Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([NH:15][C@H:16]2[CH2:21][CH2:20][C@H:19]([O:22][CH3:23])[CH2:18][CH2:17]2)[C:5]([NH:8][CH2:9][C:10](OCC)=[O:11])=[N:6][CH:7]=1.P(=O)(O)(O)O>O>[Br:1][C:2]1[N:3]=[C:4]2[N:15]([C@H:16]3[CH2:21][CH2:20][C@H:19]([O:22][CH3:23])[CH2:18][CH2:17]3)[C:10](=[O:11])[CH2:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CCOC(=O)CNc1ncc(Br)nc1N[C@H]1CC[C@H](OC)CC1
Agent: O=P(O)(O)O
Solvent: O
Product: CO[C@H]1CC[C@H](N2C(=O)CNc3ncc(Br)nc32)CC1
Temperature: 80 °C

Procedure:
Ethyl 2-(3,5-dibromopyrazin-2-ylamino)acetate (1 equiv) and trans-4-methoxycyclohexanamine hydrochloride (1.5 equiv), NMP and DIPEA were combined and heated to 127° C. and maintained at that temperature for 18 h. Upon reaction completion, the mixture was cooled to 35° C. over 4 h. The solution was transferred to a mixture of ethyl acetate and 5% brine. The aqueous layer was removed and the organic layer was washed successively with 5% brine and water. The organic layer was concentrated by vacuum distillation to a low volume, cooled to ambient temperature and the solids were collected by vacuum filtration. The solids were washed with MTBE and the product was dried in a vacuum oven to give 41% yield of ethyl 2-(5-bromo-3-(trans-4-methoxycyclohexylamino)pyrazin-2-ylamino)acetate. A mixture of ethyl 2-(5-bromo-3-(trans-4-methoxycyclohexylamino)pyrazin-2-ylamino)acetate (1 equiv), water and 85% phosphoric acid (3:1) was heated to 80° C. over 1 h. Heating was maintained for 18 h to effect reaction completion. Upon reaction completion, the mixture was cooled to 25° C. and filtered to give a crude product as tan solid. The resulting solids were washed with water, slurried in water and filtered. The solids were washed with water until the pH of the filtrate was between 4 and 8. The resulting material was dried under vacuum to give 89% yield of 7-bromo-1-(trans-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one. 7-Bromo-1-(trans-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one (1 equiv), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2-(trimethylsilyloxy)propan-2-yl)pyridine (1 equiv), sodium carbonate (3 equiv) and PdCl2(AmPhos)2 (0.003 equiv) were combined in isopropanol and heated at 70° C. for 1.5 h. Standard work-up and purification afforded the protected compound in 93% yield. Deprotection using standard conditions for removal of a trimethylsilyl-group and isolation gave the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH2:7]([O:10][C:11](=[O:22])[C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1F)[CH:8]=[CH2:9]>C(#N)C>[N:1]1([C:13]2[CH:14]=[CH:15][C:16]([N+:18]([O-:20])=[O:19])=[CH:17][C:12]=2[C:11]([O:10][CH2:7][CH:8]=[CH2:9])=[O:22])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C=CCOC(=O)c1cc([N+](=O)[O-])ccc1F
Reactant: C1COCCN1
Solvent: CC#N
Product: C=CCOC(=O)c1cc([N+](=O)[O-])ccc1N1CCOCC1
Yield: 99.2 %

Procedure:
Morpholine (7.78 mL, 88.9 mmol) was added to a solution of 2-fluoro-5-nitrobenzoic acid allyl ester (prepared as described in WO 9315078; 10 g, 44.4 mmol) in acetonitrile (100 mL) and the mixture was heated under reflux for 6 h. Volatile material was removed by evaporation and the residue was diluted with water (100 mL) and extracted with EtOAc (2×100 mL). The organic layers were dried and concentrated by evaporation to give the title compound (12.87 g, 99%) as a viscous liquid; 1H NMR δ: 8.40(1H, s), 8.20 (1H, d), 7.10 (1H, d), 6.10-5.95 (1H, m), 5.40 (1H, d), 5.30 (1H, d), 4.80 (2H, s), 3.70-3.60 (4H, m), 3.20-3.10 (4H, m); MS m/e MH 293.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]2[NH:10][CH:11]=[CH:12][N:13]=2)[CH:3]=1.Br[CH2:15][CH2:16]Br.C(=O)([O-])[O-].[K+].[K+].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8][CH2:16][CH2:15][N:10]3[C:9](=[N:13][CH:12]=[CH:11]3)[C:4]=2[CH:3]=1
Reactant: BrCCBr
Reactant: Oc1ccc(Br)cc1-c1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: CN(C)C=O
Product: Brc1ccc2c(c1)-c1nccn1CCO2
Temperature: 100 °C
Reaction time: 8 h
Yield: 37.8 %

Procedure:
Into a 20 L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of 4-bromo-2-(1H-imidazol-2-yl)phenol (835 g, 3.49 mol, 1.00 equiv) in N,N-dimethylformamide (8.5 L), 1,2-dibromoethane (2366 g, 12.59 mol, 3.60 equiv), potassium carbonate (1930 g, 4.00 equiv), and Cs2CO3 (1160 g, 1.00 equiv). The resulting solution was stirred at 100° C. overnight, quenched by the addition of 20 L of water/ice and extracted with 4×10 L of ethyl acetate. The combined organic layers were washed with 4×5 L of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was re-crystallized from EA:PE (1:2) to afford 350 g (38%) of 9-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene.
Reaction SMILES: [CH2:1]([O:13][C:14]1[CH:15]=[C:16]([CH:33]2[S:38][CH2:37][CH2:36][CH2:35][S:34]2)[CH:17]=[CH:18][C:19]=1[O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[Li]CCCC.[I:44][C:45]1[CH:52]=[CH:51][C:48]([CH:49]=[O:50])=[CH:47][CH:46]=1>C1COCC1>[CH2:1]([O:13][C:14]1[CH:15]=[C:16]([C:33]2([CH:49]([C:48]3[CH:51]=[CH:52][C:45]([I:44])=[CH:46][CH:47]=3)[OH:50])[S:34][CH2:35][CH2:36][CH2:37][S:38]2)[CH:17]=[CH:18][C:19]=1[O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCOc1ccc(C2SCCCS2)cc1OCCCCCCCCCCCC
Reactant: O=Cc1ccc(I)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCOc1ccc(C2(C(O)c3ccc(I)cc3)SCCCS2)cc1OCCCCCCCCCCCC
Temperature: 0 °C
Reaction time: 1 h
Yield: 65.1 %

Procedure:
A solution of 2-(3,4-bis-dodecyloxy-phenyl)-[1,3]dithiane (12.0 g, 21.1 mmol) in 120 mL of dry THF in a Schlenk tube was cooled down to −78° C. Under N2 atmosphere, n-BuLi (9.4 mL of 2.5 M solution in hexanes, 23.4 mmol) was added dropwise to the mixture. After stirring at 0° C. for 1 h, the reaction mixture was cooled down to −78° C. and 4-iodobenzaldehyde (3.72 g, 16.0 mmol) in 100 mL of dry THF was added dropwise. The resulting mixture was allowed to warm up to room temperature and stirred at room temperature overnight. The reaction was quenched with H2O and THF was removed under reduced pressure. The resulting slurry was extracted with CH2Cl2 and the organic layer was washed with H2O and dried over anhydrous MgSO4. The solvent was removed under reduced pressure. The product was purified by column chromatography (silica gel, hexanes:dichloromethane=3:2, 1:1, then 2:3 (v/v)) to give light yellow oil (8.3 g, 65%). 1H NMR (300 MHz, CDCl3, δ): 7.44 (d, J=8.2 Hz, 2H), 7.23 (dd, J=8.5 Hz, 2.5 Hz, 1H), 7.02 (d, J=2.5 Hz, 1H), 6.78 (d, J=8.5 Hz, 1H), 6.61 (d, J=8.5 Hz, 2H), 4.84 (s, 1H), 3.98 (t, J=6.6 Hz, 2H), 3.73 (m, 2H), 3.00 (s, 1H), 2.69 (m, 4H), 1.66-1.94 (m, 6H), 1.20-1.51 (m, 36H), 0.86 (t, J=6.7 Hz, 6H). 13C{1H} NMR (75 MHz, CDCl3, δ): 148.40, 148.31, 136.96, 135.88, 130.04, 128.93, 122.95, 115.99, 112.55, 93.82, 80.51, 69.29, 69.05, 66.33, 32.00, 29.78, 29.72, 29.55, 29.45, 29.32, 29.29, 27.41, 27.02, 26.12, 24.80, 22.78, 14.24. LRMS-EI (m/z): [M−H2O]+ calcd for C41H63IO2S2, 778.3; found, 778.5.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][C:21](=[O:23])[CH3:22])#[CH:13]>>[C:21]([N:20]1[C:15]2[C:14](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:12]=[C:13]1[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1)(=[O:23])[CH3:22]
Reactant: COC(=O)c1ccc(I)cc1
Reactant: C#Cc1ccccc1NC(C)=O
Product: COC(=O)c1ccc(-c2cc3ccccc3n2C(C)=O)cc1
Yield: 59 %

Procedure:
The general procedure was used to convert methyl 4-iodobenzoate and N-(2-ethynylphenyl)acetamide to the title product. Purification by flash chromatography gave the analytically pure product as a white solid, 59% yield. 1H NMR (300 MHz, DMSO) δ 8.20-8.17 (d, J=8.2, 1H), 8.06-8.04 (d, J=8.2, 2H), 7.70-7.67 (d, J=8.3, 2H), 7.66-7.64 (d, J=7.7, 1H), 7.41-7.28 (m, 2H), 6.91 (s, 1H), 3.89 (s, 3H), 2.20 (s, 3H). 13C NMR (75 MHz, DMSO) δ 171.63, 166.71, 139.56, 139.00, 138.06, 130.21, 129.96, 129.78, 129.56, 126.06, 124.37, 124.33, 121.81, 116.10, 113.06, 53.12, 28.53. Anal. Calcd. for C18H15NO3: C, 73.71; H, 5.15; N, 4.78. Found C, 73.50; H, 5.21; N, 4.54.
Reaction SMILES: C(N1C=CN=C1)([N:3]1C=CN=C1)=O.[Cl:13][C:14]1[CH:15]=[CH:16][C:17]2[N:23]3[CH:24]=[N:25][C:26]([C:27](O)=[O:28])=[C:22]3[CH2:21][N:20]([CH3:30])[C:19](=[O:31])[C:18]=2[CH:32]=1.C(=O)=O.N>CN(C)C=O>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]2[N:23]3[CH:24]=[N:25][C:26]([C:27]([NH2:3])=[O:28])=[C:22]3[CH2:21][N:20]([CH3:30])[C:19](=[O:31])[C:18]=2[CH:32]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CN1Cc2c(C(=O)O)ncn2-c2ccc(Cl)cc2C1=O
Agent: N
Agent: O=C=O
Solvent: CN(C)C=O
Product: CN1Cc2c(C(N)=O)ncn2-c2ccc(Cl)cc2C1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 82.6 %

Procedure:
2.7 g (16.8 mmol) of 1,1'-carbonyldiimidazole were added portionwise to a suspension of 4.7 g (16.0 mmol) of 8-chloro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid in 25 ml of N,N-dimethylformamide. After the CO2 evolution had finished the mixture was heated to 60° for 45 min. Subsequently, the solution was cooled to room temperature and 3.9 ml of conc. aqueous ammonia solution were added dropwise thereto. After stirring for a further 90 minutes the reaction mixture was poured into 90 ml of ice-water and stirred for 1 hr. The white crystals were filtered off under suction and washed with a small amount of water. After drying in a high vacuum there were obtained 3.84 g (83%) of 8-chloro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamide of m.p. 275°-277°.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([C:22]([O-])=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.C(NCC)C>C(OCC)(=O)C>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16](=[CH2:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(CCCCNC(=O)OCc1ccccc1)C(=O)[O-]
Agent: C=O
Solvent: CCNCC
Solvent: CCOC(C)=O
Product: C=C(CCCCNC(=O)OCc1ccccc1)C(=O)OCC
Temperature: 0 °C
Yield: 61.4 %

Procedure:
The monoethyl 2-(4-benzyloxycarbonylaminobutyl)malonate (3.03 g) obtained in the above step (d) was cooled to 0° C. and added with 36% formaldehyde solution (3 ml) and then with diethylamine (3 ml), and then the mixture was stirred at room temperature for 19.5 hours. Ethyl acetate was added to the reaction system to extract the organic substances, and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (150 g, hexane:acetone=5:1) to obtain ethyl 2-(4-benzyloxycarbonylaminobutyl)acrylate (1.69 g, 62%).
Reaction SMILES: C(OCCOC1C=CC([C:15]2[CH:16]=[CH:17][C:18]3[N:24](C4C=CC(S(=O)(=O)NC)=CC=4)[CH2:23][CH2:22][C:21]([C:36](O)=[O:37])=[CH:20][C:19]=3[CH:39]=2)=CC=1)CCC.C(Cl)(=O)C(Cl)=O.C[N:47](C=O)C>C1COCC1>[NH:24]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:39][C:19]=2[CH:20]=[C:21]([C:36]([NH2:47])=[O:37])[CH2:22][CH2:23]1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3c2ccc(S(=O)(=O)NC)cc2)cc1
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Product: NC(=O)C1=Cc2ccccc2NCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In THF (7 ml) was dissolved 7-[4-(2-butoxyethoxy)phenyl]-1-(N-methyl-4-sulfamoylphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.4 g). Under ice-cooling, to the solution were added oxalyl chloride (0.19 ml) and DMF (catalytic amount). The mixture was stirred at room temperature for 1 hour, and the solvent was evaporated under reduced pressure. In THF (25 ml) was dissolved the residue, and the solution was added dropwise to a suspension of 4-[N-methyl-N-(tetrahydro-2H-pyran-4-yl)aminomethyl]aniline dihydrochloride (0.28 g) and triethylamine (0.5 ml) in THF (5 ml), under ice-cooling. The mixture was stirred at room temperature under nitrogen atmosphere for 1 hour and the solvent was evaporated under reduced pressure. To the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified with basic silica gel column chromatography (ethyl acetate) to give crude crystals, which were recrystallized from ethyl acetate-hexane to give 7-[4-(2-butoxyethoxy)phenyl]-1-(N-methyl-4-sulfamoylphenyl)-N-[4-[[N-methyl-N-tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 48) (0.28 g) as pale yellow crystals.
Reaction SMILES: C([O:4][C:5](=[O:28])[CH2:6][C:7]1([CH2:13][NH:14][C:15]([O:17][CH:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20](=[O:27])[O:19]2)=[O:16])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)C=C.C(O)=O>O1CCCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[O:27]=[C:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:18]([O:17][C:15]([NH:14][CH2:13][C:7]2([CH2:6][C:5]([OH:28])=[O:4])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)=[O:16])[O:19]1
Reactant: C=CCOC(=O)CC1(CNC(=O)OC2OC(=O)c3ccccc32)CCCCC1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O=CO
Product: O=C(O)CC1(CNC(=O)OC2OC(=O)c3ccccc32)CCCCC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 74.3 %

Procedure:
To a stirred solution of (55) (0.12 g, 0.31 mmol) in dry tetrahydrofuran was added tetrakis(triphenylphosphine)-palladium(0) (5.5 mg, 4.8×10−3 mmol) and formic acid (57 mg, 1.24 mmol). The resulting reaction was stirred at room temperature for 12 h (monitored by LC/MS), then filtered through a Celite® and activated charcoal pad. The pad was washed with ethyl acetate (2×15 mL) and the combined filtrates were washed with brine (20 mL), dried over MgSO4 and concentrated in vacuo. The resulting residue was purified using preparative-LC/MS to provide 80 mg of compound (53) as a white solid (74% yield). 1H NMR (400 MHz, CDCl3) δ 1.35-1.58 (10H, m); 2.34 (2H, s); 3.23-3.40 (2H, m); 5.56 (1H, t, J=7.2 Hz); 7.42 (1H, s); 7.60-7.66 (2H, dd, J=7.6 Hz); 7.74 (1H, t, J=7.6 Hz); 7.91 (1H, d, J=7.6 Hz). MS (ESI): m/z=346.40 (M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[CH3:27][N:28]([CH3:45])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=1>>[CH3:27][N:28]([CH2:29][C:30]1[CH:31]=[C:32]([C:2]2[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]3[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=3[CH3:24])=[O:15])[C:5]3[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=3[CH:10]=2)[CH:33]=[CH:34][CH:35]=1)[CH3:45]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc3c2cnn3C(C)C)c(=O)[nH]1
Reactant: CN(C)Cc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3cccc(CN(C)C)c3)cc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 120 °C

Procedure:
The title compound was prepared from 6-bromo-N-((1,2-dihydro-4,6-dimethyl-2-oxopyridin-3-yl)methyl)-1-isopropyl-1H-indazole-4-carboxamide (500 mg, 1.14 mmol) and N,N-dimethyl(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanamine (300 mg, 1.14 mmol) in the same manner as described for example 73 wherein the contents were heated at 120° C. for 2 h. The product was collected as a pale red solid (120 mg, 21%). 1H NMR (CDCl3, 400 MHz): δ 1.568 (d, J=6.8 Hz, 6H), 2.12 (s, 3H), 2.41 (s, 8H), 2.55 (s, 3H), 3.67 (s, 2H), 4.614 (d, J=5.2 Hz, 2H), 4.899-4.834 (m, 1H), 5.90 (s, 1H), 7.326-7.308 (m, 1H), 7.408-7.368 (m, 3H), 7.558 (d, J=7.6 Hz, 1H,), 7.639 (s, 1H), 7.699 (s, 1H), 11.193 (brs, 1H). LCMS (ES+) m/z: 486.31.
Reaction SMILES: [N:1]#[N:2].[C:3]([C@@:8]1([N:16]2[C:26]3[N:25]=[C:23]([NH2:24])[NH:22][C:20](=[O:21])[C:19]=3[N:18]=[CH:17]2)[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[CH2:9]1)(=[O:7])[CH:4]([CH3:6])[CH3:5].[CH3:27][O:28][C:29]1[CH:50]=[CH:49][C:32]([C:33](Cl)([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)=[CH:31][CH:30]=1>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[N:1]#[N:2].[C:3]([C@@:8]1([N:16]2[C:26]3[N:25]=[C:23]([NH2:24])[NH:22][C:20](=[O:21])[C:19]=3[N:18]=[CH:17]2)[O:15][C@H:12]([CH2:13][O:14][C:33]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[C:32]2[CH:31]=[CH:30][C:29]([O:28][CH3:27])=[CH:50][CH:49]=2)[C@@H:10]([OH:11])[CH2:9]1)(=[O:7])[CH:4]([CH3:6])[CH3:5]
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: CC(C)C(=O)[C@]1(n2cnc3c(=O)[nH]c(N)nc32)C[C@H](O)[C@@H](CO)O1
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: c1ccncc1
Product: COc1ccc(C(OC[C@H]2O[C@@](C(=O)C(C)C)(n3cnc4c(=O)[nH]c(N)nc43)C[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reaction time: 15 h

Procedure:
The tritylation procedure of Jones45 was modified such that no DMAP was used. To 3.37 g (10.0 mmol) of N2 -isobutyryl-2'-deoxyguanosine (that was first concentrated from dry pyridine) in 50 mL of dry pyridine, was added 4.06 g (12.0 mmol, 1.20 equiv.) of 4,4'-dimethoxytrityl chloride. The reaction was stirred for 15 h, and then concentrated. The residue was partitioned between CH2Cl2 and 0.5% aq. NaHCO3, shaken, and separated. The organic layer was washed with 0.5% aq. NaHCO3 and dried. The crude product was purified by flash chromatography.
Reaction SMILES: [Cl:1][C:2]1[C:7](Cl)=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([Cl:16])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[CH:5]=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([Cl:16])[CH:10]=2)[CH:7]=1
Reactant: Fc1ccc(-c2ccnc(Cl)c2Cl)cc1Cl
Reactant: C1COCCN1
Product: Fc1ccc(-c2cc(Cl)nc(N3CCOCC3)c2)cc1Cl

Procedure:
Stir the solution of 2,3-dichloro-4-(3-chloro-4-fluoro-phenyl)-pyridine (100 mg) in morpholine (2 mL) 3 hours at 80° C., concentrate, partition between H2O and EtOAc, dry over Na2SO4, and concentrate under vacuum. Purify by preparative TLC (3:1 hexanes/EtOAc) to give 4-[6-chloro-4-(3-chloro-4-fluoro-phenyl)-pyridin-2-yl]-morpholine.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([OH:9])=O.ON1C(=O)CCC1=O.Cl.C(N=C=NCCCN(C)C)C.[NH2:30][CH2:31][CH2:32][CH2:33][S:34][C:35]1[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=1>C(Cl)Cl>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:30][CH2:31][CH2:32][CH2:33][S:34][C:35]1[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=1)=[O:9]
Reactant: NCCCSc1ccncc1
Reactant: O=C(O)Cc1cccs1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: ClCCl
Product: O=C(Cc1cccs1)NCCCSc1ccncc1
Yield: 86.3 %

Procedure:
To a solution of 913 mg (6.42 mmol) of 2-thienylacetic acid and 961 mg (8.35 mmol) of N-hydroxysuccinimide in 65 ml of methylene chloride, 1.48 g (7.70 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added under ice-cooling with stirring. The mixture was stirred at room temperature for 1 hour. Further, 1.08 g (6.42 mmol) of 4-(3-aminopropylthio)pyridine was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was washed with water and dried, and then the solvent was distilled off. The residue was purified by column chromatography (eluent: methanol/ethyl acetate=1:10) to obtain powder. The powder thus obtained was washed with ether and dried to obtain 1.62 g of the desired compound yield: 86.3%, pale yellow powder). mp: 62.0°-63.0° C.
Reaction SMILES: [CH2:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([OH:10])[C:4]=2[CH2:3][CH2:2]1.Cl[CH:12](Cl)[O:13]C>ClCCl.Cl[Ti](Cl)(Cl)Cl>[OH:10][C:5]1[C:4]2[CH2:3][CH2:2][CH2:1][C:9]=2[C:8]([CH:12]=[O:13])=[CH:7][CH:6]=1
Reactant: Oc1cccc2c1CCC2
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: O=Cc1ccc(O)c2c1CCC2
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of 2,3-dihydro-1H-inden-4-ol (3.0 g, 22.36 mmol, 1.00 equiv) in dichloromethane (20 ml) and TiCl4 (7.66 g, 40.38 mmol, 1.80 equiv). After 5 minutes, dichloro(methoxy)methane (2.81 g, 24.44 mmol, 1.10 equiv) was added at 0° C. in a water/ice bath and the resulting solution stirred for 3 h at 0° C. The reaction was then quenched by the addition of 25 mL of water. The resulting solution was extracted with 2×150 mL of dichloromethane. The organic layers were combined, washed with 1×50 mL of H2O, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:2.3). This resulted in 1.26 g (35%) of 7-hydroxy-2,3-dihydro-1H-indene-4-carbaldehyde as a light yellow solid. Mass spectrum (ESI, m/z): Calcd. for C10H10O2, 163.1 (M+H). found 163.1.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[Cl:10].[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1.O>N1C=CC=CC=1>[Cl:10][C:3]1[CH:4]=[C:5]([C:6]#[N:7])[CH:8]=[CH:9][C:2]=1[NH:1][S:17]([C:14]1[CH:15]=[CH:16][C:11]([CH3:21])=[CH:12][CH:13]=1)(=[O:19])=[O:18]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: N#Cc1ccc(N)c(Cl)c1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)Nc2ccc(C#N)cc2Cl)cc1
Yield: 54.7 %

Procedure:
4-Amino-3-chlorobenzonitrile (1.50 g (9.83 mmol)) was dissolved in 5.0 ml of pyridine. To this, p-toluenesulfonyl chloride (1.90 g (9.97 mmol)) was added under cooling with ice and with stirring. After stirring for 18 hours at room temperature, water (100 ml) was added to the reaction mixture to bring about separation of crystals. The crystals were filtered, washed with water and then dissolved in an aqueous solution of sodium hydroxide. The resulting solution was washed with diethyl ether, and the water layer was made acidic again with hydrochloric acid and extracted with chloroform. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 1.65 g (55%) of 2′-chloro-4′-cyano-p-toluenesulfonanilide as white crystals.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]#[N:11].Br[CH2:15][CH:16](Br)[CH3:17].[H-].[Na+]>CCOCC.CS(C)=O>[F:1][C:2]([F:12])([F:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1([C:10]#[N:11])[CH2:17][CH2:16][CH2:15]1
Reactant: CC(Br)CBr
Reactant: N#CCc1ccccc1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOCC
Product: N#CC1(c2ccccc2C(F)(F)F)CCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 12.6 g of (2-Trifluoromethyl-phenyl)-acetonitrile and 7.6 ml of 1,2-dibromopropane in 36 ml ether were added slowly through a dropping funnel to a suspension of 3.62 g of sodium hydride in 85 ml DMSO at 0° C. After addition, the ice-water bath was allowed to warm up to room temperature slowly and the reaction mixture was stirred at room temperature overnight. The reaction was carefully quenched with isopropyl and H2O. The suspension became clear. The organic layer was separated, and the aqueous layer was extracted twice with ether. The combined organic extracts were combined, dried and concentrated by evaporation in a vacuum. The residue was purified by column chromatography on silica-gel (EtOAc-hexane 2%-4%) to yield 8.5 g of product as a white solid.