Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH:38]=[CH:39][CH:40]=1)[CH2:18][S:19][C:20]1[CH:21]=[C:22]([CH:35]=[CH:36][CH:37]=1)[CH2:23][CH:24](C(OCC)=O)[C:25]([O:27]CC)=[O:26].[OH-].[K+].O1CCCC1>C(O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH:38]=[CH:39][CH:40]=1)[CH2:18][S:19][C:20]1[CH:21]=[C:22]([CH2:23][CH2:24][C:25]([OH:27])=[O:26])[CH:35]=[CH:36][CH:37]=1
Reactant: CCOC(=O)C(Cc1cccc(SCc2cccc(OCc3nc(-c4ccccc4)oc3C)c2)c1)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1cccc(CSc2cccc(CCC(=O)O)c2)c1
Yield: 76.6 %

Procedure:
A mixture of diethyl 2-[3-[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzylthio]benzyl]malonate (0.70 g), a 4N aqueous potassium hydroxide solution (10 mL), tetrahydrofuran (20 mL) and ethanol (20 mL) was stirred at 60° C. for 1 hr. The reaction mixture was concentrated and water was added to the residue. The mixture was neutralized with 2N hydrochloric acid, and the precipitated crystals were collected by filtration. The obtained crystals were dissolved in pyridine (40 mL) and this mixture was stirred with heating under reflux for 1 hr. The reaction mixture was concentrated, 2N hydrochloric acid was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated to give crystals (0.44 g, yield 77%) of 3-[3-[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzylthio]phenyl]propionic acid. Recrystallization from acetone-hexane gave colorless prism crystals. melting point: 120-121° C.
Reaction SMILES: [CH3:1][CH:2]([CH:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:3]([C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1)=O.Cl.[NH2:25][OH:26].C([O-])(O)=O.[Na+]>>[CH3:1][CH:2]([CH:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)/[C:3](/[C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1)=[N:25]\[OH:26]
Reactant: CC(C(=O)c1ccncc1)C(c1ccccc1)c1ccccc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(/C(=N\O)c1ccncc1)C(c1ccccc1)c1ccccc1

Procedure:
In analogy to example 151, step 3, 2-methyl-3,3-diphenyl-1-pyridin-4-yl-propan-1-one was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound as an off-white solid, MS (ESI+): m/z=317.16 [M+H]+.
Reaction SMILES: O[CH:2]([CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1)[C:3]#[C:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[N:6]=1.C(N(S(F)(F)[F:31])CC)C>C(Cl)Cl>[F:31][CH:2]([CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1)[C:3]#[C:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[N:6]=1
Reactant: Cc1cccc(C#CC(O)C2CCN(C(=O)OC(C)(C)C)CC2)n1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: Cc1cccc(C#CC(F)C2CCN(C(=O)OC(C)(C)C)CC2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.3 %

Procedure:
Into a solution of the Compound of Example 39 (300 mg, 0.91 mmol) in anhydrous CH2Cl2 (10 mL) cooled at −78° C. was dropped diethylaminosulfur trifluoride (144 μL, 1.01 mmol). The reaction mixture was kept at the same temperature for 2 h, then warmed up to r.t., quenched with water and extracted with CH2Cl2. The combined organic layers were washed with brine, dried on Na2SO4 and evaporated to dryness in vacuo to afford a residue, which was purified by automated flash liquid chromatography (Horizon™-Biotage) eluting with Petroleum Ether-EtOAc 7:3, affording the title product (140 mg) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[C:24]([O:32][CH2:33][CH3:34])=[N:25][C:26]([O:29][CH2:30][CH3:31])=[N:27][CH:28]=3)=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl.[CH3:37][S:38]([CH2:41][CH2:42][N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)(=[O:40])=[O:39]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20]([N:46]3[CH2:45][CH2:44][N:43]([CH2:42][CH2:41][S:38]([CH3:37])(=[O:39])=[O:40])[CH2:48][CH2:47]3)=[O:21])[C:10]([C:23]3[C:24]([O:32][CH2:33][CH3:34])=[N:25][C:26]([O:29][CH2:30][CH3:31])=[N:27][CH:28]=3)=[N:9]2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)CCN1CCNCC1
Reactant: CCOc1ncc(C2=NC(c3ccc(Cl)cc3)C(c3ccc(Cl)cc3)N2C(=O)Cl)c(OCC)n1
Agent: Cl
Product: CCOc1ncc(C2=N[C@@H](c3ccc(Cl)cc3)[C@@H](c3ccc(Cl)cc3)N2C(=O)N2CCN(CCS(C)(=O)=O)CC2)c(OCC)n1

Procedure:
cis-4-[4,5-Bis-(4-chloro-phenyl)-2-(2,4-diethoxy-pyrimidin-5-yl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 8) was reacted with 1-(2-methanesulfonylethyl)-piperazine dihydrochloride (example 3) to give cis-[4,5-bis-(4-chloro-phenyl)-2-(2,4-diethoxy-pyrimidin-5-yl)-4,5-dihydro-imidazol-1-yl]-[4-(2-methanesulfonyl-ethyl)-piperazin-1-yl]-methanone in an analogous manner as described in example 1. HR-MS (ES, m/z) calculated for C31H37N6O5SCl2 [(M+H)+] 675.1918, observed 675.1914.
Reaction SMILES: [NH:1]([C:8]1[N:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:16]2[N:15]=[C:14]([C:24]([O:26]CC)=O)[C:13]([F:29])=[CH:12][C:11]=2[C:10](=[O:30])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH4+:31].[Cl-]>N.CO>[NH:1]([C:8]1[N:17]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:16]2[N:15]=[C:14]([C:24]([NH2:31])=[O:26])[C:13]([F:29])=[CH:12][C:11]=2[C:10](=[O:30])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: CCOC(=O)c1nc2c(cc1F)c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Agent: N
Agent: [Cl-]
Solvent: CO
Product: NC(=O)c1nc2c(cc1F)c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.2 %

Procedure:
A suspension of ethyl 7-anilino-3-fluoro-5-oxo-8-phenyl-5,8-dihydro-1,8-naphthyridine-2-carboxylate (50 mg, 0.12 mmol), and NH4Cl (10 mg, 0.19 mmol) in concentrated NH3 (3 mL) and MeOH (8 drops) was stirred for 16 h at room temperature. The solid was collected by filtration washing with water. Trituration with Et2O, provided 7-anilino-3-fluoro-5-oxo-8-phenyl-5,8-dihydro-1,8-naphthyridine-2-carboxamide as a yellow solid (32 mg, 71%): LCMS RT: 1.93 min, MH+: 375.3. This trasformation can also be accomplished using EDCI/HOBT coupling with NH3.
Reaction SMILES: [CH3:1][C:2]([CH3:4])=O.[NH2:5][O:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:23]2[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N:16]=[C:15]([NH2:24])[C:14]=2[N:13]=[C:12]1[CH2:25][CH2:26][CH2:27][CH3:28]>CO>[NH2:24][C:15]1[C:14]2[N:13]=[C:12]([CH2:25][CH2:26][CH2:27][CH3:28])[N:11]([CH2:10][CH2:9][CH2:8][CH2:7][O:6][N:5]=[C:2]([CH3:4])[CH3:1])[C:23]=2[C:22]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N:16]=1
Reactant: CC(C)=O
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCON
Solvent: CO
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCON=C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.7 %

Procedure:
Acetone (444 mg, 7.65 mmol) was added to a solution of 1-[4-(aminooxy)butyl]-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine (0.500 g, 1.53 mmol), prepared as described in Parts A-C of Example 71, in methanol (7 mL), and the reaction was stirred overnight at room temperature. The solvent was removed under reduced pressure and then further dried under high vacuum to provide 358 mg of acetone O-[4-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]oxime as a white solid, mp 115-117° C.
Reaction SMILES: [OH:1][C:2]([P:14](=[O:17])([OH:16])[OH:15])([P:10](=[O:13])([OH:12])[OH:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.I[CH3:19]>[OH-].[Na+].O.C(O)C>[OH-:1].[OH:1][C:2]([P:14]([OH:15])([OH:16])=[O:17])([P:10]([OH:11])([OH:12])=[O:13])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N+:5]=1[CH3:19]
Reactant: CI
Reactant: O=P(O)(O)C(O)(Cc1ccccn1)P(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C[n+]1ccccc1CC(O)(P(=O)(O)O)P(=O)(O)O
Temperature: 80 °C
Yield: 165.4 %

Procedure:
[1-Hydroxy-2-(2-pyridinyl)ethylidene]bis[phosphonic acid] (3.53 mmol, 1.0 g) is dissolved in 8.8 ml of 1N sodium hydroxide solution and 8.8 ml of distilled water. To this is added iodomethane (17.67 mmol, 1.1 ml) in 18 ml of ethanol. This reaction mixture is heated at 80° C. until complete. The solvent is concentrated in vacuo and the residue is recrystallized from ethanol and water to yield 0.92 g of 2-(2 -hydroxy-2,2-diphosphonoethyl)-1-methyl pyridinium hydroxide, inner salt, monosodium salt.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:15]=[C:14]([CH:16]=O)[CH:13]=[CH:12][CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:18]([CH:23]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:20][CH2:21][CH3:22])=[O:19]>CN(C=O)C>[Si:1]([O:8][CH2:9][C:10]1[N:15]=[C:14]([CH:16]=[CH:23][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:13]=[CH:12][CH:11]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(C=O)n1
Solvent: CN(C)C=O
Product: CCOC(=O)C=Cc1cccc(CO[Si](C)(C)C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.3 %

Procedure:
6-(t-Butyldimethylsilanyloxymethyl)pyridine-2-carboxaldehyde (4.29 g) was dissolved in 50 mL of DMF, and 7.14 g of (carbethoxymethylene)triphenylphosphorane was added to the solution, and then the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into ice-water, and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure. To the residue, 100 mL of a mixture of hexane-ethyl acetate (5:1) was added, the insoluble material was filtrated off, and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on silica gel (hexane-ethyl acetate=10:1) to give 5.45 g of ethyl 3-[6-(t-butyldimethylsilanyloxymethyl)pyridin-2-yl]acrylate as a light yellow oil.
Reaction SMILES: [C:1]([C:8]1[CH:9]=[C:10](/[CH:14]=[CH:15]/[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:11]=[CH:12][CH:13]=1)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[BH4-].[Na+]>C(O)C>[OH:7][CH:1]([C:8]1[CH:9]=[C:10](/[CH:14]=[CH:15]/[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:11]=[CH:12][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCC(=O)c1cccc(/C=C/c2ccccc2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCCCCC(O)c1cccc(/C=C/c2ccccc2)c1
Reaction time: 8 h

Procedure:
The ketone, trans-3-hexanoyl stilbene of Example 20 (1 g) was dissolved in ethanol, and sodium borohydride (0.2 g) was added. The mixture was stirred overnight. Excess of the borohydride was destroyed by carefully adding a dilute HCl solution. The aqueous solution was extracted thoroughly with ether, and then the ether extract was washed with brine and dried. On removal of all volatiles, the pure alcohol was obtained as a clear, colorless liquid in quantitative yield.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([CH2:8][CH2:9][OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[S:20](Cl)([C:23]1[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=1)(=[O:22])=[O:21]>C(Cl)Cl>[S:20]([C:23]1[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=1)([O:10][CH2:9][CH2:8][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=1)(=[O:22])=[O:21]
Reactant: O=[N+]([O-])c1ccc(CCO)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
4-Nitrophenethyl alcohol (15 g, 89.7 mmol) was dissolved in 450 mL methylene chloride. Triethylamine (37.5 mL, 269 mmol) was added over 10 min and the reaction mixture was stirred at 0° C. for 1 hour (h). Tosyl chloride (20.52 g, 110 mmol) was added slowly to the mixture at 0° C. The reaction was stirred at room temperature (rt) overnight and was concentrated. The residue was dissolved in methylene chloride and washed with water, 1 N HCl, then water. The organic layer was dried over sodium sulfate and evaporated. The residue was triturated with hexanes and 25.32 g of white solid was collected. Yield 88%; 1H NMR (400 MHz, CDCl3) δ 8.07 (d, J=8 Hz, 2H), 7.63 (d, J=8 Hz, 2H), 7.24 (d, 4H), 4.26 (t, J=6 Hz, 2H), 3.04 (t, J=6 Hz, 2H), 2.41 (s, 3H).
Reaction SMILES: O1CCCCC1[O:7][CH2:8][C:9]1[CH:10]=[C:11]([C@H:15]([S:28][CH2:29][C:30]2([CH2:33][C:34]([O:36][CH3:37])=[O:35])[CH2:32][CH2:31]2)[CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]([OH:27])([CH3:26])[CH3:25])[CH:12]=[CH:13][CH:14]=1.N1C=CC=CC=1.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>CO>[OH:7][CH2:8][C:9]1[CH:10]=[C:11]([C@H:15]([S:28][CH2:29][C:30]2([CH2:33][C:34]([O:36][CH3:37])=[O:35])[CH2:32][CH2:31]2)[CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]([OH:27])([CH3:26])[CH3:25])[CH:12]=[CH:13][CH:14]=1
Reactant: COC(=O)CC1(CS[C@H](CCc2ccccc2C(C)(C)O)c2cccc(COC3CCCCO3)c2)CC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Solvent: c1ccncc1
Product: COC(=O)CC1(CS[C@H](CCc2ccccc2C(C)(C)O)c2cccc(CO)c2)CC1
Temperature: 55 °C
Reaction time: 3.5 h
Yield: 0.1 %

Procedure:
To the hydroxy ester from Step 15 (9.02 g, 17.1 mol) in anhydrous MeOH (60 mL) under nitrogen was added pyridine (50 μL) followed by PPTS (1.1 g, 4.3 mmol). The reaction mixture was stirred 3.5 hr at 55° C., then at r.t. overnight before concentrating in vacuo. The residue was diluted with EtOAc (500 mL) and washed with H2O, saturated aq. NaHCO3, NaH2PO4 buffer (pH=4.5) and with brine. After drying over MgSO4 and evaporation of the solvents, the residue was purified by flash chromatography (40% to 60% EtOAc in hexanes) giving 6.85 g (91%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:14]=[C:13]([C:15]([NH:17][C:18]2[C:19]([N:28]3[CH2:33][CH2:32][CH2:31][C@H:30]([NH:34]C(=O)OC(C)(C)C)[CH2:29]3)=[C:20]3[CH2:26][CH2:25][C:24](=[O:27])[C:21]3=[N:22][CH:23]=2)=[O:16])[CH:12]=[CH:11][C:10]=1[F:42].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:34][C@H:30]1[CH2:31][CH2:32][CH2:33][N:28]([C:19]2[C:18]([NH:17][C:15]([C:13]3[CH:12]=[CH:11][C:10]([F:42])=[C:9]([C:3]4[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=4[F:8])[N:14]=3)=[O:16])=[CH:23][N:22]=[C:21]3[C:24](=[O:27])[CH2:25][CH2:26][C:20]=23)[CH2:29]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c(NC(=O)c3ccc(F)c(-c4c(F)cccc4F)n3)cnc3c2CCC3=O)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H]1CCCN(c2c(NC(=O)c3ccc(F)c(-c4c(F)cccc4F)n3)cnc3c2CCC3=O)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 45.7 %

Procedure:
A mixture of tert-butyl {(3S)-1-[3-({[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]carbonyl}amino)-7-oxo-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]piperidin-3-yl}carbamate (6.0 mg, 0.010 mmol) in DCM (0.05 mL) and TFA (0.052 mL, 0.68 mmol) was stirred at room temperature for 20 min. The solution was then concentrated under reduced pressure. The residue was diluted with MeOH, filtered and purified by preparative LC-MS (XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min., eluting with a gradient of MeCN and water with 0.1% NH4OH) to give the title compound as a white powder (2.2 mg, 44%). LCMS calc. for C25H23F3N5O2 (M+H)+: m/z=482.2. Found: 482.3.
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C:8]2[C:9]([C:15]#[N:16])=[C:10]([F:14])[CH:11]=[CH:12][CH:13]=2)[CH:7]=1.N([O-])=O.[Na+].[BrH:22]>O1CCOCC1.O.[Cu]Br>[Br:22][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C:8]2[C:9]([C:15]#[N:16])=[C:10]([F:14])[CH:11]=[CH:12][CH:13]=2)[CH:7]=1
Reactant: N#Cc1c(F)cccc1-c1cc(N)ccc1F
Reactant: Br
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1c(F)cccc1-c1cc(Br)ccc1F
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 68 %

Procedure:
5′-Amino-3,2′-difluorobiphenyl-2-carbonitrile (2.87 g, 12.5 mmol) was dissolved in hot 1,4-dioxane (4 mL), 48% aqueous hydrobromic acid (40 mL) was added and the mixture cooled to 0° C. before dropwise addition of sodium nitrite (0.86 g, 12.5 mmol) in water (1.5 mL) over 20 min. The resulting mixture was stirred at 0° C. for 1.5 h then poured onto a cooled (0° C.) solution of copper(I) bromide (5.38 g, 37.5 mmol) in 48% hydrobromic acid (10 mL). The solution was stirred at 0° C. for 15 min then heated at 50° C. for 20 min. The mixture was cooled to ambient temperature, diluted with water (500 mL) and extracted with ethyl acetate (2×300 ml). The combined organics were washed with 10% aqueous ammonia solution (200 mL), water (200 mL) and brine (200 mL), dried over anhydrous magnesium sulfate, filtered and evaporated to give a black solid. Purification by chromatography on silica gel eluting with isohexane (containing 0.5% methanol) on a gradient of ethyl acetate (2-6%) gave 5′-bromo-3,2′-difluoro-biphenyl-2-carbonitrile (2.48 g, 68%) as a yellow solid: δH (400 MHz, CDCl3) 7.13 (1H, dd, J 9 and 9), 7.27-7.30 (2H, m), 7.53-7.59 (2H, m), 7.64-7.69 (1H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][CH2:12][CH:13]2[O:18][CH2:17][CH2:16][NH:15][CH2:14]2)=[O:10])=[CH:4][CH:3]=1.Cl[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:23][CH:22]=1>>[C:24]1([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:23]=[CH:22][C:21]([CH2:20][N:15]2[CH2:16][CH2:17][O:18][CH:13]([CH2:12][NH:11][C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[O:10])[CH2:14]2)=[CH:26][CH:25]=1
Reactant: ClCc1ccc(-c2ccccc2)cc1
Reactant: O=C(NCC1CNCCO1)Nc1ccc(Cl)cc1
Product: O=C(NCC1CN(Cc2ccc(-c3ccccc3)cc2)CCO1)Nc1ccc(Cl)cc1
Yield: 32.2 %

Procedure:
Example 30 was prepared in an analogous manner to Example 19 using a mixture of Intermediate 9 (0.01 g) and 4-(chloromethyl)-1,1′-biphenyl (0.0083 g) to give the title compound (0.0052 g). LC-MS (System A): Rt 2.95 mins, Mass Spectrum m/z 436 [MH+].
Reaction SMILES: Cl.[Cl:2][C:3]1[N:8]2[CH:9]=[C:10]([CH2:12]Cl)[N:11]=[C:7]2[CH:6]=[CH:5][CH:4]=1.[OH:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:2][C:3]1[N:8]2[CH:9]=[C:10]([CH2:12][O:14][C:15]3[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=3)[N:11]=[C:7]2[CH:6]=[CH:5][CH:4]=1
Reactant: ClCc1cn2c(Cl)cccc2n1
Reactant: O=Cc1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(OCc2cn3c(Cl)cccc3n2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 98 %

Procedure:
A mixture of 5-chloro-2-(chloromethyl)imidazo[1,2-a]pyridine hydrochloride (3.00 g), 4-hydroxybenzaldehyde (1.81 g), potassium carbonate (6.14 g) and N,N-dimethylformamide (30 ml) was stirred at room temperature for 15 hours, poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with an queous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The remaining crystals were recrystallized from ethyl acetate-hexane to obtain 4-(5-chloroimidazo[1,2-a]pyridin-2-ylmethoxy)benzaldehyde (3.55 g, yield 98%) as colorless crystals. m.p. 126-130° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].[NH:30]([CH2:34][CH2:35][OH:36])[CH2:31][CH2:32][OH:33].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(#N)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:30]([CH2:34][CH2:35][OH:36])[CH2:31][CH2:32][OH:33])=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: OCCNCCO
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(CN(CCO)CCO)ccc21
Yield: 63.3 %

Procedure:
In a similar manner to Step 2 of Example 6, 4-chloro-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (37.6 mg, 0.0922 mmol) was dissolved in acetonitrile (2 mL), and the solution was treated with diethanolamine (0.035 mL, 0.37 mmol), acetic acid (0.106 mL, 1.85 mmol) and sodium triacetoxyborohydride (98 mg, 0.46 mmol), followed by purification by preparative thin-layer chromatography (hexane/ethyl acetate=1/2) to obtain 4-chloro-7-(1-(tert-butoxycarbonyl)-5-[di(2-hydroxyethyl)aminomethyl]indol-2-yl)isoindolinone (29.2 mg, yield 64%).
Reaction SMILES: [CH:1]1([N:7]2[C:12]([OH:13])=[C:11]([C:14]([NH:16][CH2:17][C:18]([O:20]CC)=[O:19])=[O:15])[C:10](=[O:23])[NH:9][C:8]2=[O:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[Br:31][C:32]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][C:33]=1[CH2:34]Br.Cl>CC(N(C)C)=O>[Br:31][C:32]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][C:33]=1[CH2:34][N:9]1[C:10](=[O:23])[C:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])=[C:12]([OH:13])[N:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:8]1=[O:24]
Reactant: CCOC(=O)CNC(=O)c1c(O)n(C2CCCCC2)c(=O)[nH]c1=O
Reactant: COc1ccc(Br)c(CBr)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1ccc(Br)c(Cn2c(=O)c(C(=O)NCC(=O)O)c(O)n(C3CCCCC3)c2=O)c1
Reaction time: 8 h
Yield: 29.4 %

Procedure:
A mixture of ethyl N-[(1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycinate (340 mg, 1.0 mmoles), pulv. potassium carbonate (750 mg, 5.35 mmoles) and 2-bromo-5-methoxybenzyl bromide (560 mg, 2.0 mmoles) in dimethylacetamide (6 mL) was vigorously stirred at 100° C. for 3 hours. The mixture was poured into 1 molar hydrochloric acid and extracted with ethyl acetate (×2). The combined organic solutions were washed with 1 molar hydrochloric acid and evaporated. The residue was purified by flash chromatography (10-50% ethyl acetate in hexane), the required fractions evaporated, dissolved in ethanol (5 mL) and 1 molar sodium hydroxide solution (3.0 mL) added. The mixture was stirred overnight, acidified and extracted with ethyl acetate (×2), the combined extracts washed with 1 molar hydrochloric acid, dried and evaporated. Recrystallization from acetic acid-water gave the title compound (150 mg, 29%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.04 (br. s., 1 H), 10.12 (br. s., 1 H), 7.55 (d, J=8.84 Hz, 1 H), 6.84 (dd, J=8.84, 3.03 Hz, 1 H), 6.50 (d, J=2.78 Hz, 1 H), 4.94 (s, 2 H), 4.65 (t, J=11.75 Hz, 1 H), 4.13 (d, J=5.81 Hz, 2 H), 3.69 (s, 3 H), 2.25 (q, 2 H), 1.79 (d, J=13.14 Hz, 2 H), 1.54-1.74 (m, 3 H), 1.28 (q, J=12.72 Hz, 2 H), 1.10 (q, J=12.88 Hz, 1 H)
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10]#[CH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:13]1[CH:14]=[C:15]([CH:18]=[O:19])[S:16][CH:17]=1>O1CCCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(N(CC)CC)C>[C:1]1([CH2:7][CH2:8][CH2:9][C:10]#[C:11][C:13]2[CH:14]=[C:15]([CH:18]=[O:19])[S:16][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1cc(Br)cs1
Reactant: C#CCCCc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=Cc1cc(C#CCCCc2ccccc2)cs1
Temperature: 50 °C
Reaction time: 4 h
Yield: 77.8 %

Procedure:
5-Phenylpent-1-yne (18.1 g, 126 mmol) was dissolved in tetrahydrofuran (100 ml), and then 4-bromothiophen-2-carboxaldehyde (18.7 g, 98 mmol) in tetrahydrofuran (200 ml), triethylamine (150 ml, 1.07 mmol), copper(I) iodide (962 mg, 5.05 mmol), and dichlorobis(triphenylphosphine)palladium (3.54 g, 5.04 mmol) were added thereto, and the mixture was stirred at 50° C. for 4 hours under a nitrogen atmosphere. After the reaction solution was filtered, the filtrate was evaporated under reduced pressure. To the residue was added ether, and the solution was washed with water and a saturated aqueous sodium chloride solution, respectively. After the ether layer was dried over anhydrous sodium sulfate, the solvent was evaporated in vacuo. The residue was purified by chromatography on a silica gel column (elution solvent; hexane:ethyl acetate=100:1-10:1) to afford the title compound (19.4 g, 78% yield).