Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]1([C:14]2[N:19]3[N:20]=[C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:22]=[C:18]3[N:17]=[C:16]([NH:29][NH2:30])[CH:15]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[C:31]([C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)[CH:36]=O)#[N:32]>C(O)C>[C:31]([C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)[CH:36]=[N:30][NH:29][C:16]1[CH:15]=[C:14]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:19]2[N:20]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:22]=[C:18]2[N:17]=1)#[N:32]
Reactant: N#Cc1cccc(C=O)c1
Reactant: NNc1cc(N2CCOCC2)n2nc(-c3ccccc3)cc2n1
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: N#Cc1cccc(C=NNc2cc(N3CCOCC3)n3nc(-c4ccccc4)cc3n2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 109.1 %

Procedure:
There was dissolved, in ethanol (2 mL), trifluoroacetic acid salt of (7-morpholin-4-yl-2-phenyl-pyrazolo[1,5-a]pyrimidin-5-yl)-hydrazine (30.0 mg, 0.0557 mM), then 3-cyano-benzaldehyde (6.7 mg, 0.061 mM) was added to the solution and the mixture was stirred at room temperature for one hour. This reaction liquid was filtered and the resulting solid was purified by the NH-silica gel column chromatography (methanol/methylene chloride=1/20) to thus give the title compound (23.6 mg, yield: quantitative).
Reaction SMILES: C(O[C:4](=[O:17])[CH2:5][C:6]1([CH2:13][N+]([O-])=O)[CH2:10][C@@H:9]([CH3:11])[C@H:8]([CH3:12])[CH2:7]1)C.[CH3:18]O>[Ni]>[CH3:11][C@H:9]1[C@H:8]([CH3:12])[CH2:7][C:6]2([CH2:5][C:4](=[O:17])[CH2:18][CH2:13]2)[CH2:10]1
Reactant: CO
Reactant: CCOC(=O)CC1(C[N+](=O)[O-])C[C@@H](C)[C@H](C)C1
Agent: [Ni]
Product: C[C@@H]1CC2(CCC(=O)C2)C[C@H]1C
Reaction time: 4 h
Yield: 99 %

Procedure:
The nitroester (3) (0.83 g, 3.4 mmol) was dissolved in methanol (30 mL) and shaken over Raney nickel catalyst under an atmosphere of hydrogen (40 psi) at 30° C. After 4 hours, the catalyst was removed by filtration through celite. The solvent was removed in vacuo to give 567 mg (99%) of a pale yellow oil which solidified on standing.
Reaction SMILES: [F:1][C:2]([F:50])([C:46]([F:49])([F:48])[F:47])[CH2:3][CH2:4]/[CH:5]=[C:6](\[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]1[C:30]2[C:25](=[CH:26][C:27]([O:31][CH2:32][O:33][CH3:34])=[CH:28][CH:29]=2)[O:24][CH2:23][C:22]1([C:36]1[CH:41]=[CH:40][C:39]([O:42][CH2:43][O:44][CH3:45])=[CH:38][CH:37]=1)[CH3:35])/[C:7]([O:9]CC)=[O:8].Cl>C(O)C.[OH-].[K+]>[F:50][C:2]([F:1])([C:46]([F:47])([F:48])[F:49])[CH2:3][CH2:4]/[CH:5]=[C:6](\[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]1[C:30]2[C:25](=[CH:26][C:27]([O:31][CH2:32][O:33][CH3:34])=[CH:28][CH:29]=2)[O:24][CH2:23][C:22]1([C:36]1[CH:37]=[CH:38][C:39]([O:42][CH2:43][O:44][CH3:45])=[CH:40][CH:41]=1)[CH3:35])/[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)/C(=C/CCC(F)(F)C(F)(F)F)CCCCCCCCCC1c2ccc(OCOC)cc2OCC1(C)c1ccc(OCOC)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2CCCCCCCCC/C(=C\CCC(F)(F)C(F)(F)F)C(=O)O)cc1
Temperature: 70 °C
Reaction time: 5 h

Procedure:
To a stirred solution of ethyl (E)-6,6,7,7,7-pentafluoro-2-{9-[(3RS,4RS)-7-methoxymethoxy-3-(4-methoxymethoxyphenyl)-3-methylchroman-4-yl]nonyl}-2-h eptenoate (116 mg, 0.16 mmol) in ethyl alcohol (5 ml), 5 N aqueous potassium hydroxide solution was added and the mixture was stirred under N2 atmosphere at 70° C. for 5 h. After cooling to room temperature the reaction mixture was acidified by 6 N aqueous hydrochloric acid and extracted with methylene chloride. Extracts were dried over anhydrous sodium sulfate and concentrated in vacuum to give crude (E)-6,6,7,7,7-pentafluoro-2-{9-[(3RS,4RS)-7-methoxymethoxy-3-(4-methoxymethoxyphenyl)-3-methylchroman-4-yl]nonyl}-2-heptenoic acid as a colorless oil. yield: 111 mg (quant.). The sample was used in the following step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]/OC.Cl.[CH3:18][N:19]([CH3:31])[CH2:20][CH2:21][N:22]([CH3:30])[C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1.C(N(CC)CC)C>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:29][C:26]1[CH:25]=[CH:24][C:23]([N:22]([CH2:21][CH2:20][N:19]([CH3:31])[CH3:18])[CH3:30])=[CH:28][CH:27]=1
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(Br)cc21
Reactant: CN(C)CCN(C)c1ccc(N)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)CCN(C)c1ccc(N/C=C2\C(=O)NC(=O)c3ccc(Br)cc32)cc1
Yield: 54.1 %

Procedure:
(4E)-6-bromo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione (0.28 g, 1.0 mmol) and N-[2-(dimethylamino)ethyl]-N-methylbenzene-1,4-diamine hydrochloride (0.30 g, 1.0 mmol) were stirred in N,N-dimethylformamide (5 mL) with triethylamine (0.6 mL). The reaction mixture is quenched by the addition of water. The solid material is then collected, washed with diethyl ether, water, and methanol and then dried under vacuum to give (4Z)-6-bromo-4-[({4-[[2-(dimethylamino)ethyl](methyl)amino]phenyl}amino)methylene]isoquinoline-1,3(2H,4H)-dione (0.24 g, 55%) as a golden powder.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].CCN(CC)CC.[F:15][C:16]([F:23])([F:22])[C:17](OCC)=[O:18]>CO>[F:15][C:16]([F:23])([F:22])[C:17]([N:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4])=[O:18]
Reactant: CCOC(=O)C(F)(F)F
Reactant: OCCNCCO
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C(N(CCO)CCO)C(F)(F)F
Reaction time: 20 h

Procedure:
(Kamal, A.; et al J. Med. Chem. 2002, 45, 4679-4688) Diethanolamine (3.57 g, 34 mmol) was dissolved in methanol (20 mL) and treated with Et3N (4.7 mL, 34 mmol) and ethyl trifluoroacetate (4.90 g, 34 mmol) for 20 h at rt, followed by adding another 1 mL CF3COOEt. After another 20 h, removal of volatile solvents under high vacuum yielded N-trifluoroacetyl-diethanolamine compound 6 as light yellow oil, which was used without further purification.
Reaction SMILES: [NH:1]([C:3]1[N:4]=[N:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[CH:7][N:8]=1)[NH2:2].[CH:16]([O-])([O-])OCC>CCCCCC>[F:15][C:12]1[CH:11]=[CH:10][C:9]([C:6]2[CH:7]=[N:8][C:3]3[N:4]([CH:16]=[N:2][N:1]=3)[N:5]=2)=[CH:14][CH:13]=1
Reactant: NNc1ncc(-c2ccc(F)cc2)nn1
Reactant: CCOC([O-])[O-]
Solvent: CCCCCC
Product: Fc1ccc(-c2cnc3nncn3n2)cc1

Procedure:
A mixture of 3.09 g. of 3-hydrazino-6-(p-fluorophenyl)-1,2,4-triazine and 35 ml. of ethyl orthoformate is refluxed for 2 hours, cooled and poured into hexane. The solid is collected and washed with ethanol giving the desired product as a brown solid, m.p. 231°-235° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)=O)[C:5]([C:11]#[N:12])=[C:4]([C:13]2[O:14][C:15]([CH3:18])=[CH:16][CH:17]=2)[N:3]=1.[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([NH:26][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:5]([C:11]#[N:12])=[C:4]([C:13]2[O:14][C:15]([CH3:18])=[CH:16][CH:17]=2)[N:3]=1
Reactant: NCc1ccccc1
Reactant: Cc1ccc(-c2nc(N)nc(S(C)=O)c2C#N)o1
Solvent: COCCOC
Product: Cc1ccc(-c2nc(N)nc(NCc3ccccc3)c2C#N)o1

Procedure:
From 2-amino-4-methanesulfinyl-6-(5-methyl-furan-2-yl)-pyrimidine-5-carbonitrile and benzylamine in DME. ES-MS m/e (%): 306 (M+H+, 100).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[O:9][C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:11]([CH3:13])[N:12]=2)[CH2:4][C@H:3]1[O:19][CH3:20].[Cl:21][C:22]1[N:23]=[C:24]([C:29](O)=[O:30])[NH:25][C:26]=1[CH2:27][CH3:28].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>ClCCl.CC(N(C)C)=O>[Cl:21][C:22]1[N:23]=[C:24]([C:29]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]3[O:9][C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:11]([CH3:13])[N:12]=3)[CH2:4][C@H:3]2[O:19][CH3:20])=[O:30])[NH:25][C:26]=1[CH2:27][CH3:28]
Reactant: CCOC(=O)c1oc(N2CC[C@H](N)[C@H](OC)C2)nc1C
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: CCOC(=O)c1oc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OC)C2)nc1C
Yield: 69.9 %

Procedure:
The same operation as in Example (106d) was performed using ethyl cis(±)-2-(4-amino-3-methoxypiperidin-1-yl)-4-methyl-1,3-oxazole-5-carboxylate obtained in Example (107b) (0.22 g, 0.78 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid (0.16 g, 0.92 mmol), WSC hydrochloride (0.46 g, 2.4 mmol), HOBt (0.2 g, 1.2 mmol), DMA (3 mL) and dichloromethane (3 mL). The resulting residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=1/2, 1/1, 2/1, 1/0, ethyl acetate/methanol=97/3, 93/7) to obtain 0.24 g of the title compound as a light yellow solid (70%).
Reaction SMILES: [CH2:1]([C:16]1[O:17][CH:18]=[CH:19][CH:20]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].Br[CH2:22][CH2:23]CCCCCCCCCCCCC>>[CH2:1]([C:16]1[O:17][CH:18]=[CH:19][CH:20]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:22][CH3:23]
Reactant: CCCCCCCCCCCCCCCc1ccco1
Reactant: CCCCCCCCCCCCCCCBr
Product: CCCCCCCCCCCCCCCCCc1ccco1

Procedure:
2-(heptadecyl)furan (4) was prepared exactly as described above for 2-(pentadecyl)furan, substituting 1-bromo heptadecane for 1-bromopentadecane. The chromatographed product was recrystallized from methanol as described above to afford of 2-(heptadecyl)furan (4) in 48% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6][NH2:7].[CH2:13]1[O:21][CH:14]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6][NH:7][CH2:13][CH:14]([OH:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: c1ccc(C2CO2)cc1
Reactant: COc1ccc(CN)cc1OC
Solvent: CC#N
Product: COc1ccc(CNCC(O)c2ccccc2)cc1OC
Yield: 46.7 %

Procedure:
Heat a solution of 3,4-dimethoxybenzylamine (16.7 g) and styrene oxide (12.0 g) in acetonitrile (250 mL) at reflux for 16 h. Concentrate to a residue and distill the residue, collecting the fraction distilling above 120° C. (0.5 mm). Recrystallize the solidified distillate from benzene/hexane to give N-(3,4-dimethoxybenzyl)-2-hydroxy-2-phenylethylamine (13.4 g), mp=93°-94° C.
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[CH:14]=[CH:13][C:12]3[C:15]4[CH:24]=[CH:23][C:22]([O:25]C)=[CH:21][C:16]=4[C:17]([CH3:20])([CH3:19])[O:18][C:11]=3[C:7]=2[C:8](=[O:10])[CH:9]=1)([OH:3])=[O:2].C(CN)O>I.O>[C:1]([C:4]1[O:5][C:6]2[CH:14]=[CH:13][C:12]3[C:15]4[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][C:16]=4[C:17]([CH3:20])([CH3:19])[O:18][C:11]=3[C:7]=2[C:8](=[O:10])[CH:9]=1)([OH:3])=[O:2]
Reactant: COc1ccc2c(c1)C(C)(C)Oc1c-2ccc2oc(C(=O)O)cc(=O)c12
Agent: I
Solvent: O
Solvent: NCCO
Product: CC1(C)Oc2c(ccc3oc(C(=O)O)cc(=O)c23)-c2ccc(O)cc21

Procedure:
2.5 gm (0.007 mol) of 2-carboxy-4-oxo-6,6-dimethyl-8-methoxy-4H,6H-[2]-benzopyrano-[3,4-f]-[1]-benzopyran, prepared as described in Example 2, were refluxed for 4 hours in 50 ml of hydroiodic acid. Then, the reaction mixture was cooled and diluted with 200 ml of water. The precipitated yellow crystals were filtered off, washed with water, dried and recrystallized from methanol. 250 gm (10.5% of theory) of the compound named in the heading, m.p. 256°-258° C, were obtained. The ethanolamine salt, prepared in analogy with Example 1, had a melting point of 200°-202° C.
Reaction SMILES: [NH:1]([C:3]1[N:4]=[N:5][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)=[CH:7][CH:8]=1)[NH2:2].[C:19](OCC)(=O)[CH2:20][OH:21]>C(O)CCC>[OH:21][CH2:20][C:19]1[N:4]2[N:5]=[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=3)[CH:7]=[CH:8][C:3]2=[N:1][N:2]=1
Reactant: NNc1ccc(-c2cccc(C(F)(F)F)c2)nn1
Reactant: CCOC(=O)CO
Solvent: CCCCO
Product: OCc1nnc2ccc(-c3cccc(C(F)(F)F)c3)nn12

Procedure:
A mixture of 2.3 g. of 3-hydrazino-6-[3-(trifluoromethyl)phenyl]pyridazine, 188 g. of ethyl glycolate and 40 ml. of n-butyl alcohol is heated at reflux temperature for 18 hours. The mixture is evaporated in vacuo. To the residue is added dichloromethane and hexane. The mixture is filtered to give 2.0 g. of cream colored crystals. Recrystallization from ethyl acetate gives the product of the Example as off-white crystals, m.p. 224°-226° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([C:14]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[O:15])[CH2:11][C@H:10]([N:22]([C:27](=[O:31])[C:28](O)=[O:29])[CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[F:54][C:55]1[CH:61]=[CH:60][C:58]([NH2:59])=[C:57]([NH:62][CH2:63][CH2:64][CH2:65][CH2:66][O:67][CH3:68])[CH:56]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[F:54][C:55]1[CH:61]=[CH:60][C:58]([NH:59][C:28](=[O:29])[C:27]([N:22]([CH2:23][CH:24]([CH3:26])[CH3:25])[C@H:10]2[CH2:11][C@@H:12]([C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[O:15])[CH2:13][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:9]2)=[O:31])=[C:57]([NH:62][CH2:63][CH2:64][CH2:65][CH2:66][O:67][CH3:68])[CH:56]=1
Reactant: CC(C)CN(C(=O)C(=O)O)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Reactant: COCCCCNc1cc(F)ccc1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCCCCNc1cc(F)ccc1NC(=O)C(=O)N(CC(C)C)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Temperature: 60 °C
Reaction time: 2 h
Yield: 2.9 %

Procedure:
{[(3S,5R)-1-(tert-Butoxycarbonyl)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl](2-methylpropyl)amino}(oxo) acetic acid (221 mg), HOBt (95 mg) and WSC.HCl (144 mg) were dissolved in DMF (5 ml), 4-fluoro-2-(4-methoxybutylamino)aniline (106 mg) and diisopropylethylamine (97 μl) were added, and the mixture was stirred at room temperature for 15 hr and at 60° C. for 2 hr. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure. The residue was diluted with aqueous sodium bicarbonate and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object product (9.11 mg).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:12]=[C:13]1[CH:17]([CH:18]([OH:27])[C@H:19]2[C@@H:21]([C:22]([OH:24])=O)[C:20]2([CH3:26])[CH3:25])[CH2:16][CH2:15][S:14]1>C1C=CC=CC=1>[O:12]=[C:13]1[CH:17]([C@H:18]2[C@H:19]3[C@H:21]([C:20]3([CH3:25])[CH3:26])[C:22](=[O:24])[O:27]2)[CH2:16][CH2:15][S:14]1
Reactant: CC1(C)[C@H](C(=O)O)[C@@H]1C(O)C1CCSC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CC1(C)[C@@H]2[C@H]1C(=O)O[C@H]2C1CCSC1=O

Procedure:
50 mg of p-toluene sulfonic acid were added to a solution of 6.2 g of the product of Step A in 70 ml of benzene and the mixture was refluxed for 90 minutes while removing the water of reaction by passing the condensed solvent through silica gel to obtain a solution of (1R,4R,5S) 4-[dihydro-2-oxo-3-(2H)-thienyl]-6,6-dimethyl-3-oxabicyclo-(3,1,0)-hexan-2-one which was used as is for the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][CH2:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][C:3]=1B1OC(C)(C)C(C)(C)O1.Br[C:32]1[C:33]([CH3:39])=[CH:34][C:35]([Cl:38])=[N:36][CH:37]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.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:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][CH2:14][CH2:13][CH2:12]2)(=[O:9])=[O:10])=[CH:4][C:3]=1[C:32]1[CH:37]=[N:36][C:35]([Cl:38])=[CH:34][C:33]=1[CH3:39]
Reactant: Cc1cc(Cl)ncc1Br
Reactant: CC1(C)OB(c2cc(S(=O)(=O)N3CCCCc4ccccc43)ccc2Cl)OC1(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: [K+]
Solvent: C1COCCO1
Product: Cc1cc(Cl)ncc1-c1cc(S(=O)(=O)N2CCCCc3ccccc32)ccc1Cl
Temperature: 100 °C
Yield: 23.6 %

Procedure:
A mixture of 1-[4-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-benzenesulfonyl]-2,3,4,5-tetrahydro-1H-1-benzazepine (67 mg, 0.18 mmol), 5-bromo-2-chloro-4-picoline (45 mg, 0.22 mmol), Pd(PPh3)4 (11 mg, 0.01 mmol), K2CO3 (130 mg, 0.93 mmol) in 1,4-Dioxane (1 mL), was heated at 100° C. for 12 hrs. This mixture was cooled to rt and the solvent evaporated. The residue was purified by silica gel column chromatography eluted with (Hexanes/Ethyl acetate, 9/1) to yield 1-[4-chloro-3-(6-chloro-4-methyl-pyridin-3-yl)-benzenesulfonyl]-2,3,4,5-tetrahydro-1H-1-benzazepine 4-1 (0.019 g, 23% yield). MS: 447 (M+H)+; tR=9.94 min (method 2).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][C:13](=[O:16])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:17](O)[CH2:18][OH:19].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:11][CH2:12][C:13]3([O:19][CH2:18][CH2:17][O:16]3)[CH2:14][CH2:15]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(N2CCC3(CC2)OCCO3)cc1
Yield: 67.3 %

Procedure:
A mixture of 1-(4-nitrophenyl)-4-piperidone (0.6 g, 2.7 mmol), ethylene glycol (0.3 mL, 5.4 mmol) and p-toluenesulfonic acid (0.1 g in toluene (20 mL) was heated at reflux in a Dean-Stark apparatus until no more water accumulation occurred. The reaction was evaporated to dryness and the residue partitioned between ethyl acetate and water. The organic layer was separated and washed with water then brine and dried over sodium sulfate. Concentration under reduced pressure afforded 8-(4-nitrophenyl)-1,4-dioxa-8-aza-spiro[4,5]decane (0.48 g, 66%).
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH2:2][OH:3].[CH2:6](I)[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].C1CCN2C(=NCCC2)CC1>CC#N>[OH:3][CH2:2][C:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[O:4]
Reactant: CCCCCCI
Reactant: O=C(O)CO
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCCCOC(=O)CO
Yield: 73.7 %

Procedure:
To 215 mg (2.82 mmol) glycolic acid in 12.8 ml CH3CN was added 719 mg (3.39 mmol) 1-hexyl iodide and 429 mg (2.82 mmol) DBU. After stirring over night and reflux for 4 h, the solvent was evaporated, ethylacetat and 1 M KHSO4 was added and the phases were separated. The organic layer was washed with brine, dried (MgSO4), filtered and evaporated in vacuo to give 333 mg (74%) of the product.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[NH:8][N:7]=[C:6]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:16]=[C:17]=[S:18])[N:5]=1.[N:19]#[C:20]Br.O>O1CCCC1>[CH3:3][C:4]1[N:5]=[C:6]2[CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:16]=[C:17]([S:18][C:20]#[N:19])[N:7]2[N:8]=1
Reactant: N#CBr
Reactant: Cc1nc(Cc2ccccc2N=C=S)n[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc2n(n1)C(SC#N)=Nc1ccccc1C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 0.91 g of sodium hydride in 27 ml of tetrahydrofuran is added dropwise a solution of 8.74 g of 5-methyl-3-(o-isothiocyanatobenzyl)-1,2,4-triazole in 60 ml of tetrahydrofuran over a period of 20 minutes. The mixture is stirred at room temperature for 2 hours. To the resulting suspension a solution of 4.02 g of cyanogen bromide in 35 ml of tetrahydrofuran is added dropwise at 0° over a period of 15 minutes. The mixture is stirred at 0° for 1.5 hours, poured into water and extracted three times with ethyl acetate. The organic extracts are dried over magnesium sulfate, decolorized with charcoal and evaporated to give 2-methyl-5-cyanothio-11H-1,2,4-triazolo[2,3-c][1,3]benzodiazepine; IR 2150 cm-1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[F:13])/[CH:5]=[CH:6]/[C:7]([OH:9])=[O:8].S(=O)(=O)(O)O.[CH3:19]O>>[CH3:19][O:8][C:7](=[O:9])/[CH:6]=[CH:5]/[C:4]1[CH:10]=[CH:11][C:12]([F:13])=[C:2]([F:1])[CH:3]=1
Reactant: CO
Reactant: O=C(O)/C=C/c1ccc(F)c(F)c1
Agent: O=S(=O)(O)O
Product: COC(=O)/C=C/c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 100 %

Procedure:
To a solution of trans-3,4-difluorocinnamic acid (10 g, 54 mmol) in 300 mL methanol was added concentrated sulfuric acid (2 mL). The solution was stirred 48 h at ambient temperature and then concentrated in vacuo. The residue was taken up in ethyl acetate (500 mL) and washed with saturated sodium bicarbonate (2×100 mL), brine (1×100 mL), dried with magnesium sulfate, and concentrated in vacuo to provide trans-3,4-difluorocinnamic acid methyl ester (10.7 g, 54 mmol, 100%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[C@@H:10]1[CH2:19][CH2:18][C:13]2([O:17][CH2:16][CH2:15][O:14]2)[CH2:12][C@H:11]1[C:20]([O-:22])=[O:21].CO.[OH-].[Li+].Cl>O1CCCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[C@@H:10]1[CH2:19][CH2:18][C:13]2([O:14][CH2:15][CH2:16][O:17]2)[CH2:12][C@H:11]1[C:20]([OH:22])=[O:21]
Reactant: O=C([O-])[C@@H]1CC2(CC[C@H]1c1cc(F)c(F)cc1F)OCCO2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)[C@@H]1CC2(CC[C@H]1c1cc(F)c(F)cc1F)OCCO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A stirred solution of trans 8-(2,4,5-trifluorophenyl)-1,4-dioxaspiro[4.5]decane-7-carboxylate from Step E (1.82 g, 5.5 mmol) dissolved in tetrahydrofuran (11 mL) and methanol (22 mL) was treated with aqueous lithium hydroxide solution (1.OM, 18.5 mL) and the mixture was stirred at room temperature overnight. The reaction solution was acidified with hydrochloric acid (1N) to pH 1 and extracted with ethyl acetate. The organic phase was washed by saturated brine solution, dried over anhydrous sodium sulfate and evaporated to yield the title compound.
Reaction SMILES: [OH:1][C:2]1([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH:16]1[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)=[O:22])[CH2:17]1>>[OH:1][C:2]1([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH2:7][CH2:6][CH:5]([N:16]2[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[CH:27]=3)=[O:22])[CH2:17]2)[CH2:4][CH2:3]1
Reactant: O=C1CCC(O)(c2ccc(O)cc2)CC1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(O)(c3ccc(O)cc3)CC2)C1

Procedure:
The title compound was prepared as a white solid by reductive amination of 4-hydroxy-4-(4-hydroxy-phenyl)-cyclohexanone (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in step B of Example 4) using the procedure described in Step C of Example 4.