Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[N:10]=[N:9][C:8]=2[C:19]([F:22])([F:21])[F:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:23][C:24]1[CH:25]=[C:26]([CH:29]=[C:30]([F:32])[CH:31]=1)[CH2:27]Br.C(N(C(C)C)CC)(C)C>C(#N)C>[F:23][C:24]1[CH:25]=[C:26]([CH:29]=[C:30]([F:32])[CH:31]=1)[CH2:27][N:16]1[CH2:15][CH2:14][N:13]([C:11]2[N:10]=[N:9][C:8]([C:19]([F:22])([F:21])[F:20])=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:12]=2)[CH2:18][CH2:17]1
Reactant: FC(F)(F)c1nnc(N2CCNCC2)cc1-c1ccccc1
Reactant: Fc1cc(F)cc(CBr)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Fc1cc(F)cc(CN2CCN(c3cc(-c4ccccc4)c(C(F)(F)F)nn3)CC2)c1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 53.2 %

Procedure:
A mixture of 4-phenyl-6-piperazin-1-yl-3-trifluoromethyl-pyridazine (E1) (0.050 g, 0.16 mmol), 3,5-difluorobenzyl bromide (0.031 ml, 0.24 mmol) and diisopropylethylamine (0.056 ml, 0.32 mmol) in acetonitrile (2 ml) was stirred at 100° C. for 10 min., under microwave irradiation. The solvent was evaporated in vacuo and then, dichloromethane and ammonium chloride (10% aqueous solution) were added. The mixture was filtered through a diatomaceous earth cartridge. The solvent was then evaporated in vacuo and the residue was purified by CC-TLC (centrifugal circular thin-layer chromatography) on a chromatotron (a preparative, centrifugally accelerated, radial, thin-layer chromatograph). The crude product was crystallised from diethyl ether/heptane to yield E3 (0.037 g, 52%) as a solid. C22H19F5N4 requires 434. Found 435 (MH+).
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][CH:24]([N:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[C:31]([C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1)#[N:32].N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:30][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:37]3[CH:38]=[C:33]([CH:34]=[CH:35][CH:36]=3)[C:31]#[N:32])[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][CH:24]([N:27]([CH3:28])[CH3:29])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: CN(C)C1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Reactant: N#Cc1cccc(B(O)O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN(C)C1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3-c2cccc(C#N)c2)CC1
Yield: 26 %

Procedure:
The title compound was synthesized in analogy to example 66, from (4,4-difluoro-piperidin-1-yl)-[5-(4-dimethylamino-piperidine-1-carbonyl)-1H-indol-2-yl]-methanone (example 140, intermediate a)), 3-cyanophenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as an off-white foam (26%).
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]4[CH2:21][CH2:20][N:19](C5C=CC=CC=5)[C:18]4=[O:28])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[CH2:31](N=C=O)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:31]([N:19]1[CH2:20][CH2:21][N:17]([CH2:16][CH2:15][N:12]2[CH2:13][CH2:14][CH:9]([C:6]3[C:5]4[CH:29]=[CH:30][C:2]([F:1])=[CH:3][C:4]=4[O:8][N:7]=3)[CH2:10][CH2:11]2)[C:18]1=[O:28])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C=NCc1ccccc1
Reactant: O=C1N(CCN2CCC(c3noc4cc(F)ccc34)CC2)CCN1c1ccccc1
Product: O=C1N(CCN2CCC(c3noc4cc(F)ccc34)CC2)CCN1Cc1ccccc1

Procedure:
This product is obtained in the same manner as the compound of Example 5, but with replacement of the phenyl isocyanate by benzyl isocyanate in Step 1 of the synthesis. The expected product melts at 126°-130° C.
Reaction SMILES: C([N:3]1[C:10]2[N:6]([N:7]=[CH:8][C:9]=2[CH2:11][CH2:12][C:13]([O:15]CC)=O)[CH2:5][CH2:4]1)=O.[NH3:18]>CO>[NH:3]1[C:10]2[N:6]([N:7]=[CH:8][C:9]=2[CH2:11][CH2:12][C:13]([NH2:18])=[O:15])[CH2:5][CH2:4]1
Reactant: CCOC(=O)CCc1cnn2c1N(C=O)CC2
Reactant: N
Solvent: CO
Product: NC(=O)CCc1cnn2c1NCC2

Procedure:
A solution of ethyl 3-(1-formyl-2,3-dihydro-1H-imidazo[1,2-b]pyrazol-7-yl)propanoate (10 g) in a mixture of methanol (50 ml) and an aqueous solution of 28% ammonia (104 ml) was stirred at room temperature for 41 hours. After evaporation of the solvent in vacuo, the residue was triturated with diisopropyl alcohol, dried in vacuo to give 3-(2,3-dihydro-1H-imidazo[1,2-b]pyrazol-7-yl)propanamide (6.44 g).
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:17]([F:18])=[CH:16][C:13]([C:14]#[N:15])=[C:12]([NH:19][C@H:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[CH3:21])[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.N[C@H](C1C=CC(F)=CC=1)C[OH:32].CCN(C(C)C)C(C)C>CCCCO>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:17]([F:18])=[CH:16][C:13]([C:14]#[N:15])=[C:12]([NH:19][C@H:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[CH2:21][OH:32])[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: N[C@@H](CO)c1ccc(F)cc1
Reactant: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1C#N)c1ccc(F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: N#Cc1cc(F)c(Nc2cc(C3CC3)[nH]n2)nc1N[C@@H](CO)c1ccc(F)cc1
Temperature: 140 °C
Yield: 42 %

Procedure:
2-Chloro-6-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoronicotinonitrile (Method 1; 0.5 g, 1.8 mmol) and (R)-2-amino-2-(4-fluorophenyl)ethanol (0.6 g, 3.6 mmol) were added to a solution of n-BuOH (4 ml) and DIEA (0.3 g, 2.3 mmol) in a sealed tube. The reaction was heated to 140° C. for 48 hrs, then cooled to 25° C. and concentrated. The resulting residue was purified by column chromatography (DCM-MeOH=80:1) to give the title compound (0.3 g, 40%). 1H NMR (400 MHz, CD3OD) δ 7.37-7.35 (m, 3H), 7.05-7.00 (m, 2H), 5.99 (s, 1H), 5.20-5.11 (m, 1H), 3.90-3.77 (m, 2H), 1.90-1.86 (m, 1H), 1.05-0.96 (m, 2H), 0.73-0.66 (m, 2H). MS: Calcd.: 396. Found: [M+H]+ 397.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[N:5]2[C:10]3[CH:11]=[CH:12][N:13]([S:14]([C:17]4[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=4)(=[O:16])=[O:15])[C:9]=3[N:8]=[CH:7][C:6]=12.CC1(C)C(C)(C)OB(/[CH:38]=[CH:39]/[C:40]([O:42][CH2:43][CH3:44])=[O:41])O1.C([O-])([O-])=O.[Na+].[Na+].O>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH:24]1([C:4]2[N:5]3[C:10]4[CH:11]=[CH:12][N:13]([S:14]([C:17]5[CH:18]=[CH:19][C:20]([CH3:21])=[CH:22][CH:23]=5)(=[O:15])=[O:16])[C:9]=4[N:8]=[CH:7][C:6]3=[C:2](/[CH:38]=[CH:39]/[C:40]([O:42][CH2:43][CH3:44])=[O:41])[N:3]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: CCOC(=O)/C=C/B1OC(C)(C)C(C)(C)O1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2c(Br)nc(C4CCCCC4)n23)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)/C=C/c1nc(C2CCCCC2)n2c1cnc1c2ccn1S(=O)(=O)c1ccc(C)cc1
Temperature: 65 °C
Reaction time: 15 h
Yield: 163.1 %

Procedure:
To a solution of 3-bromo-1-cyclohexyl-6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine (0.026 g, 0.056 mmol, Preparation #MM.1) and PdCl2(dppf)•DCM adduct (0.005 g, 0.006 mmol) in THF (1 mL) was added (E)-ethyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)acrylate (0.052 g, 0.23 mmol) and Na2CO3 (0.021 g, 0.20 mmol) followed by water (0.25 mL). The reaction mixture was heated to about 65° C. After about 15 h, the reaction mixture was cooled to ambient temperature and directly purified by chromatography on silica gel (12 g) eluting with 20-80% EtOAc:DCM (1:1) in heptane to provide (E)-ethyl 3-(1-cyclohexyl-6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-3-yl)acrylate (0.045 g, 70%) as a yellow solid: LC/MS (Table 1, Method a) Rt=3.15 min; MS m/z: 493 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:32][C:33]1[CH:34]=[N:35][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:37][CH:38]=1)[CH2:10][CH2:11][C:12]1[S:16][C:15]([C:17]2[CH:18]=[CH:19][C:20]([N+:29]([O-])=O)=[C:21]([CH2:23][C:24](OCC)=[O:25])[CH:22]=2)=[N:14][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C([O-])(O)=O.[Na+]>CCO.O.[Fe]>[O:25]=[C:24]1[CH2:23][C:21]2[C:20](=[CH:19][CH:18]=[C:17]([C:15]3[S:16][C:12]([CH2:11][CH2:10][C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:32][C:33]4[CH:34]=[N:35][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:37][CH:38]=4)=[N:13][N:14]=3)[CH:22]=2)[NH:29]1
Reactant: CCOC(=O)Cc1cc(-c2nnc(CC[C@H](Cc3ccc(C(F)(F)F)nc3)NC(=O)OC(C)(C)C)s2)ccc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@H](CCc1nnc(-c2ccc3c(c2)CC(=O)N3)s1)Cc1ccc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Iron powder (48 mg, 853 μmol) was added to a suspension of ethyl 2-(5-(5-((R)-3-(tert-butoxycarbonylamino)-4-(6-(trifluoromethyl)pyridin-3-yl)butyl)-1,3,4-thiadiazol-2-yl)-2-nitrophenyl)acetate (104 mg, 171 μmol) in EtOH (1.5 mL). 2N aqueous HCl (256 μL, 512 μmol) was added, and the mixture was heated under reflux for 4 hours. Saturated aqueous NaHCO3 (5 mL) was added dropwise and the mixture was stirred at room temperature for 5 minutes. It was diluted with H2O (5 mL) and extracted with DCM (3×15 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure. The resulting light yellow oil was absorbed onto silica gel and purified by flash chromatography (silica gel, 2% to 6% MeOH/DCM) to deliver tert-butyl (R)-4-(5-(2-oxoindolin-5-yl)-1,3,4-thiadiazol-2-yl)-1-(6-(trifluoromethyl)pyridin-3-yl)butan-2-ylcarbamate (49 mg, 54%) as a white solid. LCMS (API-ES) m/z: 534.0 (M+H+).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8](OC)=[C:7]([N+:16]([O-:18])=[O:17])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:19]([NH2:23])([CH2:21][CH3:22])[CH3:20]>>[CH:19]([NH:23][C:8]1[C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][C:7]=1[N+:16]([O-:18])=[O:17])([CH2:21][CH3:22])[CH3:20]
Reactant: COc1c([N+](=O)[O-])cc(C(C)(C)C)cc1[N+](=O)[O-]
Reactant: CCC(C)N
Product: CCC(C)Nc1c([N+](=O)[O-])cc(C(C)(C)C)cc1[N+](=O)[O-]

Procedure:
An alternative synthesis for N-sec-butyl-4-tert-butyl-2,6-dinitroaniline is set forth in U.S. Pat. Nos. 4,289,907 and 4,395,572 to Chan. The starting material in this synthesis is a nitrophenol such as 2,6-dinitro-4-tert-butylphenol. The nitrophenol is methylated by reaction with methyl iodide/potassium carbonate to produce 4-tert-butyl-2,6-dinitroanisole. The 4-tert-butyl-2,6-dinitroanisole is then reacted with sec-butylamine to produce N-sec-butyl-4-tert-butyl-2,6-dinitroaniline. While effective in producing the desired product, this process also suffers from a number of distinct disadvantages.
Reaction SMILES: C(OC([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20](Cl)[C:19]3[C:23](=[O:33])[N:24](C(OC(C)(C)C)=O)[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=O)(C)(C)C.[F:35][C:36]([F:43])([F:42])[C:37]1[N:38]=[CH:39][NH:40][CH:41]=1.C([O-])([O-])=O.[K+].[K+].[C:50]([OH:56])([C:52]([F:55])([F:54])[F:53])=[O:51]>C(#N)C>[C:50]([OH:56])([C:52]([F:55])([F:54])[F:53])=[O:51].[NH2:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20]([N:40]3[CH:41]=[C:37]([C:36]([F:43])([F:42])[F:35])[N:38]=[CH:39]3)[C:19]3[C:23](=[O:33])[NH:24][CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1
Reactant: FC(F)(F)c1c[nH]cn1
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1COCC[C@H]1Nc1nc(-n2cnc(C(F)(F)F)c2)c2c(c1F)CNC2=O
Yield: 8.8 %

Procedure:
In a 10 mL sealed cap glass vial, tert-butyl 6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (60 mg, 0.120 mmol), 4-(trifluoromethyl)-1H-imidazole (48.9 mg, 0.359 mmol) and K2CO3 (66.2 mg, 0.479 mmol) were dissolved in ACN (2 mL). The cap was sealed and the mixture was reacted at 100° C. for 16 h. The reaction mixture was subsequently filtered through a Buchner funnel to remove un-dissolved K2CO3. The solids were washed with ACN (2×5 mL) and the filtrate was evaporated to give a residue, which was treated with TFA (2 mL) at RT for 20 min to remove the protecting groups. Next, TFA was evaporated from the reaction mixture. The product was reconstituted in DMSO (5 mL) and was then purified by preparative HPLC eluting with water (0.05% TFA) and ACN (15-45% gradient, 0.035% TFA). The pure fractions were combined, evaporated to a minimal volume, and lyophilized to give a TFA salt of the title compound as a brown solid (4.2 mg, 8.8%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.67 (m, 1H), 2.05 (td, J=12.88, 7.33 Hz, 1H), 3.30-3.90 (m, 4H), 3.78-3.99 (m, 2H), 4.44 (s, 2H), 6.49 (br s, 2H), 7.54 (d, J=5.56 Hz, 1H), 7.85 (br s, 2H), 8.67-8.80 (m, 2H). [M+H] calc'd for C16H16F4N6O2, 401. found, 401.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([OH:9])[C:6]([C:10](=[O:26])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[C:5]([CH2:27][CH2:28][CH3:29])[C:3]=1[OH:4].[BH4-].[Na+]>CO.O>[CH3:1][C:2]1[CH:8]=[C:7]([OH:9])[C:6]([CH:10]([OH:26])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[C:5]([CH2:27][CH2:28][CH3:29])[C:3]=1[OH:4]
Reactant: CCCCCCCCCCCCCCCC(=O)c1c(O)cc(C)c(O)c1CCC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCCCCCCCCCCCCCC(O)c1c(O)cc(C)c(O)c1CCC

Procedure:
6.5 g of the keto-compound of step 4 were dissolved in 90 ml of methanol and hydrogenated with a solution of 0.75 g of sodium borohydride in 8 ml of water as described for compound 17, step 5. The crude carbinol formed was recrystallized from methanol.
Reaction SMILES: CCO.C(Cl)(=O)C.[CH2:8]([O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH:24]([OH:27])[C:25]#[N:26])=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.N[C:29]1[C:34]([OH:35])=[CH:33][CH:32]=[CH:31][N:30]=1>C(Cl)(Cl)Cl>[CH2:8]([O:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:22][CH2:23][CH:24]([C:25]2[O:35][C:34]3[C:29]([N:26]=2)=[N:30][CH:31]=[CH:32][CH:33]=3)[OH:27])=[CH:20][CH:21]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Nc1ncccc1O
Reactant: N#CC(O)CCc1ccc(OCc2ccccc2)cc1
Solvent: CC(=O)Cl
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: OC(CCc1ccc(OCc2ccccc2)cc1)c1nc2ncccc2o1
Reaction time: 0.33 h

Procedure:
A mixture of anhydrous EtOH (3.6 mL) and CHCl3 (4.0 mL) at 0° C. was treated with acetyl chloride (3.4 mL, 47.6 mmol, 16.2 equiv) and was stirred for 20 min. A solution of 4-(4-(benzyloxy)phenyl)-2-hydroxybutanenitrile (S50, 750 mg, 2.94 mmol, 1 equiv) in 9 mL of CHCl3 was added dropwise and the reaction was stirred for 20 h at 25° C. The reaction mixture was concentrated and the crude product was dissolved in anhydrous EtOH. 2-Amino-3-hydroxypyridine (370 mg, 3.36 mmol, 1.1 equiv) was added and the reaction mixture was warmed at reflux overnight. Concentration followed by column chromatography (SiO2, 2.5×8 cm, 0-4% MeOH—CHCl3 gradient) afforded S51 (130 mg, 0.36 mmol, 13%) as a tan oil: 1H NMR (CDCl3, 600 MHz) 8.52 (d, 1H, J=4.8 Hz), 7.78 (d, 1H, J=7.9 Hz), 7.43 (d, 2H, J=7.0 Hz), 7.39 (t, 2H, J=7.9 Hz), 7.34-7.31 (m, 1H), 7.28-7.26 (m, 1H), 7.14 (d, 2H, J=8.3 Hz), 6.87 (d, 2H, J=8.3 Hz), 5.07-5.00 (m, 1H), 5.00 (s, 2H), 2.84-2.81 (m, 2H), 2.36-2.30 (m, 2H); 13C NMR (CDCl3, 150 MHz) 157.0, 154.6, 146.1, 143.0, 137.0, 133.0 (2C), 129.4, 128.5, 127.8, 127.4, 120.2, 118.8, 114.7, 69.9, 67.0, 36.9, 30.1; IR (film) νmax 3380, 2926, 1665, 1612, 1557, 1511, 1454, 1410, 1382, 1239, 1177, 1092, 1026, 831, 785, 737, 700 cm−1.
Reaction SMILES: [CH2:1]([C:3]1[C:8]([CH2:9][CH:10]=O)=[CH:7][CH:6]=[CH:5][C:4]=1[C:12]1[S:16][C:15]([C:17]2[CH:18]=[CH:19][C:20]([CH2:25][CH:26]([CH3:28])[CH3:27])=[C:21]([CH:24]=2)[C:22]#[N:23])=[N:14][N:13]=1)[CH3:2].[NH:29]1[CH2:34][CH2:33][CH:32]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:31][CH2:30]1.C([O-])(=O)C.[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)C.ClCCl.O.CC(O)=O>[C:22]([C:21]1[CH:24]=[C:17]([C:15]2[S:16][C:12]([C:4]3[C:3]([CH2:1][CH3:2])=[C:8]([CH2:9][CH2:10][N:29]4[CH2:34][CH2:33][CH:32]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:31][CH2:30]4)[CH:7]=[CH:6][CH:5]=3)=[N:13][N:14]=2)[CH:18]=[CH:19][C:20]=1[CH2:25][CH:26]([CH3:28])[CH3:27])#[N:23]
Reactant: CCOC(=O)C1CCNCC1
Reactant: CCc1c(CC=O)cccc1-c1nnc(-c2ccc(CC(C)C)c(C#N)c2)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)C1CCN(CCc2cccc(-c3nnc(-c4ccc(CC(C)C)c(C#N)c4)s3)c2CC)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 90 %

Procedure:
To a solution of 5-{5-[2-ethyl-3-(2-oxoethyl)phenyl]-1,3,4-thiadiazol-2-yl}-2-(2-methylpropyl)benzonitrile (D31) (52 mg) and ethyl 4-piperidinecarboxylate (105 mg) in ethanol (10 mL) stirred at room temperature was added sodium acetate (32.9 mg) and AcOH (0.15 mL). The reaction mixture was stirred at room temperature for 10 min. The residue was dissolved in dichloromethane (DCM) (10 mL), sodium triacetoxyborohydride (85 mg) was added. Stirring continued for overnight. Water was added to quench the reaction, and DCM was removed by evaporation. The mixture was extracted by EA for 3 times. The combined organic solution was washed by brine, dried over anhydrous Na2SO4. The dried solution was filtered and concentrated to afford ethyl 1-[2-(3-{5-[3-cyano-4-(2-methylpropyl)phenyl]-1,3,4-thiadiazol-2-yl}-2-ethylphenyl)ethyl]-4-piperidinecarboxylate (D33) (63.8 mg). MS (ES): C31H38N4O2S requires 530. found 531.3 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:19]=[CH:18][C:7]([CH2:8][CH:9]([C:14]([O:16][CH3:17])=[O:15])[C:10]([O:12][CH3:13])=[O:11])=[CH:6][C:5]=1[CH2:20][OH:21])[CH3:2].[Cl:22][C:23]1[CH:24]=[C:25]([N:29]=[C:30]=[O:31])[CH:26]=[CH:27][CH:28]=1>>[Cl:22][C:23]1[CH:24]=[C:25]([CH:26]=[CH:27][CH:28]=1)[NH:29][C:30]([O:21][CH2:20][C:5]1[CH:6]=[C:7]([CH:18]=[CH:19][C:4]=1[O:3][CH2:1][CH3:2])[CH2:8][CH:9]([C:14]([O:16][CH3:17])=[O:15])[C:10]([O:12][CH3:13])=[O:11])=[O:31]
Reactant: O=C=Nc1cccc(Cl)c1
Reactant: CCOc1ccc(CC(C(=O)OC)C(=O)OC)cc1CO
Product: CCOc1ccc(CC(C(=O)OC)C(=O)OC)cc1COC(=O)Nc1cccc(Cl)c1

Procedure:
Using dimethyl 2-[4-ethoxy-3-(hydroxymethyl)benzyl]-malonate and 3-chlorophenylisocyanate, the title compound was obtained in the same manner as described in Example 192b).
Reaction SMILES: [H-].[Na+].[CH2:3]([SH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.F[C:12]1[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][N:13]=1.O>CN(C)C=O>[CH3:18][C:17]1[C:12]([S:10][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: SCc1ccccc1
Reactant: Cc1cccnc1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccnc1SCc1ccccc1
Reaction time: 1 h
Yield: 122.5 %

Procedure:
A suspension of 4.8 g (100 mmole) of sodium hydride in 50 mls of dimethylformamide was cooled to 0° and 11.6 ml (100 mmole) of benzyl mercaptan was added dropwise at 0°. After addition was complete, the reaction mixture was allowed to warm to 25° and stirred at this temperature for 1 hour. The reaction mixture was then re-cooled to 0° and 10.0 g (91 mmole) of 2-fluoro-3-methyl pyridine was added dropwise. The mixture was allowed to warm to 25° and stirred at this temperature for 18 hours. The mixture was poured into 100 mls of water and extracted twice with ethyl ether and ethylacetate. The combined organic extracts were washed with a saturated solution of sodium bicarbonate and dried over sodium sulfate. Concentration gave 24 g of a yellow oil. Flash chromatography in a 10% ethyl ether/hexanes mixture gave 6.3 g clear oil.
Reaction SMILES: CC1C=CC(S(O)(=O)=O)=CC=1.CO[CH:14](OC)[CH2:15][Cl:16].C([O-])(O)=O.[Na+].[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27](Cl)[N:26]=1>O.C(O)C>[Cl:16][C:15]1[N:26]2[CH:27]=[CH:28][N:24]=[C:25]2[CH:30]=[CH:29][CH:14]=1
Reactant: Nc1cccc(Cl)n1
Reactant: COC(CCl)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Clc1cccc2nccn12
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 34.8 %

Procedure:
To a solution of pTSA (103 mg, 0.65 mmol) in water (5 ml) and ethanol (20 ml) was added chloroacetaldehyde dimethyl acetal (2.0 g, 16.0 mmol) at room temperature. The reaction was stirred at 65° C. for 30 minutes and then cooled to room temperature and a saturated solution of NaHCO3 was added dropwise until pH 7 was reached. 2-Amino-6-chloropyridine (2.1 g, 16 mmol) in 4:1 ethanol:water (20 ml) was then added and the reaction was heated at reflux for 3 hours. After cooling and concentrating at reduced pressure, the residue was purified by FCC (98:2 DCM/MeOH) to give the title compound (850 mg, 36%) as brown oil.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH2:10])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].Br[CH:14]([CH3:23])[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=O>CN1C(=O)CCC1>[CH3:23][C:14]1[O:9][C:8]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)=[N:10][C:15]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: CC(Br)C(=O)c1ccccc1
Solvent: CN1CCCC1=O
Product: Cc1oc(-c2ccc([N+](=O)[O-])cc2)nc1-c1ccccc1
Temperature: 135 °C
Reaction time: 2 h
Yield: 21.4 %

Procedure:
a mixture of 4-nitrobenzamide (6.1 g, 37 mmol) and 2-bromopropiophenone (5.233 g, 25 mmol) in 3 mL NMP was heated to 135° C. After 2 hours at 135° C., the reaction was removed from the oil bath and ca. 30 mL of toluene was added. The resulting mixture was equilibrated to room temperature. After 15 minutes the precipitate was removed by filtration, rinsing with toluene, and discarded. The filtrate was concentrated under reduced pressure and the concentrate taken up in 50 mL ethyl acetate. A precipitate developed and was collected by filtration, rinsing the solid with ethyl acetate and drying under vacuum to afford yellow crystals (1.5 g, 22%). ESI+ m/z=281.0 [MH]+.
Reaction SMILES: [C:1]1(=[N:7][C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10](O)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.P(Cl)(Cl)([Cl:19])=O>C(Cl)Cl>[Cl:19][C:10]1[C:9]2[C:8]([N:7]=[C:1]3[C:6]=1[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: O=C(O)c1ccccc1N=C1CCCCC1
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: Clc1c2c(nc3ccccc13)CCCC2
Temperature: 100 °C
Reaction time: 0.08 h

Procedure:
2-Cyclohexylideneamino-benzoic acid (1.5 g, 6.9 mmol) was added to phosphorus oxychloride (4 mL) at 0° C. and stirred for 5 minutes followed by heating to 100° C. for 45 minutes. The reaction mixture was cooled to room temperature and slowly poured onto ice (˜100 g) and stirred for 30 minutes. CH2Cl2 (100 mL) was added and the mixture stirred for 5 minutes and the organic layer separated. The aq. layer was extracted with CH2Cl2 (50 mL). The combined CH2Cl2 layers were washed with sat. aq. NaHCO3 (2×50 mL), sat. aq. NaCl (50 mL), dried over Na2SO4, decanted and concentrated to give 9-chloro-1,2,3,4-tetrahydro-acridine, which, was used without further purification.
Reaction SMILES: [Br:1][C:2]1[NH:6][CH:5]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[C:3]=1[CH2:11][CH2:12][CH3:13].[H-].[Na+].[C:16]1([S:22](Cl)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[Br:1][C:2]1[N:6]([S:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:24])=[O:23])[CH:5]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[C:3]=1[CH2:11][CH2:12][CH3:13]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCCc1c(C(=O)OC)c[nH]c1Br
Agent: [H-]
Agent: [Na+]
Product: CCCc1c(C(=O)OC)cn(S(=O)(=O)c2ccccc2)c1Br
Yield: 85.2 %

Procedure:
Using methyl 5-bromo-4-propyl-1H-pyrrole-3-carboxylate (2.96 g), sodium hydride (60% in oil, 634 mg) and benzenesulfonyl chloride (2.33 g), a procedure as in Reference Example 41 was performed to give the title compound as colorless crystals (yield 3.96 g, 85%).