Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.S(=O)=O.C1COCC1.[S:29](Cl)([Cl:32])(=[O:31])=[O:30]>C(OCC)C.C1COCC1.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:29]([Cl:32])(=[O:31])=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: Brc1ccccc1OCc1ccccc1
Agent: O=S=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: O=S(=O)(Cl)c1ccccc1OCc1ccccc1
Temperature: 25 °C
Yield: 72 %

Procedure:
To 2-benzyloxy-1-bromo benzene (4.0 g, 15.2 mmol) in diethyl ether/THF (1:1, 100 mL) at −78° C. was added n-butyllithium (2 equiv.). After 30 min sulfur dioxide/THF (1:1, 40 mL) was added. The reaction warmed to room temperature over 1.5 h and the solvent was removed under reduced pressure. Hexanes (75 mL) was added and the reaction was cooled to 0° C. prior to adding sulfuryl chloride (2 equiv.). After 15 min the reaction was poured into water, washed with brine and dried over magnesium sulfate to give a colorless oil. Chromatography silica gel, eluting with 1:1 hexanes/diethyl ether gave 2-benzyloxy-benzenesulfonyl chloride (3.11 g, 72%) as a colorless solid. 1H NMR (CDCl3) 8.00(d,1H), 7.65(t,1H), 7.54(d,2H), 7.38(m,3H), 7.12(m,2H), 5.37 (s,2H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:28]=[CH:27][C:8]([CH2:9][N:10]2[C:18]3[C:13](=[C:14]([CH2:19][CH:20]4[S:24][C:23](=[O:25])[NH:22][C:21]4=[O:26])[CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)=[CH:7][CH:6]=1)=O.O.[OH-].[Li+].O1CCCC1.O>CO>[C:3](=[C:5]1[CH:6]=[CH:7][C:8]([CH2:9][N:10]2[C:18]3[C:13](=[C:14]([CH2:19][CH:20]4[S:24][C:23](=[O:25])[NH:22][C:21]4=[O:26])[CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)=[CH:27][CH2:28]1)=[O:2]
Reactant: COC(=O)c1ccc(Cn2ccc3c(CC4SC(=O)NC4=O)cccc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C=C1C=CC(Cn2ccc3c(CC4SC(=O)NC4=O)cccc32)=CC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 83.3 %

Procedure:
To a mixture of 2.00 g of 5-[1-(4-methoxycarbonylbenzyl)indol-4-yl]methyl-2,4-thiazolidinedione prepared in Example 9 and 0.43 g of lithium hydroxide monohydrate, there were, in order, added 40 ml of tetrahydrofuran, 40 ml of water and 20 ml of methanol and the resulting mixture was stirred at 60° C. for 2 hours. After concentrating the reaction solution to about 40 ml, the concentrate was neutralized with a 10% citric acid aqueous solution, followed by extraction with dichloromethane (100 ml×3). The extract was washed with a saturated common salt solution, dried over anhydrous sodium sulfate, followed by evaporation of the solvent under reduced pressure to give 1.54 g of 5-[1-(4-carbonylbenzyl)indol-4-yl]methyl-2,4-thiazolidinedione as pale yellow crystals. The yield thereof was found to be 80%.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][CH2:7][C:8]([N:10]2[CH2:15][C@H:14]([CH3:16])[N:13]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH2:12][C@H:11]2[CH3:25])=[O:9])=[C:4]([OH:28])[CH:3]=1.Cl[C:30]1[N:38]=[CH:37][CH:36]=[CH:35][C:31]=1[C:32]([OH:34])=[O:33].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C.[Cu].[Cu]I>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][CH2:7][C:8]([N:10]2[CH2:15][C@H:14]([CH3:16])[N:13]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH2:12][C@H:11]2[CH3:25])=[O:9])=[C:4]([CH:3]=1)[O:28][C:30]1[N:38]=[CH:37][CH:36]=[CH:35][C:31]=1[C:32]([OH:34])=[O:33]
Reactant: O=C(O)c1cccnc1Cl
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1O
Agent: [Cu]
Agent: [Cu]I
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1Oc1ncccc1C(=O)O
Temperature: 145 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(4-chloro-2-hydroxy-phenoxy)-1-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-ethanone (0.10 g, 0.25 mmol), and 2-chloro-nicotinic acid (0.045 g, 0.28 mmol) in dimethylformamide (0.75 mL) were added potassium carbonate (0.084 g, 0.60 mmol), copper (0.0050 g, 0.078 mmol) and copper (I) iodide (0.0050 g, 0.0.026 mmol). The resulting mixture was stirred at 145° C. for 2 hours. The reaction was cooled and diluted with ethyl acetate and washed with water. The organic layer was washed with saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated in vacuo. Chromatography on silica gel followed by trituration with methylene chloride/hydrogen chloride in diethyl ether gave the title compound as the hydrochloride salt (0.022 g, LRMS 528.4, 530.4).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[CH3:8][C@@:9]12[C@H:19]3[C@@H:20]([OH:33])[CH2:21][C@:22]4([CH3:32])[C@@:26]([OH:31])([C:27]([CH2:29][OH:30])=[O:28])[CH2:25][CH2:24][C@H:23]4[C@@H:18]3[CH2:17][CH2:16][C:15]1=[CH:14][C:12](=[O:13])[CH2:11][CH2:10]2>C(N(CC)CC)C>[CH3:8][C@@:9]12[C@H:19]3[C@@H:20]([OH:33])[CH2:21][C@:22]4([CH3:32])[C@@:26]([OH:31])([C:27]([CH2:29][OH:30])=[O:28])[CH2:25][CH2:24][C@H:23]4[C@@H:18]3[CH2:17][CH2:16][C:15]1=[CH:14][C:12](=[O:13])[CH2:11][CH2:10]2.[Cl:1][CH2:2][CH2:3][CH2:4][C:5]([O-:6])=[O:13]
Reactant: O=C(Cl)CCCCl
Agent: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1CC[C@]2(O)C(=O)CO
Solvent: CCN(CC)CC
Product: O=C([O-])CCCCl
Reaction time: 72 h

Procedure:
4 portions of 4-chlorobutanoylchloride (0.32 ml×4) and triethylamine (0.3 g×4) were added in 24 hours to a solution of hydrocortisone (1 g) in CHCl, dried over P2O5 and stirred for 3 days. The solution was treated with water, the organic phase was separated, dried (Na2SO4) and deprived of the solvent at reduced pressure. The crude residue was ground with hexane and CH2Cl2 to give a white solid with a 53% yield by weight, which had a melting point (m.p.) of 155° C.
Reaction SMILES: [OH:1][C:2]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)([C:6]1[N:7]=[CH:8][N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4].Br[C:40]1[CH:41]=[CH:42][C:43]([F:50])=[C:44]([NH:46][C:47](=[O:49])[CH3:48])[CH:45]=1>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:50][C:43]1[CH:42]=[CH:41][C:40]([C:33]2[CH:34]=[CH:35][C:30]([C:2]([OH:1])([C:6]3[N:7]=[CH:8][N:9]([C:11]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:10]=3)[CH:3]([CH3:5])[CH3:4])=[CH:31][CH:32]=2)=[CH:45][C:44]=1[NH:46][C:47](=[O:49])[CH3:48]
Reactant: CC(C)C(O)(c1ccc(B(O)O)cc1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CC(=O)Nc1cc(Br)ccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CC(=O)Nc1cc(-c2ccc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)cc2)ccc1F
Yield: 45.2 %

Procedure:
By the reaction in the same manner as in Example 4-(ii) using 4-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]phenylboronic acid (3.50 g), N-(5-bromo-2-fluorophenyl)acetamide (1.17 g) and tetrakis(triphenylphosphine)palladium(0) (0.17 g), the title compound (1.39 g); was obtained as a colorless amorphous powder.
Reaction SMILES: [F:1][C:2]1([F:16])[CH2:7][CH2:6][C@@:5]([C:9]2[N:13]([CH3:14])[N:12]=[CH:11][CH:10]=2)(O)[C@H:4]([OH:15])[CH2:3]1.C(OC)(OC)(OC)C.[Br-].[Li+].C(Br)(=O)C.C(=O)([O-])[O-].[K+].[K+]>ClCCl.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[F:1][C:2]1([F:16])[CH2:3][C@H:4]2[C@:5]([C:9]3[N:13]([CH3:14])[N:12]=[CH:11][CH:10]=3)([O:15]2)[CH2:6][CH2:7]1
Reactant: Cn1nccc1[C@@]1(O)CCC(F)(F)C[C@H]1O
Agent: CC(=O)Br
Agent: COC(C)(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: Cn1nccc1[C@@]12CCC(F)(F)C[C@@H]1O2
Reaction time: 6 h
Yield: 70 %

Procedure:
A solution of the crude (1S,2R)-4,4-difluoro-1-(1-methyl-1H-pyrazol-5-yl)cyclohexane-1,2-diol prepared in Example 102a, trimethyl orthoacetate (1.60 mL, 12.6 mmol) and p-toluenesulfonic acid (48 mg, 0.25 mmol) in dichloromethane (25 mL) was stirred for 45 hours. The reaction solution was concentrated and diluted with acetonitrile (15 mL). Lithium bromide (220 mg, 2.53 mmol) and acetyl bromide (0.93 mL, 12.6 mmol) were added thereto with cooling on ice, and the reaction solution was stirred for 6 hours with cooling on ice. The reaction solution was concentrated and then diluted with methanol (20 mL). Potassium carbonate (1.75 g, 12.7 mmol) was added thereto, and the reaction solution was stirred at room temperature for 2 hours. To the reaction solution, water (50 mL) was added, followed by extraction with ethyl acetate (100 mL). The thus obtained organic layer was dried over anhydrous sodium sulfate. After vacuum concentration, the residue was purified with silica gel chromatography to yield the title compound (752 mg, 70%, 2 steps) as a colorless solid.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH2:10][NH:11][C:12]([C:14]2[NH:23][C:22](=[O:24])[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:25]#[N:26])[CH:20]=3)[N:15]=2)=[O:13])[CH:7]=[CH:8][CH:9]=1.[NH:27]1[CH:31]=[N:30][C:29]([CH2:32][C:33](O)=[O:34])=[N:28]1.C(N(C(C)C)CC)(C)C.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C=O)C>[C:25]([C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[N:15]=[C:14]([C:12]([NH:11][CH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH2:3][NH:2][C:33](=[O:34])[CH2:32][C:29]3[N:30]=[CH:31][NH:27][N:28]=3)[CH:5]=1)=[O:13])[NH:23][C:22]2=[O:24])#[N:26]
Reactant: N#Cc1ccc2nc(C(=O)NCc3cccc(CN)c3)[nH]c(=O)c2c1
Reactant: O=C(O)Cc1nc[nH]n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#Cc1ccc2nc(C(=O)NCc3cccc(CNC(=O)Cc4nc[nH]n4)c3)[nH]c(=O)c2c1
Temperature: 40 °C
Reaction time: 15 h
Yield: 24 %

Procedure:
A solution of N-{[3-(aminomethyl)phenyl]methyl}-6-cyano-4-oxo-3,4-dihydroquinazoline-2-carboxamide hydrochloride obtained in Reference Example 47 (170 mg, 0.460 mmol), 1H-1,2,4-triazol-3-ylacetic acid obtained in Reference Example 15 (70.0 mg, 0.551 mmol), diisopropylethylamine (0.079 mL, 0.460 mmol), 1-[3-(dimethylamino)propyl]-3-ethyl-carbodiimide hydrochloride (106 mg, 0.550 mmol) and 1-hydroxybenzotriazole (74.0 mg, 0.550 mmol) in DMF (10 mL) was stirred at 40° C. for 15 hr. The reaction mixture was concentrated under reduced pressure, and water was added to the residue. The resulting solid was collected by filtration, washed with water and IPE, and dried. The obtained crude crystals were recrystallized from ethyl acetate-IPE to give the title compound as a white powder (49.4 mg, 24%).
Reaction SMILES: O([C@:3]12[CH2:20][C@@H:19]([OH:21])[CH2:18][CH2:17][C@:16]1([CH3:22])[C@@H:15]1[C@H:6]([C@H:7]3[C@@:11]([CH2:13][CH2:14]1)([CH3:12])[C:10](=[O:23])[CH2:9][CH2:8]3)[CH:5]=[CH:4]2)O.O[C@H:25]1CC[C@@]2(C)C(=C[C@@H](O)[C@@H]3[C@@H]2CC[C@@]2(C)[C@H]3CCC2=O)[CH2:26]1>>[C:25]([C@@H:18]1[CH2:17][C@@:16]2([CH3:22])[C:3](=[CH:4][CH2:5][C@@H:6]3[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]3[CH2:8][CH2:9][C:10]2=[O:23])[CH2:20][C@H:19]1[OH:21])#[CH:26]
Reactant: C[C@]12CC[C@H](O)CC1=C[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: C[C@]12CC[C@H]3[C@@H](C=C[C@@]4(OO)C[C@@H](O)CC[C@]34C)[C@@H]1CCC2=O
Product: C#C[C@@H]1C[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]32)C[C@H]1O

Procedure:
Reaction of the less hindered 3β-hydroxy-5α-androstan-17-one 1 with t-butyldimethylsilyl chloride yields the 3β-t-butyldimethylsilyl ether 2. Treatment of this first with catechol phosphochloridate followed by displacement with iodine yields 3β-hydroxy-11β-iodo-5α-androstan-17-one 3-dimethyl-t-butylsilyl ether 3. Protection of the C-17 ketone as the 1,3-dioxolane 4 followed by alkenylation using dialkenyl dilithio cyano cuprate, (RCH=CH)2Cu(CN)Li2 yields 11α-alkenyl-3β-hydroxy-5α-androstan-17-one-3-t-butyldimethylsilyl ether 5. Deprotection of the C-17 ketone and 3β alcohol affords 11α-alkenyl 3β-hydroxy-5α-androstan-17-one 6. If 6 has R=2'-tri-n-butylstannyl ethenyl, then lead tetraacetate oxidation affords 11α-alkynyl-3β-hydroxy-5α-androstan-17-one. 6, (R=C≡CH). ##STR58##
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[C:12]2[NH:20][CH:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][NH:29][C:30](=[O:34])[O:31][CH2:32][CH3:33])[CH2:23][CH2:22]2)=[CH:6][CH:5]=1)([O-])=O.S1C=CC=C1.COCCO.[H][H]>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[C:12]2[NH:20][CH:21]2[CH2:22][CH2:23][N:24]([CH2:27][CH2:28][NH:29][C:30](=[O:34])[O:31][CH2:32][CH3:33])[CH2:25][CH2:26]2)=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: CCOC(=O)NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd]
Solvent: CO
Solvent: c1ccsc1
Solvent: COCCO
Product: CCOC(=O)NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(N)cc2)CC1
Yield: 100 %

Procedure:
A mixture of 24 parts of ethyl [2-[4-[[1-[(4-nitrophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]-ethyl]carbamate, 1 part of a solution of thiophene in methanol 4% and 250 parts of 2-methoxyethanol was hydrogenated at normal pressure and at 50° C. with 3 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 22.5 parts (100%) of ethyl [2-[4-[[1-[(4-aminophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]carbamate as a residue (170).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9]N)[CH:6]=[CH:7][CH:8]=1.[F:11][C:12]1[CH:20]=[C:19]2[C:15]([CH2:16][CH2:17][C:18]2=O)=[CH:14][CH:13]=1>C(O)C.C(O)(=O)C.ClCCl.O>[F:11][C:12]1[CH:20]=[C:19]2[C:15]([CH2:16][C:17]3[C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=4[NH:9][C:18]=32)=[CH:14][CH:13]=1
Reactant: O=C1CCc2ccc(F)cc21
Reactant: COc1cccc(NN)c1
Solvent: CCO
Solvent: ClCCl
Solvent: O
Product: COc1ccc2c3c([nH]c2c1)-c1cc(F)ccc1C3
Temperature: 85 °C

Procedure:
To a solution of 3-methoxyphenyl hydrazine (2.01 g, 11.53 mmol) and 6-fluoro-1-indanone (1.73 g, 11.50 mmol) in ethanol (22 mL) was added glacial acetic acid (3 drops). The solution was stirred at reflux (85° C.) for 15 minutes and cooled to room temperature. Ethanol was removed in vacuo and the resulting brown oil was dissolved in isopropanol (39 mL). Sulfuric acid (36N, 1.28 mL) was added via syringe and the solution was stirred at reflux (90° C.) for 15 hours and subsequently cooled to room temperature. The reaction was then basified to pH 10 via addition of aqueous sodium hydroxide (2% by mass) resulting in the formation of precipitate. The solid was collected by vacuum filtration to yield a brown residue, which was subsequently dissolved in 20 mL dichloromethane, and diluted with 15 mL H2O. The organic layer was partitioned and the aqueous layer was extracted 1×15 mL ethyl acetate and 1×15 mL dichloromethane. Organic layers were pooled, dried over anhydrous magnesium sulfate, and concentrated to yield 55 as a mixture of regioisomers (3:1 55:undesired). Crude product was brought on to the next step without further purification. 1H NMR (600 MHz, CDCl3): δ 8.17 (s, 1H), 7.50 (d, J=8.4 Hz), 7.38-7.41 (dd, 1H, J=8.4, 5.4 Hz), 7.05-7.07 (dd, 1H, J 9.0, 2.4 Hz), 6.927 (d, 1H, J=2.4 Hz), 6.83-6.86 (m, 2H), 3.87 (s, 3H), 3.63 (s, 2H). 13C NMR (150 MHz, CDCl3): δ 162.4 (d, J=241.5 Hz), 156.6, 142.4 (d, J=2.4 Hz), 141.7, 141.3 (d, J=3.0 Hz), 136.8 (d, J=9.6 Hz), 125.8 (d, J=9.2 Hz), 124.0, 119.7, 119.1, 110.3 (d, J=22.7 Hz), 110.0, 104.2 (d, J=24.5 Hz), 96.1, 60.4, 29.8. 19F NMR (CD3CD, 376 MHz): δ −113.9 (m), −115.9 (m); FTIR: cm−1 3381, 1614, 1531, 1464, 1270, 1188, 1157, 859, 814. ESI-HRMS: Calcd. for C16H12FNO+ [M]+: 253.0897, found 253.0894.
Reaction SMILES: C[Si](C)(C)CC[O:5][C:6](=[O:37])[C:7]1[CH:12]=[C:11]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])[CH:10]=[CH:9][C:8]=1[CH2:28][CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:33]([O:32][C:30]([CH2:29][CH2:28][C:8]1[CH:9]=[CH:10][C:11]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[O:19][C:20]=2[CH3:21])=[CH:12][C:7]=1[C:6]([OH:37])=[O:5])=[O:31])([CH3:36])([CH3:34])[CH3:35]
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CCC(=O)OC(C)(C)C)c(C(=O)OCC[Si](C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CCC(=O)OC(C)(C)C)c(C(=O)O)c1
Yield: 98 %

Procedure:
A solution of 2-(2-tert-butoxycarbonyl-ethyl)-5-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzoic acid 2-trimethylsilanylethyl ester (5.04 g, 9.13 mmol) in THF (100 mL) was treated with TBAF (20 mL, 1.0 M) at room temperature for 1 h. The reaction mixture was concentrated and purified using silica gel chromatography (hexanes/EtOAc 1/1) to afford the title compound as a colorless oil (4.04 g, 98%). 1H NMR (400 MHz, CDCl3): δ 1.38 (s, 9H), 2.37 (s, 3H), 2.55 (t, 2H, J=7.3 Hz), 2.98 (t, 2H, J=6.5 Hz), 3.15 (t, 2H, J=7.3 Hz), 4.26 (t, 2H, J=6.5 Hz), 4.35 (t, 2H, J=8.8 Hz), 6.99 (dd, 1H, J=2.9, 8.8 Hz), 7.18 (d, 1H, J=8.3 Hz), 7.38-7.43 (m, 3H), 7.49 (d, 1H, J=2.9 Hz), 7.97 (d, 2H, J=7.8 Hz). MS (ES) m/z 522.3 [M+H]+.
Reaction SMILES: CS([Cl:5])(=O)=O.[Cl-].[Li+].[CH3:8][C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([CH3:16])[C:10]=1[S:17]([O:20][C:21]1[C:26]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([CH2:34]O)=[CH:30][C:29]=2[O:36][CH3:37])=[C:25]([CH3:38])[N:24]=[C:23]([NH2:39])[N:22]=1)(=[O:19])=[O:18]>C1COCC1.O>[CH3:8][C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([CH3:16])[C:10]=1[S:17]([O:20][C:21]1[C:26]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([CH2:34][Cl:5])=[CH:30][C:29]=2[O:36][CH3:37])=[C:25]([CH3:38])[N:24]=[C:23]([NH2:39])[N:22]=1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(CO)ccc1Cc1c(C)nc(N)nc1OS(=O)(=O)c1c(C)cc(C)cc1C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(CCl)ccc1Cc1c(C)nc(N)nc1OS(=O)(=O)c1c(C)cc(C)cc1C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Methanesulfonyl chloride (1.4 mL) was added to a mixture of lithium chloride (0.74 g) and the product from step (iv) (4.0 g) in THF (45 mL). The mixture was stirred at RT for 1.5 h, diluted with water and extracted with EtOAc. The combined organic layer was washed with brine, dried and concentrated under reduced pressure to afford the crude product as a pale yellow oil, which was used for next reaction without further purification; 1H NMR (300 MHz, CDCl3); 6.91 (2H, s), 6.83 (1H, s), 6.81-6.74 (2H, m), 4.69 (2H, br s), 4.54 (2H, s), 3.82 (3H, s), 3.80 (2H, s), 2.54 (6H, s), 2.29 (3H, s), 2.24 (3H, s).
Reaction SMILES: [NH:1]1[CH2:5][CH:4]=[CH:3][CH2:2]1.[Br:6][C:7]1[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=1[O:9][CH2:10][CH2:11]Cl>>[Br:6][C:7]1[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=1[O:9][CH2:10][CH2:11][N:1]1[CH2:5][CH:4]=[CH:3][CH2:2]1
Reactant: C1=CCNC1
Reactant: ClCCOc1ccccc1Br
Product: Brc1ccccc1OCCN1CC=CC1

Procedure:
The title compound was prepared from 3-pyrroline and 2-(2-bromophenoxy)ethyl chloride in a similar manner to Example 42 (b).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11](/[CH:29]=[CH:30]/[C:31]([O:33]C(C)(C)C)=[O:32])[CH:12]=[CH:13][C:14]=1[C:15](=[C:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)[C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1>C(Cl)Cl>[Cl:8][C:9]1[CH:10]=[C:11](/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32])[CH:12]=[CH:13][C:14]=1[C:15](=[C:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)[C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)/C=C/c1ccc(C(=C2CCCCC2)c2ccc(O)cc2)c(Cl)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)/C=C/c1ccc(C(=C2CCCCC2)c2ccc(O)cc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.4 %

Procedure:
Trifluoroacetic acid (2.0 mL) was added dropwise to 73 (300 mg, 0.706 mmol) dissolved in CH2Cl2 (2 mL) at 0° C. The reaction mixture was stirred at RT for 3 h and the volatiles were removed under reduced pressure. The residue was chromatographed on silca gel (20:1 CH2Cl2:MeOH) to afford 225 mg (86%) of 74 as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 1.53 (br s, 6H), 1.88 (br s, 2H), 2.20 (m, 2H), 6.54 (d, J=16.0 Hz, 1H), 6.65 (d, J=8.8 Hz, 2H), 6.92 (d, J=8.4 Hz, 2H), 7.23 (d, J=7.9 Hz, 1H), 7.52 (d, J=16.0 Hz, 1H), 7.59 (d, J=7.9 Hz, 1H). LRMS (ESI): m/z 370 (M+H)+.
Reaction SMILES: [C:1]12[CH:24]=[C:22]3[N:23]=[C:19]([CH:20]=[CH:21]3)[CH:18]=[C:16]3[NH:17][C:13]([CH:14]=[CH:15]3)=[CH:12][C:10]3=[N:11][C:7]([CH:8]=[CH:9]3)=[CH:6][C:4]([NH:5]1)=[CH:3][CH:2]=2.[OH-].[Na+].[C:27]1(C)C=CC=C[CH:28]=1>>[C:27]([C:3]1[CH:2]=[C:1]2[CH:24]=[C:22]3[N:23]=[C:19]([CH:18]=[C:16]4[NH:17][C:13](=[CH:12][C:10]5[CH:9]=[CH:8][C:7](=[CH:6][C:4]=1[NH:5]2)[N:11]=5)[CH:14]=[CH:15]4)[CH:20]=[CH:21]3)#[CH:28]
Reactant: Cc1ccccc1
Reactant: C1=Cc2cc3ccc(cc4nc(cc5ccc(cc1n2)[nH]5)C=C4)[nH]3
Agent: [Na+]
Agent: [OH-]
Product: C#Cc1cc2cc3nc(cc4ccc(cc5nc(cc1[nH]2)C=C5)[nH]4)C=C3
Yield: 90 %

Procedure:
In order to obtain the deprotected ethyne, porphyrin 20 was first metalated with zinc (J. Rodriquez et al., J. Chem. Soc. Perkin Trans 11997, 709-714) under standard conditions giving porphyrin 23 (FIG. 30). Deprotection of the ethyne by refluxing with sodium hydroxide in toluene (L. Della Ciana and A. Haim, J. Heterocyclic Chem. 1984, 21, 607-608) (98% yield) gave building block 24. Demetalation of 24 with TFA (J. Lindsey et al., Tetrahedron 1994, 50, 8941-8968) afforded free base mono-ethynyl porphyrin 14 in 83% yield (FIG. 30). The metalation step was performed in order to suppress possible decomposition of the free base porphyrin upon exposure to sodium hydroxide. Subsequently, and to our surprise, we found that reaction of porphyrin 20 with sodium hydroxide in refluxing toluene proceeded smoothly to give porphyrin 14 in 90% yield.
Reaction SMILES: Br.[NH2:2][C:3]1[S:4][C:5](Br)=[CH:6][N:7]=1.[SH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[S:9][C:5]1[S:4][C:3]([NH2:2])=[N:7][CH:6]=1
Reactant: Sc1ccccn1
Reactant: Nc1ncc(Br)s1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1ncc(Sc2ccccn2)s1
Temperature: 80 °C
Reaction time: 16 h
Yield: 73.1 %

Procedure:
To a solution of 2-amino-5-bromothiazole hydrobromide (1.00 g, 3.85 mmol) in DMF (8 mL) was added 2-mercaptopyridine (428 mg, 3.85 mmol) followed by addition of powdered K2CO3 (1.81 g, 15.09 mmol). The mixture was stirred at 80° C. for 1 h and at rt for 16 h. The solvent was removed in vacuo at 80° C. and the compound was partitioned between H2O and EtOAc. The aqueous layer was extracted with EtOAc and the organic phase was extracted with HCl 1N. The acidic extract was neutralized with saturated NaHCO3 and the precipitate was extracted with EtOAc, washed with brine, dried over MgSO4 and concentrated in vacuo to afford the title compound 169 (589 mg, 73% yield). 1H NMR: (Acetone-d6) δ(ppm): 8.36 (s, 1H), 7.66 (s, 1H), 7.20 (s, 1H), 7.12-7.05 (m, 2H), 6.84 (s, 2H). m/z: 210.1 (MH+).