Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[C:16]3[CH2:21][CH2:20][N:19]([C:22]([NH:24][CH2:25][C:26]([OH:28])=O)=[O:23])[CH2:18][CH2:17]3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:29]([NH2:33])([CH3:32])([CH3:31])[CH3:30].Cl.C(N=C=NCCCN(C)C)C.O>ClCCl>[C:29]([NH:33][C:26](=[O:28])[CH2:25][NH:24][C:22]([N:19]1[CH2:18][CH2:17][C:16](=[C:6]2[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH:9]=[CH:10][C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]2=3)[CH2:21][CH2:20]1)=[O:23])([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)N
Reactant: O=C(O)CNC(=O)N1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)NC(=O)CNC(=O)N1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
300 mg (0.801 mmol) of ({[4-(5H-dibenzo[a,d][7]annulen-5-ylidene)-1-piperidinyl]carbonyl}amino)acetic acid, 1.0 ml (0.961 mmol) of t-butylamine and 230 mg (1.20 mmol) of 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride were dissolved in 10 ml of dichloromethane. The obtained solution was stirred at room temperature for 1 hour. Water was added to the reaction mixture. After extracting with dichloromethane, the dichloromethane layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue thus obtained was purified by the silica gel chromatography (dichloromethane:methanol=4:1 to 1:9) to obtain the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[CH:11]=[CH2:12]>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[CH2:11][CH3:12]
Reactant: C=Cc1c(C)cccc1C(=O)OC
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCc1c(C)cccc1C(=O)OC
Reaction time: 2 h
Yield: 93.5 %

Procedure:
A mixture of 0.105 g (0.6 mmol) of methyl-2-vinyl-3-methylbenzoate and 0.05 g of Pd/C 10% in 15 mL of ethyl acetate was hydrogenated at 50 psi for 2 h. The reaction mixture was filtered through a thin pad of celite and the filtrate was concentrated to give 0.1 g of the title compound.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[NH:13][C:12]1=[O:20])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].N1C2C=CC=CC=2NC1=O.BrCCCCCCCC.[CH3:40][O:41][C:42](=[O:51])[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49]Br>CN(C=O)C>[CH3:40][O:41][C:42](=[O:51])[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][N:13]1[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:11]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[C:12]1=[O:20]
Reactant: COC(=O)CCCCCCCBr
Reactant: CCCCCCCCn1c(=O)[nH]c2ccccc21
Agent: O=c1[nH]c2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCCCCBr
Product: CCCCCCCCn1c(=O)n(CCCCCCCC(=O)OC)c2ccccc21

Procedure:
The product is produced as described in example 1 from 0.9 g. of NaH (80% suspension in mineral oil), 7.5 g. of 1-octylbenzimidazolin-2-one (produced) by alkylation from benzimidazolin-2-one with bromooctane according to example 8), 100 cc. of DMF, 7.1 g. of 8-bromocaprylic acid methyl ester and 0.9 g. of NaJ. Eluant in chromatographic purification: hexane/ethylacetate.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8](S)[NH:9][C:5]=2[CH:4]=1.Cl.ClCC1C(C)=CC=CN=1.[OH-].[Na+]>O>[F:14][C:2]([F:1])([F:13])[C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[CH:8][NH:9][C:5]=2[CH:4]=1
Reactant: FC(F)(F)c1ccc2nc(S)[nH]c2c1
Agent: Cc1cccnc1CCl
Agent: Cl
Agent: [Na+]
Solvent: O
Product: FC(F)(F)c1ccc2nc[nH]c2c1

Procedure:
6.54 g of 5-(trifluoromethyl)-2-benzimidazolethiol are suspended in 200 ml of alcohol and treated with 5.34 g of 2-chloromethyl-3-methylpyridine hydrochloride while cooling wlth ice. Thereafter. a solution of 2.4 g of sodium hydroxide in 100 ml of water is added dropwise thereto, the mixture is left to boil at reflux overnight and subsequently evaporated to dryness in vacuo. The residue is dissolved in 950 ml of methylene chloride. The solution is washed firstly with 200 ml of 1.5N sodium hydroxide solution and then 3 x with 250 ml of water. dried over sodium sulphate and evaporated in vacuo. The crude product is purified on 100 g of silica gel with ethyl acetate/methylene chloride (1:1) as the elution agent. Crystallization from methylene chloride/petroleum ether gives 2-[[3-methyl-2-pyridyl)methyl]thio]-5-(trifluoromethyl)benzimidazole of melting point 180°-182°.
Reaction SMILES: C(OC)(C(C(C(F)(F)F)(F)F)(F)F)(F)F.[C:16]([O:29][CH2:30][Cl:31])([C:19]([C:22]([C:25]([F:28])([F:27])[F:26])([F:24])[F:23])([F:21])[F:20])([F:18])[F:17].[C:32]([O:45][C:46](Cl)([Cl:48])[Cl:47])([C:35]([C:38]([C:41]([F:44])([F:43])[F:42])([F:40])[F:39])([F:37])[F:36])([F:34])[F:33]>>[C:16]([O:29][CH2:30][Cl:31])([C:19]([C:22]([C:25]([F:28])([F:27])[F:26])([F:24])[F:23])([F:21])[F:20])([F:18])[F:17].[C:32]([O:45][CH:46]([Cl:47])[Cl:48])([C:35]([C:38]([C:41]([F:44])([F:42])[F:43])([F:40])[F:39])([F:37])[F:36])([F:34])[F:33]
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)OC(Cl)(Cl)Cl
Agent: COC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)OCCl
Product: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)OC(Cl)Cl

Procedure:
GLC at the conclusion of the addition showed the following C4F9OCH3(5%), C4F9OCH2Cl (65%) and C4F9OCHCl2 HCl2 (29%) and C4F9OCCl3 (0.2%). The reaction solution was washed first with dilute aqueous potassium hydroxide, and then with water, and distilled using a 40-plate perforated plate column to yield C4F9OCH2Cl, b.p.=87° C. and C4F9OCHCl2, b.p.=96° C. in purifies of about 99%.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][OH:5].[H-].[Na+].F[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[N+:18]([O-:20])=[O:19]>CN(C=O)C>[F:17][C:14]1[CH:15]=[CH:16][C:11]([O:5][CH2:4][CH:3]([O:6][CH3:7])[O:2][CH3:1])=[C:12]([N+:18]([O-:20])=[O:19])[CH:13]=1
Reactant: COC(CO)OC
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(COc1ccc(F)cc1[N+](=O)[O-])OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.4 %

Procedure:
A DMF solution (50 ml) of 16.7 g of 2,2-dimethoxyethanol was added to dry DMF (60 ml) suspension of 4.32 g of sodium hydride at room temperature over 20 minutes. After 1 hour of stirring at room temperature, the reaction solution was cooled to 0° C., mixed with a DMF (20 ml) solution of 23.9 g of 2,5-difluoronitrobenzene and then stirred at 0° C. for 1 hour. The reaction solution was poured into 700 ml of ice water and extracted twice with a hexane-ethyl acetate (9:1) mixed solvent. The organic layer was washed with water and saturated brine in that order and dried with anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure to obtain 35.88 g of the title compound as a light red oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][NH:8][CH2:7]1)=[O:5])[CH3:2].[O:12]1[CH2:14][C@@H:13]1[CH2:15][O:16][C:17]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:18]=1[CH:19]=[CH:20][CH:21]=[N:22]2>C(O)C>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:14][CH:13]([OH:12])[CH2:15][O:16][C:17]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:18]=2[CH:19]=[CH:20][CH:21]=[N:22]3)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCCNC1
Reactant: c1cc(OC[C@H]2CO2)c2cccnc2c1
Solvent: CCO
Product: CCOC(=O)[C@@H]1CCCN(CC(O)COc2cccc3ncccc23)C1
Temperature: 25 °C

Procedure:
Piperidine-3-carboxylic acid ethyl ester (43) (1.0 g; 6.36 mmol) and (R)-5-oxiranylmethoxy-quinoline (2) (1.28 g; 6.36 mmol) are combined in 10 mL of absolute ethanol. The mixture is heated at reflux for 16 hours. After cooling to ambient temperature, the solution is concentrated in vacuo at 40° C. The residue is chromatographed on silica gel (1:1 acetone:hexanes) affording the desired product (44) as an oil. ESMS: MH+ 359
Reaction SMILES: OC1C=CC=C2C=1N=CC=C2.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[SH:19].[OH:20][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[C:30]=1[N:29]=[C:28]([C:31](O)=O)[CH:27]=[CH:26]2.O=O>C1(C)C=CC=CC=1>[S:19]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[C:31]1[C:28]1[CH:27]=[CH:26][C:25]2[C:30](=[C:21]([OH:20])[CH:22]=[CH:23][CH:24]=2)[N:29]=1
Reactant: Nc1ccccc1S
Reactant: O=C(O)c1ccc2cccc(O)c2n1
Agent: O=O
Agent: Oc1cccc2cccnc12
Solvent: Cc1ccccc1
Product: Oc1cccc2ccc(-c3nc4ccccc4s3)nc12
Temperature: 40 °C

Procedure:
To introduce a benzo[d]thiazol group into an 8-hydroxyquinoline compound, 2-aminothiophenol (123 mg, 1.1 mmol) and 8-hydroxyquinoline-2-carboxylic acid (189 mg, 2 mmol) were dissolved in dry toluene (30 ml) with blown nitrogen to prevent oxidation which is caused by oxygen in air. The solution was heated to 40° C. and phosphrous trichloride (0.1 ml, 1.1 mmol) was slowly added thereto. Then, the reaction solution was heated at 100° C. for 24 hours and allowed to cool. The reaction mixture was extracted with a 20% aqueous sodium carbonate solution, distilled water and dichloromethane, dried and recrystallized with dichloromethane and hexane to yield 2-(benzo[d]thiazol-2-yl)quinolin-8-ol, the compound of Formula 1 as a light green solid (yield: 75%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([C:11]#[N:12])[CH:3]=1.[CH:13]1([C:16]2[C:17]([N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[N:18][CH:19]=[C:20]([CH:22]3[CH2:24][CH2:23]3)[CH:21]=2)[CH2:15][CH2:14]1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:28]2[CH2:29][CH2:30][N:25]([C:17]3[C:16]([CH:13]4[CH2:14][CH2:15]4)=[CH:21][C:20]([CH:22]4[CH2:24][CH2:23]4)=[CH:19][N:18]=3)[CH2:26][CH2:27]2)=[O:8])=[C:4]([CH:3]=1)[C:11]#[N:12]
Reactant: c1nc(N2CCNCC2)c(C2CC2)cc1C1CC1
Reactant: N#Cc1cc(Br)ccc1C(=O)O
Product: N#Cc1cc(Br)ccc1C(=O)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Yield: 92.8 %

Procedure:
Using 4-bromo-2-cyanobenzoic acid (3.39 g) described in Preparation Example 76 and 1-(3,5-dicyclopropylpyridin-2-yl)piperazine (4.02 g) described in Preparation Example 88 and by the reaction and treatment in the same manner as in Preparation Example 111, the title compound (6.28 g) was obtained.
Reaction SMILES: [O:1]=[C:2]1[NH:8][CH2:7][CH2:6][CH:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:4][CH2:3]1.Br[CH:15]([CH2:23][CH3:24])[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].[H-].[Na+]>C(#N)C>[C:19]([O:18][C:16]([CH:15]([N:8]1[C:2](=[O:1])[CH2:3][CH2:4][CH:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:6][CH2:7]1)[CH2:23][CH3:24])=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: CCOC(=O)C1CCNC(=O)CC1
Reactant: CCC(Br)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)C1CCC(=O)N(C(CC)C(=O)OC(C)(C)C)CC1
Temperature: 50 °C
Yield: 94.4 %

Procedure:
In a 150 ml three necked flask fitted with reflux condenser, magnetic stirrer and dropping funnel under inert atmosphere, 5.09 g (27.5 mmoles, 1 eq) of ethyl 7-oxo-4-azepanecarboxylate 28 and 12.27 g (55 mmoles, 2 eq) of tert-butyl 2-bromobutanoate were dissolved in 70 ml of acetonitrile. The temperature was raised to 50° C. and 1.32 g (55 mmoles, 2 eq) of sodium hydride were added portionwise (exothermic). The mixture was stirred one more hour at 50° C. and concentrated to dryness, the residue was poured on ice/water and neutralised with solid ammonium chloride. The mixture was extracted three times with CH2Cl2, the combined organic phases were dried over magnesium sulfate, filtered and concentrated to dryness. The residue was purified by PrepLC (1 kg SiO2, CH2Cl2/MTBE, 85/15) to give 8.5 g of pure diester 29, 69% yield.
Reaction SMILES: [C:1]1([CH:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:8]2[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:22][CH2:23][CH2:24][N:25]1[C:29](=[O:30])[C:28]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:27]2[C:26]1=[O:35].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:15]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:14][CH2:13][CH2:12][N:11]([CH2:22][CH2:23][CH2:24][N:25]3[C:29](=[O:30])[C:28]4=[CH:31][CH:32]=[CH:33][CH:34]=[C:27]4[C:26]3=[O:35])[CH2:10][CH2:9]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: c1ccc(C(c2ccccc2)N2CCCNCC2)cc1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C1c2ccccc2C(=O)N1CCCN1CCCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 50 °C
Reaction time: 6 h
Yield: 64.7 %

Procedure:
To a mixture of 1-(diphenylmethyl)hexahydro-1H-1,4-diazepine (2.0 g), N-(3-bromopropyl)phthalimide (2.01 g) and anhydrous potassium carbonate (3.1 g) was added acetone (10 ml) and then stirred for 6 hours at 50° C. The reaction mixture was filtered and the filtrate was concentrated in vacuo and then the resultant oily residue was subjected to a column chromatography on silica gel using a mixture of ethyl acetate and chloroform (2:3) for elution to give N-[3-{4-(diphenylmethyl)hexahydro-1H-1,4-diazepin-1-yl}propyl]phthalimide (2.2 g) as an oil.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19](O)[C:14]=3[O:13][N:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].O=P(Cl)(Cl)[Cl:23]>>[Cl:23][C:19]1[C:14]2[O:13][N:12]=[C:11]([C:8]3[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=3)[C:15]=2[N:16]=[CH:17][N:18]=1
Reactant: CS(=O)(=O)c1ccc(-c2noc3c(O)ncnc23)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: CS(=O)(=O)c1ccc(-c2noc3c(Cl)ncnc23)cc1
Yield: 80.1 %

Procedure:
3-(4-Methanesulfonyl-phenyl)-isoxazolo[4,5-d]pyrimidin-7-ol (0.5 g, 1.7 mmol) was suspended in POCl3 (10 mL) and refluxed for 12 h. The reaction was poured into ice carefully and precipitates filtered. The solid was dissolved in ethyl acetate (15 mL) and purified under SiO2 with 30% ethyl acetate in hexane to afford the desired compound (0.42 g, 80.1%).
Reaction SMILES: C([O:8][C:9]1[CH:39]=[CH:38][C:12]([CH2:13][N:14]([CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)[C:15](=[O:25])[C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=2[NH:23][CH3:24])=[CH:11][CH:10]=1)C1C=CC=CC=1>C(OC(=O)C)C.[Pd]>[Cl:22][C:20]1[CH:19]=[CH:18][C:17]([NH:23][CH3:24])=[C:16]([CH:21]=1)[C:15]([N:14]([CH2:13][C:12]1[CH:11]=[CH:10][C:9]([OH:8])=[CH:39][CH:38]=1)[CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:35])[F:36])[CH:29]=1)=[O:25]
Reactant: CNc1ccc(Cl)cc1C(=O)N(CCc1cccc(C(F)(F)F)c1)Cc1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CNc1ccc(Cl)cc1C(=O)N(CCc1cccc(C(F)(F)F)c1)Cc1ccc(O)cc1
Yield: 43.6 %

Procedure:
A solution of 930 mg (1.68 mmol) of N-(4-benzyloxy-benzyl)-5-chloro-2-methylamino-N-[2-(3-trifluoromethyl-phenyl)-ethyl]-benzamide (2 mmol) in 30 ml ethylacetate was hydrogenated over 300 mg of 5% Pd—C for 4 hours at RT. After completion of the reaction, the suspension was filtered, the catalyst washed with additional ethyl acetate and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica gel; heptane/-EtOAc 3:1) to give 339 mg 5-chloro-N-(4-hydroxy-benzyl)-2-methylamino-N-[2-(3-trifluoromethyl-phenyl)-ethyl]-benzamide (75%) as a white foam. MS (ISP) 463 (M+H)+.
Reaction SMILES: [Br-].[CH2:2]([O:4][C:5]([C:7]1[N:14]2[C:10]([S:11][CH:12]=[CH:13]2)=[N:9][C:8]=1[CH2:15][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:6])[CH3:3].[H-].[Na+].[CH:37]1([CH2:40][O:41][C:42]2[C:49]([O:50][CH3:51])=[CH:48][CH:47]=[CH:46][C:43]=2[CH:44]=O)[CH2:39][CH2:38]1>CS(C)=O.C(OCC)(=O)C>[CH:37]1([CH2:40][O:41][C:42]2[C:49]([O:50][CH3:51])=[CH:48][CH:47]=[CH:46][C:43]=2/[CH:44]=[CH:15]/[C:8]2[N:9]=[C:10]3[N:14]([C:7]=2[C:5]([O:4][CH2:2][CH3:3])=[O:6])[CH:13]=[CH:12][S:11]3)[CH2:38][CH2:39]1
Reactant: COc1cccc(C=O)c1OCC1CC1
Reactant: CCOC(=O)c1c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)nc2sccn12
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCOC(=O)c1c(/C=C/c2cccc(OC)c2OCC2CC2)nc2sccn12
Reaction time: 0.5 h

Procedure:
To a stirred suspension of Step 3 intermediate (2.0 g, 3.626 mmol) was added NaH (0.160 g, 3.989 mmol) in anhydrous DMSO (10 mL) and stirred for 30 min. A solution of 2-(cyclopropylmethoxy)-3-methoxybenzaldehyde (0.82 g, 3.989 mmol) in anhydrous DMSO (10 mL) was added drop wise to this solution at room temperature and stirred for 2 h. The reaction mixture was diluted with ethyl acetate (200 mL), washed with water (2×50 mL), brine and dried (Na2SO4) to yield a crude solid which was purified by column chromatography using 5% ethyl acetate in petroleum ether to afford 0.776 g of the product as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 0.26-0.28 (m, 2H), 0.50-0.53 (m, 2H), 1.17-1.23 (m, 1H), 1.39 (t, J=7.5 Hz, 3H), 3.75 (d, J=7.2 Hz, 2H), 3.79 (s, 3H), 4.37 (q, J=6.9 Hz, 2H), 6.95-6.99 (m, 2H), 7.08 (t, J=7.8 Hz, 1H), 7.18-7.22 (m, 1H), 7.43 (d, J=4.5 Hz, 1H), 7.69 (d, J=16.2 Hz, 1H), 7.92 (d, J=16.5 Hz, 1H), 8.10 (d, J=4.2 Hz, 1H); ESI-MS (m/z) 399.20 (MH)+.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2([CH2:23][CH2:24][CH2:25][CH2:26]Br)[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:9])=[CH:4][CH:3]=1.[CH3:30][C@@H:31]1[NH:36][CH2:35][CH2:34][N:33]([C:37]2[CH:46]=[CH:45][C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[N:38]=2)[CH2:32]1>>[F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2([CH2:23][CH2:24][CH2:25][CH2:26][N:36]3[CH2:35][CH2:34][N:33]([C:37]4[CH:46]=[CH:45][C:44]5[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=5)[N:38]=4)[CH2:32][C@@H:31]3[CH3:30])[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:9])=[CH:4][CH:3]=1
Reactant: C[C@H]1CN(c2ccc3ccccc3n2)CCN1
Reactant: O=C(NCc1ccc(F)cc1)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: C[C@H]1CN(c2ccc3ccccc3n2)CCN1CCCCC1(C(=O)NCc2ccc(F)cc2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 1 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-4-fluoro-benzylamide and 2-[(S)-3-methyl-piperazin-1-yl]-quinoline
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=2)[CH2:11][CH2:10]1.N[NH:24][C:25]([NH2:27])=[S:26].O.[OH-].[Na+]>C1(C)C=CC=CC=1.FC(F)(F)C(O)=O.C1COCC1.CO.C(OCC)(=O)C>[NH2:27][C:25]1[S:26][C:21]([C:18]2[CH:19]=[CH:20][C:15]([N:12]3[CH2:13][CH2:14][CH:9]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])[CH2:10][CH2:11]3)=[CH:16][CH:17]=2)=[N:22][N:24]=1
Reactant: COCCCCCOC1CCN(c2ccc(C#N)cc2)CC1
Reactant: NNC(N)=S
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: COCCCCCOC1CCN(c2ccc(-c3nnc(N)s3)cc2)CC1
Yield: 352.4 %

Procedure:
A solution of 4-(5-methoxypentyloxy)-N-(4-cyanophenyl)piperidine (294 mg) and thiosemicarbazide (0.68 g) in toluene (20 ml) and trifluoroacetic acid (10 ml) was stirred at 60-65° C. for 7 hours. After cooling, the reaction mixture was poured into a mixture of water (100 ml) and ethyl acetate (200 ml) and adjusted to pH 10 with 1N-sodium hydroxide. The mixture was dissolved in a mixture of THF (50 ml) and methanol (10 ml). The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuo. The resulting precipitate was washed with isopropyl ether and dried in vacuo to give 2-amino-5-[4-[4-(5-methoxypentyloxy)-piperidin-1-yl]phenyl]-1,3,4-thiadiazole (1.29 g).
Reaction SMILES: [C:1]1([CH2:11][OH:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl[C:14]([O:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1)=[O:15].O.C(OCC)(=O)C>N1C=CC=CC=1>[C:14](=[O:15])([O:16][C:17]1[CH:18]=[CH:19][C:20]([N+:23]([O-:25])=[O:24])=[CH:21][CH:22]=1)[O:12][CH2:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: OCc1cccc2ccccc12
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=C(OCc1cccc2ccccc12)Oc1ccc([N+](=O)[O-])cc1

Procedure:
In 5 ml of pyridine containing 1.0 g of 1-naphthylmethanol, 1.27 g of 4-nitrophenyl chloroformate was added under ice cooling and the resultant mixture was stirred for 3 hr. Purified water and ethyl acetate, each 20 ml, were added to the reaction mixture and the ethyl acetate layer was separated and washed with purified water. The ethyl acetate layer was dried over anhydrous sodium sulfate, evaporated under reduced pressure and crystallized by the addition of ethanol to give 1.08 g of the title compound.
Reaction SMILES: Cl.Cl.C([O:5][C:6]([C:8]1[NH:9][C:10]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)=[C:11]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[C:18](=[O:22])[CH2:17][CH2:16]3)[N:12]=1)=[O:7])C.[OH-].[Na+]>C(O)C>[O:22]=[C:18]1[C:19]2[C:15](=[CH:14][C:13]([C:11]3[N:12]=[C:8]([C:6]([OH:7])=[O:5])[NH:9][C:10]=3[C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)=[CH:21][CH:20]=2)[CH2:16][CH2:17]1
Reactant: CCOC(=O)c1nc(-c2ccc3c(c2)CCC3=O)c(-c2ccncc2)[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1nc(-c2ccc3c(c2)CCC3=O)c(-c2ccncc2)[nH]1
Yield: 91.3 %

Procedure:
A solution of the product of Step 6 (1.0 g, 2.4 mmol) in ethanol (10 ml) containing, 10% aqueous sodium hydroxide solution (10 ml) was heated at 50° C. overnight. On cooling, the solvent was removed in vacuo, the residue dissolved in water and the pH adjusted to 6 with glacial acetic acid and the solvent re-evaporated. The residue was suspended in water (50 ml) and the solid was collected, washed with water and dried over phosphorous pentoxide to give the crude title compound as an off-white solid (0.7 g); MS(AP−) m/e 318 [M−H]−.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[N:14]=[C:15]([CH3:18])[NH:16][CH:17]=1.Cl[C:20]1[N:25]=[CH:24][CH:23]=[CH:22][N:21]=1>>[CH3:18][C:15]1[N:16]([C:20]2[N:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:17]=[C:13]([C:3]2[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:5][O:6][C:2]=2[CH3:1])[N:14]=1
Reactant: Cc1nc(-c2c(-c3ccccc3)noc2C)c[nH]1
Reactant: Clc1ncccn1
Product: Cc1onc(-c2ccccc2)c1-c1cn(-c2ncccn2)c(C)n1
Yield: 48 %

Procedure:
As described for Example 57, 5-methyl-4-(2-methyl-1H-imidazol-4-yl)-3-phenyl-isoxazole (70 mg, 0.3 mmol) using 2-chloropyrimidine instead of 4-fluoroacetophenone was converted to the title compound (45 mg, 48%) which was obtained as a white solid. MS: m/e=318.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9](=O)[N:8]=[C:7]([S:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=3[F:20])[NH:6][C:5]=2[N:21]=1.P(Cl)(Cl)([Cl:24])=O.CN(C)C1C=CC=CC=1>CO.ClCCl>[Cl:24][C:9]1[C:4]2[S:3][C:2]([NH2:1])=[N:21][C:5]=2[N:6]=[C:7]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=2[F:20])[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Nc1nc2[nH]c(SCc3cccc(F)c3F)nc(=O)c2s1
Solvent: CN(C)c1ccccc1
Solvent: ClCCl
Solvent: CO
Product: Nc1nc2nc(SCc3cccc(F)c3F)nc(Cl)c2s1
Reaction time: 2 h

Procedure:
The product from example 1, step (a) (0.89 g), phosphorus oxychloride (12 ml) and N,N-dimethylaniline (1.2 ml) were heated at reflux for 2 hours. The cooled reaction mixture was poured onto ice water and stirred for 2 hours. Chromatography (SiO2, methanol/dichloromethane as eluant) gave the subtitled compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:16])=[CH:4][C:5]([F:15])=[C:6]([CH:14]=1)[C:7]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[O:8].[Br:17]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>ClCCCl>[Br:17][CH2:16][C:3]1[C:2]([Cl:1])=[CH:14][C:6]([C:7]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[O:8])=[C:5]([F:15])[CH:4]=1
Reactant: Cc1cc(F)c(C(=O)NS(C)(=O)=O)cc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClCCCl
Product: CS(=O)(=O)NC(=O)c1cc(Cl)c(CBr)cc1F
Temperature: 90 °C
Reaction time: 16 h

Procedure:
A mixture of 5-chloro-2-fluoro-4-methyl-N-(methylsulfonyl)benzamide (0.8 g, 3.0 mmol), N-bromosuccinimide (1.6 g, 9.0 mmol) and azodiisobutyronitrile (16 mg, 0.09 mmol) in 1,2-dichloroethane (20 mL) was stirred at 90° C. for 16 hrs. The reaction was quenched with Na2S2O3 (10 mL, 10%), extracted with 1,2-dichloroethane (20 mL×3), dried over anhydrous Na2SO4, concentrated and the residue was used in next step without further purification (1.1 g, crude). LCMS (ESI) m/z: 342.0 [M+H]+.