuum oven gave 2.06 g (95%) of the desired product as a brown solid. The material was used without further purification. LC-MS: RT=9.94 min., compound does not ionize.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][N:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:25]I>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([N:13]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][N:15]=2)[CH3:25])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2ccc([N+](=O)[O-])cn2)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(c1ccc([N+](=O)[O-])cn1)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of (S)-3-(5-nitro-pyridin-2-ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester described previously (300 mg, 0.97 mmol) in tetrahydrofuran cooled at 0° C. was added sodium hydride (47 mg, 1.95 mmol) gradually. The mixture was stirred at room temperature for 15 min followed by the addition of methyl iodide (166 mg, 1.17 mmol). The reaction mixture was stirred for 2 h and then extracted with ethyl acetate and washed with water. The organic layer was dried over sodium sulfate, filtered and concentrated to give (S)-3-[(5-nitro-pyridin-2-yl)-methyl-amino]-pyrrolidine-1-carboxylic acid tert-butyl ester (295 mg, crude) as a yellow solid, which was directly used in the next step without further purification. LCMS calcd for C15H22N4O4 (m/e) 322, obsd 323 (M+H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][N:3]=1.CC(C)([O-])C.[K+].[F:17][C:18]([F:22])([F:21])[CH2:19][OH:20]>>[F:17][C:18]([F:22])([F:21])[CH2:19][O:20][C:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][N:3]=1
Reactant: O=C(O)c1ccnc(Cl)c1
Reactant: OCC(F)(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: O=C(O)c1ccnc(OCC(F)(F)F)c1
Reaction time: 3 h
Yield: 75 %

Procedure:
2-Chloropyridine-4-carboxylic acid (200 mg, 1.27 mmol), potassium tert-butoxide (381 mg, 3.81 mmol) and 2,2,2-trifluoroethanol (2.6 mL) were charged to a sealed tube under nitrogen and stirred at 170 C for 3 h. 2,2,2-Trifluoroethanol (1 mL) was added and the reaction stirred at 170 C for 17 h. The mixture was evaporated under vacuum and the residue was dissolved in water (5 mL). 2M HCl was added to bring the solution to pH 5 and the mixture was extracted with DCM (3×10 mL). 2M HCl was then added to the aqueous layer to bring the solution to pH 3 and the mixture was extracted with DCM (4×6 mL). The combined organic extractions were washed with brine (5 mL), dried over sodium sulfate and evaporated under vacuum to afford the title compound as a white solid (210 mg, 75%). Method C HPLC-MS: MH+ requires m/z=222. Found: m/z=222, Rt=1.26 min (95%).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]([NH:5][CH2:6][C:7]1([CH3:22])[CH2:12][O:11][CH:10]([C:13]2[N:17]([CH3:18])[N:16]=[CH:15][C:14]=2[N+:19]([O-])=O)[O:9][CH2:8]1)=[O:4].C([O-])=O.[NH4+].[NH2:29][C:30]1[S:34][C:33]([C:35]2[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=2[F:42])=[N:32][C:31]=1[C:43](O)=[O:44].CN1CCOCC1.CCCP(=O)=O>CO.[Pd]>[NH2:29][C:30]1[S:34][C:33]([C:35]2[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=2[F:42])=[N:32][C:31]=1[C:43]([NH:19][C:14]1[CH:15]=[N:16][N:17]([CH3:18])[C:13]=1[CH:10]1[O:11][CH2:12][C:7]([CH3:22])([CH2:6][NH:5][C:3](=[O:4])[C:2]([F:24])([F:23])[F:1])[CH2:8][O:9]1)=[O:44]
Reactant: Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Reactant: Cn1ncc([N+](=O)[O-])c1C1OCC(C)(CNC(=O)C(F)(F)F)CO1
Agent: [Pd]
Agent: CCCP(=O)=O
Agent: O=C[O-]
Solvent: CO
Solvent: CN1CCOCC1
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)c1C1OCC(C)(CNC(=O)C(F)(F)F)CO1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2,2,2-trifluoro-N-((5-methyl-2-(1-methyl-4-nitro-1H-pyrazol-5-yl)-1,3-dioxan-5-yl)methyl)acetamide (171 mg, 0.49 mmol, intermediate 84) was dissolved in MeOH (30 mL) and ammonium formate (170 mg, 2.69 mmol) and 10% Pd/C (140 mg, 0.13 mmol) were added. The mixture was heated at reflux for 18 hr before being cooled to room temperature. The suspension was filtered, the cake washed with EtOAc (100 mL) and the filtrate concentrated under reduced pressure. The crude residue was dissolved in EtOAc (10 mL) and 5-amino-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid (131 mg, 0.51 mmol) was then added followed by N-methylmorpholine (0.11 mL, 1.46 mmol). Propylphosphonic anhydride solution (50% wt in EtOAc, 338 mg, 0.53 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 16 hr. The reaction mixture was concentrated under reduced pressure and purified via silica gel chromatography (0-5% 7 N NH3 in MeOH/DCM) to give 5-amino-2-(2,6-difluorophenyl)-N-(1-methyl-5-(5-methyl-5-((2,2,2-trifluoroacetamido)methyl)-1,3-dioxan-2-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide as a white solid (102 mg, 18% over three steps). A mixture of 5-amino-2-(2,6-difluorophenyl)-N-(1-methyl-5-(5-methyl-5-((2,2,2-trifluoroacetamido)methyl)-1,3-dioxan-2-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide (101 mg, 0.18 mmol) in MeOH (6 mL) and aqueous saturated K2CO3 solution (0.6 mL) was heated in a microwave at 100° C. for 1 hr. The reaction mixture was cooled to room temperature, concentrated under reduced pressure and purified via silica gel chromatography (0-20% MeOH/DCM) to give 175 as a white solid (4 mg, 5%). 1H NMR (400 MHz, CDCl3) δ 9.80 (s, 1H), 8.24 (s, 1H), 7.34-7.27 (m, 1H), 7.05-6.97 (m, 2H), 6.15 (s, 2H), 5.70 (s, 1H), 3.98-3.91 (m, 2H), 3.86 (s, 3H), 3.80 (d, J=11.0 Hz, 2H), 2.54 (s, 2H), 1.26 (s, 3H). Alkyl NH2 not observed. LCMS (ES+) m/z 465 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[C:14](=[O:15])[C@:13]([CH2:17][C:18]3[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=3)([CH3:16])[N:12]3[CH:26]=[CH:27][N:28]=[C:11]23)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8].[Al].[I:30]N1C(=O)CCC1=O.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[C:14](=[O:15])[C@:13]([CH2:17][C:18]3[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=3)([CH3:16])[N:12]3[C:26]([I:30])=[CH:27][N:28]=[C:11]23)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8]
Reactant: O=C1CCC(=O)N1I
Reactant: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)c(F)c(Cl)c2)c2nccn21
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [Al]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)c(F)c(Cl)c2)c2ncc(I)n21
Reaction time: 1 h
Yield: 82.1 %

Procedure:
A flask containing a solution of 4-[(R)-1-(3,5-dichloro-4-fluoro-phenyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[1,2-a]imidazol-3-ylmethyl]-benzonitrile (48.8 g, 117 mmol) in CH2Cl2 (900 mL) was covered with aluminum foil and partially submerged in an ice water bath. To this solution was added a solid mixture of N-iodosuccinimide (29.1 g, 129 mmol) and pyridinium p-toluenesulfonate (2.95 g, 11.7 mmol) in four separate portions over a 30 min period. The reaction was allowed to stir in the thawing ice bath for 1 h and then the bath was removed. Stirring was continued overnight. Saturated aqueous Na2S2O3 (300 mL) was added to the reaction and the mixture was transferred to a separatory funnel using CH2Cl2 (200 mL) and water (1 L). The layers were separated and the aqueous layer was further extracted with CH2Cl2 (2×500 mL) and EtOAc (500 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo to give a yellow oil. This oil was purified by flash chromatography on silica gel (0-2.5% EtOAc/toluene) to give 52 g of the title compound as a white solid, m/z 541.3 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH2:22][OH:23])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:26](Br)[CH3:27]>>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH2:22][O:23][CH2:26][CH3:27])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(CO)nc3N21
Reactant: CCBr
Agent: [H-]
Agent: [Na+]
Product: CCOCc1ccc2c(n1)N1[C@H](C2)CN(C(=O)OC(C)(C)C)C[C@H]1C

Procedure:
This compound was prepared in analogy to Example 15 intermediate c), from (4R,9aR)-6-hydroxymethyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester, sodium hydride and ethyl bromide.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][C:12](=[O:16])[NH:13]2)=[CH:8][CH:7]=1.[OH:17][C:18]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>C1(C)C=CC=CC=1>[OH:17][C:18]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:23][CH2:22][N:21]([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:15]=[C:14]3[C:9]([CH2:10][CH2:11][C:12](=[O:16])[NH:13]3)=[CH:8][CH:7]=2)[CH2:20][CH2:19]1
Reactant: OC1(c2ccccc2)CCNCC1
Reactant: O=C1CCc2ccc(OCCCCl)cc2N1
Solvent: Cc1ccccc1
Product: O=C1CCc2ccc(OCCCN3CCC(O)(c4ccccc4)CC3)cc2N1

Procedure:
2.4 Grams of 7-(3-chloropropoxy)-3,4-dihydrocarbostyril and 4.0 g of 4-hydroxy-4-phenylpiperidine were mixed with 150 ml of toluene and heated under refluxing condition for 24 hours. After cooling the reaction mixture, the precipitates formed were collected by filtration and washed with water, then recrystallized from ethanol. 2.8 Grams of 7-[3-(4-hydroxy-4-phenyl-1-piperidyl)propoxy]-3,4-dihydrocarbostyril was obtained as in the form of colorless flake-like crystals. Melting point: 215° C.
Reaction SMILES: C(OC([N:11]([C:23]1[C:24]([C:36]([O:38][CH3:39])=[O:37])=[C:25]([C:28]2[CH:33]=[N:32][C:31]([O:34][CH3:35])=[CH:30][N:29]=2)[S:26][CH:27]=1)[C:12]([C:14]1[O:15][C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[CH:18]=1)=[O:13])=O)C1C=CC=CC=1>C(O)C.C(OCC)(=O)C.ClCCl.[Pd]>[O:15]1[C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[CH:18]=[C:14]1[C:12]([NH:11][C:23]1[C:24]([C:36]([O:38][CH3:39])=[O:37])=[C:25]([C:28]2[CH:33]=[N:32][C:31]([O:34][CH3:35])=[CH:30][N:29]=2)[S:26][CH:27]=1)=[O:13]
Reactant: COC(=O)c1c(N(C(=O)OCc2ccccc2)C(=O)c2cc3ccccc3o2)csc1-c1cnc(OC)cn1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1c(NC(=O)c2cc3ccccc3o2)csc1-c1cnc(OC)cn1
Reaction time: 0.5 h

Procedure:
10% Pd/C is added to compound 160 in ethanol:ethyl acetate:dichloromethane (2:1:1). The mixture is degassed and placed under H2 (1 atm) and stirred for 30 min. The mixture is filtered through a 0.45 μm syringe filter and concentrated under reduced pressure to provide 161.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:21][CH2:22]COC)=[C:17]([NH2:20])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].ClC1C2C(=CC(OC)=C([N+]([O-])=O)C=2)N=CN=1.ClC1C(F)=C(C=CC=1[F:50])N>>[Cl:1][C:2]1[C:3]([F:50])=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:21][CH3:22])=[C:17]([NH2:20])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COCCOc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1N
Reactant: Nc1ccc(F)c(Cl)c1F
Agent: COc1cc2ncnc(Cl)c2cc1[N+](=O)[O-]
Product: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3F)c2cc1N

Procedure:
Starting material: N4-(3-chloro-2,4-difluorophenyl)-7-methoxyquinazoline-4,6-diamine was prepared according to the same method of preparation of N4-(3-chloro-4-fluorophenyl)-7-(2-methoxy)ethoxyquinazoline-4,6-diamine in WO2008/33747, but the starting materials were 4-chloro-7-methoxy-6-nitro-quinazoline and 3-chloro-2,4-difluoro-aniline; other starting materials were prepared as example 1.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C([O:9][C:10](=O)[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)C>C1COCC1>[CH2:26]([O:25][C:22]1[CH:23]=[CH:24][C:19]([C:16]2[CH:17]=[CH:18][C:13]([CH2:12][CH2:11][CH2:10][OH:9])=[CH:14][CH:15]=2)=[CH:20][CH:21]=1)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCCOc1ccc(-c2ccc(CCC(=O)OCC)cc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCCCCOc1ccc(-c2ccc(CCCO)cc2)cc1
Temperature: 0 °C
Yield: 93.5 %

Procedure:
To a cold (0° C.) stirred suspension of LiAlH4 (0.47 g, 12.4 mmol) in THF (20 ml) was added a solution of 3-(4′-heptyloxybiphenyl-4-yl)propionic acid ethyl ester (crude, 2.74 g) in THF (30 ml). After being stirred for 30 min. at room temperature, the mixture was quenched with H2O at 0° C. The mixture was filtered through a pad of Celite and washed with CH2Cl2. The filtrate and washings were combined and concentrated in vacuo. The residue was purified by column chromatography on silica gel (EtOAc/hexane, 2:3) to give 3-(4′-heptyloxy-biphenyl-4-yl)propan-1-ol (2.27 g, 96% for 2 steps) as a white amorphous powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][O:6][CH2:7][C:8]1[N:13]=[C:12]([NH2:14])[CH:11]=[CH:10][CH:9]=1.[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[S:26](Cl)(=[O:28])=[O:27]>>[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[S:26]([NH:14][C:12]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:7][O:6][CH2:5][C:4]2[CH:15]=[CH:16][CH:17]=[C:2]([F:1])[CH:3]=2)[N:13]=1)(=[O:28])=[O:27]
Reactant: Nc1cccc(COCc2cccc(F)c2)n1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1F
Product: O=S(=O)(Nc1cccc(COCc2cccc(F)c2)n1)c1ccc(F)cc1F

Procedure:
This material was prepared in analogy to example 1 from 6-(3-fluoro-benzyloxymethyl)-pyridin-2-ylamine (0.06 g) and 2,4-difluoro-benzenesulfonyl chloride (0.06 g) as a yellow solid(0.07 g). MS (ESI−): 407.2 ([M−H]−).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[C:55](Cl)(=[O:59])[CH:56]([CH3:58])[CH3:57]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([C:55](=[O:59])[CH:56]([CH3:58])[CH3:57])[CH2:49][CH2:48]1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: CC(C)C(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C(=O)N1CCC(CC(=O)Nc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 32 %

Procedure:
The desired compound was prepared according to the procedure of Example A20, using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and isobutyryl chloride as starting materials in 32% yield. LCMS for C28H33ClN7O2 (M+H)+: m/z=534.2.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:12])[CH:3]=1.CC(N=NC(C#N)(C)C)(C#N)C.C1C(=O)N([Br:32])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH2:12][Br:32])[CH:3]=1
Reactant: COC(=O)c1ccc(Br)cc1C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(Br)cc1CBr
Yield: 79.9 %

Procedure:
A solution of Example 33A (1.02 g, 4.47 mmol) in CCl4 (22 mL) was treated with AIBN (0.065 g, 0.4 mmol) and NBS (0.955 g, 5.4 mmol), heated to reflux for 4 hours, washed with water, dried (Na2SO4), filtered, and concentrated to provide the desired product (1.1 g, 79%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CS([O:11][CH2:12][CH2:13][F:14])(=O)=O.[N+:15]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[S:25][C:26]3[CH:32]=[C:31](O)[CH:30]=[CH:29][C:27]=3[CH:28]=2)=[CH:20][CH:19]=1)([O-:17])=[O:16].O>CN(C)C=O>[N+:15]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[S:25][C:26]3[CH:32]=[CH:31][CH:30]=[C:29]([O:11][CH2:12][CH2:13][F:14])[C:27]=3[CH:28]=2)=[CH:20][CH:19]=1)([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1ccc(-c2cc3ccc(O)cc3s2)cc1
Reactant: CS(=O)(=O)OCCF
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(-c2cc3c(OCCF)cccc3s2)cc1
Temperature: 80 °C
Yield: 48 %

Procedure:
Potassium carbonate (611 mg, 4.42 mmol) and 2-fluoroethyl methane sulfonate (FCH2CH2OMs, 251 mg, 1.77 mmol) were added to 2-(4-nitrophenyl)-6-hydroxybenzothiophene (1-4, 400 mg, 1.47 mmol) obtained in Example 4 dissolved in a solution of dimethylformamide (DMF, 100 mL), heated at 80° C. for 8 hours, cooled to room temperature, followed by adding water. The resulting product was extracted with ethyl acetate, evaporated after a treatment with sodium sulfate under reduced pressure. Purification was performed by column chromatograph to give the target compound 2-(4-nitrophenyl)-4-(2-fluoroethoxy)benzothiophene (1-5, 224 mg, 48%) as a yellow solid. The obtained target compound 1-5 had a melting point of 176.5-178.0° C., and the following physical data;