Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].[Br:10][CH2:11][CH2:12]Br.[OH-].[Na+]>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:12][CH2:11][Br:10])=[CH:4][C:3]=1[F:9]
Reactant: Oc1ccc(Cl)c(F)c1
Reactant: BrCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Fc1cc(OCCBr)ccc1Cl
Temperature: 80 °C
Reaction time: 24 h

Procedure:
A mixture of 4-chloro-3-fluorophenol (0.30 g, 2.05 mmol), 1,2-dibromoethane (1.15 g, 6.14 mmol), sodium hydroxide (0.12 g, 3.07 mmol), and water (3 mL) was added to a 50 mL RBF with a magnetic stirring bar. The flask was fitted with a condenser and warmed to an oil bath temperature of 80° C. The progress of the reaction was monitored by analytical HPLC with UV detection at 215 nm. Another portion of 1,2-dibromoethane (1.09 g, 5.8 mmol) was added, and heating was continued for 24 h. The mixture was allowed to cool to ambient temperature, diluted with 20 mL of water, and extracted with 30 mL of ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate (2×10 mL), saturated aqueous sodium chloride (10 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude material was purified by silical gel chromatography using a gradient elution of 0-100% ethyl acetate in hexanes. The title compound was obtained as a colorless oil (0.326 g, 63% yield). 1H NMR (DMSO-d6, 400 MHz) δ ppm: 7.48 (t, 1H), 7.12 (dd, 1H), 6.86 (dd, 1H), 4.35 (t, 2H), 3.80 (t, 2H).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[NH:21][C:19]3[C:20]4[C:11](=[N:12][NH:13][C:14](=[O:22])[C:15]=4[CH:16]=[CH:17][CH:18]=3)[CH:10]2[C:23]2[CH:33]=[CH:32][C:26]([C:27]([N:29]([CH3:31])[CH3:30])=[O:28])=[CH:25][CH:24]=2)=[CH:5][CH:4]=1)=O.C(O)(=O)C.[CH3:38][NH:39][CH3:40].[BH4-].[Na+]>C(Cl)Cl>[CH3:38][N:39]([CH2:1][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[NH:21][C:19]3[C:20]4[C:11](=[N:12][NH:13][C:14](=[O:22])[C:15]=4[CH:16]=[CH:17][CH:18]=3)[CH:10]2[C:23]2[CH:24]=[CH:25][C:26]([C:27]([N:29]([CH3:30])[CH3:31])=[O:28])=[CH:32][CH:33]=2)=[CH:7][CH:8]=1)[CH3:40]
Reactant: CNC
Reactant: CN(C)C(=O)c1ccc(C2c3n[nH]c(=O)c4cccc(c34)NC2c2ccc(C=O)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CN(C)Cc1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccc(C(=O)N(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 10 %

Procedure:
To a stirred solution of 4-(8-(4-formylphenyl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-9-yl)-N,N-dimethylbenzamide (140 mg, 0.32 mmol) in dried DCM (20 mL) was added acetic acid followed by dimethylamine (57 mg, 1.3 mmol). After the addition, the mixture was stirred at room temperature overnight. Then the mixture was cooled to 0° C. Sodium borohydride (102 mg, 0.48 mmol) was added. After the addition, the mixture was stirred at this temperature for 12 hr. DCM was removed under reduced pressure. The residue was washed with ethyl acetate/methanol (10/1) and filtered. The filtrate was concentrated to give the crude product, which was purified by prep-HPLC to give the title compound as a white solid (15 mg, yield 10%). 1H-NMR (400 MHz, CD3OD) δ (ppm): 2.19 (dd, 6H), 2.93 (s, 3H), 3.06 (s, 3H), 3.40 (dd, 2H), 4.34 (d, 1H), 4.16-7.19 (m, 5H), 7.23-7.26 (m, 4H), 7.54 (d, 1H), 7.61 (t, 1H). LC-MS (ESI) m/z: 468 (M+1)+.
Reaction SMILES: C[CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[CH:12][CH2:13][CH:14]=[CH:15][CH2:16][CH:17]=[C:18]([CH3:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:3]([OH:5])=[O:4].C(O)C.[OH-].[K+]>O>[CH3:24][C:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:17][CH2:16][CH:15]=[CH:14][CH2:13][CH:12]=[CH:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:2][C:3]([OH:5])=[O:4]
Reactant: CCCCCC(C)=CCC=CCC=CCCCCCC(C)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCC(C)=CCC=CCC=CCCCCCCC(=O)O

Procedure:
A mixture of 1.3 g. of methyl 15-methyl-8,11,14-eicosatrienoic acid, 12.8 ml of 95% ethanol, 1.1 g. of potassium hydroxide and 1.1 ml. of water under a nitrogen atmosphere was heated under reflux for 2hours, then water and Skellysolve "B" (mixed hexanes) were added. The aqueous and organic layers were separated and the aqueous layer was made acid with 3N hydrochloric acid, then extracted with ether. The ether extract was washed with water, then with saturated aqueous sodium chloride, dried over sodium sulfate, and evaporated leaving a residue comprising 15-methyl-8,11,14-eicosatrienoic acid. The residue was distilled in a short path tube at bath temperatures of about 180°C. and a pressure of about 0.007 mm. The distillate was dissolved in 5% ethyl acetate-benzene and chromatographed over 100 g. of acid washed silica gel. Elution with 600 ml. 5%, 500 ml. 10% and 200 ml. 25% ethyl acetate in benzene, then with 100 ml. of ethyl acetate, collecting 50 ml. fractions, and evaporation of the eluate fractions gave a first peak of 183 mg., followed by a 448 mg. peak comprising 15-methyl-8,11,14-eicosatrienoic acid showing one spot on TLC analysis, and having the following NMR absorptions:
Reaction SMILES: [CH3:1][N:2]1[C:6](=O)[CH:5]([C:8]([NH:10][C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH2:13][CH2:14][C:15]3([CH3:21])[CH3:20])=[O:9])[C:4]([CH3:22])=[N:3]1.P(Cl)(Cl)([Cl:25])=O.C(N(CC)C1C=CC=CC=1)C>>[Cl:25][C:6]1[N:2]([CH3:1])[N:3]=[C:4]([CH3:22])[C:5]=1[C:8]([NH:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH2:13][CH2:14][C:15]2([CH3:21])[CH3:20])=[O:9]
Reactant: CC1=NN(C)C(=O)C1C(=O)Nc1cccc2c1CCC2(C)C
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)c1ccccc1
Product: Cc1nn(C)c(Cl)c1C(=O)Nc1cccc2c1CCC2(C)C
Temperature: 0 °C

Procedure:
1.12 g (10 mmol) of 1,3-dimethylpyrazoline-5-one was suspended in 10 ml of toluene containing 1.11 g of triethylamine. To the suspension was added dropwise a solution of 1.87 g of 1,1-dimethylindane-4-yl isocyanate in 2 ml of toluene with stirring at room temperature, followed by further stirring at room temperature for 12 hours. Thereafter, the reaction mixture was extracted with water three times. The aqueous layers were made acidic with concentrated hydrochloric acid and cooled with ice. The precipitate produced was filtered and air-dried to obtain 1.81 g of 1,3-dimethyl-5-oxo-N-(1,1-dimethylindane-4-yl)4,5-dihydropyrazole-4-carboxamide (mp 141.4° C.). Then, thus obtained 1,3-dimethyl-5-oxo-N-(1,1-dimethylindane-4-yl)-4,5-dihydropyrazole-4-carboxamide was added to a mixture of 5 ml of phosphorus oxychloride and 907 mg of N,N-diethylaniline. The resultant mixture was stirred under reflux with heating for 1.5 hour. The obtained reaction mixture was poured into ice water and extracted with chloroform three times. The chloroform layer was washed with water and dried over anhydrous magnesium sulfate. Thereafter, the solvent was distilled off under reduced pressure and the residue was recrystallized with ethanol to obtain 0.96 g of 5-chloro-1,3-dimethyl-N-(1,1-dimethylindane-4-yl)pyrazole-4-carboxamide (mp 175.2° C.).
Reaction SMILES: C([C:5]1([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:10](=[O:11])[CH2:9][CH2:8][N:7]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:6]1)(OC)=O.Cl>CO>[CH2:12]([N:7]1[CH2:8][CH2:9][C:10](=[O:11])[CH:5]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:6]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)C1(Cc2ccccc2)CN(Cc2ccccc2)CCC1=O
Agent: Cl
Solvent: CO
Product: O=C1CCN(Cc2ccccc2)CC1Cc1ccccc1
Yield: 62.3 %

Procedure:
A solution of 3-carbomethoxy-1,3-dibenzyl-4-piperidone (0.61 g, 1.78 mmol), MeOH (10 mL) and 5M HCl aq. (25 mL, 125 mmol) was refluxed overnight. The reaction mixture was concentrated and chromatographed (silica gel, eluting with 4:1 hexane-EtOAc) to give 1,3-dibenzyl-4-piperidone (0.31 g).
Reaction SMILES: [CH3:1][N:2]([CH3:19])[S:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:7]=1[N+:16]([O-])=O)(=[O:5])=[O:4].[H][H]>[Pd].C(OCC)(=O)C>[NH2:16][C:7]1[CH:8]=[C:9]([C:12]([F:14])([F:13])[F:15])[CH:10]=[CH:11][C:6]=1[S:3]([N:2]([CH3:19])[CH3:1])(=[O:4])=[O:5]
Reactant: CN(C)S(=O)(=O)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CN(C)S(=O)(=O)c1ccc(C(F)(F)F)cc1N
Yield: 97.1 %

Procedure:
In a pressure vessel, 109 g of N,N-dimethyl-2-nitro-4-(trifluoromethyl)benzenesulfonamide, 250 ml of ethyl acetate and 5 g of 10% palladium-on-carbon were shaken at 130° under 500 psi hydrogen pressure until no more hydrogen was absorbed, as determined by no additional pressure drop. The reaction mixture was cooled and the catalyst filtered off. The solution was stripped in vacuo to give 95.2 g of 2-amino-N,N-dimethyl-4-(trifluoromethyl)benzenesulfonamide as a slowly crystalizing oil, m.p. 65°-70° C.
Reaction SMILES: Cl[C:2]([Cl:13])([Cl:12])[CH2:3][CH:4]1[C:7]([CH3:9])([CH3:8])[CH:6](Cl)[C:5]1=[O:11].[O:14](C1C=C(C=CC=1)CO)C1C=CC=CC=1.[H-].[Na+].Cl>C(COC)OC.O>[Cl:13][C:2]([Cl:12])=[CH:3][CH:4]1[C:7]([CH3:8])([CH3:9])[CH:6]1[C:5]([OH:11])=[O:14]
Reactant: OCc1cccc(Oc2ccccc2)c1
Reactant: CC1(C)C(Cl)C(=O)C1CC(Cl)(Cl)Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC1(C)C(C=C(Cl)Cl)C1C(=O)O
Temperature: 45 °C
Reaction time: 1 h

Procedure:
5.28 g (0.02 mol) of 2-(2',2',2'-trichloroethyl)-3,3-dimethyl-4-chlorocyclobutan-1-one, dissolved in 25 ml of absolute dimethoxyethane, are added dropwise to a solution of 4.0 g (0.02 mol) of m-phenoxybenzyl alcohol, 0.5 g (0.021 mol) of NaH and 40 ml of absolute dimethoxyethane. The reaction mixture is then stirred for 1 hour at 45° C., 2.25 g (0.02 mol) of potassium tert.-butylate are then added and the mixture is refluxed for 3 hours. After it has been discharged into water, it is acidified with dilute hydrochloric acid and extracted with benzene. The evaporated extract is chromatographed on silica gel using diethyl ether/n-hexane as the eluant (1:4 mixture by volume). This gives the m-phenoxybenzyl ester of 2-(2',2'-dichlorovinyl)-3,3-dimethylcyclopropane-1-carboxylic acid in the form of a viscous oil, which has the same properties as the substance obtained according to (a).
Reaction SMILES: [CH3:1][N:2]1[C:6]([O:7][CH:8]2[CH2:11][O:10][CH2:9]2)=[C:5]([CH:12]=[O:13])[C:4]([C:14]([F:17])([F:16])[F:15])=[N:3]1.[BH4-].[Na+]>CO>[CH3:1][N:2]1[C:6]([O:7][CH:8]2[CH2:11][O:10][CH2:9]2)=[C:5]([CH2:12][OH:13])[C:4]([C:14]([F:17])([F:15])[F:16])=[N:3]1
Reactant: Cn1nc(C(F)(F)F)c(C=O)c1OC1COC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cn1nc(C(F)(F)F)c(CO)c1OC1COC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 69.6 %

Procedure:
1-Methyl-5-(oxetan-3-yloxy)-3-trifluoromethyl-1H-pyrazole-4-carbaldehyde (11.6 g, 46.4 mmol) was dissolved in methanol (100 ml) and sodium borohydride (0.87 g, 23.0 mmol) was added in portions at 0° C. After stirring at 0° C. for 2 hours the mixture was concentrated and the oil was dissolved in dichloromethane (100 ml). The solution was washed with water and brine, dried over magnesium sulfate and concentrated to give the product as yellow solid (8.14 g) which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:3]=1[O:4][C:5]1[N:13]=[CH:12][C:11]([F:14])=[CH:10][C:6]=1[C:7]([OH:9])=O.C[C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[NH:27][CH2:26][CH2:25][CH2:24]2.N1C2C(=CC=CC=2)CCC1>>[Cl:1][C:2]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:3]=1[O:4][C:5]1[C:6]([C:7]([N:27]2[C:28]3[C:23](=[CH:22][CH:21]=[CH:30][CH:29]=3)[CH2:24][CH2:25][CH2:26]2)=[O:9])=[CH:10][C:11]([F:14])=[CH:12][N:13]=1
Reactant: O=C(O)c1cc(F)cnc1Oc1cc(Cl)ccc1Cl
Reactant: Cc1ccc2c(c1)CCCN2
Agent: c1ccc2c(c1)CCCN2
Product: O=C(c1cc(F)cnc1Oc1cc(Cl)ccc1Cl)N1CCCc2ccccc21

Procedure:
The title compound was prepared in analogy to Example 31, Step 2, replacing 2-(2,5-dichloro-phenoxy)-nicotinic acid with 2-(2,5-dichloro-phenoxy)-5-fluoro-nicotinic acid (Example 80, Step 1) and 6-methyl-1,2,3,4-tetrahydro-quinoline with 1,2,3,4-tetrahydro-quinoline ([CAS RN 635-46-1]). MS (ISP): 417.0 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:12]=[N:13][C:14]([CH3:17])=[CH:15][CH:16]=1)=[O:10].[C:18]([C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1)(=[O:20])[CH3:19]>>[C:18]([C:21]1[CH:22]=[CH:23][C:24]([S:27]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=2[C:9]([C:11]2[CH:12]=[N:13][C:14]([CH3:17])=[CH:15][CH:16]=2)=[O:10])(=[O:29])=[O:28])=[CH:25][CH:26]=1)(=[O:20])[CH3:19]
Reactant: Cc1ccc(C(=O)c2cc(Cl)ccc2N)cn1
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Product: CC(=O)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2ccc(C)nc2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using (2-Amino-5-chloro-phenyl)-(6-methyl-pyridin-3-yl)-methanone and 4-acetyl-benzenesulfonyl chloride and purified by HPLC. 1H NMR (CDCl3) δ 9.54 (br s, 1, NH), 8.30 (m, 1), 7.77 (d, 2, J=8.8 Hz), 7.71 (d, 2, J=8.8 Hz), 7.69 (m, 1), 7.54 (dd, 1, J=8.8 Hz, J=2.2 Hz), 7.33 (d, 1, J=2.2 Hz), 7.26 (m, 1), 7.21 (d, 1, J=8.0 Hz), 2.63 (s, 3), 2.52 (s, 3). MS: m/z 429 (M+1).
Reaction SMILES: [C:1]1([N:7]2[C:15]([NH2:16])=[C:14]3[C:9]([CH:10]=[CH:11][CH:12]=[CH:13]3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]1(=O)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C(O)(=O)C.[Na]>C(Cl)Cl>[CH:17]1([NH:16][C:15]2[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=[C:9]3[C:14]=2[CH:13]=[CH:12][CH:11]=[CH:10]3)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: Nc1c2ccccc2nn1-c1ccccc1
Reactant: O=C1CCCCC1
Agent: [Na]
Solvent: CC(=O)O
Solvent: ClCCl
Product: c1ccc(-n2nc3ccccc3c2NC2CCCCC2)cc1
Yield: 18 %

Procedure:
To a solution of 2-phenyl-2H-indazol-3-amine (800 mg, 4 mmol; Shirtcliff, Laura D.; Rivers, Jazmin; Haley, Michael M, Journal of Organic Chemistry (2006), 71(17), 6619-6622) in CH2Cl2 (43 ml) was added cyclohexanone (1.97 ml, 19 mmol; CAS Reg. No. 108-94-1), acetic acid (0.22 ml, 4 mmol) and sodium triacetoxyborhydride (2.43 g, 11 mmol) at ambient temperature under an argon atmosphere. The reaction mixture was heated under reflux conditions for 12 h, poured onto ice water/aqueous NaHCO3 solution 1/1 and extracted two times with CH2Cl2. The combined extracts were washed with ice water/brine 1/1 and dried over Na2SO4. After filtration the solvent was removed under reduced pressure, the resulting brown oil was dissolved in MeOH (20 ml) and heated under reflux conditions for 30 min. Removal of the solvent under reduced pressure left a brown oil which was purified by column chromatography (silica gel, iPrOAc/heptane) to give the title compound (206 mg, 0.7 mmol; 18%) as yellow oil. MS: m/e=292.4 [M+H+].
Reaction SMILES: [CH3:1][C@:2]12[C:10](=[O:11])[CH2:9][C@H:5]([C:6]1([CH3:8])[CH3:7])[CH2:4][CH2:3]2.[H-].[Na+].C(C1C=C(C=C(C(C)(C)C)C=1O)C=O)(C)(C)C.Cl>COCCOC.C(O)C.O>[C:2]12([CH3:1])[C:6]([CH3:8])([CH3:7])[CH:5]([CH2:4][CH2:3]1)[CH2:9][C:10]2=[O:11]
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)C(=O)C2
Agent: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Agent: Cl
Agent: [H-]
Solvent: O
Solvent: COCCOC
Solvent: CCO
Product: CC12CCC(CC1=O)C2(C)C
Yield: 109.1 %

Procedure:
50 g (0.328 mol) of d-camphor are dissolved in 400 cm3 of 1,2-dimethoxyethane. 17.5 g of sodium hydride (0.73 mol) are added and the mixture is brought to reflux for one hour. 70 g (0.3 mol) of 3,5-di-tert-butyl-4-hydroxybenzaldehyde are added and the mixture is heated under reflux for 10 hours. After being cooled, the reaction medium is gradually diluted with 100 cm3 of ethanol and then with 100 cm3 of water. The mixture is acidified by adding 10% strength hydrochloric acid. The precipitate formed is filtered off, washed with water and dried. After recrystallization in isopropyl ether and then in ethanol, 54.5 g (49% yield) of expected product are obtained, possessing the following characteristics:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]([CH2:14][NH2:15])[CH2:12][C@H:11]2[C@@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:16]1[CH2:21][CH2:20][O:19][C:18]2=[C:22]([C:25](O)=[O:26])[S:23][CH:24]=[C:17]12>>[C:1]([O:5][C:6]([N:8]1[C@H:13]([CH2:14][NH:15][C:25]([C:22]2[S:23][CH:24]=[C:17]3[C:18]=2[O:19][CH2:20][CH2:21][O:16]3)=[O:26])[CH2:12][C@H:11]2[C@@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(O)c1scc2c1OCCO2
Reactant: CC(C)(C)OC(=O)N1[C@H](CN)C[C@@H]2C[C@@H]21
Product: CC(C)(C)OC(=O)N1[C@H](CNC(=O)c2scc3c2OCCO3)C[C@@H]2C[C@@H]21

Procedure:
prepared by reaction of (1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester with 2,3-dihydro-thieno[3,4-b][1,4]dioxine-5-carboxylic acid. LC-MS (acidic): tR=0.98 min; [M+H]+=381.1.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[S:8][C:7]2=[N:9][C:10]([C:14]([F:17])([F:16])[F:15])=[C:11]([CH2:12]O)[N:6]2[N:5]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[F:29][C:30]([F:40])([F:39])[CH2:31][CH2:32][CH:33]1[CH2:37][NH:36][C:35](=[O:38])[NH:34]1>C1(C)C=CC=CC=1>[CH3:1][O:2][CH2:3][C:4]1[S:8][C:7]2=[N:9][C:10]([C:14]([F:17])([F:16])[F:15])=[C:11]([CH2:12][N:36]3[CH2:37][CH:33]([CH2:32][CH2:31][C:30]([F:39])([F:40])[F:29])[NH:34][C:35]3=[O:38])[N:6]2[N:5]=1
Reactant: COCc1nn2c(CO)c(C(F)(F)F)nc2s1
Reactant: O=C1NCC(CCC(F)(F)F)N1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COCc1nn2c(CN3CC(CCC(F)(F)F)NC3=O)c(C(F)(F)F)nc2s1
Temperature: 110 °C
Yield: 64 %

Procedure:
[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methanol a3 (3.26 g, 0.122 mol, 1 eq) and p-toluenesulphonic acid (2.10 g, 0.122 mol, 1 eq) are successively added to a solution of 4-(3,3,3-trifluoropropyl)imidazolidin-2-one a10 (2.22 g, 0.122 mol, 1 eq) in toluene (450 ml). The mixture is heated at 110° C. overnight. The reaction is not complete and another portion of intermediate a10 (1 g, 5.49 mmol, 0.45 eq) is added. The mixture is heated at 110° C. overnight, then the solvent is evaporated under reduced pressure. Water is added to the residue, the mixture is extracted with CH2Cl2, the organic layer is dried over MgSO4, filtered and condensed under reduced pressure. The residue is purified by chromatography over silicagel (eluent: CH2Cl2/MeOH/NH4OH 98/2/0.2) to afford 336 mg of 1-{[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl}-4-(3,3,3-trifluoropropyl)imidazolidin-2-one 5 as a yellow oil.
Reaction SMILES: C1(OC(=O)[N:9]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]4([C:38](=[O:47])[NH:39][C:40]5[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=5)[CH2:37][CH2:36]4)=[O:34])=[CH:28][CH:27]=3)[CH:22]=[CH:21][N:20]=2)[C:10](OC2C=CC=CC=2)=[O:11])C=CC=CC=1.[CH3:49][N:50]([CH3:56])[C@H:51]1[CH2:55][CH2:54][NH:53][CH2:52]1>CN(C)C=O>[CH3:49][N:50]([CH3:56])[C@H:51]1[CH2:55][CH2:54][N:53]([C:10]([NH:9][C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]4([C:38]([NH:39][C:40]5[CH:41]=[CH:42][C:43]([F:46])=[CH:44][CH:45]=5)=[O:47])[CH2:37][CH2:36]4)=[O:34])=[CH:28][CH:27]=3)[CH:22]=[CH:21][N:20]=2)=[O:11])[CH2:52]1
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2)ccn1
Reactant: CN(C)[C@H]1CCNC1
Solvent: CN(C)C=O
Product: CN(C)[C@H]1CCN(C(=O)Nc2cc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3)ccn2)C1
Reaction time: 3 h
Yield: 54 %

Procedure:
To a solution of [4-(4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamic acid phenyl ester (50 mg) in N,N-dimethylformamide (1.0 ml) was added (3S)-3-dimethylaminopyrrolidine (0.050 ml) at room temperature, followed by stirring for 3 hr. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with a saturated aqueous solution of ammonium chloride and brine in this order, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=98:2). Fractions containing the target compound were concentrated under reduced pressure. A solid was precipitated by addition of diethyl ether:heptane=1:3 to the resultant residue. The solid was collected by filtration and dried under aeration to provide the titled compound as white powder (23.0 mg, 54%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[F:14][C:15]([F:26])([F:25])[O:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1.C([BH3-])#N.[Na+].C(=O)([O-])O.[Na+]>CO.C(Cl)Cl.C(O)(=O)C>[F:14][C:15]([F:25])([F:26])[O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][N:11]2[CH2:12][CH2:13][N:8]([C:5]3[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=3)[CH2:9][CH2:10]2)=[CH:19][CH:18]=1
Reactant: Oc1ccc(N2CCNCC2)cc1
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: Oc1ccc(N2CCN(Cc3ccc(OC(F)(F)F)cc3)CC2)cc1
Reaction time: 2 h
Yield: 56.8 %

Procedure:
4-(4-hydroxyphenyl)piperazine (3 g, 16.8 mmol) and 4-trifluoromethoxy benzaldehyde (3.36 g, 17.7 mmol) were dissolved in methanol (60 ml) and methylene chloride (15 ml). Sodium cyanoborohydride (1.59 g, 25.3 mmol) and-acetic acid (1.6 ml) were added to this solution while cooling in an ice-bath, and the mixture was stirred for 2 hours. Saturated sodium hydrogencarbonate aqueous solution and methylene chloride were added to the reaction mixture, which was extracted with methylene chloride. The extract was washed with brine, dried over magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/methanol=100/1) to afford 4-[4-(4-trifluoromethoxybenzyl)piperazin-1-yl]phenol (3.36 g, yield 57%) as a colorless crystalline powder.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[C:13]([CH2:16]Cl)=[N:14][N:15]=[C:11]3[CH2:10][N:9]=[C:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:7]=2[CH:25]=1.[CH3:28][NH:29][CH2:30][CH:31]1[CH2:33][CH2:32]1>>[F:27][C:2]([F:26])([F:1])[C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[C:13]([CH2:16][N:29]([CH2:30][CH:31]4[CH2:33][CH2:32]4)[CH3:28])=[N:14][N:15]=[C:11]3[CH2:10][N:9]=[C:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:7]=2[CH:25]=1
Reactant: CNCC1CC1
Reactant: FC(F)(F)c1ccc2c(c1)C(c1ccccc1Cl)=NCc1nnc(CCl)n1-2
Product: CN(Cc1nnc2n1-c1ccc(C(F)(F)F)cc1C(c1ccccc1Cl)=NC2)CC1CC1

Procedure:
In the manner given in Preparation 29, 8-(trifluoromethyl)-1-(chloromethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine is treated with methyl(cyclopropylmethyl)amine to give 8-(trifluoromethyl)-1-[[(cyclopropylmethyl)methylamino]methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine. Preparation 33 8-Chloro-1-[[(cyclopropylmethyl)propylamino]methyl]-6-(2,6-difluorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine
Reaction SMILES: [Br:1]Br.[CH3:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]2([CH2:14][CH2:13]2)[C:5]1=[O:15].C([O-])(=O)C.[Na+].C(O)(=O)C.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[Br:1][C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][CH:10]=1)[N:4]([CH3:3])[C:5](=[O:15])[C:6]12[CH2:14][CH2:13]1
Reactant: BrBr
Reactant: CN1C(=O)C2(CC2)c2ccccc21
Agent: CC(=O)[O-]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CN1C(=O)C2(CC2)c2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.6 %

Procedure:
Add bromine (1.4 g, 8.7 mmol) dropwise to the mixture of 1′-methylspiro[cyclopropane-1,3′-indolin]-2′-one (1.5 g, 8.7 mmol), sodium acetate (0.7 g, 8.7 mmol) and acetic acid (0.52 g, 8.7 mmol) in dichloromethane (15 mL) at 0° C. After addition, stir the resulting mixture at room temperature overnight. Pour the reaction mixture to the cold sodium thiosulfate solution, extract with ethyl acetate (100 mL×2), combine the organic layers, and wash with brine (20 mL), dry over anhydrous sodium sulfate. Concentrate the solution under reduced pressure to give the crude product, purify by flash chromatography (silica gel, EtOAc:PE=1:5) to afford the title compound (1.0 g, 47.6%). MS: (M+1): 254.