Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12](=[O:19])[C:11]([F:21])([F:20])[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:30]1([C:36]2[CH:44]=[CH:43][CH:42]=[CH:41][C:37]=2[C:38](Cl)=[O:39])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(Cl)Cl>[F:20][C:11]1([F:21])[C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N:8]([C:6](=[O:7])[C:5]2[CH:22]=[CH:23][C:2]([NH:1][C:38](=[O:39])[C:37]3[CH:41]=[CH:42][CH:43]=[CH:44][C:36]=3[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[CH:3][CH:4]=2)[CH2:9][CH2:10]1
Reactant: Nc1ccc(C(=O)N2CCC(F)(F)C(=O)c3ccccc32)cc1
Reactant: O=C(Cl)c1ccccc1-c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ccc(C(=O)N2CCC(F)(F)C(=O)c3ccccc32)cc1)c1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-(4-Aminobenzoyl)-4,4-difluoro-2,3,4,5-tetrahydro-1H-1-benzazepin-5-one (200 mg) and 5 ml of pyridine were dissolved in 10 ml of methylene chloride, and 10 ml of a methylene chloride solution containing the o-phenylbenzoic acid chloride obtained above was added dropwise under ice-cooling. After 1 hour of stirring at room temperature, the solvent was evaporated under a reduced pressure, and the thus obtained residue was dissolved in ethyl acetate and washed with saturated sodium carbonate aqueous solution, 1N hydrochloric acid aqueous solution and saturated sodium chloride aqueous solution in that order. After drying on anhydrous magnesium sulfate and subsequent evaporation of the solvent under a reduced pressure, the resulting residue was applied to column chromatography, which was eluted with a mixed solvent of ethyl acetate and hexane (2:3, v/v) to obtain 283 mg of 4,4-difluoro-1-[4-(2-phenylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-1-benzazepin-5-one. This product was recrystallized from ethyl acetate-hexane.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:9](=[CH:10][CH:11]=1)[CH:8]([C:12]#[N:13])[CH2:7]2)[CH3:2]>CO.[Ni]>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:9](=[CH:10][CH:11]=1)[CH:8]([CH2:12][NH2:13])[CH2:7]2)[CH3:2]
Reactant: CCOc1ccc2c(c1)CC2C#N
Agent: [Ni]
Solvent: CO
Product: CCOc1ccc2c(c1)CC2CN

Procedure:
1.5 g (8.65 mmoles) of the product of Step 1 are dissolved in 30 mL of methanol (MeOH). 30 mL of a (7N) ammoniacal methanol solution and 0.5 g of Raney nickel. The reaction mixture is then hydrogenated overnight under a pressure of 1 bar, at ambient temperature. The catalyst is then filtered off and the filtrate is evaporated to dryness. The expected product is obtained in the form an oil.
Reaction SMILES: [CH2:1]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[C:14](=[O:18])[CH2:13][CH2:12]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Br:19]Br>C(Cl)(Cl)Cl>[Br:19][CH:13]1[CH2:12][C:11]2[C:15](=[CH:16][CH:17]=[C:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH:10]=2)[C:14]1=[O:18]
Reactant: CCCCCCCCc1ccc2c(c1)CCC2=O
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: CCCCCCCCc1ccc2c(c1)CC(Br)C2=O
Reaction time: 0.5 h
Yield: 83.8 %

Procedure:
To a solution of 2 (1.094 g, 4.48 mmol) in CHCl3 (10 mL) at 40° C. was added Br2 (0.23 mL, 4.477 mmol) dropwise over 15 minutes. The reaction was left to stir for 30 minutes. The resulting solution was concentrated and purified with silica gel chromatography eluding with hexanes-EtOAc (9:1). The reaction provided 3 (1.212 g, 3.75 mmol, 84%) as an orange liquid.
Reaction SMILES: O=[O+][O-].C(C[O:8][C:9]1[CH:10]=[CH:11][C:12]2[CH2:13][C@H:14]3[N:26]([CH3:27])[CH2:25][CH2:24][C@:20]45[C:21]=2[C:22]=1[O:23][C@H:19]4[C@@H:18]([OH:28])[CH:17]=[CH:16][C@@H:15]35)(O)=O.C([O-])(=O)C(CC([O-])=O)O>>[CH:11]1[C:12]2[CH2:13][C@H:14]3[N:26]([CH2:25][CH2:24][C@@:20]45[C@H:15]3[CH:16]=[CH:17][C@H:18]([OH:28])[C@@H:19]4[O:23][C:22]([C:21]=25)=[C:9]([OH:8])[CH:10]=1)[CH3:27]
Reactant: CN1CC[C@]23c4c5ccc(OCC(=O)O)c4O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1C5
Agent: O=C([O-])CC(O)C(=O)[O-]
Agent: O=[O+][O-]
Product: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1C5

Procedure:
1.4 O3 -Carboxymethyl morphine conjugate to malate dehydrogenase
Reaction SMILES: [CH2:1]([N:8]1[C@@H:12]([C:13](Cl)=O)[C@@H:11]([C:16]([O:18]C2CCCCC2)=[O:17])[N:10]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:9]1=[O:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Li+].Cl>O1CCCC1>[CH2:1]([N:8]1[C@H:12]2[CH2:13][O:17][C:16](=[O:18])[C@H:11]2[N:10]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:9]1=[O:32])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OC1CCCCC1)[C@@H]1[C@H](C(=O)Cl)N(Cc2ccccc2)C(=O)N1Cc1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1OC[C@H]2[C@@H]1N(Cc1ccccc1)C(=O)N2Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82.2 %

Procedure:
45.5 g (100 mmol) of cyclohexyl (4S,5R)-1,3-dibenzyl-5-chlorocarbonyl-2-oxo-4-imidazolidinecarboxylate (prepared according to Example 1) are dissolved in 50 ml of tetrahydrofuran. To the clear solution are added dropwise at 0° C. within 60 minutes 80 ml of a 1M lithium borohydride solution in tetrahydrofuran (80 mmol). The mixture is then stirred at 0° C. for a further 30 minutes. 100 ml of 1N hydrochloric acid are then cautiously added dropwise at 0° C. The mixture is then stirred at 70° C. for 30 minutes and subsequently concentrated in a rotary evaporator to 100 ml. Thereto there are added 200 ml of water and the mixture is left to crystallize at 0° C. for 18 hours. The crystallized-out crude product is filtered off under suction and washed neutral with water. After drying at 60° C. in vacuo for 4 hours, the crude product is dissolved in 100 ml of hot isopropanol and then left to crystallize at 0° C. for 18 hours. The product is then filtered off under suction and rinsed twice with 20 ml of ice-cold isopropanol each time. After drying at 60° C. in a water-jet vacuum for 6 hours, there are obtained 26.5 g of (3aS,6aR)-1,3-dibenzyldihydro-1H-furo[3,4-d]imidazole-2,4(3H,3aH)-dione with a melting point of 116°-117° C.
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]2[CH:14]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]4[CH:22]=[N:23][NH:24][C:17]=34)[CH:12]=[CH:11][N:10]=2)=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[H-].[Na+].Br[CH2:28][C:29]([NH:31][CH3:32])=[O:30]>CN(C=O)C>[F:1][C:2]1[C:3]([C:9]2[CH:14]=[C:13]([NH:15][C:16]3[C:17]4[C:18](=[CH:22][N:23]([CH2:28][C:29]([NH:31][CH3:32])=[O:30])[N:24]=4)[N:19]=[CH:20][CH:21]=3)[CH:12]=[CH:11][N:10]=2)=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1
Reactant: CNC(=O)CBr
Reactant: Cc1ccc(F)c(-c2cc(Nc3ccnc4cn[nH]c34)ccn2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNC(=O)Cn1cc2nccc(Nc3ccnc(-c4nc(C)ccc4F)c3)c2n1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
N-(3′-Fluoro-6′-methyl-2,2′-bipyridin-4-yl)-1H-pyrazolo[4,3-b]pyridin-7-amine (50 mg, 0.156 mmol) and NaH (3.75 mg, 60% in oil, 0.15 mmol) were combined in DMF (2 mL). 2-Bromo-N-methylacetamide (23.72 mg, 0.15 mmol) was added and the mixture heated in a microwave at 80° C. for 15 minutes and then at 100° C. for 30 minutes and finally at 110° C. for a further 45 minutes. The reaction mixture was cooled and purified by preparative HPLC using a Sunfire Prep 5 μm C18, 75×30 mm column eluting with a gradient of 20-25% acetonitrile (containing 10 mM NH4HCO3) in water (containing 10 mM NH4HCO3) to give the title compound. 1H NMR (400 MHz, METHANOL-d4) δ ppm 2.60 (s, 3H) 2.81 (s, 3H) 5.11 (s, 2H) 7.08 (br. s., 1H) 7.41 (d, J=8 Hz, 1H) 7.50 (br. s., 1H) 7.65 (t, J=12 Hz, 1H) 7.92 (br. s., 1H) 8.08 (d, J=8 Hz, 1H) 8.28 (br. s., 1H) 8.68 (br. s., 1H) MS [M+H] found 392.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[C:4]([C:10]([F:13])([F:12])[F:11])[N:3]=1.CI.[CH3:16]N(C)C=O.C(=O)([O-])[O-].[K+].[K+]>O>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][O:9][CH3:16])[CH:5]=[C:4]([C:10]([F:11])([F:12])[F:13])[N:3]=1
Reactant: CN(C)C=O
Reactant: OCc1cc(Cl)nc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Product: COCc1cc(Cl)nc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 40.4 %

Procedure:
To a solution of [2-chloro-6-(trifluoromethyl)pyridin-4-yl]methanol (130 mg, 0.614 mmol, from Step A) and methyl iodide (42 μL, 0.68 mmol) in N,N-dimethylformamide (0.65 mL, 8.4 mmol) was added potassium carbonate (250 mg, 1.8 mmol). The mixture was sealed and stirred at room temperature for 24 hours. Additional methyl iodide (42 μL, 0.68 mmol) was added. The mixture was stirred again for 24 hours, then was diluted with water and extracted with EtOAc. The extract was washed with water (3×), followed by brine, dried over sodium sulfate, filtered and concentrated. Flash chromatography on silica gel, eluting with a gradient from 0-20% EtOAc in Hexanes, afforded product as a colorless oil (56 mg, 40%). 1H NMR (300 MHz, CDCl3) δ 7.56 (s, 1H), 7.50 (s, 1H), 4.53 (s, 2H), 3.48 (s, 3H); 19F NMR (282 MHz, CDCl3) δ−68.45 (s); LCMS (M+H)+: 226.1.
Reaction SMILES: [CH2:1]([N:3]([C:29](=O)[C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Cl[CH2:39][C:40]([N:42]1[CH2:47][CH2:46][CH:45]([CH3:48])[CH2:44][CH2:43]1)=O>>[CH2:1]([N:3]([CH2:29][C:30]1[CH:31]=[CH:32][C:33]([O:36][CH2:39][CH2:40][N:42]2[CH2:47][CH2:46][CH:45]([CH3:48])[CH2:44][CH2:43]2)=[CH:34][CH:35]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: CC1CCN(C(=O)CCl)CC1
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCN(Cc1ccc(OCCN2CCC(C)CC2)cc1)c1cc(OC)ccc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 36.1 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (15 mg) and 2-chloro-1-(4-methylpiperidin-1-yl)ethanone (10 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (5.7 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][C:3]=1[C:4]([O:6][C:7]([CH3:15])([CH3:14])[C:8]([O:10][CH2:11][CH:12]=[CH2:13])=[O:9])=[O:5].[H][H]>C(C(C)=O)C.[Cl-].C[N+](C)(C)C>[Cl:1][C:2]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][C:3]=1[C:4]([O:6][C:7]([CH3:15])([CH3:14])[C:8]([O:10][CH2:11][CH:12]=[CH2:13])=[O:9])=[O:5]
Reactant: C=CCOC(=O)C(C)(C)OC(=O)c1cc([N+](=O)[O-])ccc1Cl
Reactant: [H][H]
Agent: C[N+](C)(C)C
Agent: [Cl-]
Solvent: CCC(C)=O
Product: C=CCOC(=O)C(C)(C)OC(=O)c1cc(N)ccc1Cl
Yield: 96.8 %

Procedure:
In a stirred autoclave, 0.33 g of a catalyst prepared according to Example H1 is added to a solution of 65.5 g of allyl 2-(2-chloro-5-nitrobenzoyloxy)-2-methylpropionate in 370 g of methyl ethyl ketone, 0.2 g (0.5 mol %) of FeCl2 4H2O and 22 mg (0.1 mol %) of tetramethylammonium chloride are added in addition, and the mixture is hydrogenated for 5 hours at a temperature of 140° C. and at a hydrogen pressure of 15 bar. After cooling and flushing the stirred autoclave with nitrogen, the catalyst is filtered off and rinsed with 40 g of methyl ethyl ketone. 435.5 g are obtained of a solution having a content of 13.22% of allyl 2-(2-chloro-5-aminobenzoyloxy)-2-methylpropionate (yield: 96.8 % of theory).
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@@H:2]([C:8]([NH:10][C@H:11]([C:19]([NH:21][C@H:22]([C:28]([NH:30][C@H:31]([C:35]([NH:37][C@H:38]([C:47]([O:49][CH3:50])=[O:48])[CH2:39][C:40]1[CH:45]=[CH:44][C:43]([OH:46])=[CH:42][CH:41]=1)=[O:36])[CH:32]([CH3:34])[CH3:33])=[O:29])[CH2:23][CH2:24][C:25](=[O:27])[OH:26])=[O:20])[CH2:12][CH2:13][CH2:14][NH:15][C:16](=[NH:18])[NH2:17])=[O:9])[CH2:3][CH2:4][CH2:5][CH2:6][NH2:7].[CH3:61][C:62]([OH:64])=[O:63]>C(O)(=O)C>[NH2:1][C@@H:2]([C:8]([NH:10][C@H:11]([C:19]([NH:21][C@H:22]([C:28]([NH:30][C@H:31]([C:35]([NH:37][C@H:38]([C:47]([O:49][CH3:50])=[O:48])[CH2:39][C:40]1[CH:45]=[CH:44][C:43]([OH:46])=[CH:42][CH:41]=1)=[O:36])[CH:32]([CH3:34])[CH3:33])=[O:29])[CH2:23][CH2:24][C:25](=[O:26])[OH:27])=[O:20])[CH2:12][CH2:13][CH2:14][NH:15][C:16](=[NH:17])[NH2:18])=[O:9])[CH2:3][CH2:4][CH2:5][CH2:6][NH2:7].[CH3:61][C:62]([OH:64])=[O:63]
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H](CCCCN)NC(=O)OCc1ccccc1)C(C)C
Solvent: CC(=O)O
Product: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](N)CCCCN)C(C)C

Procedure:
2 g (2.2 mmoles) of Z-D-Lys-Arg-Glu-Val-Tyr-OMe acetate are subjected to catalytic hydrogenation in 90 percent acetic acid and the product is worked up analogously to Example 25 I. Yield 1.8 g (98%). 800 mg are purified further by being chromatographed on a hydroxypropylated, crosslinked dextran gel (approx. 120 g, column: 90×2.5 cm) in 90 percent strength methanol. Yield 500 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[S:10][CH:11]=[C:12]([C:15]([CH3:17])=O)[C:13]=2[OH:14])[CH:5]=[CH:6][C:7]=1[Cl:8].[N:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][NH:26][C:27]([C:29]2[S:30][C:31]([C:34]([NH:36][NH2:37])=[O:35])=[CH:32][CH:33]=2)=[O:28])=[CH:20][CH:19]=1.O>CN(C)C=O>[N:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][NH:26][C:27]([C:29]2[S:30][C:31]([C:34]([NH:36][N:37]=[C:15]([C:12]3[C:13]([OH:14])=[C:9]([C:4]4[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=4)[S:10][CH:11]=3)[CH3:17])=[O:35])=[CH:32][CH:33]=2)=[O:28])=[CH:20][CH:19]=1
Reactant: NNC(=O)c1ccc(C(=O)NCCc2ccncc2)s1
Reactant: CC(=O)c1csc(-c2ccc(Cl)c(Cl)c2)c1O
Solvent: CN(C)C=O
Solvent: O
Product: CC(=NNC(=O)c1ccc(C(=O)NCCc2ccncc2)s1)c1csc(-c2ccc(Cl)c(Cl)c2)c1O
Reaction time: 5 h
Yield: 66 %

Procedure:
2-(3,4-Dichlorophenyl)-3-hydroxy-4-methylcarbonylthiophene (0.11 g, 0.38 mmol) and 5-hydrazinocarbonylthiophene-2-carboxylic acid (2-pyridin-4-yl)ethylamide (0.10 g, 0.34 mmol) prepared in Reference Synthetic Example 17 were suspended in N,N-dimethylformamide (2.0 mL) and left at 100° C. for 5 hours and then at room temperature for 20 hours. Water (0.20 mL) was added with stirring, and the precipitated solid was recovered by filtration, washed with chloroform and dried to give the desired product, 5-{1-[5-(3,4-dichlorophenyl)-4-hydroxythiophen-3-yl]ethylidenehydrazinocarbonyl}thiophene-2-carboxylic acid 2-(pyridin-4-yl)ethylamide (yield 66%).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[N:6]([CH2:10][C:11]2[N:15]3[CH:16]=[C:17]([CH3:20])[CH:18]=[CH:19][C:14]3=[N:13][C:12]=2[C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)[N:7]=[CH:8][N:9]=1)=[O:4].[CH3:28]C1C=CC2N(C(CN3C(C(OC)=O)=NC=N3)=C(C3C=CC(C)=CC=3)N=2)C=1.CNC>>[CH3:1][N:2]([CH3:28])[C:3]([C:5]1[N:6]([CH2:10][C:11]2[N:15]3[CH:16]=[C:17]([CH3:20])[CH:18]=[CH:19][C:14]3=[N:13][C:12]=2[C:21]2[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=2)[N:7]=[CH:8][N:9]=1)=[O:4]
Reactant: CNC(=O)c1ncnn1Cc1c(-c2ccc(C)cc2)nc2ccc(C)cn12
Reactant: COC(=O)c1ncnn1Cc1c(-c2ccc(C)cc2)nc2ccc(C)cn12
Agent: CNC
Product: Cc1ccc(-c2nc3ccc(C)cn3c2Cn2ncnc2C(=O)N(C)C)cc1

Procedure:
The title compound was prepared according to the procedure described for compound 68 from methyl 1-((6-methyl-2-p-tolylimidazo[1,2-a]pyridin-3-yl)methyl)-1H-1,2,4-triazole-5-carboxylate and dimethylamine. m/e 375 for C21H23N6O [M+H]+; 1H-NMR (300 MHz, CDCl3) δ 8.35 (s, 2H), 7.87 (d, J=2.1 Hz, 1H), 7.72 (d, J=7.8 Hz, 2H), 7.54 (d, J=9.0 Hz, 1H), 7.26 (d, J=7.8 Hz, 2H), 7.10 (d, J=9.0 Hz, 1H), 6.00 (s, 1H), 3.06 (s, 3H), 3.00 (s, 3H), 2.40 (s, 3H), 2.35 (s, 3H) ppm; 13C-NMR (75 MHz, CDCl3, δ) 158.440, 150.213, 147.869, 146.313, 144.771, 138.154, 131.236, 131.236, 129.600, 128.812, 128.725, 122.609, 116.939, 113.480, 43.481, 38.888, 35.781, 21.585, 18.727 ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([O:7][C@H:8]2[CH2:11][C@H:10]([C:12]#[CH:13])[CH2:9]2)=[CH:5][CH:4]=1.C([Li])CCC.[CH:21](=[O:23])[CH3:22]>C1COCC1>[CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([O:7][C@H:8]2[CH2:9][C@H:10]([C:12]#[C:13][CH:21]([OH:23])[CH3:22])[CH2:11]2)=[CH:5][CH:4]=1
Reactant: C#C[C@H]1C[C@H](Oc2ccc(OC)cc2)C1
Reactant: CC=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(O[C@H]2C[C@H](C#CC(C)O)C2)cc1
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
A solution of {trans-3-(4-methoxyphenoxy)cyclobutyl }ethyne (6.40 g, 32.0 mmol) in THF (80 ml) at -78° C. under argon atmosphere was added n-butyllithium (23.7 ml, 38.0 mmol). The mixture was stirred for 0.5 h at the same temperature and then allowed to warm to -40° C. over 1 h. The mixture was recooled to -78° C., a solution of dry acetaldehyde (3.52 g, 80.0 mmol) in THF (20 ml) added to the mixture and the whole stirred overnight at room temperature. The reaction was quenched with saturated aqueous ammonium chloride solution (100 ml) and the whole extracted with ethyl acetate (200 ml). The combined extracts were washed with brine (200 ml), dried (MgSO4) and concentrated in vacuo. Purification by column chromatography {SiO2, 500 g; hexane/ethyl acetate (3/1)} afforded 7.58 g (97%) of 4-{trans-3-(4-methoxyphenoxy)cyclobutyl }-3-butyn-2-ol as white solids: 1H NMR δ6.85-6.68 (m, 4H), 4.89-4.78 (m, 1H), 4.62-4.50 (m, 1H), 3.76 (s, 3H), 3.22-3.09 (m, 1H), 2.59-2.40 (m, 4H), 1.65 (s, 1H), 1.45 (d, J=6.9 Hz, 3H).
Reaction SMILES: [OH:1][C@H:2]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:3][CH:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1)[C:5]#[N:6].[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33]([O:1][C@H:2]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:3][CH:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=3)=[CH:9][CH:8]=2)[C:5]#[N:6])(=[O:35])=[O:34])=[CH:29][CH:28]=1
Reactant: CCCCCC[C@@H](O)CC(C#N)c1ccc(-c2ccc(OC)cc2)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CCCCCC[C@H](CC(C#N)c1ccc(-c2ccc(OC)cc2)cc1)OS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.5 %

Procedure:
To a solution of 186 mg (0.53 mmol) of (4R)-4-hydroxy-2-[4-(4-methoxyphenyl)phenyl]decanenitrile in 10 ml of pyridine were added a solution of 303 mg (1.6 mmol) of p-toluenesulfonyl chloride in 20 ml of pyridine and 10 mg of DMAP. The resulting mixture was stirred at room temperature overnight. The pyridine was then removed by evaporation under reduced pressure. The residue was separated and purified by column chromatography (hexane/ethyl acetate=4/1), thereby obtaining 130 mg (yield 49%) of (4R)-4-p-toluenesulfonyloxy-2-[4-(4-methoxyphenyl)phenyl]decanenitrile.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][NH:6][C:7]1[CH:12]=[C:11](F)[CH:10]=[CH:9][C:8]=1[N+:14]([O-:16])=[O:15].[N:20]1([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(N(CC)C(C)C)(C)C>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][NH:6][C:7]1[CH:12]=[C:11]([N:23]2[CH2:22][CH2:21][N:20]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][CH2:24]2)[CH:10]=[CH:9][C:8]=1[N+:14]([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1ccc(F)cc1NCc1cccc(Br)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])c(NCc3cccc(Br)c3)c2)CC1
Yield: 29.2 %

Procedure:
N-(3-Bromobenzyl)-5-fluoro-2-nitrobenzenamine (624 mg, 2.2 mmol), t-butyl piperazine-1-carboxylate (414 mg, 2.2 mmol), N,N-diisopropylethylamine (287 mg, 2.2 mmol) were stirred at 80° C. in dry acetonitrile (10 mL) for 16 h. The solvent was evaporated and the residue was dissolved in dichloromethane and washed with water. The dichloromethane was evaporated and the crude compound was purified by silica chromatography using 25% ethyl acetate in hexanes to afford the title compound (316 mg, 32% yield). 1H NMR (400 MHz, CDCl3): δ 8.77 (s, 1H), 8.05 (d, 1H), 7.32-7.21 (m, 4H), 6.18 (d, 1H), 5.72 (s, 1H), 4.46 (d, 2H), 3.49 (m, 4H), 3.27 (m, 4H), 1.45 (s, 9H); MS (ESI) m/z: Calculated for C22H27ClN4O4Na 469.16; Observed: 469.4 (M++Na).
Reaction SMILES: [CH3:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([S:15][CH3:16])=[C:4]([CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:3]=1.[Cl:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Cl)=[CH:28][CH:27]=1>>[Cl:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][N:7]2[C:6]3[C:5]([S:15][CH3:16])=[C:4]([CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:3]=[C:2]([CH3:1])[C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)=[CH:28][CH:27]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: CSc1c(CC(=O)OC(C)(C)C)cc(C)c2c1[nH]c1ccccc12
Product: CSc1c(CC(=O)OC(C)(C)C)cc(C)c2c3ccccc3n(Cc3ccc(Cl)cc3)c12
Yield: 92 %

Procedure:
Following a procedure and using relative proportions of starting materials similar to those described in Example 4, but using tert-butyl (4-methyl-1-methylthiocarbazol-2-yl)acetate and 4-chlorobenzyl chloride as starting materials, the title compound was obtained in a yield of 92% as an oil.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[C:7]1([OH:13])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.F[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[N+:22]([O-:24])=[O:23].O>C1COCC1.C(OCC)(=O)C>[F:21][C:18]1[CH:19]=[CH:20][C:15]([O:13][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:16]([N+:22]([O-:24])=[O:23])[CH:17]=1
Reactant: Oc1ccccc1
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(F)ccc1Oc1ccccc1
Temperature: 40 °C
Reaction time: 0.25 h
Yield: 85.9 %

Procedure:
Cs2CO3 (12.1 g, 62.9 mmol) was added to a solution of phenol (5.9 g, 62.9 mmol) in 400 mL of THF under N2. After stirring for 15 min. 2,5-difluoronitrobenzene (6.82 mL, 62.9 mmol) in 50 mL of THF was added. The resulting mixture was heated to 40° C. for 25 h. Reaction was followed by HPLC to detect disappearance of 2,5-difluoronitrobenzene. Water and ethyl acetate were added, followed by extraction with ethyl acetate (2×). The combined organic layers were successively washed with saturated aq. sodium bicarbonate (3×), water and brine, dried (Na2SO4) and evaporated. The crude compound was chromatographed on silica to remove excess of phenol. Elution with toluene/ethyl acetate 95:5 gave the title compound (12.6 g, 86%). Data: (m/z)=234 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].CC(C)([O-])C.[K+].[Cl:15][C:16]1[CH:21]=[CH:20][N:19]=[C:18](S(C)(=O)=O)[N:17]=1>C1COCC1>[Cl:15][C:16]1[CH:21]=[CH:20][N:19]=[C:18]([O:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[N:17]=1
Reactant: CS(=O)(=O)c1nccc(Cl)n1
Reactant: Oc1ccccc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Clc1ccnc(Oc2ccccc2Cl)n1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-chlorophenol (10.5 g) in 150 mL dry THF) at 0° C. under argon was added 88 mL of a 1.0 M solution of potassium t-butoxide in THF. The reaction mixture was stirred for 15 minutes and then cooled to −78° C. A solution of 4-Chloro-2-methanesulfonyl-pyrimidine (14.2 g, 2.6 mmol) in 160 mL of dry THF was slowly added over 25 minutes. The reaction mixture was stirred for an additional 30 minutes at −78° C., and then quenched by addition of 60 mL saturated aqueous ammonium chloride, and evaporated under reduced pressure to remove THF. 200 mL water, and 200 mL EtOAc were added, the organic phase was collected, and the aqueous phase was washed twice with 150 mL EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered, and evaporated under reduced pressure. The residue was purified by flash chromatography (5% to 10% EtOAc/Hexanes) to 10.2 g of 4-Chloro-2-(2-chloro-phenoxy)-pyrimidine. Mass Spec. M+H=242.