Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.S(Cl)([Cl:14])=O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([Cl:14])=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1ccc(F)cc1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)Cc1ccc(F)cc1
Temperature: 60 °C

Procedure:
4-Fluorophenylacetic acid [starting compound B] (15 g) was dissolved in thionyl chloride (15 ml) to prepare a solution which was then heated at 60° C. for one hr. Excess thionyl chloride was removed by evaporation under the reduced pressure to give 4-fluorophenylacetyl chloride. The acid chloride was dissolved in acetone (200 ml). Ammonium acetate (112 g) was added to the solution, and the mixture was stirred at room temperature for 17 hr. An aqueous saturated sodium hydrogencarbonate solution (150 ml) was added thereto, and the mixture was stirred at room temperature for one hr. The reaction solution was then extracted with chloroform, and the solvent in the extract was removed by evaporation to give a crude crystal. The resultant crude crystal was washed with a hexane/ethyl acetate (2/1) mixed solution to give 4-fluorophenylacetamide (10.5 g, yield 70%).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:20])[NH:10][C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[NH2:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:28][CH2:29][C:30](Cl)=[O:31]>C1COCC1>[CH2:1]([O:8][C:9](=[O:20])[NH:10][C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[NH:19][C:30](=[O:31])[CH2:29][Cl:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)CCl
Reactant: COc1cccc(N)c1NC(=O)OCc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cccc(NC(=O)CCl)c1NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a cool solution of (2-amino-6-methoxyphenyl)carbamic acid benzyl ester (9.5 g; 34.9 mmol) and triethylamine (5.8 ml; 42 mmol) in anhydrous THF (90 ml), chloroacetylchloride (3.3 ml; 42 mmol) was added dropwise. The mixture was stirred at 0° C. for 2 hours, the solvent was evaporated and the residue was dissolved in ethyl acetate. The organic layer was washed with 10% aqueous HCl and diluted aqueous Na2 CO3 then it was dried and evaporated. The crude residue was crystallized with n-hexane to give the title compound as a white solid. 10.8 g.
Reaction SMILES: [BH4-].[Na+].[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)[C:12]([CH3:22])([CH3:21])[N:11]=2)=[CH:6][CH:5]=1>CO>[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([C@H:10]2[NH:11][C:12]([CH3:22])([CH3:21])[C@@H:13]([C:15]3[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=3)[CH2:14]2)=[CH:6][CH:5]=1
Reactant: CC1(C)N=C(c2ccc(N)cc2)CC1c1ccncc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC1(C)N[C@H](c2ccc(N)cc2)C[C@@H]1c1ccncc1
Reaction time: 8 h

Procedure:
0.55 G. of sodium borohydride are added to a solution of 1.85 g. of 4-[2-(p-aminophenyl)-5,5-dimethyl-1-pyrrolin-4-yl]-pyridine in 18.5 ml. of methanol and the mixture is stirred at room temperature for 2 hours. Then, an additional 0.55 g. of sodium borohydride are added and the reaction mixture is left to stand at room temperature overnight. The reaction mixture is then evaporated under reduced pressure and the resulting residue taken up in water and extracted three times with methylene chloride. The organic phase is dried over sodium sulfate and evaporated under reduced pressure. The resulting crude product is chromatographed on silica gel with chloroform/methanol/ethyl acetate/ammonia (60:10:2:1). The material obtained, after crystallization with ether, yields 4-[cis-5-(p-aminophenyl)-2,2-dimethyl-3-pyrrolidinyl]-pyridine of melting point 119°-120° C. The trihydrochloride, recrystallized from methanol/ether, has a melting point of 223°-226° C.
Reaction SMILES: [CH3:1][C:2]([CH3:16])=[CH:3][CH2:4][CH2:5][C:6]1[CH2:11][CH2:10][CH:9]([CH2:12][C:13](Cl)=[O:14])[CH2:8][CH:7]=1.[C:17]1([O:23][CH3:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl>ClCCl>[CH3:1][C:2]([CH3:16])=[CH:3][CH2:4][CH2:5][C:6]1[CH2:11][CH2:10][CH:9]([CH2:12][C:13]([C:20]2[CH:21]=[CH:22][C:17]([O:23][CH3:24])=[CH:18][CH:19]=2)=[O:14])[CH2:8][CH:7]=1
Reactant: COc1ccccc1
Reactant: CC(C)=CCCC1=CCC(CC(=O)Cl)CC1
Agent: Cl
Solvent: ClCCl
Product: COc1ccc(C(=O)CC2CC=C(CCC=C(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of acid chloride 2C (R=4-Methyl-3-pentenyl) (10 g) in anhydrous dichloromethane (100 mL) is added dropwise to a mixture of ferric chloride (7.8 g) and anisole 2D (4.5 g) in dichloromethane (175 mL), cooled in an ice/ethanol bath. The resulting mixture is gradually warmed to room temperature and stirred overnight. The mixture is poured into 25% HCl (150 mL) and stirred for 30 minutes. The aqueous layer is extracted with dichloromethane, and the combined organic layers are sequentially washed with water, sodium bicarbonate, and water, then dried over magnesium sulfate. The solution is concentrated in vacuo.
Reaction SMILES: [CH3:1][CH:2]([CH3:16])[CH2:3][C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9]2)=[O:5].[Cl:17][C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([Cl:27])[C:25]=1[OH:26])[CH:21]=O>>[Cl:17][C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([Cl:27])[C:25]=1[OH:26])[CH:21]=[C:9]1[C:8]2[C:12](=[CH:13][CH:14]=[C:6]([C:4](=[O:5])[CH2:3][CH:2]([CH3:16])[CH3:1])[CH:7]=2)[NH:11][C:10]1=[O:15]
Reactant: O=Cc1cc(Cl)c(O)c(Cl)c1
Reactant: CC(C)CC(=O)c1ccc2c(c1)CC(=O)N2
Product: CC(C)CC(=O)c1ccc2c(c1)C(=Cc1cc(Cl)c(O)c(Cl)c1)C(=O)N2

Procedure:
The title compound was synthesized in an identical manner to example 2 except 5-(3-methyl-butanoyl)-1,3-dihydro-indol-2-one was used in place of 5-(2methyl-thiazol4-yl)- 1,3-dihydro-indol-2-one and 3,5-dichloro-4-hydroxy-benzaldehyde was used in place of 3,5-bromo-4-hydroxy-benzaldehyde. 1H NMR (DMSO-d6): δ11.05 (s, 1H); 10.99 (s, 1H1); 8.63 (s, 1H); 8.28 (s, 1H); 7.92 (s, 1H); 7.85 (d, J=8.2, 1H); 7.77 (s, 1H); 6.89 (d, J=8.2, 1H); 2.84 (d, J=6.8, 2H); 2.21-2.08 (m, 1H); 0.92 (d, J=6.8, 6H). ESI-MS: m/z 388 (m−H)−.
Reaction SMILES: C(O)(=O)CCCCCCCCC#CC#CCCCCCCCCCC.CO.C(Cl)(Cl)Cl.[C:32]([O:58][CH3:59])(=[O:57])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]#[C:42][C:43]#[C:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54]CC>S(=O)(=O)(O)O.C(O)C>[C:32]([O:58][CH3:59])(=[O:57])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]#[C:42][C:43]#[C:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54]
Reactant: CCCCCCCCCCCCC#CC#CCCCCCCCCC(=O)OC
Agent: CCCCCCCCCCC#CC#CCCCCCCCCC(=O)O
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCCCCCCCCCC#CC#CCCCCCCCCC(=O)OC
Temperature: 25 °C

Procedure:
10,12-tricosadiynoic acid (10 gm, GFS Chemicals) was dissolved in a solution containing 10 ml methanol (HPLC grade) and 10 ml chloroform (HPLC grade). The solution was stirred at room temperature and 10 drops of neat sulfuric acid was added drop wise. The solution was warmed to 100° F. for 2 hour. The reaction mixture was purified using column chromatography. The product (MeTDA) was dried using a rotovap and the material stored in a chloroform solution. The solid form of MeTDA was very unstable to polymerization and therefore kept dissolved in organic solutions. Alcoholic solutions of MePDA and MeTDA: Solids MePDA or MeTDA were dissolved in reagent grade ethanol to a concentration of 150 mg/ml. An residual polymer was removed by filtration through Whatman No. 1 filter paper. The solutions was held at room temperature or slightly above (70-75° F.) to avoid crystallization or precipitation.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[CH:18][C:17]([C:20]3[N:25]4[CH:26]=[C:27]([C:29](OCC)=[O:30])[N:28]=[C:24]4[C:23]([N:34]4[CH2:39][CH2:38][S:37](=[O:41])(=[O:40])[CH2:36][CH2:35]4)=[N:22][CH:21]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3].[NH4+].[Cl-]>C1COCC1>[O:41]=[S:37]1(=[O:40])[CH2:38][CH2:39][N:34]([C:23]2[C:24]3[N:25]([CH:26]=[C:27]([CH2:29][OH:30])[N:28]=3)[C:20]([C:17]3[CH:16]=[CH:15][C:14]([N:11]4[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]4)=[N:19][CH:18]=3)=[CH:21][N:22]=2)[CH2:35][CH2:36]1
Reactant: CCOC(=O)c1cn2c(-c3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)nc3)cnc(N3CCS(=O)(=O)CC3)c2n1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cnc(N4CCS(=O)(=O)CC4)c4nc(CO)cn34)cn2)CC1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of compound 89a (107 mg, 0.183 mmol) in 18 mL of THF at 0° C. was added LiAlH4 (0.183 mL, 0.183 mmol, 1.0M in THF). The reaction was stirred at 0° C. for 3 h. The mixture was treated with 20 mL of saturated NH4Cl solution and then extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, and filtered. The solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography on silica gel (0-100% EtOAc/heptane) to give compound 89b as an off white solid. 1H-NMR (2:1 CDCl3/CD3OD; 400 MHz) δ: 8.34 (s, 1H), 7.76 (d, J=8.8 Hz, 1H), 7.65 (s, 1H), 7.34 (s, 1H), 6.88 (d, J=8.8 Hz, 1H), 4.78 (br. s., 6H), 3.68 (d, J=3.2 Hz, 4H), 3.60 (br. s., 4H), 3.23 (br. s., 4H), 1.51 (s, 9H). Mass spectrum (LCMS, ESI pos.): Calcd. for C25H33N7O5S, 544.2 (M+H). found 544.3.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([CH3:8])[CH:7]=1.C([N-]C(C)C)(C)C.[Li+].CN(C)[CH:20]=[O:21].C(OCC)(=O)C>C1COCC1.C(=O)=O.CC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([F:9])=[C:4]([CH:3]=1)[CH:20]=[O:21]
Reactant: Cc1cc(Br)ccc1F
Reactant: CN(C)C=O
Agent: CC(C)[N-]C(C)C
Agent: O=C=O
Agent: [Li+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(Br)cc(C=O)c1F
Temperature: 25 °C
Yield: 94.1 %

Procedure:
To a solution of 5-bromo-2-fluorotoluene 169 (1.0 g, 5.29 mmol.) in anhydrous THF (4 mL) cooled in dry ice/acetone bath was added a 2 M solution of lithium diisopropylamide (2.6 mL, 5.2 mmol.). The reaction mixture was stirred for 1 hour in the dry ice/acetone bath. Anhydrous dimethylformamide (0.46 g, 6.35 mmol.) was added in a dropwise manner. The reaction mixture was allowed to warm to room temperature in 3 hours. Ethyl acetate (100 mL) was added. The organic layer was washed with 1 N hydrochloric acid, water and brine. The organic layer was dried over sodium sulfate. The organic solvent was evaporated under reduced pressure to afford 5-bromo-2-fluoro-3-methylbenzaldehyde 170 (1.08 g, 4.98 mmol.). The crude product was used in the next step without further purification.
Reaction SMILES: [H-].[Na+].[F:3][CH2:4][CH2:5][CH2:6][OH:7].[Br:8][C:9]1[CH:10]=[CH:11][C:12](Cl)=[N:13][CH:14]=1>>[F:3][CH2:4][CH2:5][CH2:6][O:7][C:12]1[CH:11]=[CH:10][C:9]([Br:8])=[CH:14][N:13]=1
Reactant: OCCCF
Reactant: Clc1ccc(Br)cn1
Agent: [H-]
Agent: [Na+]
Product: FCCCOc1ccc(Br)cn1
Yield: 98.6 %

Procedure:
2-(3-Fluoropropoxy)-5-bromopyridine (97c, 600 mg, 98%) was prepared in the same manner as in Preparation Example 13 using sodium hydride (94 mg, 3.90 mmol), 3-fluoropropanol (305 mg, 3.90 mmol) and 5-bromo-2-chloropyridine (96, 500 mg, 2.60 mmol).
Reaction SMILES: C1N2CN3CN(C2)CN1C3.[CH3:11][O:12][C:13](=[O:31])[CH2:14][C:15]1[CH:20]=[C:19]([Br:21])[C:18]([O:22][C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)=[C:17]([Br:30])[CH:16]=1.FC(F)(F)[C:34](O)=[O:35].Cl>>[CH3:11][O:12][C:13](=[O:31])[CH2:14][C:15]1[CH:20]=[C:19]([Br:21])[C:18]([O:22][C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([CH:34]=[O:35])[CH:24]=2)=[C:17]([Br:30])[CH:16]=1
Reactant: COC(=O)Cc1cc(Br)c(Oc2ccc(O)cc2)c(Br)c1
Reactant: O=C(O)C(F)(F)F
Agent: C1N2CN3CN1CN(C2)C3
Agent: Cl
Product: COC(=O)Cc1cc(Br)c(Oc2ccc(O)c(C=O)c2)c(Br)c1
Temperature: 95 °C
Reaction time: 16 h
Yield: 38 %

Procedure:
Hexamethylenetetramine (262 mg, 1.87 mmol) was added to a solution of methyl[3,5-dibromo-4-(4-hydroxyphenoxy)phenyl]acetate (370 mg, 0.89 mmol) and trifluoroacetic acid (1.5 mL). The reaction mixture was stirred for 16 hours at 95° C. before cooling to room temperature. Hydrochloric acid (3 mL, 2 N) was added and the reaction mixture was stirred for one hour and extracted with chloroform. The organic phase was concentrated in vacuo and dissolved in ethyl acetate. The organic phase was washed with hydrochloric acid (2 N), water and brine, dried over Na2SO4 and concentrated. The residue was purified on a column (MPLC, silica, gradient eluent: n-heptane/ethyl acetate from 1:0 to 4:1) to give yielded methyl[3,5-dibromo-4-(3-formyl-4-hydroxyphenoxy)phenyl]acetate as a white solid (150 mg, 38%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[C:19]([F:27])[CH:18]=3)[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:12]=2)=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:33]1[N:34]=[CH:35][S:36][CH:37]=1)CCC.[Cl-]>O1CCOCC1.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>[F:27][C:19]1[CH:18]=[C:17]([N:9]2[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:12]=[C:8]2[C:5]2[CH:6]=[CH:7][C:2]([C:33]3[N:34]=[CH:35][S:36][CH:37]=3)=[CH:3][CH:4]=2)[CH:22]=[CH:21][C:20]=1[S:23]([CH3:26])(=[O:25])=[O:24]
Reactant: CS(=O)(=O)c1ccc(-n2cc(C(F)(F)F)nc2-c2ccc(Br)cc2)cc1F
Reactant: CCCC[Sn](CCCC)(CCCC)c1cscn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccc(-n2cc(C(F)(F)F)nc2-c2ccc(-c3cscn3)cc2)cc1F
Yield: 87.5 %

Procedure:
To a stirred solution of 2-(4-bromophenyl)-1-[3-fluoro-4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazole (0.361 g, 0.78 mmol) in 1,4-dioxane (12 mL) was added 4-(tributylstannyl)thiazole (0.35 g, 0.94 mmol), lithiun chloride (0.083 g, 1.95 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.090 g, 0.078 mmol) at room temperature under nitrogen. The mixture was heated at reflux temperature for 3 hours. After cooling, volatiles were removed by evaporation. The residue was redissolved in ethyl acetate (30 mL) and the whole washed with water and brine. After dried over MgSO4 and concentration in vacuo. The crude mixture was purified by flash chromatography eluting with hexane/ethyl acetate (3/1). The resulting solid was recrystallized from ethyl acetate-hexane to give the title compound (0.319 g, 87.6% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:16]3=[C:17]([C@@H:19]4[CH2:24][NH:23][CH2:22][CH2:21][C@@H:20]4[N:15]3[CH2:14][CH2:13][CH2:12]2)[CH:18]=1.C=O.[CH:27](O)=O.C([O-])([O-])=O.[Na+].[Na+]>O>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:16]3=[C:17]([C@@H:19]4[CH2:24][N:23]([CH3:27])[CH2:22][CH2:21][C@@H:20]4[N:15]3[CH2:14][CH2:13][CH2:12]2)[CH:18]=1
Reactant: Fc1cccc(F)c1-c1cc2c3c(c1)[C@@H]1CNCC[C@@H]1N3CCC2
Reactant: O=CO
Agent: C=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CN1CC[C@H]2[C@@H](C1)c1cc(-c3c(F)cccc3F)cc3c1N2CCC3
Temperature: 80 °C
Yield: 62.7 %

Procedure:
A mixture of (7aS,11aR)-2-(2,6-difluorophenyl)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3′,4′:4,5]pyrrolo[3,2,1-ij]quinoline (0.050, 0.15 mmol), HCHO (0.20 mL, 2.9 mmol) and formic acid (1.0 mL, 2.9 mmol) was heated at 80° C. for 4 h and cooled to room temperature. Water (5.0 mL) was added and the solution was basified with saturated Na2CO3 until pH>8. The mixture was extracted with CH2Cl2 (3×10 mL), dried (Na2SO4) and flash column chromatography (1–5% MeOH in CHCl3) gave the title compound (0.032 g, 62%) as a white foam. 1H NMR (CDCl3, 300 MHz) δ 2.00–2.20 (m, 5H), 2.20–2.50 (m, 4H), 2.55–2.68 (m, 1H), 2.68–2.82 (m, 3H), 2.86–2.98 (m, 1H), 3.28–3.42 (m, 3H), 6.90–7.08 (m, 4H), 7.14–7.25 (m, 1H) ppm. MS (ESI): 341 (base, M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([CH3:13])([CH3:12])[CH:6]=[CH:5]2.[CH3:14][C:15]([CH:17]=[CH2:18])=O.[N+](C1C=C(S(O)(=O)=O)C=CC=1)([O-])=O.Cl>C(O)C.[Cl-].[Zn+2].[Cl-]>[CH3:12][C:7]1([CH3:13])[O:8][C:9]2=[CH:10][C:11]3[C:17]([CH3:18])=[CH:15][CH:14]=[N:1][C:2]=3[CH:3]=[C:4]2[CH:5]=[CH:6]1
Reactant: C=CC(C)=O
Reactant: CC1(C)C=Cc2cc(N)ccc2O1
Agent: Cl
Agent: O=[N+]([O-])c1cccc(S(=O)(=O)O)c1
Agent: [Cl-]
Solvent: CCO
Product: Cc1ccnc2cc3c(cc12)OC(C)(C)C=C3
Temperature: 110 °C
Reaction time: 5 h
Yield: 38 %

Procedure:
To a solution of 6-amino-2,2-dimethylchromene (10.1 g, 57.7 mmol) in ethanol (500 mL), methylvinylketone (33.0 mL, 404 mmol), m-nitrobenzenesulfonic acid (21.1 g, 104 mmol), zinc chloride (1.97 g, 14.4 mmol) and 35% hydrochloric acid (24 mL, 289 mmol) were added at room temperature and the resulting mixture was stirred at 110° C. for 5 hours. Upon the completion of the reaction, ethanol was distilled off, water was added, and the resulting solution was neutralized with sodium hydrogencarbonate and extracted with ethyl acetate. The resulting organic phase was washed with sodium chloride aqueous solution, and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by medium pressure column chromatography (hexane/ethyl acetate=3/1) and the aimed product was obtained (yield: 38%).
Reaction SMILES: [CH3:1][CH:2]([O:4][CH2:5][CH2:6][O:7][C:8]1[N:16]=[C:15]2[C:11]([N:12]=[C:13]([O:23][CH3:24])[N:14]2C2CCCCO2)=[C:10]([NH2:25])[N:9]=1)[CH3:3].[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29]>CO>[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29].[CH3:3][CH:2]([O:4][CH2:5][CH2:6][O:7][C:8]1[N:16]=[C:15]2[C:11]([N:12]=[C:13]([O:23][CH3:24])[NH:14]2)=[C:10]([NH2:25])[N:9]=1)[CH3:1]
Reactant: COc1nc2c(N)nc(OCCOC(C)C)nc2n1C1CCCCO1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: COc1nc2c(N)nc(OCCOC(C)C)nc2[nH]1
Reaction time: 0.17 h

Procedure:
To 2-({2-[(1-methylethyl)oxy]ethyl}oxy)-8-(methoxy)-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (4.5 g, 14 mmol) in methanol (30 ml) was added trifluoroacetic acid (8 ml), stirred for 10 min and held at room temperature for 2 days. Filtered to give the crude product which was purified by preparative hplc (Gilson GX-281 instrument with YMC C18 5.0 um column (250×20 mm) eluting with water containing TFA (0.1%): acetonitrile 30-60%. This gave the title compound 2.1 g.
Reaction SMILES: N1(C(OC(C)(C)C)=O)CCC[C@H]1[C:3]([NH:5][C@@H:6]([C:17]([NH:19][C@H:20]([C:28]([NH:30][C@@H:31]([C:42]([NH:44][C@H:45]([C:50]([N:52]([CH3:61])[C@H:53]([C:58]([NH2:60])=[O:59])[CH2:54][CH2:55][S:56][CH3:57])=[O:51])CC(C)C)=[O:43])[CH2:32][C:33]1C2C(=CC=CC=2)[NH:35][CH:34]=1)=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:18])[CH2:7][C:8]1[C:16]2[C:11](=CC=CC=2)[NH:10][CH:9]=1)=[O:4].F[C:73](F)(F)[C:74](O)=O>CSC.C(S)(S)C>[NH:30]1[CH2:74][CH2:73][CH2:21][CH2:20][C@H:28]1[C:3]([NH:5][C@@H:6]([C:17]([NH:19][C@H:20]([C:28]([NH:30][C@@H:31]([C:42]([NH:44][C@H:45]([C:50]([N:52]([CH3:61])[C@H:53]([C:58]([NH2:60])=[O:59])[CH2:54][CH2:55][S:56][CH3:57])=[O:51])[CH2:16][CH:8]([CH3:9])[CH3:7])=[O:43])[CH2:32][C:33]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[NH:35][CH:34]=1)=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:18])[CH2:7][C:8]1[C:16]2[C:11](=[CH:33][CH:32]=[CH:31][CH:42]=2)[NH:10][CH:9]=1)=[O:4]
Reactant: CSCC[C@@H](C(N)=O)N(C)C(=O)[C@H](CC(C)C)NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Reactant: O=C(O)C(F)(F)F
Agent: CC(S)S
Solvent: CSC
Product: CSCC[C@@H](C(N)=O)N(C)C(=O)[C@H](CC(C)C)NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@@H]1CCCCN1

Procedure:
Condensation of BocPro-DTrp-PheOH (Example 33, 1.49 g.) and HDTrp-Leu-MeMetNH2 trifluoroacetate salt (1.25 g.) using dicyclohexylcarbodiimide and 1-hydroxybenzotriazole gave BocPro-DTrp-Phe-DTrp-Leu-MeMetNH2 in 60% yield. De-t-butoxycarbonylation of BocPro-DTrp-Phe-DTrp-Leu-MeMetNH2 (1.50 g.) using trifluoroacetic acid in dimethyl sulfide and ethanedithiol gave HPro-DTrp-Phe-DTrp-Leu-MeMetNH2, which was isolated as the amorphous white solid phosphate (1:2) salt dihydrate in 57% yield.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([NH:11][C:12](=[O:14])[CH3:13])=[C:4]([F:15])[CH:3]=1>C(OCC)(=O)C.[Ni]>[NH2:8][C:7]1[C:2]([Cl:1])=[CH:3][C:4]([F:15])=[C:5]([NH:11][C:12](=[O:14])[CH3:13])[CH:6]=1
Reactant: CC(=O)Nc1cc([N+](=O)[O-])c(Cl)cc1F
Agent: [Ni]
Solvent: CCOC(C)=O
Product: CC(=O)Nc1cc(N)c(Cl)cc1F
Temperature: 77.5 °C
Yield: 93.3 %

Procedure:
In a 1 L autoclave, 23.25 g (0.1 mole) of N-(4-chloro-2-fluoro-5-nitrophenyl)acetamide and 1.2 g of Ni-catalyst were suspended under nitrogen in 500 mL of ethyl acetate. The autoclave was purged two times with nitrogen at 500 kPa (5 atmospheres) and once with hydrogen at 500 kPa (5 atmospheres). 500 kPa (5 atmospheres) of hydrogen was then applied and the reactor heated to 75-80° C. After 6 hours the autoclave was cooled to room temperature. The catalyst was filtered off and the solvent removed under reduced pressure. The solid was triturated with petroleum ether and filtered to give 18.9 g of the title compound as a crystalline solid melting at 142-143° C. (purity: 99.4% by HPLC).
Reaction SMILES: Cl[CH:2]([CH3:14])[C:3]([NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].[Cl-].[Cl-].[Cl-].[Al+3]>O.CO>[CH3:14][CH:2]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6][NH:5][C:3]1=[O:4]
Reactant: CC(Cl)C(=O)NCCc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CO
Solvent: O
Product: CC1C(=O)NCCc2ccccc21
Temperature: 150 °C

Procedure:
8.0 g (37 mmol) 2-chloro-N-(2-phenylethyl)-propanamide and 15 g (112 mmol) aluminium trichloride are carefully mixed at 90° C. and heated to 150° C. for 6 h. The mixture is diluted with water and methanol and extracted with EtOAc. The combined organic phases are dried with Na2SO4, concentrated i. vac. and purified by chromatography.
Reaction SMILES: OS(O)(=O)=O.[Br:6][C:7]1[CH:23]=[CH:22][C:10]([O:11][C:12]2[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:13]=2[C:14]([OH:16])=O)=[CH:9][CH:8]=1>>[Br:6][C:7]1[CH:8]=[CH:9][C:10]2[O:11][C:12]3[C:13](=[CH:17][C:18]([I:21])=[CH:19][CH:20]=3)[C:14](=[O:16])[C:22]=2[CH:23]=1
Reactant: O=C(O)c1cc(I)ccc1Oc1ccc(Br)cc1
Agent: O=S(=O)(O)O
Product: O=c1c2cc(Br)ccc2oc2ccc(I)cc12
Temperature: 60 °C
Yield: 84.9 %

Procedure:
H2SO4 (73.3 ml, 1375 mmol) was added to 2-(4-bromophenoxy)-5-iodobenzoic acid (28.800 g, 68.7 mmol) at rt. The resulting dark mixture was heated to 60° C. for 45 minutes. The brown solution was poured slowly onto ice-water (1 L) with stirring. The resulting tan precipitant was collected by filtration, washed with water a 1 N solution of NaOH, again with water, and dried under reduced pressure to afford 2-bromo-7-iodo-9H-xanthen-9-one (23.4 g) as a tan solid that was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](=O)[N:7](C)[C:6]=2[CH:12]=1.O.[OH-].[K+]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([SH:9])=[C:6]([NH:7][CH3:8])[CH:12]=1
Reactant: Cn1c(=O)sc2ccc(Cl)cc21
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CNc1cc(Cl)ccc1S
Reaction time: 3 h
Yield: 98.1 %

Procedure:
5-Chloro-3-methyl-2-benzothiazolinone (70.0 g) was added to a mixture of water (118 ml), ethanol (350 ml) and potassium hydroxide (78.6 g). The solution was refluxed with stirring for three hours. After the solvent was evaporated under reduced pressure, the residual oil was dissolved in water. After removal of insoluble yellow crystals by filtration, the filtrate was neutralized with 2N-acetic acid, then resulting oily substance was extracted with ethyl acetate. The extract was washed with water, dried (Na2SO4), and evaporated to give oily 4-chloro-2-methylaminothiophenol (59.7 g). To a solution of sodium hydroxide (14.0 g) in water (100 ml) was added 4-chloro-2-methylaminothiophenol (59.6 g) with stirring, and then was added dropwise a solution of chloroacetic acid (34.0 g) in water (50 ml) at 20-25° C., followed by heating almost to boiling for three hours.