Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]#[C:2][NH2:3].CC(C)([O-])C.[K+].[CH3:10][C:11]([C:14]1[CH:15]=[C:16]([CH:25]=[C:26]2[O:30][C:29](SC)=[N:28][C:27]2=[O:33])[CH:17]=[C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:19]=1[OH:20])([CH3:13])[CH3:12]>C(O)C>[CH3:10][C:11]([C:14]1[CH:15]=[C:16]([CH:25]=[C:26]2[O:30][C:29]([NH:3][C:2]#[N:1])=[N:28][C:27]2=[O:33])[CH:17]=[C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:19]=1[OH:20])([CH3:13])[CH3:12]
Reactant: N#CN
Reactant: CSC1=NC(=O)C(=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)O1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCO
Product: CC(C)(C)c1cc(C=C2OC(NC#N)=NC2=O)cc(C(C)(C)C)c1O
Reaction time: 0.25 h
Yield: 39.1 %

Procedure:
A suspension of 0.38 g (0.0090 mole) of cyanamide in 50 mL of ethanol is cooled in ice and treated in small portions with 0.93 g (0.0083 mole) of potassium tert-butoxide. After stirring for 15 minutes, 2.6 g (0.0075 mole) of 5-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene]-2-(methylthio)-4(5H)-oxazolone is added, followed by an additional 25 mL of ethanol. The mixture is stirred at reflux for 3 hours, then cooled to allow precipitation of the potassium salt of the product. The salt is filtered, washed several times with ether, suspended in 100 mL of cold water, and acidified with 1.0 mL of acetic acid. The mixture is stirred for 30 minutes and extracted with ethyl acetate (4×75 mL). The combined organic layers are washed with brine (2×150 mL), dried (anhydrous sodium sulfate), and evaporated to yield 1.0 g (38%) of the nitrile product, [5-[[3,5-bis(1,1 -dimethylethyl)-4-hydroxyphenyl]methylene]-4,5-dihydro-4-oxo-2-oxazolyl]cyanamide. A sample recrystallized from hexane:ethyl acetate had mp 220° C. dec.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH3:11])[N:8]([C:12]2[CH:13]=[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][C:25]([F:28])([F:27])[F:26])[CH:15]=[CH:16][CH:17]=2)[N:7]=1)=[O:5])C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO.[OH-].[Na+].O>[CH3:11][C:9]1[N:8]([C:12]2[CH:13]=[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][C:25]([F:28])([F:26])[F:27])[CH:15]=[CH:16][CH:17]=2)[N:7]=[C:6]([C:4]([OH:5])=[O:3])[CH:10]=1
Reactant: CCOC(=O)c1cc(C)n(-c2cccc(-c3ccccc3OC(F)(F)F)c2)n1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(C(=O)O)nn1-c1cccc(-c2ccccc2OC(F)(F)F)c1

Procedure:
A solution of ethyl-5-methyl-1-[2′-(trifluoromethoxy)-1,1′-biphenyl-3-yl]-1H-pyrazole-3-carboxylate (0.39 g, 1 mmol) (from EXAMPLE 3) in a mixture of MeOH (5 ml) and 2N NaOH (2 ml) was refluxed for 16 hours. The reaction was then cooled, diluted with water, acidified with 10% citric acid and extracted with ethylacetate. The organic phase was washed with water, dried (sodium sulfate) and concentrated in vacuo to give the titled product.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:11]=[CH:10][C:9]([CH2:12][N:13]2[CH2:18][C@@H:17]([CH3:19])[O:16][C@@H:15]([CH3:20])[CH2:14]2)=[CH:8][C:5]=1[C:6]#[N:7].Cl[C:22]([O:24][CH2:25][CH3:26])=[O:23].C(=O)(O)[O-].[Na+]>C1COCC1>[C:6]([C:5]1[C:4]([NH:3][C:22](=[O:23])[O:24][CH2:25][CH3:26])=[N:11][CH:10]=[C:9]([CH2:12][N:13]2[CH2:14][C@@H:15]([CH3:20])[O:16][C@@H:17]([CH3:19])[CH2:18]2)[CH:8]=1)#[N:7]
Reactant: C[C@@H]1CN(Cc2cnc(N)c(C#N)c2)C[C@H](C)O1
Reactant: CCOC(=O)Cl
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)Nc1ncc(CN2C[C@@H](C)O[C@@H](C)C2)cc1C#N
Reaction time: 0.08 h
Yield: 79.7 %

Procedure:
Sodium hydride in mineral oil (60%, 25 mg, 0.61 mmol) was added to 2-amino-5-(((2S,6R)-2,6-dimethylmorpholino)methyl)nicotinonitrile (100 mg, 0.41 mmol) in THF (2 mL) and the mixture was stirred for 5 minutes. Ethyl chloroformate (0.05 ml, 0.48 mmol) was added followed by additional sodium hydride (16 mg, 0.41 mmol) and the reaction stirred at room temperature for 3 hours. The reaction was poured into a saturated solution of sodium bicarbonate (10 mL), extracted with ethyl acetate (3×5 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was taken up in methanol (10 mL) and stirred with potassium carbonate (170 mg) for 10 minutes. It was then poured into saturated sodium bicarbonate (10 mL) and extracted with ethyl acetate (3×5 mL). The extracts were dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by flash chromatography, eluting with ethyl acetate in hexanes gave the title compound as a white powder (104 mg, 80%). 1H NMR (400 MHz, DMSO-d6) δ 1.04 (d, J=6.27 Hz, 6H), 1.26 (t, J=7.03 Hz, 3H), 1.69 (t, J=10.60 Hz, 2H), 2.67 (d, J=10.67 Hz, 2H), 3.51 (s, 2H), 3.54-3.62 (m, 2H), 4.17 (q, J=7.11 Hz, 2H), 8.12-8.24 (m, 1H), 8.56 (d, J=2.01 Hz, 1H), 10.37 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:16]=[C:15]([N+:17]([O-])=O)[C:14]([F:20])=[CH:13][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH2:11])[C:6]=1[I:12].O.O.[Sn](Cl)Cl>CCO>[NH2:17][C:15]1[C:14]([F:20])=[CH:13][C:3]([O:4][C:5]2[CH:10]=[CH:9][N:8]=[C:7]([NH2:11])[C:6]=2[I:12])=[C:2]([F:1])[CH:16]=1
Reactant: Nc1nccc(Oc2cc(F)c([N+](=O)[O-])cc2F)c1I
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: Nc1cc(F)c(Oc2ccnc(N)c2I)cc1F
Temperature: 80 °C
Reaction time: 3 h
Yield: 51.1 %

Procedure:
To a solution of 4-(2,5-difluoro-4-nitrophenoxy)-3-iodopyridin-2-amine (0.78 g, 1.78 mmol) in EtOH (15 mL) added tin(II) chloride dihydrate (2.0 g, 8.93 mmol) and the reaction mixture was stirred at 80° C. for 3 h. The mixture was cooled to RT, the solvent was removed in vacuo and crude residue was basified with NaHCO3 solution (40 mL). EtOAc (50 mL) was added to the resultant white suspension and the mixture was stirred for few minutes. It was filtered though a Celite® pad which was washed with EtOAc (4×5 mL), and water (3×4 mL). The organic layer was separated and was washed with brine, dried (Na2SO4) and concentrated to afford crude product which was purified by silica gel chromatography (EtOAc-hexanes) to afford 4-(4-amino-2,5-difluorophenoxy)-3-iodopyridin-2-amine as an off-white solid (0.33 g, 51% yield). 1H NMR (400 MHz, DMSO-d6): δ 7.69 (d, J=5.6 Hz, 1H), 7.12 (dd, J=11.2 Hz, 7.6 Hz, 1H), 6.69 (dd, J=12.0 Hz, 8.0 Hz, 1H), 6.13 (s, 2H), 5.74 (d, J=5.6 Hz, 1H), 5.47 (s, 2H); MS (ESI) m/z: 364.0 (M+H+).
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.I[C:37]1[CH:42]=[CH:41][NH:40][C:39](=[O:43])[CH:38]=1>>[OH:1][C:2]([CH3:34])([CH3:35])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:37]3[CH:42]=[CH:41][NH:40][C:39](=[O:43])[CH:38]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: O=c1cc(I)cc[nH]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2cc[nH]c(=O)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-an-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 4-iodopyridin-2(1H)-one following a procedure analogous to that described in Example 1. LC-MS Method 1 tR=1.23 min, m/z=389, 447 (M+1); 1H NMR (CD3OD) 7.40 (d, J=6.7 Hz, 1H), 7.31 (d, J=8.2 Hz, 2H), 7.29-7.20 (m, 5H), 6.96 (d, J=8.2 Hz, 2H), 6.57-6.52 (m, 2H), 5.49 (q, J=7.0 Hz, 1H), 2.98-2.93 (m, 1H), 2.47-2.34 (m, 2H), 2.16-2.09 (m, 1H), 2.07 (s, 2H), 1.45 (d, J=7.0 Hz, 3H), 1.19 (s, 3H), 0.87 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:17]([F:19])[F:18])[N:6]2[CH2:13][C:14](O)=[O:15].[NH2:20][NH2:21]>C1COCC1>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:17]([F:19])[F:18])[N:6]2[CH2:13][C:14]([NH:20][NH2:21])=[O:15]
Reactant: N#Cc1ccc2c(cc(C(F)F)n2CC(=O)O)c1Cl
Reactant: NN
Solvent: C1CCOC1
Product: N#Cc1ccc2c(cc(C(F)F)n2CC(=O)NN)c1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 51.7 %

Procedure:
To a solution of [4-chloro-5-cyano-2-(difluoromethyl)-1H-indol-1-yl]acetic acid (0.050 g, 0.175 mmol) in anhydrous THF (2 mL), under N2, was added CDl (0.030 g, 0.184 mmol). The mixture was stirred at rt for 4 h and additional CDl (0.030 g, 0.184 mmol) was added. After 45 min, additional CDl (0.079 g, 0.49 mmol) was added. After 5 min, hydrazine (0.112 g, 3.5 mmol) was added and the mixture was stirred at rt for 30 min. The mixture was partitioned between EtOAc and 0.2N NaOH. The organic phase was washed with 0.2N NaOH and sat'd brine. The combined aqueous phases were extracted with EtOAc (×2). The second EtOAc phases were washed with sat'd NaHCO3 solution and brine. The organic phases were combined, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography (0-10% MeOH—CH2Cl2 gradient) to afford the title compound (0.027 g, 52% yield): MS (ES) m/z 299 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[CH2:11](O)[CH3:12].S(Cl)(Cl)=O>CN(C)C=O>[CH2:11]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([NH2:1])=[N:3][CH:4]=1)[CH3:12]
Reactant: Nc1ccc(C(=O)O)cn1
Reactant: CCO
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1ccc(N)nc1
Temperature: 80 °C

Procedure:
6-Aminonicotinic acid, 40 g (or 6-aminonicotinic acid phosphoric salt, 62 g), was mixed with anhydrous ethanol 500 ml. The mixture was externally cooled by an ice water bath. Thionyl chloride, 50 ml, was slowly added into the mixture. (N,N-Dimethylformamide, 50 ml, may be added to dissolve any still undissolved phosphoric salt.) The reaction mixture was heated to 80° C. for 5 hours and was then evaporated to a syrupy reside which crystallized on addition of acetone. These crystals were separated by filtration and were redissolved in 400 g of ice water. 4N KOH was added to the solution to adjust the pH to 8. The white crystals thus formed were separated again by filtration and were washed with water. The yield of practically pure 6-aminonicotinic acid ethyl ester was 41.8 g. This product had an Rf value of 0.79 on thin-layer chromatogram using a solvent system of benzene:methanol, 1:1.
Reaction SMILES: [CH3:1][N:2]1[C:16]2[C:17]3[C:4]([CH2:5][C@@H:6]4[C@@:11]([O:18][CH3:19])([C:12]=3[CH:13]=[CH:14][CH:15]=2)[CH2:10][C@@H:9]([CH2:20]Cl)[CH2:8][N:7]4[CH3:22])=[CH:3]1.[C-:23]#[N:24].[Na].[C-]#N.[K+]>CS(C)=O>[CH3:1][N:2]1[C:16]2[C:17]3[C:4]([CH2:5][C@@H:6]4[C@@:11]([O:18][CH3:19])([C:12]=3[CH:13]=[CH:14][CH:15]=2)[CH2:10][C@@H:9]([CH2:20][C:23]#[N:24])[CH2:8][N:7]4[CH3:22])=[CH:3]1
Reactant: [C-]#N
Reactant: CO[C@]12C[C@@H](CCl)CN(C)[C@@H]1Cc1cn(C)c3cccc2c13
Agent: [K+]
Agent: [Na]
Solvent: CS(C)=O
Product: CO[C@]12C[C@@H](CC#N)CN(C)[C@@H]1Cc1cn(C)c3cccc2c13

Procedure:
The starting material for preparing compounds of the present invention is, preferably, 1-methyl-lumilysergol-10-methylether or 1,6-dimethyl-8β-hydroxymethyl-10α-methoxyergoline (I), described and claimed in the Bernardi et al. U.S. Pat. No. 3,228,943. It is reacted at a temperature between 40° and 50° C with the chloride of an aryl- or alkylsulphonic-acid, such as tosyl chloride or mesyl chloride, in pyridine and in the presence of pyridinium chloride, to give the corresponding 8-chloromethyl derivative. This compound, that is, 1,6-dimethyl-8β-chloromethyl-10α-methoxyergoline (II), is treated with an alkaline cyanide, such as sodium or potassium cyanide in a suitable solvent, such as dimethylsulphoxide, at the temperature of 100°-120° C for a period between 4 and 8 hours. The product thus formed, that is, 1,6-dimethyl-8β-cyanomethyl-10α-methoxyergoline (III), is isolated and characterized: it has never been described in the previous literature. This product is subjected to alkaline hydrolysis, preferably with potassium hydroxide in water/ethanol/dioxan solution, under reflux conditions for a few hours.
Reaction SMILES: [CH3:1][C:2]1[C:19]([F:20])=[C:18]([F:21])[C:17]([F:22])=[C:16]([F:23])[C:3]=1[C:4]([C:6](=[CH:12]OCC)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[F:24][C:25]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:26]=1[NH2:27]>>[CH3:1][C:2]1[C:19]([F:20])=[C:18]([F:21])[C:17]([F:22])=[C:16]([F:23])[C:3]=1[C:4]([C:6](=[CH:12][NH:27][C:26]1[CH:28]=[CH:29][C:30]([F:32])=[CH:31][C:25]=1[F:24])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: Nc1ccc(F)cc1F
Reactant: CCOC=C(C(=O)OCC)C(=O)c1c(C)c(F)c(F)c(F)c1F
Product: CCOC(=O)C(=CNc1ccc(F)cc1F)C(=O)c1c(C)c(F)c(F)c(F)c1F

Procedure:
Employing ethyl 2-(2-methyl-3,4,5,6-tetrafluorobenzoyl)-3-ethoxyacrylate (5.0 g) and 2,4-difluoroaniline (2.02 g), the procedure of Reference Example 21 is repeated to give ethyl 2-(2-methyl-3,4,5,6-tetrafluorobenzoyl)-3-(2,4-difluorophenyl)aminoacrylate, which is then treated with 60% sodium hydride as in Reference Example 22 to give ethyl 1-(2,4-difluorophenyl)-5-methyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (4.6 g), as pale yellow prisms (recrystallized from dichloromethane - n-hexane), m.p. 156°-157.5° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.[CH3:18][O:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23]>>[CH3:18][O:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22]([NH:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1)=[O:23]
Reactant: COc1ccccc1C(=O)Cl
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Product: COc1ccccc1C(=O)Nc1ccc2[nH]c3c(c2c1)CC(N(C)C)CC3
Yield: 80.1 %

Procedure:
Beginning with 10.4 mg (0.046 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 8.6 μL (0.051 mMol) 2-methoxybenzoyl chloride, 13.4 mg (80%) of the title compound were recovered as a beige solid.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[N:5]=[CH:4][C:3]=1[C:16]([O:18][CH3:19])=[O:17].[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=1>>[CH2:14]([O:13][C:11]([C:10]1[CH:9]=[N:8][N:7]2[C:2]([NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=3)=[C:3]([C:16]([O:18][CH3:19])=[O:17])[CH:4]=[N:5][C:6]=12)=[O:12])[CH3:15]
Reactant: CCOC(=O)c1cnn2c(Cl)c(C(=O)OC)cnc12
Reactant: Cc1cccc(N)c1
Product: CCOC(=O)c1cnn2c(Nc3cccc(C)c3)c(C(=O)OC)cnc12
Yield: 572.6 %

Procedure:
In the same manner as in Example 19, step 5 and using methyl 7-chloro-3-ethoxycarbonylpyrazolo[1,5-a]pyrimidine-6-carboxylate (3.00 g, 10.6 mmol) obtained in Example 21, step 2 and m-toluidine (1.70 g, 1.73 mmol), the title compound (3.51 g, 94%) was obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([C:16]2[N:17]=[N:18][N:19]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])[CH:20]=2)[OH:15])=[CH:4][CH:3]=1.[CH2:29]([O:31][C:32]([C:34]1([C:37]2[CH:42]=[CH:41][C:40](B3OC(C)(C)C(C)(C)O3)=[CH:39][CH:38]=2)[CH2:36][CH2:35]1)=[O:33])[CH3:30]>>[CH2:29]([O:31][C:32]([C:34]1([C:37]2[CH:42]=[CH:41][C:40]([C:2]3[CH:3]=[CH:4][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH:14]([C:16]4[N:17]=[N:18][N:19]([CH2:21][C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=5[Cl:28])[CH:20]=4)[OH:15])=[CH:6][CH:7]=3)=[CH:39][CH:38]=2)[CH2:35][CH2:36]1)=[O:33])[CH3:30]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)c1cn(Cc2ccccc2Cl)nn1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)c4cn(Cc5ccccc5Cl)nn4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using [5-(4-Bromo-phenyl)-3-methyl-isoxazol-4-yl]-[1-(2-chloro-benzyl)-1H-[1,2,3]triazol-4-yl]-methanol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:13][CH2:12][CH2:11][CH:10]([N:14]([C:30](=[O:32])[CH3:31])[CH2:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=2)[C:9]2[CH:33]=[C:34](Br)[C:35]([CH3:37])=[CH:36][C:8]1=2)=[O:6])([CH3:3])[CH3:2].[C:39]([N:42](CC1C=C(C(F)(F)F)C=C(C(F)(F)F)C=1)[CH:43]1CCCN(C(OC(C)C)=O)C2C=C(Cl)C(N(C)C)=CC1=2)(=O)C>>[CH:1]([O:4][C:5]([N:7]1[CH2:13][CH2:12][CH2:11][CH:10]([N:14]([C:30](=[O:32])[CH3:31])[CH2:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=2)[C:9]2[CH:33]=[C:34]([N:42]([CH3:43])[CH3:39])[C:35]([CH3:37])=[CH:36][C:8]1=2)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2cc(C)c(Br)cc21
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2cc(Cl)c(N(C)C)cc21
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2cc(C)c(N(C)C)cc21

Procedure:
This compound was prepared utilizing the same methodology described in Example 50 wherein replacement of isopropyl-5-[acetyl-(3,5-bistrifluoromethylbenzyl)amino]-7-bromo-8-chloro-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate with isopropyl-5-[acetyl-(3,5-bistrifluoromethylbenzyl)amino]-7-bromo-8-methyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate the procedure of Example 50 for the synthesis of isopropyl 5-[acetyl-(3,5-bistrifluoromethylbenzyl)amino]-8-chloro-7-dimethylamino-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate. ESI MS m/z 574 (M+H).
Reaction SMILES: N[C:2]1[CH:12]=[N:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].S(=O)(=O)(O)[OH:14].N([O-])=O.[Na+].C(=O)([O-])O.[Na+]>O>[OH:14][C:2]1[CH:12]=[N:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)c1ccncc1N
Reactant: O=S(=O)(O)O
Agent: O=C([O-])O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1ccncc1O
Reaction time: 1.33 h

Procedure:
Ethyl 3-aminoisonicotinate (5.55 g) is suspended in water (70 ml), and thereto added conc. sulfuric acid (4.0 ml). The reaction solution is cooled with ice, and a solution of sodium nitrite (2.79 g) in water (30 ml) is added dropwise thereto. The reaction solution is stirred under the same cooling conditions for 20 minutes and then at 90° C. for 80 minutes. The reaction solution is diluted with water (100 ml) and the solution is adjusted to pH 8 to 9 by addition of saturated aqueous sodium hydrogen carbonate solution, followed by extraction with chloroform. The organic layer is dried over sodium sulfate and evaporated to remove the solvent under reduced pressure. The resulting residue is purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=5/1) to give ethyl 3-hydroxyisonicotinate (2.64 g).
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[CH:24]1([C:30]2[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH:24]1([C:30]2[CH:31]=[CH:32][C:33]([O:36][CH:2]([C:7]3[CH:12]=[CH:11][C:10]([O:13][C:14]4[CH:19]=[CH:18][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=4)=[CH:9][CH:8]=3)[C:3]([O:5][CH3:6])=[O:4])=[CH:34][CH:35]=2)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: COC(=O)C(Br)c1ccc(Oc2ccc(C(C)(C)C)cc2)cc1
Reactant: Oc1ccc(C2CCCCC2)cc1
Product: COC(=O)C(Oc1ccc(C2CCCCC2)cc1)c1ccc(Oc2ccc(C(C)(C)C)cc2)cc1
Yield: 78.8 %

Procedure:
In a manner similar to Example 16, 7.54 g of methyl α-bromo-α-[p-(p-tert-butylphenoxy)phenyl]acetate was treated with 4.4 g of p-cyclohexylphenol to give 7.44 g of product as a pale yellow glass.
Reaction SMILES: Cl.[CH3:2][O:3][CH2:4][C:5]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[C:6]=1[CH2:7][NH2:8].[OH-].[Na+].C(O)C.[C:21]([O:25][CH2:26][CH3:27])(=[O:24])[CH:22]=[CH2:23]>O>[CH3:2][O:3][CH2:4][C:5]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[C:6]=1[CH2:7][NH:8][CH2:23][CH2:22][C:21]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: COCc1cccc([N+](=O)[O-])c1CN
Reactant: C=CC(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOC(=O)CCNCc1c(COC)cccc1[N+](=O)[O-]
Reaction time: 8 h

Procedure:
2-Methoxymethyl-6-nitrobenzylamine hydrochloride (20.4 g., 0.114 mole) is dissolved in a minimum volume of water and the solution is made strongly basic by the addition of 10% sodium hydroxide. The clear oil which forms is extracted into two 120-ml. portions of ether. The ether is dried with 10 g. of anhydrous sodium sulfate, filtered, and finally dried over Drierite. The dried solution is filtered and evaporated, leaving a yellow oil. The oil is dissolved in 100 ml. of absolute ethanol and 11.4 g (0.114 mole) of freshly distilled ethyl acrylate is added. This solution is allowed to stand overnight and the solvent removed by distillation from a steamcone. The oily residue is dissolved in 200 ml. of dry ether, the solution is cooled in an ice bath, and treated with dry hydrogen chloride. When precipitation is complete, the solid is filtered and dissolved in 120 ml. of boiling absolute ethanol. The hydrochloride crystallizes from this solution on cooling yielding the title product. By concentrating and cooling the mother liquor, additional title product g. is obtained. ##SPC43##
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:17]#[N:18])([CH3:16])[CH3:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=[O:20].[K+].[K+].OO.O>CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]([C:17](=[O:20])[NH2:18])([CH3:16])[CH3:15])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(C(C)(C)C#N)CC1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCN(C(C)(C)C(N)=O)CC1
Temperature: 40 °C
Yield: 309.7 %

Procedure:
To a cooled (ice/water bath) solution of 4-(cyano-dimethyl-methyl)-piperazine-1-carboxylic acid tert-butyl ester (102.9 mg) in dry DMSO was added K2CO3 (9.8 mg) followed by 28% hydrogen peroxide solution (200 μL) dropwise. The resultant was heated at 40° C. overnight. Water was added and the white solid collected, washed with water and air dried to give 4-(1-carbamoyl-1-methyl-ethyl)-piperazine-1-carboxylic acid tert-butyl ester (59.6 mg). (See Tetrahedron 2002, 58, 3217). Treatment of this compound with HCl in DCM/MeOH yielded the desired amine, which was isolated as the hydrochloride salt.
Reaction SMILES: [CH2:1]([O:8][CH:9]([CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[CH2:10][CH:11]=[CH2:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].B(F)(F)F.CC[O:30]CC.O>O1CCCC1>[CH2:1]([O:8][CH:9]([CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=1)[CH2:10][CH2:11][CH2:12][OH:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOCC
Reactant: C=CCC(COc1ccc(F)cc1)OCc1ccccc1
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: OCCCC(COc1ccc(F)cc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 100 %

Procedure:
To a mixture of 4-benzyloxy-5-(4-fluorophenoxy)-1-pentene (2.86 g., 10 mmoles), sodium borohydride (0.47 g., 12.5 mmoles), and tetrahydrofuran (25 ml.) is added dropwise a solution of boron fluoride etherate (2.1 ml., 16.7 mmoles) in tetrahydrofuran (5 ml.) at ice-bath temperatures under a nitrogen atmosphere. The resulting mixture is further stirred at room temperature overnight (ca. 15 hours). The reaction flask is chilled in an ice bath and water (2 ml.) is very cautiously added to destroy the excess hydride, followed by the additions of sodium hydroxide (5N, 4ml.) and hydrogen peroxide (30%, 8 ml.). The final mixture is stirred at room temperature for one half hour, diluted with cold water and then extracted with chloroform three times. The combined extracts are washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent is evaporated in vacuo leaving the title compound as a viscous oil (3.00 g., 10 mmoles, 100%). ir (neat) 2.97, 3.30, 3.41, 6.22, 6.68, 6.90, 8.03, 8.30, 9.16, 9.44, 12.10, 13.20, 13.60, 14.40μ; pmr (CCl4)δ1.4-1.9 (4H, m), 3.2-4.2 (6H, m), 4.58 (2H, broad s), 6.6-7.1 (4H, m), 7.20 (5H, s).