Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCCCC.[CH2:6]=[CH:7][C:8](=[CH2:10])[CH3:9].C=CC=CC.[CH:16]1[CH2:20][CH:19]=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[C:8]([C:7]1[CH:6]=[CH:16][CH:20]=[CH:19][C:18]=1[CH3:17])([CH3:10])=[CH2:9]
Reactant: C=CC(=C)C
Reactant: C1=CCC=C1
Solvent: Cc1ccccc1
Solvent: CCCCC
Solvent: C=CC=CC
Product: C=C(C)c1ccccc1C

Procedure:
90 g of isopropenyltoluene, 10 g of C5 fraction (n-pentane/isoprene/1,3-pentadiene/cyclopentadiene=5/6/3/3) obtained by thermal cracking of petroleum naphtha, and 150 g of toluene were charged into an autoclave, and the mixture was reacted by adding in drops, as a catalyst, 1.5 g of BF3 phenol complex over a period of about 10 minutes, keeping the temperature at 0° C. while stirring. Then, the stirring was continued for another 3 hours. Then, 50 ml of a 5 wt % aqueous sodium hydroxide solution was added, and after the mixture was vigorously stirred for 30 minutes to decompose the catalyst, the aqueous phase was separated and polymer oil was obtained. Further, after the polymer oil was washed with water until it became neutral, and the unreacted oil and solvent were distilled off under reduced pressure with heating to obtain a hydrocarbon resin in the form of a white lump. This resin had a softening point Tm of 125° C., a number average molecular weight of 1150, and a weight average molecular weight Mw of 1950.
Reaction SMILES: C(O)(=O)CC[C@H](NC(C1C=CC(NCC2N=C3C(N=C(NC3=O)N)=NC=2)=CC=1)=O)C(O)=[O:6].ON1C(=O)CCC1=O.ON1C2C=CC=CC=2N=N1.[CH:51]1([N:57]=[C:58]=[N:59][CH:60]2[CH2:65][CH2:64][CH2:63][CH2:62][CH2:61]2)[CH2:56][CH2:55][CH2:54][CH2:53][CH2:52]1>CS(C)=O>[C:58]([NH:57][CH:51]1[CH2:52][CH2:53][CH2:54][CH2:55][CH2:56]1)([NH:59][CH:60]1[CH2:65][CH2:64][CH2:63][CH2:62][CH2:61]1)=[O:6]
Reactant: Nc1nc2ncc(CNc3ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc3)nc2c(=O)[nH]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Agent: On1nnc2ccccc21
Solvent: CS(C)=O
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Folic Acid (Sigma Chemical Co., St. Louis, MO. 1 g, 2.1 mmol) was dissolved in 10 ml of dimethyl sulfoxide (Fluka) pre-dried with a molecular sieve. To this solution, N-hydroxysuccinimide (NHS) (Pierce, 0.242 g., 2 mmol) or N-hydroxybenzotriazole (Fluka, 0.270 g., 2 mmol) was added. At this point 1,3-dicyclohexylcarbodiimide (Fluka, 0.872 g., 4 mmol) dissolved in a small volume of dimethyl sulfoxide was then slowly added to this solution. The reaction was allowed to proceed overnight in the dark at room temperature under stirring. Dicyclohexylurea formed as a white precipitate was removed by filtering twice the reaction mixture through 40 mesh filter paper. The DMSO was then removed by distillation under vacuum at 45° C. until the solution became viscous gel. The product (NHS-folate or benzotriazole-folate) was then crystallized in an excess volume of anhydrous ether. A small amount of methanol was added to accelerate the crystallization process. A fine yellow powder of NHS-folate or benzotriazole-folate formed at this point was subsequently washed twice with anhydrous ether. The product was then dried under vacuum and stored at 4° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH2:14])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[Cl:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][C:17]=1[F:25]>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:2]2[CH:3]=[C:4]([NH2:14])[CH:5]=[N:6][C:7]=2[O:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[CH:18][C:17]=1[F:25]
Reactant: OB(O)c1ccc(Cl)c(F)c1
Reactant: Nc1cnc(OCC(F)(F)F)c(Br)c1
Product: Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)c(F)c2)c1

Procedure:
The title compound was synthesized in analogy to Example E, using 5-bromo-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylamine (example C) and B-(4-chloro-3-fluorophenyl)-boronic acid (CAN 137504-86-0) as starting materials; MS (EI) 379.3 (M+OAc)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:12][CH2:13][O:14][CH3:15])[C:5]([O:10][CH3:11])=[C:6]([O:8][CH3:9])[CH:7]=1.C([Li])CCC.[CH:21](N1CCOCC1)=[O:22].[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[CH3:9][O:8][C:6]1[CH:7]=[C:2]([CH:3]=[C:4]([CH2:12][CH2:13][O:14][CH3:15])[C:5]=1[O:10][CH3:11])[CH:21]=[O:22]
Reactant: O=CN1CCOCC1
Reactant: COCCc1cc(Br)cc(OC)c1OC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCCc1cc(C=O)cc(OC)c1OC
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1.3 g of 5-bromo-1,2-dimethoxy-3-(2-methoxy -ethyl)benzene in 20 ml of THF there was added dropwise 2 ml of n-butyllithium (2.66 M, hexane solution) at −70° C. under a nitrogen atmosphere. After stirring at −70° C. for 30 minutes, 0.7 ml of N-formylmorpholine was added and the temperature was raised from −70° C. to 0° C. over a period of 30 minutes. Saturated aqueous ammonium chloride was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (806 mg) as an oil.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].Br[CH2:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17]>C1(C)C=CC=CC=1>[CH3:17][C:16]([CH3:19])([CH3:18])[C:15](=[O:20])[CH2:14][N:5]1[C:1](=[O:11])[C:2]2[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4]1=[O:6]
Reactant: CC(C)(C)C(=O)CBr
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: Cc1ccccc1
Product: CC(C)(C)C(=O)CN1C(=O)c2ccccc2C1=O
Yield: 76.2 %

Procedure:
Potassium phthalimide (82.86 g, 0.447 mol) is added to a stirred solution of bromopinacolone (80.10 g, 0.447 mol) in toluene (300 ml). The-suspension is refluxed for 19 h, cooled, and then the precipitate is filtered off and discarded. The filtrate is cooled in an ice-bath and treated with petroleum ether (550 ml). The resulting precipitate is collected by filtration. The mother liquor is reduced to circa 100 ml by evaporation in vacuo, and a further quantity of precipitate which forms is collected by filtration and combined with the first crop, giving 2-(3,3-dimethyl-2-oxo-butyl)-isoindole-1,3-dione (total yield 83.5 g, 76%) as colourless crystals, m.p. 96-99° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([NH:11][CH3:12])[CH:3]=1.[Li+].[Cl-].CCN(C(C)C)C(C)C.[C:24]([O:28][CH2:29][CH2:30][CH2:31][CH3:32])(=[O:27])[CH:25]=[CH2:26].CN1C=CN=C1>CC(N(C)C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:12][NH:11][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9])[CH:26]=[CH:25][C:24]([O:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:27]
Reactant: C=CC(=O)OCCCC
Reactant: CNc1cc(Cl)ccc1[N+](=O)[O-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cn1ccnc1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CCCCOC(=O)C=Cc1ccc([N+](=O)[O-])c(NC)c1
Temperature: 110 °C
Reaction time: 12 h

Procedure:
To a mixture of 4-chloro-2-methylaminonitrobenzene (50.0 g, 268.0 mmol, 1.0 eq), Pd(OAc)2 (0.30 g, 1.3 mmol, 0.005 eq) and LiCl (11.4 g 268.0 mmol, 1.0 eq) in DMAc (250 mL) was added iPr2NEt (56 mL, 321.5 mmol, 1.2 eq) followed by n-butyl acrylate (40 mL, 281.4 mmol, 1.05 eq) under nitrogen. The reaction mixture was stirred at 110° C. for 12 h, then cooled to 50° C. 1-methylimidazole (10.6 mL, 134.0 mmol, 0.5 eq) was added and the mixture was stirred for 30 min before filtering and adding water (250 mL). The resulting mixture was cooled to r.t. over 1 h. The resulting solid was filtered and washed with water and dried to yield n-butyl 3-methylamino-4-nitrocinnamate (71.8 g, 96%, 99.2 A % purity).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([NH:11][C:12]3[NH:16][N:15]=[CH:14][CH:13]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.N12CCCN=C1CCCCC2.[C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:36]1[CH:41]=[CH:40][C:39]([CH2:42][CH:43]([C:49](=O)[CH2:50][CH2:51][CH3:52])[C:44](OCC)=[O:45])=[CH:38][CH:37]=1)#[N:29].C(OCC)(=O)C>C(N(CC)C1C=CC=CC=1)C.O>[O:4]1[C:5]2([CH2:6][CH2:7][CH:8]([N:11]3[C:44](=[O:45])[C:43]([CH2:42][C:39]4[CH:40]=[CH:41][C:36]([C:31]5[C:30]([C:28]#[N:29])=[CH:35][CH:34]=[CH:33][CH:32]=5)=[CH:37][CH:38]=4)=[C:49]([CH2:50][CH2:51][CH3:52])[N:16]4[N:15]=[CH:14][CH:13]=[C:12]34)[CH2:9][CH2:10]2)[O:1][CH2:2][CH2:3]1
Reactant: c1cc(NC2CCC3(CC2)OCCO3)[nH]n1
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OCC
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCN(CC)c1ccccc1
Solvent: O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC3(CC2)OCCO3)c2ccnn12
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.5 %

Procedure:
To a solution of N-(1,4-dioxaspiro[4.5]dec-8-yl)-1H-pyrazol-5-amine (11.8 g) and 1,8-diazabicyclo[5.4.0]undec-7-ene (1.6 mL) in N,N-diethylaniline (60 mL) was added dropwise a solution of ethyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate (24 g) in N,N-diethylaniline (40 mL) at 180° C. The mixture was stirred for 3 hr and allowed to cool to room temperature, and ethyl acetate and water were added. The mixture was extracted with ethyl acetate, and the organic layer was successively washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (19.5 g, 73%).
Reaction SMILES: Cl.C([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:21]3[N:22]=[C:23]([NH2:25])[N:24]=[C:20]3[N:19]=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)C1C=CC=CC=1>C(O)(=O)C>[OH:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[N:21]3[N:22]=[C:23]([NH2:25])[N:24]=[C:20]3[N:19]=[CH:18][CH:17]=2)=[CH:14][CH:15]=1
Reactant: Nc1nc2nccc(-c3ccc(OCc4ccccc4)cc3)n2n1
Agent: Cl
Solvent: CC(=O)O
Product: Nc1nc2nccc(-c3ccc(O)cc3)n2n1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
Acetic acid (40 ml) and concentrated hydrochloric acid (40 ml) were added to 7-(4-benzyloxyphenyl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylamine (the compound obtained in Reference Example 2; 5.70 g), and the obtained mixture was stirred at 80° C. for 3 hours. The resultant product was concentrated under a reduced pressure, and the residue was then washed by suspension in acetone (200 ml) and then in a 50% ethanol solution (100 ml) to obtain the captioned compound (2.60 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:11][N:12]1[CH:16]=[C:15](B2OC(C)(C)C(C)(C)O2)[CH:14]=[N:13]1.C(=O)([O-])[O-].[Na+].[Na+]>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.CN(C=O)C>[CH3:11][N:12]1[CH:16]=[C:15]([C:2]2[CH:3]=[C:4]3[CH:10]=[CH:9][NH:8][C:5]3=[N:6][CH:7]=2)[CH:14]=[N:13]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Brc1cnc2[nH]ccc2c1
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: CN(C)C=O
Product: Cn1cc(-c2cnc3[nH]ccc3c2)cn1
Temperature: 100 °C
Reaction time: 12 h
Yield: 90.3 %

Procedure:
25 g of 5-bromo-1H-pyrrolo[2,3-b]pyridine 1 and 40 g of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole are dissolved 350 ml of DMF, and 20 g of tetrakis(triphenylphosphine)palladium are added under protective gas. After addition of 190 ml of 2N sodium carbonate solution, the batch is stirred at 100° C. for 12 h. All volatile constituents are removed in vacuo, and the residue is partitioned between ethyl acetate and water. Insoluble constituents are filtered off. After extraction of the aqueous phase, the combined organic phases are dried over sodium sulfate, filtered and evaporated to ¼ of the volume in vacuo. The crystal batch formed after 12 h at 0° C. is filtered off and combined with the first solid fraction, giving 22.7 g of compound 2; HPLC-MS: Rt=1.400 min; [M+H+]: 199.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:13][CH2:12][C:11](=O)[CH2:10]2)=[CH:5][CH:4]=1.[Cl-].[CH3:16][O:17][CH2:18][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].O>O1CCCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:13][CH2:12][C:11](=[CH:16][O:17][CH3:18])[CH2:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C2CCC(=O)C2)cc1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COC=C1CCC(c2ccc(OC)cc2)C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 48.4 %

Procedure:
3-(4-Methoxyphenyl)cyclopentanone (8.51 g) and methoxymethyltriphenylphosphonium chloride (16.9 g) were dissolved in tetrahydrofuran (200 ml). After gradually adding potassium tert-butoxide (6.70 g) while maintaining an internal temperature of 10° C. or below, the mixture was stirred at room temperature for 2.5 hours. The reaction solution was poured into water, and extraction with ethyl acetate was followed by washing with water. After drying with anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to produce a brown oily substance which was then purified by silica gel column chromatography (n-hexane:ethyl acetate=20:1) to give 4.73 g of 1-methoxy-4-(3-methoxymethylenecyclopentyl) benzene (48.4% yield).
Reaction SMILES: C([Li])CCC.Br[C:7]1[S:8][CH:9]=[CH:10][N:11]=1.[CH3:12][Si:13](Cl)([CH3:15])[CH3:14].C>O1CCCC1>[CH3:12][Si:13]([CH3:15])([CH3:14])[C:7]1[S:8][CH:9]=[CH:10][N:11]=1
Reactant: Brc1nccs1
Reactant: C[Si](C)(C)Cl
Agent: C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[Si](C)(C)c1nccs1
Temperature: -90 °C
Reaction time: 0.5 h

Procedure:
To a cooled solution (-98° C.) of n-butyllithium (2.5M in hexane, 5.39 mL, 13.4 mmol, 1.1 eq) in tetrahydrofuran (100 mL) under nitrogen was added a solution of 2-bromothiazole (2.00 g, 12.2 mmol) in tetrahydrofuran (30 mL). A suspension formed as the substrate was added. After stirring at -90° C. for 30 min, freshly distilled trimethylsilyl chloride (1.55 mL, 12.2 mmol, 1.0 eq) was added. The reaction was warmed to -30° C. over 1 h and quenched with saturated aqueous sodium bicarbonate (50 mL). The aqueous phase was extracted with diethyl ether (2×40 mL). Combined organic extracts were washed with aqueous bicarbonate (2×40 mL), saturated brine (1×40 mL) and dried with anhydrous sodium sulfate. The solvents were removed and the product purified by Kugelrohr distillation at reduced pressure (2400 pascal, 110° C.). By NMR the title compound was contaminated with small amounts of starting material but no further purification was considered necessary. No accurate yield was established. MS (CI, CH4) m/z 158 (M+1,100), 186 (M+29,17).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[N:8][N:7]([CH2:10][C:11]3[CH:12]=[CH:13][C:14]4[N:15]([CH:17]=[C:18]([C:20]([O:22]CC)=[O:21])[N:19]=4)[N:16]=3)[C:6]=2[CH:25]=1.[Li+].[OH-]>O.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[N:8][N:7]([CH2:10][C:11]3[CH:12]=[CH:13][C:14]4[N:15]([CH:17]=[C:18]([C:20]([OH:22])=[O:21])[N:19]=4)[N:16]=3)[C:6]=2[CH:25]=1
Reactant: CCOC(=O)c1cn2nc(Cn3nnc4ccc(Br)cc43)ccc2n1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cn2nc(Cn3nnc4ccc(Br)cc43)ccc2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.4 %

Procedure:
To a solution of ethyl 6-((6-bromo-1H-benzo[d][1,2,3]triazol-1-yl)methyl)imidazo[1,2-b]pyridazine-2-carboxylate 13A (5 g, 12.46 mmol) in 10% H2O/MeOH (200 mL), LiOH (0.597 g, 24.92 mmol) was added. The reaction was stirred at ambient temperature for 18 hrs and then concentrated to remove the MeOH. H2O (100 mL) was added and the pH was adjusted to 4 with concentrated HCl. The resulting solid was collected by filtration, rinsed with water followed by EtOAc, and dried in vacuum over P2O5 to provide the title compound, 6-((6-bromo-1H-benzo[d][1,2,3]triazol-1-yl)methyl)imidazo[1,2-b]pyridazine-2-carboxylic acid 13B (3.6 g 9.65 mmol, 77%). The filtrate was extracted with EtOAc (3×150 mL) and the organics were combined, dried with MgSO4, filtered and concentrated to dryness to give an additional 0.6 g of product. 1H NMR (400 MHz, DMSO-d6) δ ppm 6.24 (s, 2 H) 7.24 (d, J=9.35 Hz, 1 H) 7.58 (dd, J=8.84, 1.77 Hz, 1 H) 8.04-8.14 (m, 2H) 8.32 (d, J=1.01 Hz, 1 H) 8.47 (s, 1 H). MS:m/z 373.2 (M+H)+.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH:13]([CH:15]([C:25]([NH2:27])=[O:26])[C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=2)[CH3:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:28]O.S(=O)(=O)(O)O>ClCCCl>[CH3:28][O:21][C:20](=[O:22])[C:19]1[CH:18]=[CH:17][C:16]([CH:15]([CH:13]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH3:14])[C:25]([NH2:27])=[O:26])=[CH:24][CH:23]=1
Reactant: CO
Reactant: CC(c1ccccc1N1CCCCC1)C(C(N)=O)c1ccc(C(=O)O)cc1
Agent: O=S(=O)(O)O
Solvent: ClCCCl
Product: COC(=O)c1ccc(C(C(N)=O)C(C)c2ccccc2N2CCCCC2)cc1

Procedure:
A mixture of 2 gm (5.46 m mol) of 4-[(1-(2-piperidinophenyl)-ethyl)-aminocarbonylmethyl]-benzoic acid, 0.53 gm of methanol, 0.38 ml of conc. sulfuric acid, and 1.65 ml of 1,2-dichloro-ethane was refluxed for 24 hours, then evaporated in vacuo, dissolved in chloroform, and extracted with dilute sodium bicarbonate solution. The organic phase was washed with water, dried, filtered, and evaporated in vacuo. The evaporation residue was purified by column chromatography on silica gel (toluene/acetone=5:1).
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.F[C:15]1[CH:53]=[CH:52][C:18]([C:19]([C:21]2[CH:22]=[CH:23][C:24]3[N:25]([C:43]4[CH:48]=[CH:47][C:46]([C:49](=[O:51])[CH3:50])=[CH:45][CH:44]=4)[C:26]4[C:31]([C:32]=3[CH:33]=2)=[CH:30][C:29]([C:34](=[O:42])[C:35]2[CH:40]=[CH:39][C:38](F)=[CH:37][CH:36]=2)=[CH:28][CH:27]=4)=[O:20])=[CH:17][CH:16]=1>>[CH:10]1[C:11]2[N:12]([C:15]3[CH:53]=[CH:52][C:18]([C:19]([C:21]4[CH:22]=[CH:23][C:24]5[N:25]([C:43]6[CH:48]=[CH:47][C:46]([C:49](=[O:51])[CH3:50])=[CH:45][CH:44]=6)[C:26]6[C:31]([C:32]=5[CH:33]=4)=[CH:30][C:29]([C:34](=[O:42])[C:35]4[CH:40]=[CH:39][C:38]([N:12]5[C:13]7[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=7[C:6]7[C:11]5=[CH:10][CH:9]=[CH:8][CH:7]=7)=[CH:37][CH:36]=4)=[CH:28][CH:27]=6)=[O:20])=[CH:17][CH:16]=3)[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: CC(=O)c1ccc(-n2c3ccc(C(=O)c4ccc(F)cc4)cc3c3cc(C(=O)c4ccc(F)cc4)ccc32)cc1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Product: CC(=O)c1ccc(-n2c3ccc(C(=O)c4ccc(-n5c6ccccc6c6ccccc65)cc4)cc3c3cc(C(=O)c4ccc(-n5c6ccccc6c6ccccc65)cc4)ccc32)cc1

Procedure:
1-{4-[3,6-Bis-(4-carbazol-9-yl-benzoyl)-carbazol-9-yl]-phenyl}-ethanone is prepared by the same method as described in example 6.a with an excess amount of carbazole and 1-{4-[3,6-bis-(4-fluoro-benzoyl)-carbazol-9-yl]-phenyl}-ethanone.
Reaction SMILES: [NH2:1][C:2]1[C:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=[CH:9][C:3]=1[NH:4][CH2:5][CH2:6][CH2:7][OH:8].[C:21](N1C=CN=C1)(N1C=CN=C1)=[S:22]>C(Cl)(Cl)Cl>[CH2:14]([O:13][C:12]1[C:2]2[NH:1][C:21](=[S:22])[N:4]([CH2:5][CH2:6][CH2:7][OH:8])[C:3]=2[CH:9]=[CH:10][CH:11]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Nc1c(NCCCO)cccc1OCc1ccccc1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: ClC(Cl)Cl
Product: OCCCn1c(=S)[nH]c2c(OCc3ccccc3)cccc21
Reaction time: 2 h
Yield: 65 %

Procedure:
To a solution of 2-amino-3-benzyloxy-N-(3-hydroxypropyl)aniline (100 mg) in chloroform (2 ml) was added 1,1′-thiocarbonyldiimidazole (72.7 mg) at ambient temperature, and the mixture was stirred for 2 hours at the same temperature and refluxed for 5 hours. The reaction mixture was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin layer chromatography (chloroform:methanol=10:1, v/v) to give 4-benzyloxy-1-(3-hydroxypropyl)-2-thioxo-2,3-dihydro-1H-benzimidazole (75 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:23])[CH2:13][CH:12]([C:14]([O:16][CH3:17])=[O:15])[CH2:11][C:10](C(OC)=O)=[C:9]2[OH:22])=[CH:4][C:3]=1[C:24]([F:27])([F:26])[F:25].[Cl-].[Na+].O>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:23])[C:9](=[O:22])[CH2:10][CH2:11][CH:12]([C:14]([O:16][CH3:17])=[O:15])[CH2:13]2)=[CH:4][C:3]=1[C:24]([F:25])([F:26])[F:27]
Reactant: COC(=O)C1=C(O)C(C)(c2ccc(Cl)c(C(F)(F)F)c2)CC(C(=O)OC)C1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)C1CCC(=O)C(C)(c2ccc(Cl)c(C(F)(F)F)c2)C1
Temperature: 155 °C
Yield: 45.2 %

Procedure:
A solution of dimethyl 5-(4-chloro-3-(trifluoromethyl)phenyl)-4-hydroxy-5-methylcyclohex-3-ene-1,3-dicarboxylate (mixture of diastereomers, 485 mg, 1.192 mmol) in DMSO (5 mL) was treated with sodium chloride (139 mg, 2.385 mmol) and water (0.107 mL, 5.96 mmol). The resulting mixture was bubbled with nitrogen for 15 min, and then heated under nitrogen on an oil bath at 150-160° C. for 4.5 h. After this time, the mixture was cooled to rt, diluted with water and then extracted three times with ethyl acetate. The combined organic layers were washed with water followed by saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under vacuum to yield a residue. The residue was purified by column chromatography on silica gel, eluting with 20-35% ethyl acetate-hexanes, to provide methyl (1RS,3RS)-3-(4-chloro-3-(trifluoromethyl)-phenyl)-3-methyl-4-oxocyclohexanecarboxylate (137 mg, 33%) and methyl (1SR,3RS)-3-(4-chloro-3-(trifluoro-methyl)phenyl)-3-methyl-4-oxocyclohexanecarboxylate (188 mg, 45%). The (1SR, 3RS) diastereomer could be partially converted to the (1RS, 3RS) diastereomer as described in the procedure of Example 7, Part 3.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[O:26])=[CH:20][CH:19]=1>C(Cl)Cl>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:25]([NH:24][C:21]2[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][CH:20]=2)=[O:26])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: COc1ccc(N)cc1-c1c(Br)cnn1C
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2ccc(Cl)cc2)cc1-c1c(Br)cnn1C
Yield: 84.8 %

Procedure:
3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.260 g, 0.92 mmol) was treated with 4-chlorophenyl isocyanate (0.144 g, 0.92 mmol, 1.0 equiv.) in CH2Cl2 (5 mL), in a similar manner as described in Example 1.2 to afford Compound 1 (0.340 g, 0.78 mmol, 84%) as a white solid. LCMS m/z (%)=435 (M+H79Br35Cl, 77), 437 (M+H81Br35Cl, 100), 439 (M+H81Br37Cl, 25). 1H NMR (400 MHz, CDCl3) δ: 7.56 (s, 1H), 7.44 (dd, J=2.7, 8.9 Hz, 1H), 7.34 (d, J=9.0 Hz, 1H), 7.29 (d, J=9.0 Hz, 1H), 7.19 (d, J=2.7 Hz, 1H), 6.59 (s, 1H), 6.47 (s, 1H), 3.84 (s, 3H), 3.74 (s, 3H).
Reaction SMILES: B(F)(F)F.CCOCC.[Cl:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][N:19]=1)[C:14](O)=[O:15].[BH4-].[Na+]>C1COCC1>[Cl:10][C:11]1[CH:12]=[C:13]([CH2:14][OH:15])[CH:17]=[CH:18][N:19]=1
Reactant: O=C(O)c1ccnc(Cl)c1
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: OCc1ccnc(Cl)c1
Yield: 85.8 %

Procedure:
Boron trifluoride diethyl etherate (71 g, 0.5 mol) was added dropwise to a suspension of 2-chloroisonicotinic acid (20 g, 0.125 mol) and sodium borohydride (14.3 g, 0.376 mol) in THF (200 mL) with stirring at −10˜−5° C., then the mixture was stirred at room temperature overnight. The reaction mixture was quenched with water (100 mL), and extracted with ethyl acetate (3×200 mL). The organic layers were combined, washed with brine (200 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness. The crude material was further purified by silica gel chromatography (EtOAc/Hexane=1/4) and afforded 2-chloro-4-(hydroxymethyl)pyridine (15.4 g, 85.8% yield) as an oil.