Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:81]C(=O)OCC)[C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH:18]3[CH2:23][CH:22]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH:21]([O:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH3:61])[CH:20]([O:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH3:80])[CH2:19]3)=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.C(O)C.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH2:81])[C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH:18]3[CH2:19][CH:20]([O:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH3:80])[CH:21]([O:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH3:61])[CH:22]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:23]3)=[CH:14][CH:15]=2)=[CH:5][CH:4]=1
Reactant: CCCCCCCCCCCCCCCCCCOC1CC(COc2ccc(C(NC(=O)OCC)c3ccc(OC)cc3)cc2)CC(OCCCCCCCCCCCCCCCCCC)C1OCCCCCCCCCCCCCCCCCC
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCCCCCCCCCCCCCCCCOC1CC(COc2ccc(C(N)c3ccc(OC)cc3)cc2)CC(OCCCCCCCCCCCCCCCCCC)C1OCCCCCCCCCCCCCCCCCC
Temperature: 100 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To crude crystals (127 mg) of ethyl {(4-methoxy-phenyl)-[4-(3,4,5-tris-octadecyloxy-cyclohexylmethoxy)-phenyl]-methyl}-carbamate were added toluene (2 mL), ethanol (2 mL), and sodium hydroxide (21 mg, 525 μmol), and the mixture was stirred at 100° C. for 2 hours. The reaction mixture was cooled to room temperature, toluene (2 mL) was added, and washed with water (4 mL×3 times) to allow partitioning. The organic layer was evaporated, and the residue was crystallized from acetonitrile (5 mL) to give {(4-methoxy-phenyl)-[4-(3,4,5-tris-octadecyloxy-cyclohexylmethoxy)-phenyl]-methyl}-amine (123 mg, 100% vs —OH form).
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][CH2:8][NH:9][CH:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2[O:20]C)[CH2:11]1.B(Br)(Br)Br.[NH4+].[OH-]>ClCCl>[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][CH2:8][NH:9][CH:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2[OH:20])[CH2:11]1
Reactant: COc1cccc2c1CCC(NCCc1cccs1)C2
Agent: BrB(Br)Br
Agent: Cl
Agent: [NH4+]
Solvent: ClCCl
Product: Oc1cccc2c1CCC(NCCc1cccs1)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 24.4 %

Procedure:
To a solution of 4.95 g (0.015 mol) of the product of Step 3 in dry dichloromethane was added 80 mL of boron tribromide under N2. The mixture was stirred 1 hour at room temperature then poured over NH4OH and ice. The organic layer was separated and dried over MgSO4, and concentrated to yield 1.0 g of product: NMR (CDCl3)δ7.2-6.6(6H,m), 3.1-2.8(7H,m), 2.7-2.5(2H,m), 2.15(1H,m), 1.65(1H,m).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:15]=[CH:16][C:17]4[O:21][CH2:20][CH2:19][C:18]=4[CH:22]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[CH:4][C:3]=1[CH3:23].[CH3:24][O:25][C:26]1[C:31]([CH3:32])=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][N:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.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>[O:21]1[C:17]2[CH:16]=[CH:15][C:14]([C:11]3([C:9]([NH:8][C:6]4[N:7]=[C:2]([C:29]5[CH:28]=[N:27][C:26]([O:25][CH3:24])=[C:31]([CH3:32])[CH:30]=5)[C:3]([CH3:23])=[CH:4][CH:5]=4)=[O:10])[CH2:13][CH2:12]3)=[CH:22][C:18]=2[CH2:19][CH2:20]1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)CCO4)CC2)nc1Cl
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COc1ncc(-c2nc(NC(=O)C3(c4ccc5c(c4)CCO5)CC3)ccc2C)cc1C
Temperature: 80 °C
Yield: 80.2 %

Procedure:
To N-(6-chloro-5-methylpyridin-2-yl)-1-(2,3-dihydrobenzofuran-5-yl)cyclopropanecarboxamide (0.1 g, 0.3 mmol) in 1,2-dimethoxyethane (3 mL) was added 2-methoxy-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (98 mg, 0.4 mmol), tetrakis(triphenylphosphine)palladium (0) (35 mg, 0.03 mmol), and 2 M sodium carbonate (0.45 mL, 0.9 mmol) and the reaction mixture was heated to 80° C. overnight. The reaction was diluted with ethyl acetate (5 mL) and washed with water (5 mL). The aqueous layer was back extracted with ethyl acetate (5 mL). The organics were dried over sodium sulfate and evaporated. The resulting crude material was purified by silica gel chromatography (eluting with 0-30% ethyl acetate in hexanes) to yield the product (0.1 g, 84%). ESI-MS m/z calc. 415.48. found 416.1 (M+1)+. Retention time 2.03 minutes.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.[NH:12]1[CH2:20][CH2:19][CH:15]([C:16]([NH2:18])=[O:17])[CH2:14][CH2:13]1.C(N(CC)CC)C>O1CCOCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:20][CH2:19][CH:15]([C:16]([NH2:18])=[O:17])[CH2:14][CH2:13]2)[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1
Reactant: NC(=O)C1CCNCC1
Reactant: Clc1nc(Cl)c2cc[nH]c2n1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: NC(=O)C1CCN(c2nc(Cl)nc3[nH]ccc23)CC1
Temperature: 70 °C
Reaction time: 20 h
Yield: 98.8 %

Procedure:
A mixture of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (140 mg, 0.744 mmol), isonipecotamide (95 mg, 0.742 mmol) and triethylamine (0.300 mL, 2.15 mmol) in dioxane (4 mL) was stirred at 70° C. for 20 h. The precipitates were collected and dried on vacuum to give 1-(2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (205 mg). MS 280.3 and 282.3 (M+H, Cl pattern).
Reaction SMILES: [N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:34]=[C:33]([Cl:35])[C:32]([Cl:36])=[CH:31][C:15]=3[C:16]([NH:18][C@@H:19]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[C:20](O)=[O:21])=[O:17])(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12.[NH3:37]>>[N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:34]=[C:33]([Cl:35])[C:32]([Cl:36])=[CH:31][C:15]=3[C:16]([NH:18][C@H:19]([C:20](=[O:21])[NH2:37])[CH2:23][C:24]3[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=3)=[O:17])(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12
Reactant: N
Reactant: O=C(N[C@@H](Cc1ccc(Cl)cc1)C(=O)O)c1cc(Cl)c(Cl)cc1NS(=O)(=O)c1cccc2nsnc12
Product: NC(=O)[C@H](Cc1ccc(Cl)cc1)NC(=O)c1cc(Cl)c(Cl)cc1NS(=O)(=O)c1cccc2nsnc12
Yield: 20 %

Procedure:
The title compound (3 mg, 20%) was prepared from (S)-2-[2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4,5-dichloro-benzoylamino]-3-(4-chloro-phenyl)-propionic acid and NH3 (0.5 M in dioxane) as in Example 1, Part C. HPLC: RT=10.08 min. MS (ESI−): mass calcd. for C22H16Cl3N5O4S2, 582.97; m/z found, 582/584 [M−H]−. 1H NMR (400 MHz, CDCl3): 11.34 (s, 1H), 8.37 (dd, J=7.1, 1.0, 1H), 8.24 (dd, J=8.8, 1.0, 1H), 7.84 (s, 1H), 7.73 (dd, J=8.8, 7.1, 1H), 7.36 (s, 1H), 7.36-7.32 (m, 2H), 7.24-7.20 (m, 2H), 6.84 (br d, J=6.9, 1H), 5.47 (br s, 1H), 5.41 (br s, 1H), 4.68 (ddd, J=8.6, 7.0, 5.0, 1H), 3.18 (dd, J=13.7, 4.9, 1H), 3.01 (dd, J=13.6, 8.6, 1H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][S:9][CH2:10][CH2:11][C:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[C:20]([O:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])[C:15]=3[O:14][C:13]=2[CH3:27])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C(=O)N(Br)C(=[O:31])C1.O>CO>[C:1]1([CH2:7][CH2:8][S:9]([CH2:10][CH2:11][C:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[C:20]([O:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])[C:15]=3[O:14][C:13]=2[CH3:27])=[O:31])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)COc1cccc2c(CCSCCc3ccccc3)c(C)oc12
Solvent: O
Solvent: CO
Product: COC(=O)COc1cccc2c(CCS(=O)CCc3ccccc3)c(C)oc12
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 63.5 %

Procedure:
Methyl (3-(2-(2-phenylethylthio)ethyl)-2-methylbenzofuran-7-yloxy)acetate (340 mg) was dissolved in methanol (15 ml) and the obtained solution was cooled to −10° C. To this solution, NBS (190 mg) was added for 5 minutes and the resulting mixture was stirred at −10° C. for 30 minutes. This reaction solution was poured into water layer (100 ml) and the resultant was extracted twice with ethyl acetate (30 ml). The organic layers were combined and washed with saturated brine, followed by drying over sodium sulfate. After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure and the residue was purified by column chromatography (solvent: dichloromethane/ethyl acetate=2/1) using silica gel to obtain the desired compound (225 mg, yield: 64%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[Cl:13])[C:5]([CH2:7][C:8]#[N:9])=O.O.[NH2:15][NH2:16]>C(O)C>[NH2:9][C:8]1[CH:7]=[C:5]([C:4]2[CH:10]=[CH:11][C:12]([Cl:13])=[C:2]([Cl:1])[CH:3]=2)[NH:16][N:15]=1
Reactant: N#CCC(=O)c1ccc(Cl)c(Cl)c1
Reactant: NN
Solvent: CCO
Solvent: O
Product: Nc1cc(-c2ccc(Cl)c(Cl)c2)[nH]n1

Procedure:
3,4-Dichlorobenzoylacetonitrile (3.0 g) was dissolved in ethanol (15 ml) to which was subsequently added hydrazine monohydrate (0.67 ml) while cooling with ice. The mixture was heatedunder reflux for 5 hours and allowed to cool. Then, the solvent was distilled away under a reduced pressure. The resulting residue was recrystallized from ethyl acetate-hexane to obtain the title compound (1.72 g) as colorless crystals (melting point: 169-170° C.).
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:14](=[O:15])[CH2:13][CH2:12][C@@H:11]1/[CH:16]=[CH:17]/[CH:18]([OH:32])[C:19]1[CH:20]=[C:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])[CH:22]=[CH:23][CH:24]=1>CO>[OH:32][CH:18]([C:19]1[CH:20]=[C:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])[CH:22]=[CH:23][CH:24]=1)/[CH:17]=[CH:16]/[C@H:11]1[CH2:12][CH2:13][C:14](=[O:15])[N:10]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:33])=[O:2]
Reactant: COC(=O)CCCCCCN1C(=O)CC[C@@H]1/C=C/C(O)c1cccc(-c2ccccc2C)c1
Solvent: CO
Product: Cc1ccccc1-c1cccc(C(O)/C=C/[C@H]2CCC(=O)N2CCCCCCC(=O)O)c1
Reaction time: 6 h
Yield: 73.6 %

Procedure:
To a methanol solution (5 mL) of 7-{(R)-2-[(E)-3-Hydroxy-3-(2′-methyl-biphenyl-3-yl)-propenyl]-5-oxo-pyrrolidin-1-yl}-heptanoic acid methyl ester (87 mg) was added an aqueous solution (2.5 mL) of LiOH monohydrate. The reaction mixture was stirred for 6 h and then concentrated to remove the methanol. The aqueous concentrate was diluted with CH2Cl2 and 1N HCl was added, extracted with CH2Cl2 and dried over MgSO4. This mixture was filtered and concentrated to yield 62 mg of 7-{(R)-2-[(E)-3-Hydroxy-3-(2′-methyl-biphenyl-3-yl)-propenyl]-5-oxo-pyrrolidin-1-yl}-heptanoic acid as an oil (42) (50).MS:435 [(M+H)+].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15]2)[CH:10]([CH2:23][OH:24])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[Si:30](Cl)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15]2)[CH:10]([CH2:23][O:24][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(n2ccc3ccccc32)C(CO)C1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(n2ccc3ccccc32)C(CO[Si](C)(C)C(C)(C)C)C1
Yield: 100.9 %

Procedure:
Dissolve 3-Hydroxymethyl-4-indol-1-ylpiperidine-1-carboxylic acid tert-butyl ester (1.1 g, 3.3 mmol) in dichloromethane (20 ml). Add imidazole (340 mg, 5.0 mmol) and tert-butyldimethylsilyl chloride (754 mg, 5.0 mmol) and stir at ambient temperature for 72 hours. Dilute with dichloromethane, wash with 1N HCl, water, brine. Dry with sodium sulfate, filter, and concentrate to an oil. Purify by flash chromatography (10% ethyl acetate:hexanes) to yield the title compound (1.48 g, 100%). ES (M++1): 389.2
Reaction SMILES: C[O:2][C:3](=[O:55])[C:4]([CH3:54])([CH3:53])[CH2:5][C@@H:6]1[CH2:11][C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][O:19][CH2:20][C@@H:21]([CH3:25])[CH2:22][O:23][CH3:24])=[CH:14][CH:13]=2)[C@@H:9]([O:26][CH2:27][C:28]2[CH:29]=[CH:30][C:31]3[O:36][CH2:35][CH2:34][N:33]([CH2:37][CH2:38][CH2:39][O:40][CH3:41])[C:32]=3[CH:42]=2)[CH2:8][N:7]1[S:43]([C:46]1[CH:51]=[CH:50][C:49]([CH3:52])=[CH:48][CH:47]=1)(=[O:45])=[O:44].[OH-].[Li+]>C1COCC1.CO>[CH3:24][O:23][CH2:22][C@H:21]([CH3:25])[CH2:20][O:19][CH2:18][C:15]1[CH:16]=[CH:17][C:12]([C@@H:10]2[C@@H:9]([O:26][CH2:27][C:28]3[CH:29]=[CH:30][C:31]4[O:36][CH2:35][CH2:34][N:33]([CH2:37][CH2:38][CH2:39][O:40][CH3:41])[C:32]=4[CH:42]=3)[CH2:8][N:7]([S:43]([C:46]3[CH:51]=[CH:50][C:49]([CH3:52])=[CH:48][CH:47]=3)(=[O:44])=[O:45])[C@H:6]([CH2:5][C:4]([CH3:54])([CH3:53])[C:3]([OH:55])=[O:2])[CH2:11]2)=[CH:13][CH:14]=1
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@H](CC(C)(C)C(=O)OC)C[C@@H]3c3ccc(COC[C@@H](C)COC)cc3)cc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@H](CC(C)(C)C(=O)O)C[C@@H]3c3ccc(COC[C@@H](C)COC)cc3)cc21
Temperature: 65 °C
Reaction time: 4 h

Procedure:
To a solution of 1.0 mmol of 3-[(2S,4R,5R)-4-[4-((S)-3-methoxy-2-methyl-propoxymethyl)-phenyl]-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-2,2-dimethyl-propionic acid methyl ester in 10 ml of THF and 10 ml of MeOH are added 10 ml of a 3M lithium hydroxide solution. The reaction mixture is stirred for 4 h at 65° C. The organic solvents are evaporated under reduced pressure and the remaining solution is acidified with 3M aqueous HCl until pH 2. This mixture is extracted with 100 ml of EtOAc (3×). The combined organic layers are washed with brine and dried with Na2SO4. The organic layer is filtered and evaporated under reduced pressure. The residue is purified by flash chromatography (SiO2 60 F) to afford the title compound as a pale orange foam. Rf=0.28 (EtOAc/heptane/HCOOH 2:1:0.1); Rt=5.50 (gradient I).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:16]=[C:17]([CH:22]=[CH:23][C:24]=2[N+:25]([O-])=O)[C:18]([O:20][CH3:21])=[O:19])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1>[C].[Pt].CO>[NH2:25][C:24]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:15]=1[NH:14][CH:11]1[CH2:10][CH2:9][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:13][CH2:12]1
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(NC2CCN(Cc3ccccc3)CC2)c1
Agent: [Pt]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccc(N)c(NC2CCN(Cc3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.4 %

Procedure:
A mixture of methyl 3-[(1-benzylpiperidin-4-yl)amino]-4-nitrobenzoate (17.1 g, 46.3 mmol), 5% platinum carbon (5.13 g), tetrahydrofuran (115 mL) and methanol (115 mL) was stirred under a hydrogen atmosphere at room temperature overnight. The m reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=2/1) and recrystallized from diisopropyl ether/ethyl acetate to give the title compound (8.40 g, yield 53%) as pale-red crystals.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[C:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[CH:7][N:6]=1)(=O)=O.[F:26][C:27]1[CH:28]=[C:29]([OH:33])[CH:30]=[CH:31][CH:32]=1>>[F:26][C:27]1[CH:28]=[C:29]([O:33][C:5]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=3[Cl:18])[C:8]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)=[CH:7][N:6]=2)[CH:30]=[CH:31][CH:32]=1
Reactant: CS(=O)(=O)c1ncc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Reactant: Oc1cccc(F)c1
Product: Fc1cccc(Oc2ncc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)n2)c1

Procedure:
2-Methylsulfonyl-4-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyrimidine from Reference Example 3 was reacted with 3-fluorophenol according to the procedure described in Example 74 to afford 2-(3-fluorophenyloxy)-4-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyrimidine: HPLC/MS: m/e=445 (M++1); Rt=4.50 min; 1H-NMR 400 MHz (CDCl3): δ 7.05. (m, 3H), 7.21-7.30 (m, 6H), 7.38-7.42 (m, 2H), 8.60 (s, 1H).
Reaction SMILES: [CH:1]1([C:6]([C:8]2[CH:9]=[C:10](OS(C(F)(F)F)(=O)=O)[CH:11]=[C:12]([OH:14])[CH:13]=2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:23]1[O:31][C:30]2[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][C:25]=2[O:24]1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.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>[O:24]1[C:25]2[CH:26]=[CH:27][C:28]([C:10]3[CH:9]=[C:8]([C:6]([CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)=[O:7])[CH:13]=[C:12]([OH:14])[CH:11]=3)=[CH:29][C:30]=2[O:31][CH2:23]1
Reactant: O=C(c1cc(O)cc(OS(=O)(=O)C(F)(F)F)c1)C1CCCC1
Reactant: OB(O)c1ccc2c(c1)OCO2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: O=C(c1cc(O)cc(-c2ccc3c(c2)OCO3)c1)C1CCCC1
Temperature: 90 °C
Reaction time: 3 h
Yield: 36.3 %

Procedure:
To a solution of trifluoro-methanesulfonic acid 3-cyclopentanecarbonyl-5-hydroxy-phenyl ester (300 mg) in 1,2-dimethoxyethane (4 mL) were added 3,4-methylenedioxyphenylboronic acid (295 mg), 2 M aq. sodium carbonate solution (0.9 mL) and Pd(PPh3)4 (10 mg) and the resulting mixture was stirred at 90° C. for 3 h. Then the reaction mixture was diluted with ethyl acetate, filtered through Celite and washed with water and brine. The organic extract was dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column using ethyl acetate and hexanes to yield 100 mg of the title compound (36% yield). HRMS calcd for C19H18O4 [M+H]+ 311.1278, observed 311.1277.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:12](O)[CH2:13][OH:14].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:8]2[O:14][CH2:13][CH2:12][O:9]2)=[CH:10][CH:11]=1)([O-:3])=[O:2]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(C2OCCO2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 92 %

Procedure:
A stirred solution of p-nitrobenzaldehyde (101.5 g, 672 mmol), ethylene glycol (112 mL) and p-toluenesulfonic acid (12.8 g, 67.2 mmol) in toluene (800 mL) was heated in flask equipped with a Dean-Stark trap at 120° C. for 4 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. To the residue was added saturated aqueous sodium bicarbonate (800 mL) and this mixture was stirred at room temperature for 15 min. The resulting solid was isolated by filtration and dried under vacuum to give the title compound (121.8 g, 92% yield) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[OH:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:35][CH2:36][NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41].N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[O:13][CH2:35][CH2:36][NH:37][C:38]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:44]
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1O
Reactant: CC(C)(C)OC(=O)NCCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc([N+](=O)[O-])cc1OCCNC(=O)OC(C)(C)C
Reaction time: 48 h
Yield: 115 %

Procedure:
To a solution of 2-hydroxy-4-nitro benzoic acid methyl ester (7.0 g, 0.035 mol), triphenylphosphine (9.31 g, 0.035 mol) and t-butyl N-(2-hydroxyethyl)carbamate (3.82 g, 0.023 mol) in anhydrous THF (400 mL) (stirring for 1 hr.) was added diisopropyl azodicarboxylate (7.03 mL, 0.035 mol) and stirred for 2 days. The reaction was evaporated and the residue purified by ISCO chromatography to give 2-(tert-butoxycarbonylamino-ethoxy)-4-nitro-benzoic acid methyl ester (9.0 g) as a white solid. 1H-NMR (DMSO-d6) δ 7.90 (s, 1H), 7.86 (s, 2H), 6.86-92 (br, 1H), 4.18-9 d, 2H), 3.85 (s, 2H), 3.31 (d, 2H), 1.37 (s, 9H); LC/MS (ESI+): 363 (M+Na).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[NH:12][C:11]([C:13]3[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=3[Cl:23])=[C:10]([C:24]([OH:26])=O)[CH:9]=2)[CH:5]=[CH:4][N:3]=1.CC[N:29](C(C)C)C(C)C.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.N>CN(C=O)C.O>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[NH:12][C:11]([C:13]3[CH:18]=[C:17]([C:19]([F:20])([F:22])[F:21])[CH:16]=[CH:15][C:14]=3[Cl:23])=[C:10]([C:24]([NH2:29])=[O:26])[CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: Nc1nccc(-c2cc(C(=O)O)c(-c3cc(C(F)(F)F)ccc3Cl)[nH]2)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1cc(-c2ccnc(N)n2)[nH]c1-c1cc(C(F)(F)F)ccc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.9 %

Procedure:
A solution of 5-(2-amino-pyrimidin-4-yl)-2-(2-chloro-5-trifluoromethyl-phenyl)-1H-pyrrole-3-carboxylic acid (581 mg, 1.52 mmol) in DMF (5 mL) and DIPEA (1.06 mL, 6.08 mmol) was stirred at 0° C. EDCl (582 mg, 3.04 mmol) and HOBT.NH3 (469 mg, 3.04 mmol) were added and the reaction mixture was stirred for 3 h at room temperature. The mixture was diluted with water and the resulting precipitate was collected by filtration to afford the title compound (475 mg, 82%).
Reaction SMILES: [CH3:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[C:5]([CH:10]=[O:11])=[CH:4][CH:3]=1.C/C(/C=C/C=C(C)C)=C\C=O>>[CH3:7][CH:2]([CH2:3][CH2:4][CH:5]([CH:6]([CH3:9])[CH3:8])[CH2:10][OH:11])[CH3:1]
Reactant: CC1=CC=C(C=O)C(C)(C)C1
Agent: CC(C)=C/C=C/C(C)=C/C=O
Product: CC(C)CCC(CO)C(C)C

Procedure:
After comparison of the proton NMR spectral data to published spectral data for dehydrocitral (2) (Kann et al., J. Org. Chem. 55, 5312-5323 (1990)) and 4,6,6-trimethyl-1,3-cyclohexadiene-1-carboxaldehyde (3) (Hong et al., Org. Letters, 8, 2217 (2006)), the mixture was shown to contain dehydrolavandulal (1), (2E,4E)-3,7-dimethyl-2,4,6-octatrienal (2) (dehydrocitral), and 4,6,6-trimethyl-1,3-cyclohexadiene-1-carboxaldehyde (3) in a 76:12:12 ratio, respectively. The proton NMR spectrum of dehydrolavandulal (1) exhibited a singlet at δ 9.44 (CH═O); a doublet (J=12 Hz) at δ 7.10 (vinyl H at C3); a broad doublet (J=12 Hz) at δ 6.35 (vinyl H at C4); broad singlets at δ 5.27 and δ 4.80 (C═CH2); and broad singlets at δ 1.97, 1.94, and 1.90 (three CH3 groups). The proton NMR spectrum of dehydrocitral (2) was characterized by a doublet (J=8.1 Hz) at δ 10.10 (CH═O, E stereoisomer); a doublet of doublets (J=15, 11 Hz) at δ 6.97 (vinyl H at C5); a doublet (J=15 Hz) at δ 6.24 (vinyl H at C4); a broad doublet (J=11 Hz) at δ 6.00 (vinyl H at C6); a broad doublet (J=8.1 Hz) at δ 5.95 (vinyl H at C2); a doublet (J=1.2 Hz) at δ 2.30 (CH3 at C3); and overlapping broad singlets at δ 1.88 (two CH3 groups at C7). The assignment of dehydrolavandulal was further confirmed by hydrogenation of dehydrolavandulal to obtain the known compound tetrahydrolavandulol, as shown in Example 5. The presence of 4,6,6-trimethyl-1,3-cyclohexadiene-1-carboxaldehyde as a minor component in the product mixture was indicated by a singlet at δ 9.40 (CH═O) and a singlet at δ 1.20 (6H; two CH3 groups at C6). For a full spectral characterization of the latter cyclic aldehyde, see B. C. Hong, et al., Org. Letters, 8, 2217 (2006).