Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=CC(N2CCN(CCC3C=CC=CC=3)CC2)=CC=1.[F:23][C:24]1[CH:29]=[C:28]([O:30]C)[C:27]([F:32])=[CH:26][C:25]=1[N:33]1[CH2:38][CH2:37][CH:36](/[CH:39]=[CH:40]\[CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH2:35][CH2:34]1>>[F:32][C:27]1[CH:26]=[C:25]([N:33]2[CH2:38][CH2:37][CH:36](/[CH:39]=[CH:40]\[CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH2:35][CH2:34]2)[C:24]([F:23])=[CH:29][C:28]=1[OH:30]
Reactant: COc1cc(F)c(N2CCC(/C=C\Cc3ccccc3)CC2)cc1F
Agent: COc1ccc(N2CCN(CCc3ccccc3)CC2)cc1
Product: Oc1cc(F)c(N2CCC(/C=C\Cc3ccccc3)CC2)cc1F
Yield: 278 %

Procedure:
Production Example 2 was repeated except that 1-(4-methoxyphenyl)-4-phenethylpiperazine was replaced with (Z)-1-(2,5-difluoro-4-methoxyphenyl)-4-(3-phenyl-1-propen-1-yl)piperidine (18 mg), to provide crude (Z)-2,5-difluoro-4-[4-(3-phenyl-1-propen-1-yl)-piperidino]phenol (48 mg).
Reaction SMILES: [CH2:1]([N:8]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[O:11][C:10](=[CH:18][NH:19][C:20](=[O:33])[CH2:21][CH:22]([C:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[NH:26][CH:25]=2)C)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C2C(=CC=CC=2)C=C1CCCC(O)=O>>[CH2:1]([N:8]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[O:11][C:10](=[CH:18][NH:19][C:20](=[O:33])[CH2:21][CH2:22][C:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[NH:26][CH:25]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(CC(=O)NC=C1CN(Cc2ccccc2)c2ccccc2O1)c1c[nH]c2ccccc12
Agent: O=C(O)CCCc1cc2ccccc2[nH]1
Product: O=C(CCc1c[nH]c2ccccc12)NC=C1CN(Cc2ccccc2)c2ccccc2O1
Yield: 63 %

Procedure:
N-(4-Benzyl-3,4-dihydro-2H-benzo[1,4]oxazin-2-ylylmethyl)-3-(1H-indol-3-yl)-butyramide. (4-Benzyl-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-methylamnine (1.2 g, 4.7 mmol) was coupled to indole butyric acid (1.8 g, 8.9 mmol) according to the procedure used to prepare intermediatel 1 above to afford 1.3 g (63%) of the title compound as a yellow solid: mp 61-63.5° C.; MS (EI) m/e 439 (M+)
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][CH:6]=1.C([Mg]Br)C.[C:11](Cl)(=[O:14])[CH2:12][CH3:13]>>[CH3:1][C:2]1[N:3]=[C:4]([C:11](=[O:14])[CH2:12][CH3:13])[S:5][CH:6]=1
Reactant: Cc1cscn1
Reactant: CCC(=O)Cl
Agent: CC[Mg]Br
Product: CCC(=O)c1nc(C)cs1

Procedure:
b. 4-Methyl-2-propionyl-thiazole was prepared according to the method described in Bull. 20, 702 (1953) by reacting 4-methyl-thiazole with ethyl-magnesium bromide and acylating the obtained Grignard intermediate with propionyl chloride. The product has a b.p. of 83°-88°C./9 mm. Hg.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:23][CH:24]1[C:51](=[O:52])[N:26]2[CH:27]([C:41]([O:43][CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[O:42])[C:28]3([S:40][C@H:25]12)[CH2:33][CH2:32][N:31]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:30][CH2:29]3.C(N(CC)CC)C.[C:60]1([CH2:66][C:67](Cl)=[O:68])[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1>ClCCl>[C:34]1([N:31]2[CH2:32][CH2:33][C:28]3([CH:27]([C:41]([O:43][CH2:44][C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=4)=[O:42])[N:26]4[C:51](=[O:52])[CH:24]([NH:23][C:67](=[O:68])[CH2:66][C:60]5[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=5)[C@H:25]4[S:40]3)[CH2:29][CH2:30]2)[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: NC1C(=O)N2C(C(=O)OCc3ccccc3)C3(CCN(c4ccccc4)CC3)S[C@H]12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OCc3ccccc3)C3(CCN(c4ccccc4)CC3)S[C@H]12
Temperature: 15 °C
Reaction time: 3 h
Yield: 87.7 %

Procedure:
To a suspension of 1.53 g (0.002 mole) of benzyl 6-amino-1'-phenyl-spiro[penam-2,4'-piperidine]-3-carboxylate di-p-toluenesulfonate (prepared according to the method described in Example 1.8.3. of our Application Ser. No. 06/162,616, filed June 24, 1980) in 100 ml of anhydrous dichloromethane is added all at once 404 mg (0.004 mole) of triethylamine in 10 ml of dichloromethane. The solution is cooled to a temperature of from 0° to -5° C. and then there are simultaneously added dropwise a solution of 340 mg (0.022 mole) of phenylacetyl chloride in 30 ml of dichloroemethane and a solution of 220 mg (0.022 mole) of triethylamine in 30 ml of dichloromethane, the addition taking place over the course of about 1 hour. Thereafter, the reaction mixture is stirred for 3 hours at 15° C., then successively washed with water, with a saturated aqueous solution of sodium hydrogen carbonate and again with water. After evaporating the solution to dryness and recrystallizing the residue from ethyl acetate/hexane (1:3 v/v), there are obtained 950 mg of benzyl 1'-phenyl-6-(2-phenylacetamido)-spiro[penam-2,4'-piperidine]-3-carboxylate. Yield: 88%; M.P. 120°-121° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]2[C:23]([CH3:25])([CH3:24])[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:26](O)=[O:27])[CH:20]=3)[NH:15]2)[CH:5]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:7]=1.Cl.CN(C)CCCN=C=NCC.[CH3:41][S:42]([NH2:45])(=[O:44])=[O:43]>CN(C)C1C=CN=CC=1.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]2[C:23]([CH3:25])([CH3:24])[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:26]([NH:45][S:42]([CH3:41])(=[O:44])=[O:43])=[O:27])[CH:20]=3)[NH:15]2)[CH:5]=[C:6]([N:8]2[CH2:9][CH2:10][O:11][CH2:12][CH2:13]2)[CH:7]=1
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cc(Cl)cc(N2CCOCC2)c1
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC1(C)Cc2cc(C(=O)NS(C)(=O)=O)ccc2NC1c1cc(Cl)cc(N2CCOCC2)c1
Temperature: 65 °C
Yield: 30 %

Procedure:
A mixture of 2-(3-chloro-5-morpholin-4-yl-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (100 mg, 0.25 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (72 mg, 0.38 mmol), 4-dimethylaminopyridine (46 mg, 0.38 mmol), methane sulfonamide (47.5 mg, 0.50 mmol) in dichloromethane (4 mL) was heated for at 65° C. for 12 hours. Removal of the solvent to afforded an oil residue. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded N-[2-(3-chloro-5-morpholin-4-yl-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonyl]-methanesulfonamide (35.8 mg, 30%) as a light yellow solid: LC/MS m/e calcd for C23H28ClN3O4S (M+H)+: 479.1, observed: 478.2.
Reaction SMILES: [CH2:1]([O:3][CH:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH:19]=[CH:20][CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][CH:30]([O:36][CH2:37][CH3:38])[C:31]([O:33]CC)=[O:32])=[CH:25][CH:24]=2)=[CH:13][CH:12]=1)[C:5]([O:7]CC)=[O:6])[CH3:2].[OH-].[Na+]>C(O)C>[CH2:37]([O:36][CH:30]([CH2:29][C:26]1[CH:25]=[CH:24][C:23]([O:22][CH2:21][CH:20]=[CH:19][CH2:18][O:17][C:14]2[CH:15]=[CH:16][C:11]([CH2:10][CH:4]([O:3][CH2:1][CH3:2])[C:5]([OH:7])=[O:6])=[CH:12][CH:13]=2)=[CH:28][CH:27]=1)[C:31]([OH:33])=[O:32])[CH3:38]
Reactant: CCOC(=O)C(Cc1ccc(OCC=CCOc2ccc(CC(OCC)C(=O)OCC)cc2)cc1)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(Cc1ccc(OCC=CCOc2ccc(CC(OCC)C(=O)O)cc2)cc1)C(=O)O
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
Ethyl 2-ethoxy-3-(4-(4-(4-(2-ethoxy-2-ethoxycarbonyl-ethyl)-phenyloxy)-but-2-enyloxy)-phenyl)-propionate (0.210 mmol, 109 mg) was dissolved in ethanol (7 ml) by heating to 60° C. 1M NaOH (2.3 ml) was added and the reaction mixture was stirred at 90° C. for 90 min. The reaction mixture was evaporated and 1 N HCl (6.5 ml) and methylene chloride (30 ml) was added to the residue. The organic phase was collected and the aqueous phase was further extracted with methylene chloride (2×25 ml). The combined organic phases were dried and evaporated to give the title compound in 87 mg (88%) yield. 1H-NMR δ (CDCl3) 9.55 (br. s, 2H), 7.17 (d, 4H), 6.80 (d, 4H), 5.91 (m, 2H), 4.65 (d, 4H), 4.05 (m, 2H), 3.70-3.57 (m, 2H), 3.50-3.35 (m, 2H), 3.10-2.90 (m, 4H), 1.21 (t, 6H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]#[N:10])[CH:5]=[C:6]([CH:8]=1)[NH2:7].[Cl:11][C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=1[N:22]=[C:23]=[O:24]>O1CCCC1>[Cl:11][C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=1[NH:22][C:23]([NH:7][C:6]1[CH:8]=[C:2]([F:1])[CH:3]=[C:4]([C:9]#[N:10])[CH:5]=1)=[O:24]
Reactant: N#Cc1cc(N)cc(F)c1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1Cl
Solvent: C1CCOC1
Product: N#Cc1cc(F)cc(NC(=O)Nc2ccc(C(F)(F)F)cc2Cl)c1
Yield: 84.4 %

Procedure:
A solution of 15 g (110.2 mmol) of 5-fluoro-3-cyanoaniline in 150 ml of tetrahydrofuran is stirred at ambient temperature under an argon atmosphere. Next, 17.5 ml (121.22 mmol) of 2-chloro-4-trifluoromethylphenylisocyanate are added. The reaction medium is heated at reflux for 3 hours then concentrated to dryness using a rotary evaporator. The solid residue obtained is recrystallized at high temperature in 60 ml of ethyl acetate in order to give 33.25 g of 1-(2-chloro-4-trifluoromethylphenyl)-3-(3-cyano-5-fluorophenyl)urea in the form of a white solid.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH:6]([C:13]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]2[C:14]=1[CH:15]=[CH:16][NH:17]2)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.CC(C[AlH]CC(C)C)C.CCO.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:23][O:22][C:20]1[CH:19]=[C:18]2[C:14]([CH:15]=[CH:16][NH:17]2)=[C:13]([CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][CH:4]=[O:3])[CH:21]=1
Reactant: CCOC(=O)CC(c1ccccc1)c1cc(OC)cc2[nH]ccc12
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: COc1cc(C(CC=O)c2ccccc2)c2cc[nH]c2c1
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
To a −78° C. solution of 3-(6-Methoxy-1H-Indol-4-yl)-3-phenyl-propionic acid ethyl ester CXVII (0.39 g, 1.2 mmol) in DCM (10 ml) was added DIBALH (1M in hexane, 4.0 ml, 4.0 mmol). After stirring for 90 minutes at −78° C., more DIBALH (1M in hexane, 1.2 ml, 1.2 mmol) was added. The resulting mixture was stirred for 2.25 hours, after which EtOH (2 ml) and a saturated solution of NaHCO3 (2 ml) were added. The mixture was then stirred at room temperature for 30 min, filtered, and the filter cake was washed with EtOAc. The filtrate was concentrated and washed with a saturated solution of NaHCO3, dried over Na2SO4, filtered, concentrated, and purified via flash chromatography (hexane/EtOAc) affording 3-(6-Methoxy-1H-Indol-4-yl)-3-phenyl-propionaldeyde CXVIII as a colorless syrup (0.27 g, 82% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][N:10]=[C:9]2I)=[CH:4][CH:3]=1.C(NC(C)C)(C)C.[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:28]=1[C:34]#[CH:35]>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.[Cu]I.C1COCC1>[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:28]=1[C:34]#[C:35][C:9]1[N:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][N:10]=1
Reactant: C#Cc1c(F)cccc1Cl
Reactant: CCOC(=O)c1cnc(I)n1-c1ccc(F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc(C#Cc2c(F)cccc2Cl)n1-c1ccc(F)cc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Ethyl 1-(4-fluorophenyl)-2-iodo-1H-imidazole-5-carboxylate (38) (847 mg, 2.35 mmol), PdCl2(PPh3)2 (82 mg, 0.12 mmol), copper (I) iodide (22 mg, 0.12 mmol), and THF (50 mL) were added to a pressure tube. Diisopropyl amine (6 mL) and 1-chloro-2-ethynyl-3-fluorobenzene (41) (400 mg, 2.59 mmol) were added to the pressure tube and the reaction was stirred at 50° C. overnight. The reaction was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (0-30% EtOAc in hexanes) to provide ethyl 2-((2-chloro-6-fluorophenyl)ethynyl)-1-(4-fluorophenyl)-1H-imidazole-5-carboxylate (42).
Reaction SMILES: CO[CH2:3][N:4]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5][Si](C)(C)C.[Cl:17][C:18]1[CH:23]=[CH:22][C:21](/[CH:24]=[CH:25]/[N+:26]([O-:28])=[O:27])=[CH:20][C:19]=1[F:29].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:10]([N:4]1[CH2:5][CH:25]([N+:26]([O-:28])=[O:27])[CH:24]([C:21]2[CH:22]=[CH:23][C:18]([Cl:17])=[C:19]([F:29])[CH:20]=2)[CH2:3]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: O=[N+]([O-])/C=C/c1ccc(Cl)c(F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=[N+]([O-])C1CN(Cc2ccccc2)CC1c1ccc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.1 %

Procedure:
A solution of N-(methoxymethyl)-N-(phenylmethyl)-N-(trimethylsilyl)methylamine (1.00 g, 4.2 mmol) in CH2Cl2 (5 ml) was added drop wise, over a 30 minutes period, to a stirred solution of 1-chloro-2-fluoro-4-((E)-2-nitro-vinyl)-benzene (0.68 g, 3.37 mmol) and trifluoroacetic acid (30 ul) in CH2Cl2 (5 ml) at 0° C. The ice bath was removed, and the solution was stirred at 25° C. for an additional 48 h. It was then concentrated and purification by flash chromatography (SiO2, EtOAc/H 1:4) afforded 0.78 g (55%) of the title compound as a colorless oil. ES-MS m/e: 335.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[NH:4][C:5]3[CH:6]=[C:7]4[C:11](=[C:12]([CH:26]=3)[CH2:13][CH2:14][C:15]3[CH:25]=[C:19]([NH:20][C:21]([N:24]=2)=[N:22][CH:23]=1)[CH:18]=[CH:17][CH:16]=3)[O:10][C:9](=[O:27])[N:8]4COCC[Si](C)(C)C.N.O.C(OCC)(=O)C>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[C:3]2[NH:4][C:5]3[CH:6]=[C:7]4[C:11](=[C:12]([CH:26]=3)[CH2:13][CH2:14][C:15]3[CH:25]=[C:19]([NH:20][C:21]([N:24]=2)=[N:22][CH:23]=1)[CH:18]=[CH:17][CH:16]=3)[O:10][C:9](=[O:27])[NH:8]4
Reactant: C[Si](C)(C)CCOCn1c(=O)oc2c3cc(cc21)Nc1nc(ncc1Cl)Nc1cccc(c1)CC3
Agent: N
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: O=c1[nH]c2cc3cc(c2o1)CCc1cccc(c1)Nc1ncc(Cl)c(n1)N3
Temperature: 20 °C
Reaction time: 1 h
Yield: 102.1 %

Procedure:
A solution of 4-chloro-20-{[2-(trimethylsilyl)ethoxy]methyl}-18-oxa-2,6,8,20,25-pentaazapentacyclo[14.6.1.1(3,7).1(9,13).0(17,21)]pentacosa-1(23),3(25),4,6,9(24),10,12,16,21-nonaen-19-one (25 mg, 49 μmol) in TFA (1.5 mL) was stirred at 20° C. for 30 min. The reaction mixture was concentrated and reconcentrated from dichloromethane to a residue. This residue was dissolved in THF (1.5 mL) and treated with 20 M of ammonia in water (1 mL, 20 mmol) dropwise and stirred at 20° C. for 1 h. The reaction mixture was poured into water (20 mL) and ethyl acetate (50 mL). The organic layer was separated and washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to give the desired product (19 mg, quantitative) as a white solid. LCMS for C19H15ClN5O2 (M+H)+: m/z=380.0.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C@H:14]([O:18][CH3:19])[C:15]([OH:17])=[O:16])=[CH:9][CH:8]=1.[O:20]([C:27]1[CH:32]=[CH:31][C:30](O)=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH3:19][O:18][C@@H:14]([CH2:13][C:10]1[CH:9]=[CH:8][C:7]([C:6]#[C:5][CH2:4][CH2:3][CH2:2][O:1][C:30]2[CH:31]=[CH:32][C:27]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:28][CH:29]=2)=[CH:12][CH:11]=1)[C:15]([OH:17])=[O:16]
Reactant: CO[C@@H](Cc1ccc(C#CCCCO)cc1)C(=O)O
Reactant: Oc1ccc(Oc2ccccc2)cc1
Product: CO[C@@H](Cc1ccc(C#CCCCOc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(5-hydroxy-pent-1-ynyl)-phenyl]-2-methoxy-propionic acid (Example 21, Step A) and 4-phenoxyphenol via the standard Mitsunobu coupling-hydrolysis procedure (Standard Procedure A) to produce a white oily solid. 1H-NMR (200.15 MHz, CDCl3): δ 7.26–7.19 (m, 4H), 7.07 (d, 2H, J=8.3), 6.98–6.78 (m, 7H), 4.01 (t, 2H, J=5.9), 3.91 (dd, 1H, J=7.3, 4.3), 3.30 (s, 3H), 3.05 (dd, 1H, J=14.2, 4.3), 2.90 (dd, 1H, J=14.2, 7.5), 2.54 (t, 2H, J=6.7), 1.98 (qn, 2H, J=6.4). MS (ES) for C27H26O5[M+NH4]+: 448, [M+Na]+: 453.
Reaction SMILES: Cl[CH2:2][C:3]([CH2:12]Cl)=[CH:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].C(=O)([O-])[O-].[K+].[K+].Cl.Cl.[CH2:22]([NH:24][NH:25][CH2:26][CH3:27])[CH3:23].[I-].[K+]>C(#N)C>[CH2:22]([N:24]1[CH2:12][C:3](=[CH:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])[CH2:2][N:25]1[CH2:26][CH3:27])[CH3:23]
Reactant: CCNNCC
Reactant: CC(C)(C)OC(=O)C=C(CCl)CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC#N
Product: CCN1CC(=CC(=O)OC(C)(C)C)CN1CC
Temperature: 25 °C
Reaction time: 72 h
Yield: 82.4 %

Procedure:
A suspension of tert-butyl 4-chloro-3-(chloromethyl)-2-butenoate (1.2 g, 5.3 mmol), potassium carbonate (4.0 g, 29 mmol), diethylhydrazine dihydrochloride (1.3 g, 8.0 mmol) and potassium iodide (0.86 g, 5.2 mmol) in acetonitrile was stirred at room temperature for 3 days. The mixture was filtered through celite, concentrated and purified by flash chromatography on silica gel eluting ethyl acetate:hexane (20:80, v;v) to give the tert-butyl (1,2-diethyl-4-pyrazolidinylidene)acetate (1.05 g, 82%) as an oil, MS (M+H)+=241.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].[CH3:13][P:14](Cl)(Cl)=[O:15]>C1COCC1>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][P:14]([CH3:13])(=[O:15])[O:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CP(=O)(Cl)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CP(=O)(Oc1ccc([N+](=O)[O-])cc1)Oc1ccc([N+](=O)[O-])cc1
Yield: 88 %

Procedure:
Methylphosphonic acid bis-(4-nitrophenyl) ester is prepared according to procedure E using 1 g of 4-nitrophenol, 12 ml of THF, 345 mg of sodium hydride at 50% in oil and 478 mg of methylphosphonic dichloride. 1.07 g of crude methylphosphonic acid bis-(4-nitrophenyl) ester are obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:18]=[C:11]3[CH:12]=[CH:13][C:14]([C:16]#[N:17])=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.C1C(=O)N([Br:26])C(=O)C1.O>CN(C=O)C>[Br:26][C:18]1[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[N:9][N:10]2[CH:15]=[C:14]([C:16]#[N:17])[CH:13]=[CH:12][C:11]=12
Reactant: O=C1CCC(=O)N1Br
Reactant: N#Cc1ccc2cc(-c3ccc(F)cc3)nn2c1
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc2c(Br)c(-c3ccc(F)cc3)nn2c1
Yield: 60.4 %

Procedure:
A solution of 2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine-6-carbonitrile (0.6 g 2.53 mmol) and NBS (0.5 g 2.8 mmol) in DMF (10 ml) was stirred at room temperature for 2 hr. The reaction was poured into water (100 ml) and extracted with ethyl acetate (2×30 ml). The combined extracts were washed with water (30 ml), brine (30 ml), dried and purified by biotage chromatography. Elution with cyclohexane/ethyl acetate (20:1) gave the title compound as a white solid (0.483 g 61%). NMR: (CDCl3): δ 7.21 (2H, t) 7.30 (1H, dd) 7.62 (1H, dd) 8.06 (2H, m) 8.80 (1H, s).
Reaction SMILES: [CH3:1][Si]([N-][Si](C)(C)C)(C)C.[Na+].[O:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[C:16]1[CH:21]=[CH:20][C:19]([C:22]([CH3:26])([CH3:25])[CH:23]=O)=[CH:18][CH:17]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1.CCOCC>[CH3:25][C:22]([C:19]1[CH:20]=[CH:21][C:16]([C:12]2[O:11][CH:15]=[CH:14][CH:13]=2)=[CH:17][CH:18]=1)([CH3:26])[CH:23]=[CH2:1]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(C)(C=O)c1ccc(-c2ccco2)cc1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CC(C)(C)c1ccc(-c2ccco2)cc1
Reaction time: 0.5 h
Yield: 111 %

Procedure:
To a cooled slurry (0° C.) of methyltriphenylphosphonium bromide (18.8 g, 52.6 mmol) in THF (60 mL) is added dropwise (1M)sodium bis(trimethylsilyl)amide (52.6 mL, 52.6 mmol) and the resulting mixture stirred for 30 min. To the mixture is added a solution of 2-(4-furan-2-yl-phenyl)-2-methyl-propionaldehyde (5.64 g, 26.3 mmol) (reference example 52) in THF (25 mL) and the resulting mixture stirred for 45 min. The mixture is diluted with ether, washed with water and brine, dried over MgSO4 and concentrated. The residue is purified by flash chromatography (eluting with 10% ethyl acetate in hexanes) to give 6.2 g of title compound as a yellow oil. 1H NMR (CDCl3) δ 1.41 (s, 6H), 5.03 (s, 1H), 5.08 (d, J=7 Hz, 1H), 6.03 (m, 1H), 6.45 (m, 1H), 6.60 (d, J=3 Hz, 1H), 7.36 (d, 8 Hz, 2H), 7.44 (s, 1H), 7.60 (d, J=8 Hz, 2H). MS (EI) m/z 212 (M+).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:8])=[N:4][NH:5][C:6]=1[CH3:7].Br[CH2:10][C:11]([NH:13][CH:14]([CH3:16])[CH3:15])=[O:12].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[Br:1][C:2]1[C:3]([CH3:8])=[N:4][N:5]([CH2:10][C:11]([NH:13][CH:14]([CH3:16])[CH3:15])=[O:12])[C:6]=1[CH3:7]
Reactant: Cc1n[nH]c(C)c1Br
Reactant: CC(C)NC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1nn(CC(=O)NC(C)C)c(C)c1Br
Temperature: 70 °C

Procedure:
To a 4 mL vial equipped with a magnetic stir bar were added 4-bromo-3,5-dimethyl-1H-pyrazole (50 mg, 0.286 mmol), 2-bromo-N-isopropylacetamide (51.4 mg, 0.286 mmol), K2CO3 (118 mg, 0.857 mmol), and acetonitrile (2 mL). The contents of the vial were stirred to give a white suspension. The vial was heated in a sand bath to 70° C. for 24 hours. The reaction mixture was subsequently partitioned between water (10 mL) and ethyl acetate (15 mL). The layers were separated, and the aqueous layer was back-extracted with ethyl acetate (15 mL). The combined organic layers were concentrated to give the title compound as a white solid, which was used without further purification (80 mg).
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].C(N(CC)CC)C.[CH2:13]([O:20][C:21]1[C:29]([Br:30])=[CH:28][C:24]([C:25](Cl)=[O:26])=[C:23](C)[CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)(Cl)Cl.O>[CH2:13]([O:20][C:21]1[C:29]([Br:30])=[CH:28][C:24]([C:25]([N:3]([O:4][CH3:5])[CH3:2])=[O:26])=[CH:23][CH:22]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CNOC
Reactant: Cc1cc(OCc2ccccc2)c(Br)cc1C(=O)Cl
Agent: Cl
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1ccc(OCc2ccccc2)c(Br)c1
Temperature: 25 °C

Procedure:
To a suspension of 4-(benzyloxy)-5-bromo-2-methylbenzoic acid (16.6 g, 51.7 mmol) in chloroform (80 mL) were added oxalyl chloride (5 mL, 56.9 mmol) and N,N-dimethylformamide (6 drops), and the mixture was stirred for an hour at room temperature. And then the reaction solution was concentrated to obtain 4-(benzyloxy)-5-bromo-2-methylbenzoyl chloride. Then to a chloroform suspension (60 mL) of N,O-dimethylhydroxylamine hydrochloride (5.55 g, 56.9 mmol) and triethylamine (15 mL, 103 mmol) cooled in ice was added dropwise a chloroform solution (60 mL) of 4-(benzyloxy)-5-bromo-2-methylbenzoyl chloride, and the mixture was stirred for an hour at room temperature. To the reaction solution cooled in ice were added water and chloroform to separate an organic layer. The organic layer was washed with a saturated sodium bicarbonate aqueous solution and brine, and dried with anhydrous magnesium sulfate. The drying agent was filtered off, and the solvent was evaporated under reduced pressure to obtain 4-(benzyloxy)-5-bromo-N-methoxy-N-methylbenzamide. To a tetrahydrofuran solution (150 mL) of the 4-(benzyloxy)-5-bromo-N-methoxy-N-methylbenzamide was added at −10° C. lithium aluminum hydride (1.96 g, 51.7 mmol), and the mixture was stirred for an hour at the same temperature. To the reaction solution were added 1 M hydrochloric acid, and then ethyl acetate to separate an organic layer. The organic layer was washed with 1 M hydrochloric acid, a saturated sodium bicarbonate aqueous solution and brine, and dried with anhydrous magnesium sulfate. The drying agent was filtered off, and the solvent was evaporated under reduced pressure to obtain 4-(benzyloxy)-5-bromo-2-methylbenzaldehyde. To a toluene solution (120 mL) of the 4-(benzyloxy)-5-bromo-2-methylbenzaldehyde were added ethylene glycol (30 mL, 517 mmol) and p-toluenesulfonic acid monohydrate (0.50 g, 2.58 mmol), and heated to reflux for 1.5 hours with a Dean-Stark apparatus. To the reaction solution was added ethyl acetate to separate an organic layer. The organic layer was washed with water, a saturated sodium bicarbonate aqueous solution and brine, and dried with anhydrous magnesium sulfate. The drying agent was filtered off, and the solvent was evaporated under reduced pressure. Thus obtained residue was purified with silica gel column chromatography (hexane:ethyl acetate=5:1). In addition, the residue was further purified with NH type silica gel column chromatography (chloroform) to obtain the title compound (12.8 g, 71%, 3 steps) as a colorless powder.