Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH:24][CH:25]([CH3:27])[CH3:26])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28](O)(=[O:35])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>>[Si:1]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]([CH:25]([CH3:27])[CH3:26])[C:28](=[O:35])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])([C:14]([CH3:16])([CH3:17])[CH3:15])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)NCCCCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: CCCCCCC(=O)O
Product: CCCCCCC(=O)N(CCCCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(C)C
Yield: 90.8 %

Procedure:
Following literature precedent,2 5-(tert-butyldiphenylsilyloxy)-N-isopropylpentan-1-amine (0.90 g, 2.30 mmol) was condensed with heptanoic acid (0.26 g, 2.0 mmol) to give the title amide (0.90 g, 79%) as a viscous oil. TLC: EtOAc/hexanes (3:8), Rf˜0.60; 1H NMR (300 MHz, 1:1 mixture of rotamers) δ 7.65-7.67 (m, 4H), 7.30-7.40 (m, 6H), 4.62-4.72 (m, 0.5H), 4.00-4.80 (m, 0.5H), 3.62 (t, J=4.8 Hz, 1H), 3.68 (t, J=4.8 Hz, 1H), 3.02 (t, J=5.2 Hz, 1H), 3.16 (t, J=5.2 Hz, 1H), 2.38 (t, J=5.3 Hz, 1H), 2.24 (t, J=5.3 Hz, 1H), 1.50-1.68 (m, 6H), 1.26-1.44 (m, 8H), 1.18 (d, J=7.3 Hz 3H), 1,12, (d, J=7.3 Hz 3H), 1.03 (s, 4.5H), 1.04 (s, 4.5H), 0.88 (t, J=7.3 Hz, 3H); 13C NMR (125 MHz) δ 173.38, 172.76, 135.80, 135.78, 134.36, 134.12, 129.85, 129.73, 127.88, 127.82, 64.22, 63.68, 48.43, 45.62, 43.64, 41.27, 34.13, 34.05, 32.61, 32.36, 31.96, 31.93, 31.51, 29.63, 29.47, 27.10, 27.03, 25.94, 25.78, 24.03, 23.77, 22.81, 21.63, 20.78, 19.47, 14.33, 14.28. HRMS calcd for C31HsoNO2Si [M+1]+ 496.3611. found 496.3615.
Reaction SMILES: [O:1]=[C:2]1[CH:7]([N:8]2[CH2:16][C:15]3[C:14]([C:17]#[N:18])=[CH:13][CH:12]=[CH:11][C:10]=3[C:9]2=[O:19])[CH2:6][CH2:5][C:4](=[O:20])[NH:3]1.[ClH:21]>CO.[Pd]>[ClH:21].[NH2:18][CH2:17][C:14]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:15]=1[CH2:16][N:8]([CH:7]1[CH2:6][CH2:5][C:4](=[O:20])[NH:3][C:2]1=[O:1])[C:9]2=[O:19]
Reactant: N#Cc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Reaction time: 17 h
Yield: 99 %

Procedure:
A mixture of 2-(2,6-dioxo(3-piperidyl))-1-oxoisoindoline-4-carbonitrile (1.0 g, 3.71 mmol) and 10% Pd/C (0.2 g) in 4N HCl (20 mL) and methanol (600 mL) was hydrogenated at 50 psi for 17 hours. The mixture was filtered through celite and the filtrate was concentrated. The residue was stirred with ether (30 mL) to give 3-[4-(aminomethyl)-1-oxoisoindolin-2-yl]piperidine-2,6-dione hydrochloride (1.1 g, 99%) as a white solid: 1H NMR (DMSO-d6) δ 11.06 (s, 1H), 8.64 (s, 3H), 7.79 (d, J=7.5 Hz, 1H), 7.74 (d, J=7.4 Hz, 1H), 7.59 (t, J=7.5 Hz, 1H), 5.21-5.14 (dd, J=5.0 and 13.2 Hz, 1H), 4.69 (d, J=17.4 Hz, 1H), 4.51 (d, J=17.4 Hz, 1H), 4.09 (d, J=4.9 Hz, 2H), 3.00-2.87 (m, 1H), 2.66-2.35 (m, 2H), 2.03-1.98 (m, 1H); 13C NMR (DMSO-d6) δ 172.87, 170.92, 167.77, 141.58, 132.50, 131.88, 129.39, 128.48, 123.25, 51.52, 46.19, 38.39, 31.17, 22.69.
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7]Cl.[F:9][C:10]1[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=1[NH2:12].C(=O)([O-])[O-].[K+].[K+].Cl>C(O)CCC>[ClH:2].[F:9][C:10]1[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=1[N:12]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1
Reactant: ClCCNCCCl
Reactant: Nc1ccccc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Product: Fc1ccccc1N1CCNCC1
Yield: 20.5 %

Procedure:
This compound was prepared according to the procedure used in Preparation 1. A mixture of 15.1 g (0.09 mol) of bis(2-chloroethyl)amine hydrochloride, 10.0 g (0.09 mol) of 2-fluoroaniline and 25.0 g of solid potassium carbonate in a total volume of 100 mL of 1-butanol gave an oil as residue. The oil was converted to the hydrochloric acid salt (ethereal HCl) and recrystallized from methanol-ether to give 4.0 g (20%) of white solid, mp 185°-187° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[S:23]([N:26]1[CH2:31][CH2:30][CH2:29][CH:28]([C:32](O)=[O:33])[CH2:27]1)(=[O:25])=[O:24]>>[CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[S:23]([N:26]1[CH2:31][CH2:30][CH2:29][CH:28]([C:32]([N:10]2[CH2:9][CH2:8][N:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[CH2:12][CH2:11]2)=[O:33])[CH2:27]1)(=[O:24])=[O:25]
Reactant: O=C(O)C1CCCN(S(=O)(=O)c2ccc3ccccc3c2)C1
Reactant: c1cc(N2CCNCC2)ccn1
Product: O=C(C1CCCN(S(=O)(=O)c2ccc3ccccc3c2)C1)N1CCN(c2ccncc2)CC1
Yield: 25 %

Procedure:
Using an analogous procedure to that described in Example 14, 1-(4-pyridyl)piperazine was reacted with 1-(2-naphthylsulphonyl)piperidine-3-carboxylic acid to give 1-[1-(2-naphthylsulphonyl)-piperidin-3-ylcarbonyl]-4-(4-pyridyl)piperazine as a foam in 25% yield;
Reaction SMILES: [OH-:1].[Na+].[CH2:3]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([C:15]([F:18])([F:17])[F:16])[CH:9]=1)[CH2:4][CH2:5][CH3:6]>>[CH2:3]([N:7]([C:3]1[O:1][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=1)[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([C:15]([F:18])([F:16])[F:17])[CH:9]=1)[CH2:4][CH2:5][CH3:6]
Reactant: [OH-]
Reactant: CCCCNc1ccc(Cl)c(C(F)(F)F)c1
Agent: [Na+]
Product: CCCCN(c1ccc(Cl)c(C(F)(F)F)c1)c1nc2ccccc2o1

Procedure:
Hydrolysis of this N-(n-butyl)benzanilide (33 ., 0.093 mole) was accomplished by adding it to a solution of sodium hydroxide (10.8 g., 0.372 mole) in 200 ml. of water and 100 ml. of ethanol. The resulting solution was heated under reflux for 20 hours. The ethanol was then removed by distillation under vacuum. The remaining basic solution was extracted with diethyl ether; the ether extract was dried over magnesium sulfate and filtered. The filtrate was evaporated to dryness by distillation under vacuum. The crude product obtained was purified by addition of 6 N hydrochloric acid and separation of the water-insoluble salts thus formed. The acidic solution was then made basic by the addition of an aqueous 10% sodium hydroxide solution. The product was again extracted with ether and dried, as described above, to give 16.9 g. of N-(n-butyl)-4-chloro-3-(trifluoromethyl)aniline.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:5]=1[CH:6]=O)([O-:3])=[O:2].C(N(C(C)C)C(C)C)C.[Cl-].[Li+].C(OP([CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])(OCC)=O)C>CC#N>[N+:1]([C:4]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:5]=1/[CH:6]=[CH:34]/[C:35]([O:37][CH2:38][CH3:39])=[O:36])([O-:3])=[O:2]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: O=Cc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [Li+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)/C=C/c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 12 h
Yield: 79.8 %

Procedure:
To a mixture of 2,4-dinitrobenzaldehyde (12.0 g, 61.2 mmol), N-ethyl-N-isopropylpropan-2-amine (11.9 g, 91.8 mmol) and lithium chloride (3.1 g, 24.1 mmol) in CH3CN (100 mL) was added slowly ethyl 2-(diethoxyphosphoryl)acetate (16.5 g, 64.3 mmol) and the reaction mixture was stirred at ambient temperature for 12 h. After filtration, the solvent was removed in vacuo and the residue was purified by column chromatography on silica gel (eluting with 4% EtOAc in petroleum ether) to give (E)-ethyl 3-(2,4-dinitrophenyl)acrylate (13 g, 84%). 1H NMR (CDCl3, 400 MHz): δ 8.83 (s, 1H), 8.42 (d, J=8.8 Hz, 1H), 8.02 (d, J=16.0 Hz, 1H), 7.77 (d, J=8.8 Hz, 1H), 6.39 (d, J=16.0 Hz, 1H), 4.24 (q, J=7.2 Hz, 2H), 1.29 (t, J=7.2 Hz, 3H).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:29](/[CH:30]=[CH:31]/[CH:32]=[O:33])=[C:28]([CH3:34])[N:27]=[C:26]([CH3:35])[N:25]=2)=[CH:20][CH:19]=1>O1CCCC1>[F:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[C:29]([CH:30]=[CH:31][CH:32]([OH:33])[CH2:5][C:3](=[O:4])[CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6])=[C:28]([CH3:34])[N:27]=[C:26]([CH3:35])[N:25]=2)=[CH:22][CH:23]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: Cc1nc(C)c(/C=C/C=O)c(-c2ccc(F)cc2)n1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)CC(O)C=Cc1c(C)nc(C)nc1-c1ccc(F)cc1
Temperature: 0 °C

Procedure:
A solution of ethyl acetoacetate (11.65 mL, 0.0914 mol) in 50 mL of anhydrous tetrahydrofuran was added dropwise with stirring to a suspensionof sodium hydride (2.39 g, 0.0992 mol) in anhydrous tetrahydrofuran at 0° C. under nitrogen. The resulting mixture was stirred at 0° C. for ten minutes, after which n-butyl lithium (38.1 mL, 2.4M solution in tetrahydrofuran, 0.0914 mol) was added dropwise. The resultingorange solution was stirred for an additional ten minutes and then cooled to -78° C. A solution of (E)-3-[4-(4-fluorophenyl)-2,6-dimethyl-5-pyrimidinyl]-2-propenal (21.27 g,0.083 mol) in 100 mL of anhydrous tetrahydrofuran was added dropwise. The resulting solution was stirred for thirty minutes, and the cooling bath was removed, after which the reaction was quenched by the addition of 12 mL of glacial acetic acid.
Reaction SMILES: [C:1]([NH:5][NH:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[N+:17]([C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23])([O-:19])=[O:18]>C1(C)C=CC=CC=1.O>[C:1]([N:5]([C:22](=[O:23])[C:21]1[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=1[N+:17]([O-:19])=[O:18])[NH:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Reactant: CC(C)(C)NNC(=O)c1ccccn1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)N(NC(=O)c1ccccn1)C(=O)c1ccccc1[N+](=O)[O-]
Temperature: 23 °C
Reaction time: 8 h
Yield: 22.6 %

Procedure:
A solution of N'-t-butyl-N-(2-pyridinecarbonyl)hydrazine (1.0 g, 0.00518 mol) in 20 ml of toluene was treated dropwise simultaneously with a solution of sodium hydroxide (1.24 g of 50% aqueous solution) in 5 ml of water and 2-nitrobenzoyl chloride (0.96 g). The resulting mixture was stirred at 23° C. overnight. Water was added and the mixture was extracted with ether. A second extraction was performed with methylene chloride and the combined organic extracts were dried over magnesium sulfate. Evaporation afforded 0.4 g of N'-t-butyl-N-(2-pyridinecarbonyl)-N'(2-nitrobenzoyl)hydrazine as a yellow solid. m.p. 137°-140° C.
Reaction SMILES: [CH3:1][N:2]1[C@H:16]2[C@@:6]([O:18][CH3:19])([C:7]3[CH:8]=[CH:9][CH:10]=[C:11]4[C:17]=3[C:14]([CH2:15]2)=[CH:13][NH:12]4)[CH2:5][C@@H:4]([CH2:20][OH:21])[CH2:3]1.S(=O)(=O)(O)O.[Na].C(O)[CH2:29][OH:30]>>[CH3:1][N:2]1[C@H:16]2[C@@:6]([O:18][CH2:19][CH2:29][OH:30])([C:7]3[CH:8]=[CH:9][CH:10]=[C:11]4[C:17]=3[C:14]([CH2:15]2)=[CH:13][NH:12]4)[CH2:5][C@@H:4]([CH2:20][OH:21])[CH2:3]1
Reactant: CO[C@]12C[C@@H](CO)CN(C)[C@@H]1Cc1c[nH]c3cccc2c13
Reactant: OCCO
Agent: O=S(=O)(O)O
Agent: [Na]
Product: CN1C[C@H](CO)C[C@]2(OCCO)c3cccc4[nH]cc(c34)C[C@@H]12
Temperature: 0 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
A stirred solution of 10 g of 6-methyl-8β-hydroxymethyl-10α-methoxy-ergoline in 100 ml of ethylen glycol was treated with 7.5 ml of concentrated sulphuric acid at room temperature. After stirring for 3 hour, the solution was poured into ice water then made alkaline with concentrated sodium hydroxyde. The precipitated was collected washed with water, and crystallised from ehanol to provide the title compound in 75% yield, m.p. 201-205° C.
Reaction SMILES: O.[CH2:2]([N:9]1[C@H:13]2[CH2:14][S:15]/[C:16](=[CH:17]\[CH2:18][CH2:19][CH2:20][C:21]([O:23]CC)=[O:22])/[C@H:12]2[N:11]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:10]1=[O:33])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[H][H]>[OH-].[OH-].[Pd+2].CO>[CH2:2]([N:9]1[C@H:13]2[CH2:14][S:15][C@@H:16]([CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])[C@H:12]2[N:11]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:10]1=[O:33])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: [H][H]
Reactant: CCOC(=O)CCC/C=C1\SC[C@H]2[C@@H]1N(Cc1ccccc1)C(=O)N2Cc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CCCC[C@@H]1SC[C@H]2[C@@H]1N(Cc1ccccc1)C(=O)N2Cc1ccccc1
Temperature: 117 °C
Reaction time: 4 h
Yield: 72.4 %

Procedure:
400 ml of purified water, 12.85 g of 20% palladium hydroxide on carbon (50% wet), 900 ml of a methanol solution containing 249.5 g of ethyl (5Z)-5-[(3aS,6aR)-1,3-dibenzyl-hexahydro-2-oxo-4H-thieno[3,4-d]imidazol-4-yliden]pentanoate were added successively in this order, and the atmosphere was replaced with 490 kPa hydrogen three times. Moreover, 627 kPa hydrogen pressure was applied at 6.5° C., and the mixture was stirred at 500 rpm. The reaction temperature and the pressure became 92.5° C. and 843 kPa at 50 minutes after initiation of heating, 117° C. and 921 kPa after 4 hours, and 116° C. and 853 kPa after 11 hours, so that hydrogen was charged up to 882 kPa. After 24 hours, the reaction mixture was cooled at 115° C. and 892 kPa, washed with methanol, and the catalyst was filtered off. The filtrate was concentrated, 400 ml of toluene was added to the residue, and replacement and concentration were carried out three times with an outer bath at 65° C. To the above-mentioned residue were added 1206 ml of methanol, 402 ml of water and 53.3 g of sodium hydroxide, the resulting mixture was stirred at 40° C. for 2 hours. To the reaction mixture was added 300 g of 10% aqueous hydrochloric acid, the mixture was neutralized to pH 7, 6 g of activated charcoal was added to the mixture and the resulting mixture was stirred at room temperature for 40 minutes. The reaction mixture was subjected to precoat filtration with 6 g of activated charcoal. Methanol was distilled of under reduced pressure, and 600 ml of ethyl acetate was added. 10% aqueous hydrochloric acid was added to the mixture to carry out extraction (pH of the aqueous layer was 0.7), and the organic layer was washed with 10% brine. The organic layer was dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and when no ethyl acetate was distilled off, the residue was subjected to replacement with 170 ml of mesitylene and concentration two times to give 170.1 g of (3aS,4S,6aR)-1,3-dibenzyl-hexahydro-2-oxo-4H-thieno[3,4-d]imidazol-4-pentanoic acid as colorless oily product.
Reaction SMILES: N[C:2](N)=[O:3].[NH2:5][C:6]([CH3:13])([CH3:12])[CH2:7][NH:8][CH2:9][CH2:10][OH:11].N>>[OH:11][CH2:10][CH2:9][N:8]1[CH2:7][C:6]([CH3:13])([CH3:12])[NH:5][C:2]1=[O:3]
Reactant: CC(C)(N)CNCCO
Reactant: NC(N)=O
Agent: N
Product: CC1(C)CN(CCO)C(=O)N1
Yield: 41.7 %

Procedure:
A mixture of urea (5.4 g, 91 mmol) and 2-((2-amino-2-methylpropyl)amino)ethanol (12 g, 91 mmol) was heated in a 200° C. sand bath for approximately 45 min until ammonia evolution had ceased. The crude mixture was purified by column chromatography, eluting from silica gel with a gradient of 0-10% methanol in dichloromethane to give 6.0 g of a white solid. 1H NMR (CDCl3, 400 MHz) δ 1.33 (s, 6H), 3.21 (s, 2H), 3.27-3.30 (t, J=5.2, 2H), 3.69-3.71 (q, J=5.2 Hz, 2H), 4.01-4.04 (t, J=5.4, 1H), 5.31 (br s, 1H); LRMS (ESI/APCI) m/z 159 [M+H]+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)=O.[CH3:13][NH:14][C:15](=[S:18])[NH:16][NH2:17]>C(O)C>[Cl:1][CH2:2][CH2:3][CH2:4][C:5](=[N:17][NH:16][C:15](=[S:18])[NH:14][CH3:13])[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C(CCCCl)c1cccnc1
Reactant: CNC(=S)NN
Solvent: CCO
Product: CNC(=S)NN=C(CCCCl)c1cccnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 112.2 %

Procedure:
A mixture of 4-chloro-1-(3-pyridinyl)-1-butanone (4.4 g, 24 mmol) and 4-methylthiosemicarbazide (2.5 g, 24 mmol) in 150 mL of ethanol under a nitrogen atmosphere was warmed to dissolve all the solids and then allowed to stir at room temperature overnight. By TLC the reaction was not complete. The reaction was then heated at 70° C. for 5 hours and overnight at room temperature. The solvent was removed under reduced pressure to give 7.29 g of a yellow oil. Purification of this oil on 700 g of silica gel (230-400 mesh) using 50-70% EtOAc-hexane as the eluent gave 4.14 g (64%) of the title compound as a white solid, mp 100-102° C.
Reaction SMILES: [C:1](/[C:3](=[C:8]1/[C:9](=[O:22])[NH:10][C:11]2[C:16]/1=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=2)/[C:4]([O:6][CH3:7])=[O:5])#[N:2].[C-:23]#[N:24].[K+]>>[C:1]([CH:3]([C:8]1([C:23]#[N:24])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][C:18]([F:19])([F:21])[F:20])[CH:15]=2)[NH:10][C:9]1=[O:22])[C:4]([O:6][CH3:7])=[O:5])#[N:2]
Reactant: [C-]#N
Reactant: COC(=O)/C(C#N)=C1\C(=O)Nc2ccc(OC(F)(F)F)cc21
Agent: [K+]
Product: COC(=O)C(C#N)C1(C#N)C(=O)Nc2ccc(OC(F)(F)F)cc21
Yield: 90 %

Procedure:
Following the general method as outlined for Intermediate 5, starting from methyl (2Z)-cyano[2-oxo-5-(trifluoromethoxy)-1,2-dihydro-3H-indol-3-ylidene]acetate (intermediate 3) and potassium cyanide, the title compound was isolated, after evaporation, as a pale brown solid in 90% yield. This was a mixture of diastereomers.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]=[O:11])[C:5]=1[NH:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14].Cl.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32]Cl)[CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]=[O:11])[C:5]=1[N:12]([S:13]([C:16]1[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=1)(=[O:14])=[O:15])[CH2:32][C:28]1[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=1
Reactant: ClCc1cccnc1
Reactant: COC(=O)c1cccc(C=O)c1NS(=O)(=O)c1ccc(OC)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(C=O)c1N(Cc1cccnc1)S(=O)(=O)c1ccc(OC)cc1
Reaction time: 18 h
Yield: 62.6 %

Procedure:
To a solution of 0.20 g (0.573 mmol) of the product of Example 321 in 2.5 mL of DMF was added 0.099 g (0.602 mmol) of 3-picolyl chloride hydrochloride and 0.249 g (1.805 mmol) of potassium carbonate. The reaction was stined for 18 h at room temperature and then the reaction was then diluted with water and extracted with ether. The combined organics were washed with water, dried over Na2SO4, filtered and concentrated in vacuo. The residue was triturated with ether to give 0.158 g (63%) of the product as tan crystals. Electrospray Mass Spec: 440.9 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:18][C:19]#[N:20]>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[C:18](/[C:17]2[CH:21]=[CH:22][C:23]([O:24][CH3:25])=[C:15]([O:14][CH3:13])[CH:16]=2)\[C:19]#[N:20])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: COc1ccc(CC#N)cc1OC
Reactant: O=Cc1ccc(Cl)c([N+](=O)[O-])c1
Product: COc1ccc(/C(C#N)=C/c2ccc(Cl)c([N+](=O)[O-])c2)cc1OC
Yield: 35.9 %

Procedure:
4-Chloro-3-nitrobenzaldehyde (557 mg) and 3,4-dimethoxybenzyl cyanide (532 mg) were subjected to condensation in accordance with process B of (production process 2), to thereby produce the target product (372 mg, yield: 36%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].C([O-])([O-])=O.[K+].[K+].[CH2:21]([O:28][C:29](Cl)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O.O1CCOCC1>[CH2:21]([O:28][C:29]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCCCCCCCCCC(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)CCCCCCCCCCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35 %

Procedure:
To a suspension of 11-aminoundecanoic acid (17) in 1:1 water/dioxane (160 mL total) was added K2CO3 (10.28 g, 74.51 mmol) followed by the slow addition over 30 min of benzylchloroformate (CbzCl, 4.55 mL, 32.29 mmol), and the mixture was stirred at room temperature for 2 h. The solid was then removed by filtration, washed with water (3×30 mL) and dried in a vacuum oven at 40° C. for 72 h to afford a white solid 18 (2.91 g, 35% yield): 1H NMR (500 MHz, CD3OD) δ 1.36 (m, 12H), 1.50 (m, 2H), 1.62 (m, 2H), 2.18 (m, 2H), 3.08 (m, 2H), 5.14 (s, 2H), 7.38 (m, 5H); m/z (ESI) 336 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:14])=[C:8]([CH2:12][CH3:13])[C:9]=2[CH3:11])[S:4][C:3]=1[C:15]([OH:17])=O.N=C=N.[C:21]1([C:27]2NN=[N:29][N:28]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>ClC(Cl)C.CN(C=O)C>[CH2:12]([C:8]1[C:9]([CH3:11])=[C:10]2[C:2]([NH2:1])=[C:3]([C:15]3[O:17][C:27]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:28][N:29]=3)[S:4][C:5]2=[N:6][C:7]=1[CH3:14])[CH3:13]
Reactant: CCc1c(C)nc2sc(C(=O)O)c(N)c2c1C
Reactant: c1ccc(-c2nnn[nH]2)cc1
Agent: N=C=N
Solvent: CN(C)C=O
Solvent: CC(Cl)Cl
Product: CCc1c(C)nc2sc(-c3nnc(-c4ccccc4)o3)c(N)c2c1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 56.2 %

Procedure:
To a solution of 3-amino-5-ethyl-4,6-dimethyl-thieno[2,3-b]pyridine-2-carboxylic acid (0.16 g, 0.63 mmol) in a mixture of dichloroethane (8 mL) and DMF (2 mL) was added PS-carbodiimide (1.0 g, 1.26 mmol). The mixture was shaken for 15 min at room temperature, followed by the addition of 5-phenyltetrazole (0.042 g, 0.32 mmol). Then, the mixture was shaken at 80° C. overnight. The resin was then removed by filtration and washed with hot chloroform (2×5 mL). The filtrate was evaporated in vacuum to dryness and purified by chromatography (silica gel, dichloromethane/ethyl acetate, 9/1) to furnish the product 5-ethyl-4,6-dimethyl-2-(5-phenyl-[1,3,4]oxadiazol-2-yl)-thieno[2,3-b]pyridin-3-yl amine (0.063 g, 56%).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([C:6]1[CH:7]=[C:8]([C:12](OC)=[O:13])[CH:9]=[N:10][CH:11]=1)([OH:5])[CH3:4].[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1.ClCCl>[F:17][C:2]([F:1])([F:16])[C:3]([C:6]1[CH:7]=[C:8]([CH:12]=[O:13])[CH:9]=[N:10][CH:11]=1)([OH:5])[CH3:4]
Reactant: COC(=O)c1cncc(C(C)(O)C(F)(F)F)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(O)(c1cncc(C=O)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a cooled (−78° C.) solution of the title compound from Step B (0.14 g, 0.56 mmol) in toluene (3.23 mL) and dichloromethane (3.23 mL) was added a solution of di-isobutyl aluminum hydride in toluene (1.0 M, 1.29 mL, 1.29 mmol). After 10 min, the reaction was quenched with water (1 mL), allowed to warm to room temperature, and dried over magnesium sulfate. Concentration of the filtrate under reduced pressure provided the title compound: 1H NMR (500 MHz, CDCl3) δ 10.16 (s, 1 H), 9.08 (s, 1 H), 9.07 (s, 1 H), 8.41 (s, 1 H), 3.30 (br s, 1 H), 1.88 (s, 3 H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([B:14]2[O:18][C:17]([CH3:20])([CH3:19])[C:16]([CH3:22])([CH3:21])[O:15]2)=[C:8]([CH:13]=1)[C:9](OC)=[O:10])([O-:3])=[O:2].[H-].C([Al+]CC(C)C)C(C)C.CO.Cl>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([B:14]2[O:18][C:17]([CH3:20])([CH3:19])[C:16]([CH3:22])([CH3:21])[O:15]2)=[C:8]([CH2:9][OH:10])[CH:13]=1)([O-:3])=[O:2]
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1B1OC(C)(C)C(C)(C)O1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: CO
Solvent: ClCCl
Product: CC1(C)OB(c2ccc([N+](=O)[O-])cc2CO)OC1(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
Methyl 5-nitro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (C) (2.5 g, 8.14 mmol) was dissolved in DCM (25 mL), flushed with argon and cooled in an ice bath to 0° C. A solution of 1 M diisobutylaluminum hydride in DCM (20.5 mL, 20.35 mmol) was added dropwise so that the temperature remained below 3° C. over 2 h. The black reaction mixture was stirred at 0° C. for an additional 2 h. After this time, MeOH (3 mL) was added causing a yellow precipitate to form. 1 M aqueous HCl (50 mL) was then added and reaction was stirred for 30 min at 0° C. The layers were separated and the aqueous phase was extracted with EtOAc (3×50 mL). The combined organic phases were washed with brine and dried over anhydrous MgSO4 to produce (5-nitro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol (CI) as a black oil (1.25 g, 4.48 mmol, 55% yield, purity 85%). The product was used without further purification for step 3.