Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:27][O:28][C:29]1[C:30](=[O:53])[C:31]([CH3:52])=[C:32]([CH2:38][C:39]2[CH:40]=[CH:41][C:42]([O:48][C:49](=[O:51])[CH3:50])=[C:43]([CH:47]=2)[C:44](O)=[O:45])[C:33](=[O:37])[C:34]=1[O:35][CH3:36]>C(Cl)Cl>[CH3:27][O:28][C:29]1[C:30](=[O:53])[C:31]([CH3:52])=[C:32]([CH2:38][C:39]2[CH:40]=[CH:41][C:42]([O:48][C:49](=[O:51])[CH3:50])=[C:43]([CH:47]=2)[C:44]([NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N+:1]([O-:3])=[O:2])=[O:45])[C:33](=[O:37])[C:34]=1[O:35][CH3:36]
Reactant: Nc1ccccc1[N+](=O)[O-]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)O)c2)=C(C)C1=O
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3ccccc3[N+](=O)[O-])c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 52.9 %

Procedure:
2-Nitroaniline (0.222 g, 1.604 mmol), triethylamine (0.162 g, 1.604 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.271 g, 1.604 mmol) were added to a methylene chloride solution (50 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.200 g, 0.535 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (hexand:ethyl acetate=1:1) and then recrystallized from ether to obtain the titled compound (0.140 g, 0.283 mmol, 53%).
Reaction SMILES: F[H-]F.[NH4+].[C:5]1(=[O:12])[CH:10]=[CH:9][C:8](=[O:11])[CH:7]=[CH:6]1.C([Si](CC)(CC)[C:16]([F:19])([F:18])[F:17])C>C(#N)C>[OH:11][C:8]1([C:16]([F:19])([F:18])[F:17])[CH:9]=[CH:10][C:5](=[O:12])[CH:6]=[CH:7]1
Reactant: CC[Si](CC)(CC)C(F)(F)F
Reactant: O=C1C=CC(=O)C=C1
Agent: F[H-]F
Agent: [NH4+]
Solvent: CC#N
Product: O=C1C=CC(O)(C(F)(F)F)C=C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 42.4 %

Procedure:
A mixture of 74 mg (1.3 mmol) of ground ammonium bifluoride (NH4HF2), 119 mg (1.1 mmol) of 1,4-benzoquinone, and 2 mL of acetonitrile was treated with 239 mg (1.3 mmol) of triethyltrifluoromethylsilane and stirred vigorously at room temperature for 4 hours. The mixture was filtered and the filter cake was washed with dichloromethane. Concentration of the combined filtrates gave a black solid which was triturated with dichloromethane. The resulting mixture was filtered and the filter cake was washed with dichloromethane. Concentration of the combined filtrates afforded a brown solid which was purified by PTLC (one 2 mm silica gel plate eluted with a 2% methanol-98% dichloromethane) to give 83 mg (42% yield) of 4-hydroxy-4-tri -fluoromethyl-2,5-cyclohexadien-1-one.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[N:10]=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[F:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:19][S:27]([C:24]2[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=2)(=[O:29])=[O:28])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[N:10]=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: Nc1cnc(Oc2cc3ccccc3cn2)c(Cl)c1
Product: O=S(=O)(Nc1cnc(Oc2cc3ccccc3cn2)c(Cl)c1)c1ccc(F)cc1

Procedure:
The title compound was prepared by reacting 5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-amine (obtained as per procedure described in preparation 2) and 4-fluorobenzene-1-sulfonyl chloride.
Reaction SMILES: N(C(C)C)C(C)C.C([Li])CCC.[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][N:21]2[CH:25]=[CH:24][N:23]=[N:22]2)[N:15]=1.N1([CH2:35][OH:36])C2C=CC=CC=2N=N1>C1COCC1>[Br:13][C:14]1[N:15]=[C:16]([CH:20]([N:21]2[CH:25]=[CH:24][N:23]=[N:22]2)[CH2:35][OH:36])[CH:17]=[CH:18][CH:19]=1
Reactant: Brc1cccc(Cn2ccnn2)n1
Reactant: OCn1nnc2ccccc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: OCC(c1cccc(Br)n1)n1ccnn1
Temperature: -20 °C
Reaction time: 0.25 h

Procedure:
A solution of i-Pr2NH (370 μL, 2.59 mmol) in THF (3.0 mL) was cooled to −20° C., and n-butyllithium (970 μL, 2.43 mmol) was added dropwise. After stirring for 15 minutes at −20° C., the colorless solution was cooled to −78° C. before adding 2-bromo-6-(1H-1,2,3-triazol-1-ylmethyl)pyridine (200 mg, 0.84 mmol) in THF (2.0 mL) dropwise over 30 minutes. After stirring for an additional 30 minutes at −78° C., 1H-benzotriazole-1-methanol (250 mg, 1.67 mmol) in THF (5.0 mL) was added dropwise over 25 minutes. The solution was stirred at −78° C. for 2 h. The reaction was quenched (while cold) with water and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried (MgSO4), filtered, and evaporated. Flash chromatography (50-100% EtOAc/hexanes) afforded the title compound as a colorless oil.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:11][C:12]1[CH:13]=[C:14]([CH2:17][NH2:18])[O:15][CH:16]=1.C(=O)([O-])O.[Na+]>C(O)C>[CH3:11][C:12]1[CH:13]=[C:14]([CH2:17][NH:18][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)[O:15][CH:16]=1
Reactant: Cc1coc(CN)c1
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1coc(CNc2ncccc2[N+](=O)[O-])c1
Reaction time: 8 h
Yield: 91.2 %

Procedure:
A mixture of 10.4 parts of 2-chloro-3-nitropyridine, 8 parts of 4-methyl-2-furanmethanamine, 7.6 parts of sodium hydrogen carbonate and 120 parts of ethanol was stirred overnight at reflux temperature. The reaction mixture was evaporated and the residue was taken up in water. The product was extracted with 1,1'-oxybisethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using trichloromethane as eluent. The pure fractions were collected and the eluent was evaporated, yielding 14.9 parts (91.2%) of N-[(4-methyl-2-furanyl)methyl]-3-nitro-2-pyridinamine as a residue (int. 3).
Reaction SMILES: [CH2:1]([C:3]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][CH2:22][CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[CH:17][CH:16]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].[CH3:29][C:30]([CH3:32])=O.C([BH3-])#N.[Na+].O>C(O)C.CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[CH2:1]([C:3]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][CH2:22][CH:23]3[CH2:28][CH2:27][N:26]([CH:30]([CH3:32])[CH3:29])[CH2:25][CH2:24]3)=[CH:17][CH:16]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2]
Reactant: CC(C)=O
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(NCC2CCNCC2)cc1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH3-]C#N
Solvent: CCO
Solvent: O
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(NCC2CCN(C(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 12.8 %

Procedure:
A solution of Compound 143 (0.150 g, 0.40 mmol) in ethanol was added with acetone (0.029 mL, 0.40 mmol) and titanium tetraisopropoxide (0.149 mL, 0.50 mmol). After 1 hour, the mixture was added with sodium cyanoborohydride (17 mg, 0.27 mmol) followed by stirring at room temperature overnight. The reaction mixture was added with water and extracted with chloroform three times. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:2 mol/L ammonia-methanol solution=19:1). The obtained crystals were recrystallized from ethanol-diisopropyl ether to obtain Compound 156 (21.5 mg, 0.051 mmol, 13%).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([F:21])[C:18]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[NH:24][C:23]2=[O:33])=[CH:17][C:3]=1[O:4][C:5]1[CH:16]=[CH:15][CH:14]=[CH:13][C:6]=1[O:7][CH2:8][C:9]([O:11][CH3:12])=[O:10].[C:34](=O)([O-])[O-].[K+].[K+].CI.Cl>CN(C)C=O>[Cl:1][C:2]1[CH:20]=[C:19]([F:21])[C:18]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:30])([F:31])[F:32])[N:24]([CH3:34])[C:23]2=[O:33])=[CH:17][C:3]=1[O:4][C:5]1[CH:16]=[CH:15][CH:14]=[CH:13][C:6]=1[O:7][CH2:8][C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)COc1ccccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c(F)cc1Cl
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)COc1ccccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.7 %

Procedure:
To a mixture of 0.93 g of methyl [2-{2-chloro-4-fluoro-5-[2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenoxy]acetate, 0.31 g of potassium carbonate, and 10 ml of N,N-dimethylformamide was added 0.58 g of methyl iodide, and the mixture was stirred at room temperature for 2 hours. Then 50 ml of diluted hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.82 g of methyl [2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenoxy]acetate (compound a-5).
Reaction SMILES: C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:54]1[CH:63]=[CH:62][C:61]2[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=2)[N:55]=1.[N:64]1([C:70]([O:72][C:73]([CH3:76])([CH3:75])[CH3:74])=[O:71])[CH2:69][CH2:68][NH:67][CH2:66][CH2:65]1>O1CCOCC1.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:56]1[C:61]2[C:62](=[CH:57][CH:58]=[CH:59][CH:60]=2)[CH:63]=[C:54]([N:67]2[CH2:66][CH2:65][N:64]([C:70]([O:72][C:73]([CH3:76])([CH3:75])[CH3:74])=[O:71])[CH2:69][CH2:68]2)[N:55]=1
Reactant: Clc1ccc2ccccc2n1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(c2cc3ccccc3cn2)CC1
Temperature: 110 °C
Reaction time: 3 h
Yield: 32.1 %

Procedure:
Palladium acetate (63 mg, 0.8 mmol), BINAP (250 mg, 0.4 mmol) and caesium carbonate (1.3 g, 4 mmol) were suspended in anhydrous 1,4-dioxane (9 ml) under an argon atmosphere and sonicated for 40 minutes. 2-Chloroquinoline (343 mg, 2 mmol) and tert-butyl piperazine-1-carboxylate (373 mg, 2 mmol) were dissolved in anhydrous 1,4-dioxane (3 ml) and the resulting solution was added to the catalyst-containing mixture. The resulting mixture was stirred at 110° C. for three hours, cooled to room temperature and diluted with ethyl acetate. The solids were removed by centrifugation and decantation, the supernatant was evaporated to dryness under reduced pressure and the resulting residue was dissolved in DCM and filtered through a silica column. The product was eluted with a mixture of DCM and diethylether. After removal of the solvent under reduced pressure, 201 mg of a solid were obtained (0.64 mmol, 32%) MS (ESI) m/z=314.2 [M+1]+.
Reaction SMILES: [N:1]1([CH2:11][CH2:12][C:13]([NH:15][CH2:16][CH2:17][N:18]([CH3:20])[CH3:19])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.O=P(Cl)(Cl)Cl.CN([CH:29]=[O:30])C>>[CH3:20][N:18]([CH3:19])[CH2:17][CH2:16][NH:15][C:13](=[O:14])[CH2:12][CH2:11][N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:29]=[O:30])=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)CCNC(=O)CCN1CCCc2ccccc21
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CN(C)CCNC(=O)CCN1CCCc2cc(C=O)ccc21

Procedure:
The procedure was carried out as described previously in step (a) of Example 5 with Compound 8 (0.74 g, 2.7 mmol), POCl3 (506 μL, 5.4 mmol), and DMF (8.6 mL). Compound 9 was obtained (0.31 g) as a viscous yellow liquid and used without any further purification. The structure of Compound 9 is given below:
Reaction SMILES: [OH:1][C:2]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[OH:34])[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][C:10]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[CH2:4][CH2:3]1.Br[CH2:36][CH2:37][CH2:38][CH2:39][O:40]C(=O)C.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O.C(Cl)(Cl)Cl.O>[OH:1][C:2]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[O:34][CH2:36][CH2:37][CH2:38][CH2:39][OH:40])[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][C:10]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[CH2:4][CH2:3]1
Reactant: CN(C)C(=O)C(CCN1CCC(O)(c2ccccc2O)CC1)(c1ccccc1)c1ccccc1
Reactant: CC(=O)OCCCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CN(C)C(=O)C(CCN1CCC(O)(c2ccccc2OCCCCO)CC1)(c1ccccc1)c1ccccc1
Temperature: 80 °C
Yield: 24.5 %

Procedure:
In 10 mL of anhydrous dimethylformamide was dissolved 920 mg (2 mmol) of 4-(4-hydroxy-4-(2-hydroxyphenyl)piperidino)-N,N-dimethyl-2,2-diphenylbutaneamide. To the resulting solution were added 585 g (3 mmol) of 4-bromobutylacetate, 414 mg (3 mmol) of potassium carbonate and a small amount of potassium iodide. The resulting mixture was stirred under heating at 80° C. for 4 hours. After cooling, the reaction mixture was poured into water, followed by extraction with ethyl acetate, washing with water and drying. The residue obtained by distilling off the solvent under reduced pressure was dissolved in 15 mL of methanol. To the resulting solution was added 3 mL of a 1N aqueous solution of sodium hydroxide, followed by stirring at room temperature for 1 hour. From the reaction mixture, the solvent was distilled off under reduced pressure. The residue thus obtained was dissolved in chloroform. The resulting solution was washed with water and dried. The residue obtained by distilling off the solvent under reduced pressure was purified by chromatography on a silica gel column, whereby 260 mg (yield: 24.5%) of 4-(4-hydroxy-4-(2-(4-hydroxybutyloxy)phenyl)piperidino)-N,N-dimethyl-2,2-diphenylbutaneamide (Compound No. 34) was obtained.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[N:20]=[C:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]([OH:32])=[O:31])[CH:18]=[C:17]3C(O)=O)[C:7]([CH2:11][OH:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].S(=O)(=O)(O)O.O.C(=O)([O-])[O-].[Na+].[Na+]>N1C2C(=CC=CC=2)C=CC=1>[CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[N:20]=[C:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]([OH:32])=[O:31])[CH:18]=[CH:17]3)[C:7]([CH2:11][OH:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc2nc(-c3ccccc3C(=O)O)cc(C(=O)O)c2c1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: c1ccc2ncccc2c1
Product: CCCCc1nc(Cl)c(CO)n1Cc1ccc2nc(-c3ccccc3C(=O)O)ccc2c1
Temperature: 170 °C
Yield: 62.1 %

Procedure:
In 10 ml of quinoline were dissolved 44.2 mg of the 6-[(2-butyl-4-chloro-5-hydroxymethyl-1H-imidazol-1-yl)methyl]-2-(2-carboxyphenyl)-4-quinolinecarboxylic acid obtained in Example 9. After adding 100 mg of conc. sulfuric acid, the mixture was heated at 170° C. for 1 hour. Then the reaction mixture was poured into water, made alkaline by adding sodium carbonate and washed with toluene. The aqueous layer was neutralized with 3M hydrochloric acid until a precipitate was formed. Then the precipitate was collected by filtration and purified by flash chromatography on silica gel with the use of chloroform/methanol. Thus 25 mg of 2-{6-[(2-butyl-4-chloro-5-hydroxymethyl-1H-imidazol-1-yl)methyl]quinolin-2-yl}benzoic acid were obtained. NMR (270 MHz, CDCl3): δ 7.2-8.2 (m,9H); 5.4 (s,2H); 4.5 (s,2H); 2.6 (t,J=8Hz,2H); 1.2-1.8 (m,4H); 1.4 (m,2H); 0.8 (t,J=8Hz,3H).
Reaction SMILES: C[Al](C)C.[Br:5][C:6]1[CH:7]=[C:8]([CH:10]=[CH:11][C:12]=1[CH3:13])[NH2:9].C[O:15][C:16](=O)[C:17]1[CH:22]=[CH:21][C:20]([CH2:23][N:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)=[CH:19][CH:18]=1>C1(C)C=CC=CC=1>[CH3:13][C:12]1[CH:11]=[CH:10][C:8]([NH:9][C:16](=[O:15])[C:17]2[CH:18]=[CH:19][C:20]([CH2:23][N:24]3[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]3)=[CH:21][CH:22]=2)=[CH:7][C:6]=1[Br:5]
Reactant: COC(=O)c1ccc(CN2CCN(C)CC2)cc1
Reactant: Cc1ccc(N)cc1Br
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)cc2)cc1Br
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of trimethylaluminium (2M in toluene, 15.0 ml) is added over a period of 30 min to a solution of 3-bromo-4-methyl-aniline (2.15 g, 11.5 mmol) and 4-(4-methyl-piperazin-1-ylmethyl)-benzoic acid methyl ester (2.87 g, 11.5 mmol) in toluene (20 ml) at 40° C. under an atmosphere of argon. After gas evolution ceases, the reaction mixture is stirred 30 min before being cooled to 0° C. and partitioned between cold aqueous 1N NaOH (100 ml) and toluene (100 ml). The organic layer is extracted with aqueous saturated NH4Cl (100 ml) and aqueous saturated NaCl (100 ml). The organic layer is concentrated in vacuo to give 4.69 g (97 area % by HPLC) of the title compound as pale yellow crystals.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[CH:5]=[CH:4][N:3]=1.[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>CC(O)C>[N:13]1([C:2]2[N:7]=[C:6]([C:8]3[S:9][CH:10]=[CH:11][CH:12]=3)[CH:5]=[CH:4][N:3]=2)[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1
Reactant: C1CNCCN1
Reactant: Clc1nccc(-c2cccs2)n1
Solvent: CC(C)O
Product: c1csc(-c2ccnc(N3CCNCC3)n2)c1
Temperature: 160 °C

Procedure:
To a microwave tube was added 2-chloro-4-thiophen-2-yl-pyrimidine (20 mg, 0.1 mmol), piperazine (26 mg, 0.3 mmol) and 2-propanol (0.6 mL). The resulting mixture was heated at 160° C. for 60 minutes using the microwave instrument. The resulting mixture was extracted with EtOAc. The organic layer was dried and concentrated, and the residue was purified by preparative TLC (hexanes/EtOAc) to yield the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:23])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=[O:15])=[C:10]([F:22])[CH:9]=2)[CH:7]=1.CC1C=CC(O[C@H:30]([CH3:35])[C:31]([O:33]C)=[O:32])=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][C@@H:30]([CH3:35])[C:31]([OH:33])=[O:32])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH:17]([CH2:18][CH3:19])[CH2:20][CH3:21])=[O:15])=[C:10]([F:22])[CH:9]=2)[CH:7]=1
Reactant: COC(=O)[C@@H](C)Oc1ccc(C)cc1
Reactant: CCC(CC)NC(=O)c1ccc(-c2cc(Cl)ccc2O)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCC(CC)NC(=O)c1ccc(-c2cc(Cl)ccc2O[C@@H](C)C(=O)O)cc1F
Temperature: 50 °C
Reaction time: 16 h

Procedure:
The product of step c) (300 mg), the product of step d) (219 mg) and potassium carbonate (135 mg) in acetonitrile (10 ml) were charged to a flask and stirred at 50° C. for 16 h. The reaction mixture was cooled, diluted with water (20 ml) and extracted with diethyl ether (3×10 ml). The organic fractions were washed with brine, dried (MgSO4) and concentrated in vacuo. The resulting yellow oil was dissolved in a 1:1 mixture of THF/methanol (10 ml) and 1M NaOH added (1.1 ml). The mixture was stirred at room temperature for 4 h and then concentrated in vacuo. The residue was purified by RPHPLC to give the title compound as a white solid (175 mg).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH:9]([OH:38])[CH2:10][NH:11][C:12](=[O:37])[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH2:23][C:22]([C:28]3[CH:33]=[C:32]([Cl:34])[CH:31]=[C:30]([Cl:35])[CH:29]=3)([C:24]([F:27])([F:26])[F:25])[O:21][N:20]=2)=[CH:15][C:14]=1[CH3:36])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][CH2:8][CH:9]([OH:38])[CH2:10][NH:11][C:12](=[O:37])[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH2:23][C:22]([C:28]3[CH:29]=[C:30]([Cl:35])[CH:31]=[C:32]([Cl:34])[CH:33]=3)([C:24]([F:26])([F:27])[F:25])[O:21][N:20]=2)=[CH:15][C:14]=1[CH3:36]
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NCC(O)CNC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NCC(O)CN
Reaction time: 10 h
Yield: 78.3 %

Procedure:
A solution of (3{4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoylamino}-2-hydroxy-propyl)-carbamic acid tert-butyl ester (0.2 g) in dichloromethane (10 ml) was cooled to 0° C., treated with trifluoroacetic acid (0.5 ml) and stirred for 10 h. The reaction mixture was concentrated in vacuo and diluted with dichloromethane (50 ml), washed with saturated aqueous solution of sodium bicarbonate (20 ml) and finally with water (2×20 ml). The organic layer was separated, dried over sodium sulfate and concentrated to give the title compound (0.13 g). LCMS (Method G) 2.84 min, MH+ 490. 1HNMR (CDCl3, 400 MHz): 8.05 (t, 1H), 7.81 (m, 1H), 7.80 (brs, 2H), 7.59 (m, 4H), 7.48 (d, 1H), 4.36 (dd, 2H), 3.85 (m, 2H), 3.28 (m, 2H), 2.50 (m, 1H), 2.37 (s, 3H).
Reaction SMILES: Cl.[N:2]1[CH2:3][CH2:4][N:5]2[C:9]3[CH:10]=[C:11]([C:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[O:15])[CH:12]=[CH:13][C:8]=3[S:7][C:6]=12.C[O-].[Na+].CO.[BH4-].[Na+]>O>[C:16]1([CH:14]([C:11]2[CH:12]=[CH:13][C:8]3[S:7][C:6]4=[N:2][CH2:3][CH2:4][N:5]4[C:9]=3[CH:10]=2)[OH:15])[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(c1ccccc1)c1ccc2c(c1)N1CCN=C1S2
Agent: C[O-]
Agent: Cl
Agent: [BH4-]
Solvent: O
Solvent: CO
Product: OC(c1ccccc1)c1ccc2c(c1)N1CCN=C1S2
Reaction time: 0.08 h

Procedure:
To a stirred mixture of 4 parts of (2,3-dihydroimidazo[2,1-b]benzothiazol-6-yl)phenylmethanone monohydrochloride, 3 parts of sodium methoxide and 60 parts of methanol are added portionwise 1.5 parts of sodium borohydride. Upon completion, stirring is continued for 5 minutes at reflux temperature. The reaction mixture is cooled and upon the addition of water, the product is allowed to crystallize. It is filtered off and recrystallized from 4-methyl-2-pentanone. The product is filtered off and dried, yielding 0.4 parts of 2,3-dihydro-α-phenylimidazo[2,1-b]benzothiazole-6-methanol; mp. 175.2° C.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:6]([CH3:18])=[C:7]([CH:11]=[CH:12][C:13]=1[S:14]([CH3:17])(=[O:16])=[O:15])[C:8]([OH:10])=O)[CH:2]=[CH2:3].[OH:19][C:20]1[N:24]([CH3:25])[N:23]=[CH:22][CH:21]=1.Cl.CN(C)CCCN=C=NCC.CCN(CC)CC.[Si](C#N)(C)(C)C.[C-]#N.[K+]>CC#N>[CH2:1]([NH:4][C:5]1[C:6]([CH3:18])=[C:7]([CH:11]=[CH:12][C:13]=1[S:14]([CH3:17])(=[O:16])=[O:15])[C:8]([C:21]1[CH:22]=[N:23][N:24]([CH3:25])[C:20]=1[OH:19])=[O:10])[CH:2]=[CH2:3]
Reactant: Cn1nccc1O
Reactant: C=CCNc1c(S(C)(=O)=O)ccc(C(=O)O)c1C
Agent: CCN=C=NCCCN(C)C
Agent: C[Si](C)(C)C#N
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C=CCNc1c(S(C)(=O)=O)ccc(C(=O)c2cnn(C)c2O)c1C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Under nitrogen, 0.31 g (1.2 mmol) of 3-allylamino-2-methyl-4-(methylsulfonyl)benzoic acid, 0.15 g (1.5 mmol) of 5-hydroxy-1-methylpyrazole and 0.27 g (1.4 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were dissolved in dry CH3CN. The mixture was stirred at RT for 5 h. 0.32 ml (2.3 mmol) of NEt3, 0.06 ml (0.5 mmol) of Me3SiCN and a spatula tip of KCN were added, and the mixture was stirred at RT for 1 day. The solvent was removed under reduced pressure, and the residue was taken up in CH2Cl2 and 10% strength H2SO4. The aqueous phase was removed and extracted once with CH2Cl2. The combined organic phases were dried over MgSO4, and the solvent was removed under reduced pressure. The residue was crystallized from tert-butyl methyl ether. This gave 0.15 g of a colorless solid of a purity of 100%.