Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C(C)=C(Cl)C(Cl)=C(C)C=1Cl.[Cl:13][C:14]1[C:19]([Cl:20])=[C:18]([CH2:21][OH:22])[C:17]([Cl:23])=[C:16]([Cl:24])[C:15]=1[CH2:25]O.S(=O)=O.II>>[Cl:13][C:14]1[C:19]([Cl:20])=[C:18]([CH:21]=[O:22])[C:17]([Cl:23])=[C:16]([Cl:24])[C:15]=1[CH3:25]
Reactant: OCc1c(Cl)c(Cl)c(CO)c(Cl)c1Cl
Agent: Cc1c(Cl)c(Cl)c(C)c(Cl)c1Cl
Agent: II
Agent: O=S=O
Product: Cc1c(Cl)c(Cl)c(C=O)c(Cl)c1Cl
Temperature: 25 °C

Procedure:
When the procedure of Example 64 was carried by replacing tetrachloro-p-xylene with an equimolar amount (27.6g) of 2,3,5,6-tetrachloro-p-xylene-α ,α'-diol, a strong evolution of sulfur dioxide was observed (identified qualitatively by iodine paper), but the resultant solution did not turn purple, instead it acquired a brown amber color. After a 4 hour of heating period between 90° and 94° C, the clear solution was poured, after it cooled to room temperature, onto ice, yielding a yellow slurry. Since filtration was sluggish, the slurry was extracted with diethyl ether, yielding, after evaporation of the solvent 19.0 g of bright yellow solids, whose identity was determined by infrared and nuclear magnetic resonance spectra, which matched those described in Example 64.
Reaction SMILES: [C:1]([O-:10])(=[O:9])[CH2:2][C:3]([C:6]([O-:8])=[O:7])(O)[CH3:4].C(O)(=O)C(CC(O)=O)O>>[C:6]([OH:8])(=[O:7])[C:3]([CH2:2][C:1]([OH:10])=[O:9])=[CH2:4]
Reactant: CC(O)(CC(=O)[O-])C(=O)[O-]
Agent: O=C(O)CC(O)C(=O)O
Product: C=C(CC(=O)O)C(=O)O

Procedure:
Citramalate (=(2S)-2-hydroxy-2-methylbutanedioate or (S)-2-Methylmalic acid) is an derivative of malic acid and produced from itaconic acid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1.[CH3:12][C:13]12[CH2:20][CH2:19][C:16]([CH2:21][C:22]#[N:23])([CH2:17][CH2:18]1)[CH2:15][CH2:14]2>O>[CH3:12][C:13]12[CH2:20][CH2:19][C:16]([CH2:21][CH2:22][NH2:23])([CH2:17][CH2:18]1)[CH2:15][CH2:14]2
Reactant: CC12CCC(CC#N)(CC1)CC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC12CCC(CCN)(CC1)CC2
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
0.043 Mole of lithium aluminum hydride is dissolved in 100 ml. of anhydrous tetrahydrofuran, under nitrogen, at 0° C and then 0.043 mole of 4-methylbicyclo[2.2.2]oct-1-yl acetonitrile in 100 ml. of anhydrous tetrahydrofuran is added dropwise. The solution is allowed to warm to room temperature, then stirred for five minutes and then 5 ml. of water is added dropwise. The solution is then filtered and the filter cake is washed with ethyl ether, the washings combined with the filtrate, and the solution is then dried over potassium hydroxide pellets, and filtered. The filtrate is then distilled affording 2-(4-methylbicyclo[2.2.2]oct-1-yl)ethylamine as a residue.
Reaction SMILES: P(Br)(Br)[Br:2].[Br:5][C:6]1[C:7]([F:15])=[C:8]([CH2:13]O)[C:9]([Cl:12])=[CH:10][CH:11]=1.O>ClCCl>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([CH2:13][Br:2])[C:7]=1[F:15]
Reactant: BrP(Br)Br
Reactant: OCc1c(Cl)ccc(Br)c1F
Solvent: O
Solvent: ClCCl
Product: Fc1c(Br)ccc(Cl)c1CBr
Reaction time: 0.33 h
Yield: 29.6 %

Procedure:
Add phosphorous tribromide (1.8 mL, 19.2 mmol) to (3-bromo-6-chloro-2-fluoro-phenyl)methanol (Preparation 8) (4.6 g, 19 mmol) in dichloromethane (50 mL) at 0° C. Stir for 20 minutes. Add the reaction mixture into ice and water. Extract with dichloromethane (100 mL), dry with magnesium sulfate, filter and evaporate solvent under reduced pressure. Purify the residue by biotage chromatography to yield the product to give 1.7 g (30%) of the title compound as a white solid. 1HNMR (CDCl3) 7.48-7.44 (m, 1H), 7.14-7.11 (m, 1H), 4.62-4.61(m, 2H).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16](C)[CH:15]=[CH:14][C:13]=1[C:19]1C=NN(C)C=1)=[O:11].CC1C=CC=C([N:35]2[N:39]=[CH:38][CH:37]=[N:36]2)C=1C(O)=O>>[NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[C:17]([N:35]2[N:39]=[CH:38][CH:37]=[N:36]2)=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:19])=[O:11]
Reactant: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Reactant: Cc1cccc(-n2nccn2)c1C(=O)O
Product: Cc1cccc(-n2nccn2)c1C(=O)N1CCC[C@@H](C)[C@H]1CN

Procedure:
The title compound was prepared following the same general protocol as described for ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)methanone in Example A1 using 2-methyl-6-(2H-1,2,3-triazol-2-yl)benzoic acid. ESI-MS m/z: 314 [M+1]+.
Reaction SMILES: [CH:1]([N:4](CC)C(C)C)(C)[CH3:2].BrCC#N.[NH:14]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C@H:15]([C:30]([OH:32])=[O:31])[CH2:16][CH2:17][CH2:18][NH:19][C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]>C(#N)C>[CH2:23]([O:22][C:20]([NH:19][CH2:18][CH2:17][CH2:16][C@H:15]([NH:14][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:30]([O:32][CH2:2][C:1]#[N:4])=[O:31])=[O:21])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)O
Agent: N#CCBr
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)OCC#N
Reaction time: 1 h
Yield: 105.4 %

Procedure:
N,N-Diisopropylethylamine (84 μL, 0.480 mmol) and subsequently bromoacetonitrile (152 μL, 2.183 mmol) were added to a solution of Boc-Orn(Z)—OH (Compound tk65) (160 mg, 0.437 mmol) in acetonitrile (0.5 mL) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at the same temperature for 1 hours and then concentrated under reduced pressure, and the resulting crude product was purified by normal-phase silica gel column chromatography (hexane/ethyl acetate) to afford (S)-cyanomethyl 5-(((benzyloxy)carbonyl)amino)-2-((tert-butoxycarbonyl)amino)pentanoate (Compound tk66) (186.7 mg, quant.).
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]([NH:12][C@H:13]1[CH2:17][N:16](C(OC(C)(C)C)=O)[C@H:15]([CH2:25][O:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:29][CH:28]=2)[CH2:14]1)=[O:11])=O)(C)(C)C>Cl.O1CCOCC1>[NH2:8][CH2:9][C:10]([NH:12][C@H:13]1[CH2:17][NH:16][C@H:15]([CH2:25][O:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:29][CH:28]=2)[CH2:14]1)=[O:11]
Reactant: CC(C)(C)OC(=O)NCC(=O)N[C@@H]1C[C@@H](COc2ccc(-c3ccccc3)cc2)N(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Product: NCC(=O)N[C@H]1CN[C@H](COc2ccc(-c3ccccc3)cc2)C1
Reaction time: 2 h
Yield: 95.2 %

Procedure:
(2S,4R)-4-(N-tert-Butoxycarbonylglycylamino)-2-(4-biphenyloxy)methyl-N-tert-butoxycarbonylpyrrolidine (B, 431 mg) was dissolved in 4 N hydrogen chloride in 1,4-dioxane (4 mL). After stirring for 2 hr, the reaction mixture was evaporated in vacuo to give a white solid. The solid was washed with ether to afford the titled compound (254 mg): 1H NMR (400 MHz, D2O) δ 2.33 (m, 1H), 2.44 (m, 1H), 3.45 (dd, J=12.7, 4.4 Hz, 1H), 3.79 (dd, J=12.7, 6.8 Hz, 1H), 3.84 (s, 2H), 4.27 (dd, J=10.7, 6.8 Hz, 1H), 4.36 (m, 1H), 4.47 (d, J=10.7 Hz, 1H), 4.67 (m, 1H), 7.16 (d, J=8.3 Hz, 2H), 7.43 (d, J=7.3 Hz, 1H), 7.53 (t, J=7.3 Hz, 2H), 7.68-7.72 (m, 4H).
Reaction SMILES: [CH2:1]([C:5]12[CH2:14][CH2:13][CH2:12][CH:11]=[C:10]([CH3:15])[C:9]1(O)[C:8]1[CH:17]=[CH:18][C:19]([O:21][CH2:22][O:23][CH3:24])=[CH:20][C:7]=1[CH2:6]2)[CH2:2][CH2:3][CH3:4].[Cr](Cl)([O-])(=O)=[O:26].[NH+]1C=CC=CC=1>ClCCl>[CH2:1]([C:5]12[CH2:14][CH2:13][CH2:12][C:11](=[O:26])[C:10]([CH3:15])=[C:9]1[C:8]1[CH:17]=[CH:18][C:19]([O:21][CH2:22][O:23][CH3:24])=[CH:20][C:7]=1[CH2:6]2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC12CCCC=C(C)C1(O)c1ccc(OCOC)cc1C2
Reactant: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCCCC12CCCC(=O)C(C)=C1c1ccc(OCOC)cc1C2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 9a-butyl-2-(methoxymethoxy)-5-methyl-8,9,9a,10-tetrahydrobenzo[a]azulen-4b(7H)-ol (32 mg, 0.1 mmol) in dichloromethane (1 mL) was treated with pyridinium chlorochromate (PCC, 32 mg, 0.15 mmol). After stirring at room temperature for 5 hours, the mixture was treated with additional PCC (5 mg, 0.023 mmol). The mixture was concentrated and purified by preparative layer chromatography on a 0.1×20×20 cm silica gel GF plate (Analtech, Newark, Del.), developing with 10% EtOAc in hexane. The UV visible product band was eluted with EtOAc and the eluant was evaporated under vacuum to provide 9a-butyl-2-(methoxymethoxy)-5-methyl-8,9,9a,10-tetrahydrobenzo[a]azulen-6(7H)-one as an oil.
Reaction SMILES: O[CH:2]([C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=1)[CH:3]([NH:6][C:7]([O:9]CC)=[O:8])[CH2:4][OH:5]>C1(C)C=CC=CC=1>[CH3:19][S:18][C:15]1[CH:14]=[CH:13][C:12]([CH:2]2[O:9][C:7](=[O:8])[NH:6][CH:3]2[CH2:4][OH:5])=[CH:17][CH:16]=1
Reactant: CCOC(=O)NC(CO)C(O)c1ccc(SC)cc1
Solvent: Cc1ccccc1
Product: CSc1ccc(C2OC(=O)NC2CO)cc1

Procedure:
Compound (H) (5 g; 17.5 mmols) has been dissolved in warm toluene (25 ml). To this solution, an equimolar amount of potassium tert. butylate has been added and the reaction mixture has been refluxed for 3 hours. Afterwards, almost all of the solvent has been evaporated; water and ice have been added to the residue and the precipitate has been collected by filtration. The thus obtained crude (J) has been recrystallized from ethanol (3.7 g; yield, 88%); m.p. 130°-131° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][C:7]2=[O:12])[CH3:2].[BH4-].[Na+].CO.O>O1CCCC1>[CH2:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][CH:7]2[OH:12])[CH3:2]
Reactant: CCc1cccc2c1CCC2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCc1cccc2c1CCC2O
Temperature: 0 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
4-Ethylindan-1-one (160 mg, 0.998 mmol) synthesized in (44A) was dissolved in tetrahydrofuran (5 mL), and the resulting solution was cooled to 0° C. Thereafter, sodium borohydride (57 mg, 1.50 mmol) was added thereto, and methanol (2 mL) was added dropwise thereto, and then, the resulting mixture was stirred at room temperature for 8 hours. Water was added to the reaction solution, and the organic matter was extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution, then dried over anhydrous magnesium sulfate and filtered. Then, the solvent was distilled off under reduced pressure, whereby a crude product was obtained. This crude product was purified by silica gel column chromatography (hexane:ethyl acetate=100:0 to 70:30 (v/v)), whereby the objective title compound was obtained as a yellow oily substance (162 mg, yield: 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:14]([C:17]([OH:19])=[O:18])[CH2:15][OH:16])[CH2:9][N:8]=[C:7]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:6]=2[CH:26]=1.[N+](=[CH2:29])=[N-]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:14]([C:17]([O:19][CH3:29])=[O:18])[CH2:15][OH:16])[CH2:9][N:8]=[C:7]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:6]=2[CH:26]=1
Reactant: C=[N+]=[N-]
Reactant: O=C(O)C(CO)=NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Product: COC(=O)C(CO)=NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1

Procedure:
In the manner given in Example 10, a solution of 7-chloro-2-[(1-carboxy-2-hydroxyethylidene)hydrazino]-5-phenyl-3H-1,4-benzodiazepine can be treated with ethereal diazomethane to give 7-chloro-2-[[1-(methoxycarbonyl)-2-hydroxyethylidene]hydrazino]-5-phenyl-3H-1,4-benzodiazepine.
Reaction SMILES: [C:1]1([CH:7]=[C:8]2[C:13](=O)[C:12](=[CH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11][S:10](=[O:23])(=[O:22])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:24]([NH:27][NH2:28])[CH2:25][CH3:26]>CO.C(Cl)(Cl)(Cl)Cl>[C:1]1([CH:7]2[N:27]([CH2:24][CH2:25][CH3:26])[N:28]=[C:13]3[C:12](=[CH:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:11][S:10](=[O:23])(=[O:22])[CH2:9][CH:8]23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCNN
Reactant: O=C1C(=Cc2ccccc2)CS(=O)(=O)CC1=Cc1ccccc1
Solvent: CO
Solvent: ClC(Cl)(Cl)Cl
Product: CCCN1N=C2C(=Cc3ccccc3)CS(=O)(=O)CC2C1c1ccccc1
Yield: 48.7 %

Procedure:
A mixture of 3.24g of tetrahydro-3,5-bis-(phenylmethylene)-4H-thiopyran-4-one-1,1-dioxide and 0.6g of n-propyl hydrazine in 100ml of absolute methanol is heated at reflux temperature for 2 hours. The mixture is allowed to cool, and is then filtered to give 2.8g of crude product. The crude material is stirred for about 16 hours in 200ml of carbon tetrachloride and filtered. The mother liquor is concentrated in vacuo and the residue is crystallized from methanol to give 1.5g of the title compound, melting point 197°-199°C.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:10].Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>>[CH2:12]([N:3]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:10])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: O=C1CCCCCN1
Reactant: CCCCCCCBr
Agent: [H-]
Agent: [Na+]
Product: CCCCCCCN1CCCCCC1=O
Yield: 89.7 %

Procedure:
Following example 10, 10.2 g of 50% sodium hydride-mineral oil dispersion (15.1 g of NaH, 0.2125 M), 20 g (0.177 M) of azacycloheptan-2-one and 35.8 g (0.2 M) of 1-bromoheptane on 18 hr. reflux gave 33.5 g (90%) of colorless product; b.p. 155°-158°/0.5 mm.
Reaction SMILES: [OH:1][CH2:2][C@H:3]([CH3:33])[O:4][C:5]1[CH:6]=[C:7]([CH:20]=[C:21]([C:23]([NH:25][C:26]2[CH:31]=[N:30][C:29]([CH3:32])=[CH:28][N:27]=2)=[O:24])[CH:22]=1)[O:8][C:9]1[CH:19]=[CH:18][C:12]([C:13]([O:15]CC)=[O:14])=[CH:11][CH:10]=1.O.[OH-].[Li+]>C1COCC1.O>[OH:1][CH2:2][C@H:3]([CH3:33])[O:4][C:5]1[CH:6]=[C:7]([CH:20]=[C:21]([C:23]([NH:25][C:26]2[CH:31]=[N:30][C:29]([CH3:32])=[CH:28][N:27]=2)=[O:24])[CH:22]=1)[O:8][C:9]1[CH:19]=[CH:18][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1
Reactant: CCOC(=O)c1ccc(Oc2cc(O[C@@H](C)CO)cc(C(=O)Nc3cnc(C)cn3)c2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cnc(NC(=O)c2cc(Oc3ccc(C(=O)O)cc3)cc(O[C@@H](C)CO)c2)cn1
Temperature: 25 °C
Reaction time: 72 h
Yield: 59 %

Procedure:
A solution of ethyl 4-(3-[(1S)-2-hydroxy-1-methylethoxy]-5-{[(5-methylpyrazin-2-yl)amino]carbonyl}phenoxy)benzoate (0.4 g, 0.88 mmol) in THF (16 mL) was added to a solution of lithium hydroxide monohydrate (0.19 g, 4.43 mmol) in water (8 mL). The mixture was stirred at RT for 72 hours and the THF removed in vacuo. The aqueous layer was acidified with 1M hydrochloric acid (10 mL), and the solid precipitate filtered off, washed with water and dried in vacuo to give the desired compound (0.22 g). The material was used without further purification.
Reaction SMILES: [OH:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[C:11](=[O:14])([O-])[O-:12].[K+].[K+].[Cl:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH2:20]Cl.O>CCO>[Cl:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH2:20][O:1][C:2]1[C:9]([O:10][CH2:20][C:19]2[CH:22]=[CH:23][CH:24]=[CH:25][C:18]=2[Cl:17])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]([OH:5])[C:11]([OH:12])=[O:14]
Reactant: ClCc1ccccc1Cl
Reactant: O=Cc1cccc(O)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: O=C(O)C(O)c1cccc(OCc2ccccc2Cl)c1OCc1ccccc1Cl
Yield: 75.1 %

Procedure:
To a stirred slurry of 2,3-dihydroxybenzaldehyde (6.91 g, 50.0 mmol) and potassium carbonate (17.2 g, 125 mmol) in EtOH (60 mL) at room temperature under argon was added 2-chlorobenzyl chloride (15 mL, 120 mmol). The reaction mixture was heated to reflux for 16 h, then cooled and poured into water (150 mL). The resulting solids were collected, washed with water, air-dried and recrystallized from methanol to give the title compound as white needles (16.28 g, 71% yield), mp 98-100° C. LC/MS gave the correct molecular ion [(M+H)+=387] for the desired compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:9]=1[OH:10])[CH:5]=O.[C:15](#[N:19])[CH2:16][C:17]#[N:18]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:9]=1[OH:10])[CH:5]=[C:16]([C:15]#[N:19])[C:17]#[N:18]
Reactant: CC(C)(C)c1cc(C=O)cc(Br)c1O
Reactant: N#CCC#N
Product: CC(C)(C)c1cc(C=C(C#N)C#N)cc(Br)c1O

Procedure:
In a similar manner as described in Example 2 reaction of 3-bromo-5-tert-butyl-4-hydroxybenzaldehyde and malononitrile gave 3-bromo-5-tert-butyl-4-hydroxybenzylidenemalononitrile as pale yellow needles from alcohol m.p. 185°.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH:3]1[C:7]2([CH2:9][CH2:8]2)[CH2:6][N:5](CC2C=CC=CC=2)[CH2:4]1.[ClH:18]>CO.[Pd]>[ClH:18].[ClH:18].[CH3:1][N:2]([CH3:17])[CH:3]1[C:7]2([CH2:9][CH2:8]2)[CH2:6][NH:5][CH2:4]1
Reactant: CN(C)C1CN(Cc2ccccc2)CC12CC2
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CN(C)C1CNCC12CC2
Yield: 108.7 %

Procedure:
To a solution of racemic N,N-dimethyl-5-(phenylmethyl)-5-azaspiro[2.4]heptan-7-amine (0.8015 g, 3.479 mmol) in MeOH (18 mL) was added 1 N aq. HCl (6.96 mL, 6.96 mmol) and 10% Pd/C (50% water, 160 mg). The mixture was hydrogenated under balloon pressure overnight and then filtered. The solution was concentrated in vacuo to give crude racemic N,N-dimethyl-5-azaspiro[2.4]heptan-7-amine dihydrochloride (0.8060 g, >100% crude yield). LCMS: (M+H)+: 141.1.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([S:8]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([C:20]([CH:22]2[CH2:24][CH2:23]2)=[O:21])[CH2:15][CH2:14]3)(=[O:10])=[O:9])[CH2:4][CH2:3]1.C(N(C(C)C)CC)(C)C.[C:34](Cl)(=[O:37])[CH:35]=[CH2:36]>C1COCC1.CCOC(C)=O>[CH:22]1([C:20]([N:16]2[C:17]3[C:13](=[CH:12][C:11]([S:8]([N:5]4[CH2:6][CH2:7][CH:2]([NH:1][C:34](=[O:37])[CH:35]=[CH2:36])[CH2:3][CH2:4]4)(=[O:10])=[O:9])=[CH:19][CH:18]=3)[CH2:14][CH2:15]2)=[O:21])[CH2:23][CH2:24]1
Reactant: C=CC(=O)Cl
Reactant: NC1CCN(S(=O)(=O)c2ccc3c(c2)CCN3C(=O)C2CC2)CC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)NC1CCN(S(=O)(=O)c2ccc3c(c2)CCN3C(=O)C2CC2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 34.7 %

Procedure:
[5-(4-Amino-piperidine-1-sulfonyl)-2,3-dihydro-indol-1-yl]-cyclopropyl-methanone (0.09 g, 0.25 mmol) was dissolved in THF (5 ml). To this was added diisopropylethylamine (0.2 ml, 1.0 mmol) in one portion followed by the drop wise addition of acryloyl chloride (0.02 ml, 0.27 mmol) and the mixture was stirred at room temperature under a nitrogen atmosphere for 3 hours. After this time the mixture was diluted with EtOAc (50 ml) and washed sequentially with HCl (1M solution, 20 ml), NaOH (1M solution, 20 ml) and brine (20 ml), the organic layer was separated, dried (MgSO4), filtered and concentrated. The resulting residue was purified by flash column chromatography (elution: 100% EtOAc) to give the title compound (0.035 g, 35% yield) as a white powder.
Reaction SMILES: N[C:2]1C(I)=C(CCCCCCCCCCCC(O)=O)C(I)=C[C:7]=1I.[Br:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([OH:38])=[O:37].OS(O)(=O)=O>C(O)C>[CH2:2]([O:37][C:36](=[O:38])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][Br:25])[CH3:7]
Reactant: O=C(O)CCCCCCCCCCBr
Reactant: Nc1c(I)cc(I)c(CCCCCCCCCCCC(=O)O)c1I
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CCOC(=O)CCCCCCCCCCBr

Procedure:
In this example, 12-(3-amino-2,4,6-triiodophenyl)dodecanoic acid is synthesized. 11-Bromoundecanoic acid (54.0 g, 200 mmol) was refluxed overnight with 150 ml absolute ethanol and a catalytic amount (1.0 ml) H2SO4. The solvent was removed in vacuo and the residue was dissolved in 100 ml CHCl3 and extracted with 100 ml H2O, twice with 100 ml 10% aq. NaHCO3, 100 ml water, and brine, and was dried with MgSO4Removal of the solvent in vacuo and distillation of the remaining yellow liquid under vacuum yielded ethyl-11-bromoundecanoate as a colorless liquid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH2:19][C:20]([OH:22])=O)[C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[N:6][CH:7]=1.[CH2:23]([NH:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[N:28]=1)[CH3:24]>>[CH2:23]([N:25]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[N:28]=1)[C:20](=[O:22])[CH2:19][N:11]([S:8]([C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=1)(=[O:10])=[O:9])[C:12]1[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=1)[CH3:24]
Reactant: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ccc(C)cn2)cc1
Reactant: CCNCc1cccc(C)n1
Product: CCN(Cc1cccc(C)n1)C(=O)CN(c1ccc(C)cc1)S(=O)(=O)c1ccc(C)cn1

Procedure:
prepared by reaction of [(5-methyl-pyridine-2-sulfonyl)-p-tolyl-amino]-acetic acid with ethyl-(6-methyl-pyridin-2-ylmethyl)-amine
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH3:16])([CH3:7])[CH3:6])[CH3:2].Cl[CH2:19][C:20]1[C:21]([CH:36]2[CH2:38][CH2:37]2)=[N:22][C:23]([C:26]2[CH:27]=[N:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=2)=[N:24][CH:25]=1.C1(C(=O)CC(OC)=O)CC1.Cl.FC(F)(F)C1C=CC(C(N)=N)=CC=1>>[CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:19][C:20]2[C:21]([CH:36]3[CH2:38][CH2:37]3)=[N:22][C:23]([C:26]3[CH:27]=[N:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=3)=[N:24][CH:25]=2)=[CH:11][C:10]=1[CH3:16])([CH3:6])[CH3:7])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1C
Reactant: FC(F)(F)c1ccc(-c2ncc(CCl)c(C3CC3)n2)cn1
Agent: COC(=O)CC(=O)C1CC1
Agent: Cl
Agent: N=C(N)c1ccc(C(F)(F)F)cc1
Product: CCOC(=O)C(C)(C)Oc1ccc(OCc2cnc(-c3ccc(C(F)(F)F)nc3)nc2C2CC2)cc1C

Procedure:
In analogy to the procedures described in example 101A], 2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (described in WO 02/092590) was reacted with 5-chloromethyl-4-cyclopropyl-2-(6-trifluoromethyl-pyridin-3-yl)-pyrimidine (prepared from methyl 3-cyclopropyl-3-oxopropanoate and 4-(trifluoromethyl)benzamidine hydrochloride, in analogy to the procedures described in examples 101C] to 101F]) to give 2-{4-[4-cyclopropyl-2-(6-trifluoromethyl-pyridin-3-yl)-pyrimidin-5-ylmethoxy]-2-methyl-phenoxy}-2-methyl-propionic acid ethyl ester, which was subsequently saponified in analogy to the procedure described in example 101B] to yield the title compound as off-white crystalls of mp. 185.0–185.5° C.
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH:38]([C:40]1[CH:41]=[C:42]([N:46]([CH2:52][C:53]2[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=2)[S:47]([CH2:50][CH3:51])(=[O:49])=[O:48])[CH:43]=[CH:44][CH:45]=1)=O>C1COCC1>[C:3]1([CH:2]=[CH:38][C:40]2[CH:41]=[C:42]([N:46]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=3)[S:47]([CH2:50][CH3:51])(=[O:49])=[O:48])[CH:43]=[CH:44][CH:45]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCS(=O)(=O)N(Cc1cccnc1)c1cccc(C=O)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCS(=O)(=O)N(Cc1cccnc1)c1cccc(C=Cc2ccccc2)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Benzyltriphenylphosphonium bromide (0.765 g, 1.77 mmol) was dispersed into THF (12 ml) and cooled at 0° C. To the cooled suspension was added dropwise a solution of potassium bis(trimethylsilyl)amide (0.5 M, 3.5 ml, 1.75 mmol). After stirring at 0° C. for 1 h, a solution of). N-(3-formyl-phenyl)-N-(ethylsulfonyl)pyrid-3-ylmethylamine (0.304 g, 1.0 mmol) in THF was added. The reaction mixture was stirred at ambient temperature for 2 h. Evaporation and chromatography on silica-gel eluting with toluene-EtOAc to give the title compound. 1H NMR: 8.48 (d,1H,J=3.4 Hz), 8.30 (d,1H,J=2.0 Hz), 7.65 (d,1H,J=7.8 Hz), 7.30-6.74 (m,8H), 6.60 (q,2H,J=12.2, 37.1 Hz), 4.68 (s,2H), 2.87 (q,2H,J=7.3 Hz), 1.28 (t,3H,J=7.4 Hz). MS calcd 378.1; MS (M+1) 379.1.