Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[C:10]([CH:15]3[O:19]CCO3)[CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:20].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([SH:28])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].C(#N)C>C(OCC)(=O)C.O>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([S:28][CH2:2][CH2:3][CH2:4][N:5]2[C:14]3[CH:13]=[CH:12][CH:11]=[C:10]([CH:15]=[O:19])[C:9]=3[CH2:8][CH2:7][C:6]2=[O:20])=[CH:24][CH:23]=1
Reactant: O=C1CCc2c(C3OCCO3)cccc2N1CCCBr
Reactant: Sc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=Cc1cccc2c1CCC(=O)N2CCCSc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.1 %

Procedure:
1-(3-Bromopropyl)-5-(1,3-dioxolan-2-yl)-3,4-dihydro-1H-quinolin-2-one (797 mg, 2.34 mmol), 4-chlorothiophenol (407 mg, 2.81 mmol) and potassium carbonate (421 mg, 3.05 mmol) were added to acetonitrile (16 ml), followed by heating under reflux for 5 hours. After cooling to room temperature, water was added to the reaction mixture, and extraction with ethyl acetate was performed. The extract was dried over sodium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1→2:1). The purified product was concentrated under reduced pressure, and the residue was dissolved in acetone (16 ml). p-Toluenesulfonic acid monohydrate (53.5 mg) and water (3 ml) were added, followed by stirring at room temperature overnight. An aqueous solution of potassium carbonate was added to the reaction mixture, and extraction with dichloromethane was performed. The organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to thereby obtain 700 mg (yield: 83%) of 1-[3-(4-chlorophenylsulfanyl)propyl]-2-oxo-1,2,3,4-tetrahydroquinoline-5-carboxaldehyde as a colorless oil.
Reaction SMILES: [C:1]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)[Br:21].C(N(CC)CC)C.[Si:32]([O:39][C:40]1[CH:47]=[CH:46][C:43](C=O)=[CH:42][CH:41]=1)([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33]>ClCCl>[Br:21][C:20]([Br:24])=[CH:1][C:47]1[CH:46]=[CH:43][CH:42]=[CH:41][C:40]=1[O:39][Si:32]([C:35]([CH3:36])([CH3:37])[CH3:38])([CH3:33])[CH3:34]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C=O)cc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: BrC(Br)(Br)Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)Oc1ccccc1C=C(Br)Br
Reaction time: 0.17 h
Yield: 107.7 %

Procedure:
Triphenylphosphine (3.44 g, 13.1 mmol) was dissolved in dichloromethane (25 ml) in nitrogen atmosphere, carbon tetrabromide (2.18 g, 6.56 mmol) was added little by little under cooling with ice, and triethylamine (4.4 ml, 26.2 mmol) was dropwise added, followed by stirring for 10 minutes. Then, under cooling with ice, a dichloromethane solution (20 ml) of 4-(tert-butyldimethylsilyloxy)benzaldehyde (10.0 g, 73.4 mmol) prepared in 1) was dropwise added, followed by stirring for 1 hour. Silica gel (50 g) was added to the reaction solution, the reaction solution was concentrated under reduced pressure to dryness, and the resulting product was purified by silica gel column chromatography (hexane:ethyl acetate=20:1, containing 0.1% v/v triethylamine) to give 1,1-dibromo-2-(tert-butyldimethylsilyloxyphenyl)ethylene (2.77 g, 81%) as a pale yellow oily substance.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[C:11]([CH3:17])[CH:10]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br.O>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[C:11]([CH3:17])[CH:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2ccc(C#N)c(C)c2)cc1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: Cc1cc(-c2ccc(O)cc2)ccc1C#N
Temperature: 25 °C
Reaction time: 14 h
Yield: 94.8 %

Procedure:
The product from Example 164A (5.60 g, 25.4 mmol) in CH2Cl2 (120 mL) at 78° C. was treated with 1.0 M BBr3 (in CH2Cl2, 76 mL, 76.0 mmol) dropwise over 1 hour. After stirring for 14 hours at room temperature, the mixture was warmed to 0° C. (ice bath) and treated with water (0.5 mL). After 10 minutes, additional water was added (2.0 mL), ice bath was removed, and 5.0 mL of water was added. The mixture was then treated with another 20 mL of water and allowed to stir for 45 minutes. The mixture was filtered and the filtrate extracted with CH2Cl2. The CH2Cl2 layers were combined, dried over sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to provide the title compound as an off-white powder (5.04 g, 94% yield). 1HNMR (300 MHz, CDCl3) δ2.35 (s, 3H), 5.0 (s, 1H), 6.79-7.50 (m, 7H); MS (DCI) m/z 210 (M+H)+.
Reaction SMILES: [C:1]([NH:5][NH2:6])([CH3:4])([CH3:3])[CH3:2].S([O-])([O-])(=O)=O.[Na+].[Na+].[CH2:14]1[CH2:20][CH:19](Cl)[C:17](=O)[CH2:16][CH2:15]1>C(Cl)Cl>[C:1]([N:5]=[N:6][C:14]1[CH2:20][CH2:19][CH2:17][CH2:16][CH:15]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NN
Reactant: O=C1CCCCC1Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)N=NC1=CCCCC1
Reaction time: 1 h
Yield: 97 %

Procedure:
To a solution of 11 g. (.125 m.) tert.-butylhydrazine in 80 ml. of methylene chloride containing 2 g. anhydrous sodium sulfate, was added 6.8 g. (0.052 m.) alpha-chlorocyclohexanone. The addition was carried out dropwise and the reaction temperature was maintained at 20° C. ±5° by an ice bath. The solution immediately turned yellow, but the reaction was stirred for an additional 1 hour after the addition was complete before filtering it. The filtered methylene chloride solution was washed with 100 ml. water, dried over anhydrous sodium sulfate, filtered and the methylene chloride evaporated off. A viscous, gelatinous liquid remained. The material was cooled in the freezer and then filtered. A white solid, 0.1 g., remained on the filter. The filtrate weighed 8.4 g. (97% yield) and its infra-red spectrum was consistent with the proposed structure. It showed the absence of N-H and carbonyl bands and the presence of a carbon-carbon double bond (1650 cm-1) and a conjugated azo bond (1510 cm-1). The product evolves nitrogen at 60 ° C. 1(-tert.-butylazo)eyeclohexane gelled the unsaturated polyester-styrene resin of Example III at room temperature.
Reaction SMILES: [CH3:1][I:2].[CH2:3]([O:7][C:8]1[C:9]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[N:10][S:11][N:12]=1)[CH:4]([CH3:6])[CH3:5]>CC(C)=O>[I-:2].[CH2:3]([O:7][C:8]1[C:9]([C:13]2[CH2:14][N:15]([CH3:1])[CH:16]=[CH:17][CH:18]=2)=[N:10][S:11][N:12]=1)[CH:4]([CH3:6])[CH3:5]
Reactant: CC(C)COc1nsnc1-c1cccnc1
Reactant: CI
Solvent: CC(C)=O
Product: CC(C)COc1nsnc1C1=CC=CN(C)C1
Product: [I-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of methyl iodide (0.6 ml, 10 mmol) and 3-(4-isobutoxy-1,2,5-thiadiazol-3-yl)pyridine (588 mg, 2.5 mmol) in acetone (5 ml) was stirred at room temperature for 18 h. The title compound precipitated from the solution and was collected by filtration to yield 0.88 g (87%).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1)[CH3:2].[CH3:10][NH:11][CH3:12]>>[CH2:1]([N:3]1[CH2:8][CH2:7][C:6]([N:11]([CH3:12])[CH3:10])=[CH:5][CH2:4]1)[CH3:2]
Reactant: CCN1CCC(=O)CC1
Reactant: CNC
Product: CCN1CC=C(N(C)C)CC1
Yield: 73.5 %

Procedure:
The respective starting substance is prepared from 90 g of 1-ethyl-4-piperidone with dimethylamine gas introduced into the reaction mixture on three subsequent days for a total 20 hours introduction time as described in Example 1, 1-ethyl-4-dimethylamino-1,2,5,6-tetrahydropyridine is obtained with a yield of 73.5%, bp.: 90°-93° C./1.47 kPa; nD20 =1.4931.
Reaction SMILES: Br[C:2]1[N:6](S(C2C=NC=CC=2)(=O)=O)[CH:5]=[C:4]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:3]=1.[Cl:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[C:29]([F:36])[CH:28]=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>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([C:2]2[NH:6][CH:5]=[C:4]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])[CH:3]=2)=[C:29]([F:36])[CH:28]=1
Reactant: OB(O)c1ccc(Cl)cc1F
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
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+]
Product: CN(Cc1c[nH]c(-c2ccc(Cl)cc2F)c1)C(=O)OC(C)(C)C

Procedure:
By a similar operation as in Reference Example 301 and using tert-butyl {[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (300 mg), (4-chloro-2-fluorophenyl)boronic acid (243 mg), tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (220 mg), the title compound was obtained as a colorless oil (yield 127 mg, 54%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:9][CH3:10])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[Cl:11][S:12](O)(=[O:14])=[O:13]>>[CH3:10][O:9][C:4]1[CH:5]=[C:6]([CH3:8])[C:7]([S:12]([Cl:11])(=[O:14])=[O:13])=[C:2]([CH3:1])[CH:3]=1
Reactant: COc1cc(C)cc(C)c1
Reactant: O=S(=O)(O)Cl
Product: COc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
3,5-Dimethylanisole (102.5 g, 753 mmol) was dissolved in MC (1,000 ml) and the solution was cooled to 0° C. Chlorosulfonic acid (251 ml, 3.763 mmol, in 250 ml of MC) was slowly added dropwise to this solution. After 10 minutes, the reaction mixture was poured on to ice (1,000 ml) and extracted with MC (1×250 ml). The combined organic phases were washed with water (1,000 ml) and NaCl solution (1,000 ml), dried with Na2SO4 and concentrated in vacuo. Purification of the crude product was carried out by chromatography on silica gel (heptane/MC, 5:1). The yield was 63.50 g (36%).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][CH:6]=1.[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([O:28][CH2:29][CH2:30][O:31][CH3:32])=[C:23]([CH:27]=1)[C:24](Cl)=[O:25]>>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([O:28][CH2:29][CH2:30][O:31][CH3:32])=[C:23]([CH:27]=1)[C:24]([NH:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][CH:6]=1)=[O:25].[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([O:28][CH2:29][CH2:30][O:31][CH3:32])=[C:23]([CH:27]=1)[C:24]([NH:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([CH:11]([CH3:17])[C:12]([OH:14])=[O:13])=[CH:9][CH:10]=1)=[O:25]
Reactant: COCCOc1ccc(Cl)cc1C(=O)Cl
Reactant: CCOC(=O)C(C)c1ccc(CCN)cc1
Agent: Cl
Product: CCOC(=O)C(C)c1ccc(CCNC(=O)c2cc(Cl)ccc2OCCOC)cc1
Product: COCCOc1ccc(Cl)cc1C(=O)NCCc1ccc(C(C)C(=O)O)cc1

Procedure:
In a manner analogous to that described in Example 11, by the reaction of ethyl 2-[4-(2-aminoethyl)-phenyl]-propionate hydrochloride with 5-chloro-2-(2-methoxyethoxy)-benzoyl chloride (m.p. 49°-51° C.), there is obtained, via ethyl 2-{4-[2-(5-chloro-2-(2-methoxyethoxy)-benzamido)-ethyl]-phenyl}-propionate (oil), 2-{4-[2-(5-chloro-2-(2-methoxyethoxy)-benzamido)-ethyl]-phenyl}-propionic acid; m.p. 94°-96° C., after recrystallization from isopropanol/water.
Reaction SMILES: [O:1]([C:3]#[N:4])[K].Br[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17](=[O:21])[C:18]([CH3:20])=[CH2:19].[CH2:22]([O:24][P:25]([CH2:30][CH:31]([CH2:41][OH:42])[CH2:32][P:33](=[O:40])([O:37][CH2:38][CH3:39])[O:34][CH2:35][CH3:36])(=[O:29])[O:26][CH2:27][CH3:28])[CH3:23]>[N+](CCCC)(CCCC)(CCCC)CCCC.[Br-].C(#N)C.ClCCl>[CH2:35]([O:34][P:33]([CH2:32][CH:31]([CH2:41][O:42][C:3](=[O:1])[NH:4][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17](=[O:21])[C:18]([CH3:20])=[CH2:19])[CH2:30][P:25](=[O:29])([O:26][CH2:27][CH3:28])[O:24][CH2:22][CH3:23])(=[O:40])[O:37][CH2:38][CH3:39])[CH3:36]
Reactant: N#CO[K]
Reactant: C=C(C)C(=O)OCCCCCCCCCCBr
Reactant: CCOP(=O)(CC(CO)CP(=O)(OCC)OCC)OCC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CC#N
Solvent: ClCCl
Product: C=C(C)C(=O)OCCCCCCCCCCNC(=O)OCC(CP(=O)(OCC)OCC)CP(=O)(OCC)OCC
Reaction time: 64 h
Yield: 90 %

Procedure:
KOCN (3.33 g, 41.0 mmol, 5.85 eq.) and Bu4NBr (1.77 g, 5.49 mmol, 0.8 eq.) were added to a solution of the 10-bromodecylmethacrylate from the 1st step (8.36 g, 27.4 mmol, 3.9 eq.) in anhydrous acetonitrile (55 ml) and the reaction mixture was stirred for 64 h. The reaction mixture was subsequently concentrated in vacuo and hexane (100 ml) was added. After filtration of the obtained solution and concentrating in vacuo 4.75 g of a yellow oil was obtained. To this oil a solution of 2-hydroxymethyl-1,3-propylene-bisphosphonic acid tetraethylester (2.41 g, 7.0 mmol) in anhydrous dichloromethane (2.0 ml) and a 1% solution of Metatin 712 in dichloromethane (2.0 ml) were added and the reaction mixture was stirred for 15 h at room temperature. After concentrating in vacuo the obtained crude product was purified by column chromatography (eluent: ethyl acetate/methanol 95:5). 3.85 g (90% yield) of the product was obtained as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[C:5]([O:10][CH2:11][C:12]2([CH2:15][C:16]#[N:17])[CH2:14][CH2:13]2)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-])=O>C(O)(=O)C.C(O)C>[NH2:1][C:4]1[C:5]([O:10][CH2:11][C:12]2([CH2:15][C:16]#[N:17])[CH2:14][CH2:13]2)=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: N#CCC1(COc2ncccc2[N+](=O)[O-])CC1
Solvent: CC(=O)O
Solvent: CCO
Product: N#CCC1(COc2ncccc2N)CC1
Temperature: 100 °C

Procedure:
2-(1-((3-Nitropyridin-2-yloxy)methyl)cyclopropyl)acetonitrile (466 mg) was dissolved in a mixture of glacial acetic acid (4 ml) and ethanol (8 ml). Ferrum (1.1 g) was added and the reaction mixture was heated to 100° C. for 2 h. The mixture was concentrated in vacuo and the residue was dissolved in dichloromethane, extracted with an aqueous solution of K2CO3 (2M) and concentrated in vacuo
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=2[NH:3][CH:2]=1.[CH3:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH2:22]Br)[CH:18]=2)[N:13]=1.C([O-])([O-])=O.[K+].[K+]>>[CH3:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH2:22][N:10]([CH2:22][C:17]3[CH:18]=[C:19]4[C:14](=[CH:15][CH:16]=3)[N:13]=[C:12]([CH3:11])[CH:21]=[CH:20]4)[C:8]3[CH:7]=[CH:6][C:5]4[NH:1][CH:2]=[N:3][C:4]=4[CH:9]=3)[CH:18]=2)[N:13]=1
Reactant: Cc1ccc2cc(CBr)ccc2n1
Reactant: Nc1ccc2nc[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc2cc(CN(Cc3ccc4nc(C)ccc4c3)c3ccc4[nH]cnc4c3)ccc2n1

Procedure:
The compound was synthesized starting from benzimidazol-5-amine (133 mg; 1 mmol; 1 eq.), (2-methylquinolin-6-yl)methylbromide (519 mg; 2.2 mmol; 2.2 eq.) and K2CO3 (304 mg; 2.2 mmol; 2.2 eq.) according to method 5; Yield: 0.067 g (15.1%); MS m/z: 444.5 [M+H]+, 222.8 [M+2H]2+; 1H-NMR (500 MHz, DMSO d6): δ 2.60 (s, 6H); 4.92 (s, 4H); 6.77-6.82 (m, 2H); 7.33-7.35 (m, 3H); 7.67 (dd, 2H, 4J=2.1 Hz, 3J=8.5 Hz); 7.77 (br s, 2H); 7.85-7.87 (m, 3H); 8.14 (d, 2H, 3J=8.5 Hz); 11.81 (br s, 1H); HPLC (METHOD [A]): doublepeak rt 6.61 min (61.2%), 6.84 min (38.8%)
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1O.C(=O)=O>S([O-])([O-])(=O)=O.[Cu+2]>[O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH2:2]1
Reactant: OC1CCc2ccccc2O1
Agent: [Cu+2]
Agent: O=C=O
Agent: O=S(=O)([O-])[O-]
Product: C1=Cc2ccccc2OC1

Procedure:
In 50 cc of anhydrous ether was dissolved 3.06 g. (0.01 mole) of the chromanone compound obtained in Example 32, represented by the following formula: ##STR160## and the solution was cooled to 0° C. and Grignard reagent CH3MgI (0,012 mole) newly prepared in 50 cc of anhydrous ether was dropped into the solution over a period of about 1 hour. After termination of the dropwise addition, the mixture was stirred at room temperature for 2 hours and quietly poured into cold water to extract the product with ether. The ether extract was dried on magnesium sulfate to form a chromanol compound from the chromanone compound. Then, the chromanol compound was heated at 200° C. together with anhydrous copper sulfate in a carbon dioxide current for about 10 minutes. The obtained brown viscous liquid was purified by the chromatography on silica gel to obtain 2.47 g of a chromene compound represented by the following formula: ##STR161##
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([OH:9])=O.S(Cl)([Cl:12])=O>>[Br:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([Cl:12])=[O:9]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1occc1Br
Product: O=C(Cl)c1occc1Br

Procedure:
Compounds of this invention with Formulae I-IX may be prepared as illustrated by the exemplary reaction in Scheme 2. Reaction of 3-bromo-furan-2-carboxylic acid with thionyl chloride produces intermediate, 3-bromo-furan-2-carbonyl chloride, followed by refluxing with 4-trifluoromethyl-benzamidoxime in pyridine produces the product 5-(3-bromo-furan)-3-(4-trifluoromethyl-phenyl)-[1,2,4]-oxadiazole.
Reaction SMILES: [Cl-].[Li+].[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH2:9][C:8](C(OCC)=O)([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:7]2.CS(C)=O>O>[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:7]2
Reactant: CCOC(=O)C1(C(=O)OCC)Cc2ccc(Br)cc2C1
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)C1Cc2ccc(Br)cc2C1
Temperature: 160 °C
Reaction time: 8 h
Yield: 76.9 %

Procedure:
Lithium chloride (66 mg, 1.55 mmol) was added to a solution of diethyl 5-bromo-1H-indene-2,2(3H)-dicarboxylate (200 mg, 0.58 mmol), DMSO (2 mL), and H2O (0.2 mL). The mixture was stirred overnight at 160° C. After cooled to room temperature, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3×15 mL). The combined organic layers were washed with saturated aqueous NaHCO3 (2×20 mL), dried over MgSO4 and concentrated in vacuo to afford the title compound (120 mg, 76%). 1HNMR (400 MHz, DMSO-d6): δ 7.42 (s, 1H), 7.31 (d, 1H), 7.18 (d, 1H), 4.10 (q, 2H), 3.39-3.34 (m, 1H), 3.17-3.01 (m, 4H), 1.19 (t, 3H).
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][C@H:7]([NH:29][C:30]([C:32]1[CH:33]=[N:34][C:35]2[C:40]([CH:41]=1)=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:31])[C:8]([O:10][C@@H:11]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:12][C:13]([NH2:15])=[O:14])=[O:9])([OH:3])=[O:2].[CH3:42][Si](C=[N+]=[N-])(C)C>CO.CCCCCC>[CH3:42][O:2][C:1]([CH2:4][CH2:5][CH2:6][C@H:7]([NH:29][C:30]([C:32]1[CH:33]=[N:34][C:35]2[C:40]([CH:41]=1)=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:31])[C:8]([O:10][C@@H:11]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:12][C:13]([NH2:15])=[O:14])=[O:9])=[O:3]
Reactant: CCCCCCCCCCCCC[C@@H](CC(N)=O)OC(=O)[C@H](CCCC(=O)O)NC(=O)c1cnc2ccccc2c1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: CCCCCC
Product: CCCCCCCCCCCCC[C@@H](CC(N)=O)OC(=O)[C@H](CCCC(=O)OC)NC(=O)c1cnc2ccccc2c1
Reaction time: 48 h

Procedure:
To a solution of (3S)-3-[(2S)-5-carboxy-2-{(3-quinolyl)carbonylamino}pentanoyl]oxyhexadecanamide (100 mg) in methanol (10 ml) was added 2M solution of trimethylsilyldiazomethane in hexane (2 ml) at room temperature. After being stirred at the same temperature for 2 days, the solvent was removed under reduced pressure and the resulting solid was triturated with ethyl ether to give (3S)-3-[(2S)-5-methoxycarbonyl-2-{(3-quinolyl)carbonylamino}pentanoyl]oxyhexadecanamide (68.4 mg).
Reaction SMILES: [CH2:1]([C:8]1O[C:10]([O:20]CC)=[C:11]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:23]1[CH2:27][CH:26]=[CH:25][CH2:24]1>>[CH2:1]([C:8]1[C:25]2[CH2:24][O:23][CH2:27][C:26]=2[C:10]([OH:20])=[C:11]([CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1=CCOC1
Reactant: CCOc1oc(Cc2ccccc2)nc1Cc1ccccc1
Product: Oc1c(Cc2ccccc2)nc(Cc2ccccc2)c2c1COC2
Yield: 37 %

Procedure:
44 g (150 millimoles) of 2,4-dibenzyl-5-ethoxyoxazole and 210 g (3 moles) of 2,5-dihydrofuran are heated for 8 hours at 180° C. Excess 2,5-dihydrofuran is distilled off and the residue is digested in ether. The undissolved constituent is recrystallized from ethanol. 17.6 g of 4,6-dibenzyl-1,3-dihydro-furo[3,4-c]pyridin-7-ol are obtained, melting point 204°-205° C.
Reaction SMILES: [OH:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH:17]([NH:19][C:20](=[O:22])[CH3:21])[CH3:18])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.I[CH:24]([CH3:26])[CH3:25]>>[CH:24]([N:7]1[C:2](=[O:1])[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH:17]([NH:19][C:20](=[O:22])[CH3:21])[CH3:18])=[CH:11][CH:10]=2)=[CH:6]1)([CH3:26])[CH3:25]
Reactant: CC(C)I
Reactant: CC(=O)NC(C)CCc1ccc(Oc2ccc(O)nc2)cc1
Product: CC(=O)NC(C)CCc1ccc(Oc2ccc(=O)n(C(C)C)c2)cc1

Procedure:
N-{3-[4-(6-Hydroxypyridin-3-yloxy)phenyl]-1-methylpropyl}acetamide (168 mg, 1.49 mmol) was reacted with 2-iodopropane in analogy to example 36f. Yield: 26 mg (15%), M+H+: 343.20. N-{3-[4-(1-Isopropyl-6-oxo-1,6-dihydropyridin-3-yloxy)phenyl]1-methylpropyl}acetamide was obtained as by-product.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C:11]2([C:28]([F:31])([F:30])[F:29])[CH2:15][C:14]([C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[C:21]3([CH2:27][NH:26][CH2:25]3)[O:20][CH2:19]4)=[N:13][CH2:12]2)[CH:6]=[C:7]([Cl:10])[C:8]=1[Cl:9].CCN(C(C)C)C(C)C.[CH3:41][S:42]([CH2:45][C:46](O)=[O:47])(=[O:44])=[O:43].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C1COCC1>[CH3:41][S:42]([CH2:45][C:46]([N:26]1[CH2:25][C:21]2([C:22]3[C:18](=[CH:17][C:16]([C:14]4[CH2:15][C:11]([C:5]5[CH:4]=[C:3]([Cl:2])[C:8]([Cl:9])=[C:7]([Cl:10])[CH:6]=5)([C:28]([F:30])([F:29])[F:31])[CH2:12][N:13]=4)=[CH:24][CH:23]=3)[CH2:19][O:20]2)[CH2:27]1)=[O:47])(=[O:44])=[O:43]
Reactant: CS(=O)(=O)CC(=O)O
Reactant: FC(F)(F)C1(c2cc(Cl)c(Cl)c(Cl)c2)CN=C(c2ccc3c(c2)COC32CNC2)C1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)CC(=O)N1CC2(C1)OCc1cc(C3=NCC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)ccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.5 %

Procedure:
To a stirred solution of 5′-(3-(3,4,5-trichlorophenyl)-3-(trifluoromethyl)-3,4-dihydro-2H-pyrrol-5-yl)-3′H-spiro[azetidine-3,1′-isobenzofuran]hydrochloride (Preparation 5, 900 mg, 1.77 mmol) in THF (20 mL) was added DIPEA (3.01 mL, 17.65 mmol), methanesulfonyl acetic acid (488 mg, 3.53 mmol) followed by addition of T3P (5.12 mL, 8.82 mmol, 50% solution in ethyl acetate) at room temperature. The resulting reaction mixture was stirred at room temperature for 16 hours. Reaction was monitored by TLC, after complete consumption of staring material reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (3×25 mL). Combined organic layer was washed with NaHCO3 solution (30 mL) & brine (30 mL), dried over sodium sulphate and concentrated to get crude sticky solid 1 g. The crude was purified by column chromatography using 100-200 mesh silica gel. Desired compound was eluted in 0.5% MeOH in DCM to get desired compound as pale green solid 490 mg, 46.6%. 1H NMR (400 MHz, DMSO-d6) δ: 3.14 (s, 3H), 3.75 (d, J=18.04 Hz, 1H), 3.88 (d, J=18.52 Hz, 1H), 4.23 (d, J=10.36 Hz, 4H), 4.44 (d, J=17.6 Hz, 1H), 4.57 (s, 2H), 4.82 (d, J=17.4 Hz, 1H), 5.10 (s, 2H), 7.66 (d, J=7.96 Hz, 1H), 7.80 (s, 2H), 7.86 (s, 1H), 7.95 (d, J=7.96 Hz, 1H). LC-MS (m/z): 594.8 (M+H).