Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][NH:13][CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])[CH3:3].C(=O)(O)[O-].[Na+].C1COCC1.F[C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][C:27]=1[N+:36]([O-:38])=[O:37]>O>[N+:36]([C:27]1[CH:28]=[C:29]([C:32]([F:33])([F:34])[F:35])[CH:30]=[CH:31][C:26]=1[N:13]1[CH2:12][CH2:11][CH2:10][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:2]([CH3:1])([CH3:3])[CH3:4])[CH2:14]1)([O-:38])=[O:37]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccc(C(F)(F)F)cc2[N+](=O)[O-])C1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a 200-mL RBF was added (s)-3-n-boc-amino piperidine (10.9 g, 54.4 mmol), Sodium bicarbonate (11.4 g, 136 mmol), THF, and 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (7.62 ml, 54.4 mmol). The yellow mixture was heated to 70° C. with a water-cooled reflux condenser. The orange mixture was allowed to stir for 14 h, and was then cooled to ambient temperature, and filtered through a glass frit, rinsing with EtOAc. Concentration in vacuo afforded an orange oil, which crystallized on standing to an orange solid. The material was treated with 250 mL hexanes and heated on the rotovap (no vacuum) to 60° C. Small amounts of EtOAc were added until all solid dissolved, total volume of EtOAc was approx 10 mL. The solution was allowed to cool overnight, resulting in the formation of orange crystals. The liquid was decanted and the crystals rinsed twice with 50 mL hexanes. The crystals were collected to give (S)-tert-butyl 1-(2-nitro-4-(trifluoromethyl)phenyl)piperidin-3-ylcarbamate as orange crystals. The filtrate was concentrated to an orange solid. This material was treated with 150 mL hexanes and was heated to 65° C. Almost all of the material had dissolved. The hot liquid was decanted into a flask and allowed to cool overnight, resulting in an orange solid. The liquid was discarded, and additional crystals of (S)-tert-butyl 1-(2-nitro-4-(trifluoromethyl)phenyl)piperidin-3-ylcarbamate were collected. MS m/z=390 [M+H]+. Calc'd for C17H20F3N3: 389.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[NH:5][C:6]1[N:15]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([O:24][CH3:25])[CH:18]=2)[C:9]2=[N:10][CH:11]=[C:12]([I:14])[CH:13]=[C:8]2[N:7]=1)[CH3:2].[OH-].[Na+].CC1C=CC(S(O[CH2:40][C:41]2[CH:46]=[CH:45][C:44]([C:47]([F:53])([F:52])[C:48]([F:51])([F:50])[F:49])=[CH:43][CH:42]=2)(=O)=O)=CC=1>O1CCCC1.O>[CH2:1]([O:3][C:4](=[O:26])[NH:5][C:6]1[N:15]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:40][C:41]3[CH:42]=[CH:43][C:44]([C:47]([F:52])([F:53])[C:48]([F:49])([F:50])[F:51])=[CH:45][CH:46]=3)=[C:19]([O:24][CH3:25])[CH:18]=2)[C:9]2=[N:10][CH:11]=[C:12]([I:14])[CH:13]=[C:8]2[N:7]=1)[CH3:2]
Reactant: CCOC(=O)Nc1nc2cc(I)cnc2n1Cc1ccc(O)c(OC)c1
Reactant: Cc1ccc(S(=O)(=O)OCc2ccc(C(F)(F)C(F)(F)F)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)Nc1nc2cc(I)cnc2n1Cc1ccc(OCc2ccc(C(F)(F)C(F)(F)F)cc2)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 25.6 %

Procedure:
To a stirred solution of ethyl(3-(4-hydroxy-3-methoxybenzyl)-6-iodo-3H-imidazo[4,5-b]pyridin-2-yl)carbamate (Example 3-36-1) (0.24 g, 0.52 mmol) in tetrahydrofuran (20 mL) was added 5M aqueous sodium hydroxide solution (0.2 mLs, 1.00 mmol). The resulting mixture was allowed to stir at room temperature. After 2 h, the mixture was concentrated, and the residue was dissolved in N,N-dimethylformamide (10 mL). The mixture was treated with 4-(perfluoroethyl)benzyl 4-methylbenzenesulfonate (0.40 g, 1.04 mmol), and the mixture was warmed to 80° C. After 3 h, the mixture was allowed to cool to room temperature and was diluted with water (20 mL). The mixture was extracted with ethyl acetate (3×40 mL), and the combined organic phases were dried over sodium sulfate, filtered, and concentrated to provide 0.090 g of ethyl(6-iodo-3-(3-methoxy-4-((4-(perfluoroethyl)benzyl)oxy)benzyl)-3H-imidazo[4,5-b]pyridin-2-yl)carbamate as a brown solid.
Reaction SMILES: C[O:2][C:3]1[CH:28]=[CH:27][C:6]([C:7]([NH:9][CH:10]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2F)[CH3:11])=[O:8])=[CH:5][CH:4]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>O1CCCC1.C(OCC)(=O)C>[F:25][C:22]1[CH:21]=[CH:20][C:19]2[C:13]3[C:12]([CH:10]([CH3:11])[N:9]([C:7]([C:6]4[CH:27]=[CH:28][C:3]([OH:2])=[CH:4][CH:5]=4)=[O:8])[C:24]=2[CH:23]=1)=[CH:17][C:16]([F:18])=[CH:15][CH:14]=3
Reactant: COc1ccc(C(=O)NC(C)c2cc(F)ccc2-c2ccc(F)cc2F)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1c2cc(F)ccc2-c2ccc(F)cc2N1C(=O)c1ccc(O)cc1
Temperature: 70 °C
Yield: 40.2 %

Procedure:
3,8-Difluoro-5-(4-methoxybenzoyl)-6-methyl-5,6-dihydrophenanthridine—A stirred solution of 4-methoxy-N-[1-(2′,4,4′-trifluoro-1,1′-biphenyl-2-yl)ethyl]benzamide (0.95 g, 2.46 mmol) in tetrahydrofuran was treated under nitrogen with a 1.0 M solution of lithium bis(trimethylsilyl) amide in tetrahydrofuran (5 mL, 5.0 mmol) and heated at 70° C. for fifteen hours. The reaction mixture was cooled to room temperature and the solvent removed in vacuo to afford a residue. The residue was dissolved in ethyl acetate and washed sequentially with a 1 N hydrochloric acid solution and water. The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent removed in vacuo to afford a crude solid. The crude solid was purified by preparative liquid chromatography on a Biotage® 40 Mi column of pre-packed silica gel (90 g), eluting with a gradient of between 3% and 15% methyl tert-butyl ether in hexane to afford, after crystallization from ethyl acetate-hexane, the title compound (0.36 g, 0.99 mmol, 40%) as a homogeneous, colorless, crystalline solid, m.p. 98-100° C.; MS [(+ESI), m/z]: 366 [M+H]+; IR (Solid), vmax: 2920, 1630, 1600, 1580, 1510, 1495, 1385, 1320, 1250, 870, 840, 810 cm−1; 1H NMR (400 MHz, DMSO-d6) δ: 1.22 (d, J=7.0 Hz, 3H), 3.77 (s, 3H), 5.73 (q, J=6.7 Hz, 1H), 6.59 (dd, J=10.3, 2.3 Hz, 1H), 6.90 (d, J=8.8 Hz, 2H), 7.07 (td, J=8.6, 2.7 Hz, 1H), 7.27 (d, J=8.3 Hz, 2H), 7.27 (td, J=8.5, 3.2 Hz, 1H), 7.39 (dd, J=9.2, 2.7 Hz, 1H), 7.98 (dd, J=8.9, 6.3 Hz, 1H), 8.02 (dd, J=8.5, 5.4 Hz, 1H); Anal. calcd for C22H17F2NO2: C, 72.32; H, 4.69; N, 3.83. Found: C, 71.82; H, 4.52; N, 3.76.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[N:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=1>Cl.O1CCOCC1.ClCCl>[I:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][N:3]=[C:2]2[NH:19][C:16]1[CH:17]=[CH:18][N:13]=[CH:14][CH:15]=1
Reactant: Nc1ccncc1
Reactant: Clc1ncnc2ccc(I)cc12
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Ic1ccc2ncnc(Nc3ccncc3)c2c1

Procedure:
To a vial was added 4-chloro-6-iodo-quinazoline (100 mg; 0.34 mmol, commercially available), pyridin-4-amine (3 equiv., 1.03 mmol, 97.19 mg, commercially available), and 2 drops of 4M HCl/dioxane. The reaction vial was heated until solids melted. LCMS of resultant solution showed clean product formation. Upon cooling the product re-solidified. The solid was suspended in dichloromethane:water, and collected by filtration. 95 mg of 6-iodo-N-(4-pyridyl)quinazolin-4-amine was recovered as an orange solid, which was carried on directly to the Suzuki step. LCMS M/Z (M+H)=350.
Reaction SMILES: FC(F)(F)S(O[CH:7]([C:12]1[CH:13]=[N:14][C:15]([Cl:18])=[CH:16][CH:17]=1)[C:8]([F:11])([F:10])[F:9])(=O)=O.C([O-])([O-])=O.[K+].[K+].[NH:27]1[CH2:31][CH2:30][C@H:29]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:28]1.O>C1COCC1.C(OCC)(=O)C>[Cl:18][C:15]1[N:14]=[CH:13][C:12]([CH:7]([N:27]2[CH2:31][CH2:30][C@H:29]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:37])([CH3:36])[CH3:38])[CH2:28]2)[C:8]([F:11])([F:10])[F:9])=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Reactant: O=S(=O)(OC(c1ccc(Cl)nc1)C(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CCN(C(c2ccc(Cl)nc2)C(F)(F)F)C1
Yield: 74.1 %

Procedure:
A solution of 1-(6-chloropyridin-3-yl)-2,2,2-trifluoroethyl trifluoromethanesulfonate (0.55 g, 1.60 mmol), K2CO3 (0.33 g, 2.40 mmol), and (S)-tert-butyl pyrrolidin-3-ylcarbamate (0.42 g, 2.24 mmol) in THF (8 mL) was stirred at 50° C. for 20 hours. Water (20 mL) and ethyl acetate (30 mL) were added. The organic layer was separated, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (3:1 hexane/ethyl acetate) to give tert-butyl (3S)-1-(1-(6-chloropyridin-3-yl)-2,2,2-trifluoroethyl)pyrrolidin-3-ylcarbamate (0.45 g, 74.0%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[CH2:13](I)[CH2:14][CH3:15]>>[Cl:1][C:2]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][CH3:15])[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCCI
Reactant: COC(=O)c1ccc(O)cc1Cl
Product: CCCOc1ccc(C(=O)O)c(Cl)c1

Procedure:
Using methyl 2-chloro-4-hydroxybenzoate and propyl iodide, 2-chloro-4-propoxybenzoic acid was obtained in the same manner as in Example 277b).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([C:31]2[CH:32]=[C:33](/[C:43](=[CH:47]\[CH:48]3[CH2:53][CH2:52][O:51][CH2:50][CH2:49]3)/[C:44]([OH:46])=O)[CH:34]=[CH:35][C:36]=2[S:37]([CH:40]2[CH2:42][CH2:41]2)(=[O:39])=[O:38])[CH2:30][CH2:29]1.[CH3:54][N:55]1[CH:59]=[CH:58][C:57]([NH2:60])=[N:56]1>ClCCl.N1C=CC=CC=1.O>[CH:28]1([C:31]2[CH:32]=[C:33](/[C:43](=[CH:47]\[CH:48]3[CH2:49][CH2:50][O:51][CH2:52][CH2:53]3)/[C:44]([NH:60][C:57]3[CH:58]=[CH:59][N:55]([CH3:54])[N:56]=3)=[O:46])[CH:34]=[CH:35][C:36]=2[S:37]([CH:40]2[CH2:41][CH2:42]2)(=[O:38])=[O:39])[CH2:30][CH2:29]1
Reactant: Cn1ccc(N)n1
Reactant: O=C(O)/C(=C/C1CCOCC1)c1ccc(S(=O)(=O)C2CC2)c(C2CC2)c1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: Cn1ccc(NC(=O)/C(=C/C2CCOCC2)c2ccc(S(=O)(=O)C3CC3)c(C3CC3)c2)n1
Reaction time: 0.25 h
Yield: 80.2 %

Procedure:
To a solution of triphenylphosphine (131 mg) in dichloromethane (2 mL) was added N-bromosuccinimide (89 mg) under ice-cooling, followed by stirring for 15 minutes under ice-cooling. A solution of (2E)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-3-(tetrahydro-2H-pyran-4-yl)acrylic acid (100 mg) in dichloromethane (1 mL) was added thereto, followed by stirring at room temperature for 30 minutes. A solution of 1-methyl-1H-pyrazol-3-amine (39 mg) in dichloromethane (1 mL) and pyridine (0.086 mL) were added thereto at room temperature, followed by stirring at room temperature for 15 hours. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was sequentially washed with 1 M hydrochloric acid, a saturated aqueous sodium hydrogen carbonate solution, and saturated brine, and dried over anhydrous magnesium sulfate. The crude product obtained by concentration was purified by silica gel column chromatography to obtain (2E)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-N-(1-methyl-1H-pyrazol-3-yl)-3-(tetrahydro-2H-pyran-4-yl)acrylamide (97 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([NH:13][C@@H:14]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:15]([OH:17])=O)=[O:12])[NH:8][C:5]2=[CH:6][N:7]=1.Cl.[NH:27]1[CH2:32][CH2:31][CH:30]([NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[CH2:29][CH2:28]1>>[F:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][C@H:14]([NH:13][C:11]([C:9]2[NH:8][C:5]3=[CH:6][N:7]=[C:2]([Cl:1])[CH:3]=[C:4]3[CH:10]=2)=[O:12])[C:15]([N:27]2[CH2:28][CH2:29][CH:30]([NH:33][S:34]([CH3:37])(=[O:35])=[O:36])[CH2:31][CH2:32]2)=[O:17])=[CH:20][CH:21]=1
Reactant: CS(=O)(=O)NC1CCNCC1
Reactant: O=C(N[C@@H](Cc1ccc(F)cc1)C(=O)O)c1cc2cc(Cl)ncc2[nH]1
Agent: Cl
Product: CS(=O)(=O)NC1CCN(C(=O)[C@H](Cc2ccc(F)cc2)NC(=O)c2cc3cc(Cl)ncc3[nH]2)CC1

Procedure:
The title compound was prepared according to EXAMPLE 229 from 2-(S)-[(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]-3-(4-fluorophenyl)propionic acid (EXAMPLE 228) and N-piperidin-4-yl methanesulfonamide hydrochloride (Preparation 92). Purification gave the title compound as an off-white powder. m/z (ES+)=522.30 [M+H]+; RT=3.29 min.
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]([CH3:13])[C:5]([C:7]1[CH:8]=[N:9][N:10]([CH3:12])[CH:11]=1)=[O:6].CN(C)CCN(C)CCN(C)C.[Li]C(C)(C)C.[C:31](=[O:33])=[O:32]>C1COCC1>[F:1][CH2:2][CH2:3][N:4]([CH3:13])[C:5]([C:7]1[CH:8]=[N:9][N:10]([CH3:12])[C:11]=1[C:31]([OH:33])=[O:32])=[O:6]
Reactant: CN(CCF)C(=O)c1cnn(C)c1
Reactant: O=C=O
Agent: CN(C)CCN(C)CCN(C)C
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CN(CCF)C(=O)c1cnn(C)c1C(=O)O
Temperature: -100 °C
Reaction time: 0.08 h
Yield: 50 %

Procedure:
In a 50 mL three-necked flask, N-(2-fluoroethyl)-N,1-dimethyl-1H-pyrazole-4-carboxamide (500 mg, 2.7 mmol) was combined with THF (10.0 ml) to give a colorless solution. 1,1,4,7,7-Pentamethyldiethylenetriamine (621 μl, 2.97 mmol) was added, and, after cooling down to −100° C., tBuLi (1.6 M in pentane, 2.53 ml, 4.05 mmol) was added dropwise. After stirring 30 min an excess of dry ice was carefully added. After 5 min, the cooling bath was removed and the mixture was allowed to warm up to RT. H2O was added and un-reacted starting material was removed by extraction with CH2Cl2. The aqueous layer was then acidified using 1 N HCl solution, and the acid was extracted using CH2Cl2. After drying over Na2SO4, filtration and concentration in vacuum, the viscous oil was dried in HV to yield 307 mg (50%) of product as a light brown viscous oil. MS: m/z=230.2 [M+H]+.
Reaction SMILES: [C:1]([CH2:3][S:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:6]=1[NH:15][C:16](=[O:18])[CH3:17])#[N:2].I([O-])(=O)(=O)=[O:20].[Na+].[K+].[Br-]>O1CCOCC1.O>[C:1]([CH2:3][S:4]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:12])([F:14])[F:13])=[CH:7][C:6]=1[NH:15][C:16](=[O:18])[CH3:17])=[O:20])#[N:2]
Reactant: CC(=O)Nc1cc(C(F)(F)F)ccc1SCC#N
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Br-]
Agent: [K+]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)Nc1cc(C(F)(F)F)ccc1S(=O)CC#N
Temperature: 40 °C

Procedure:
A solution of N-(2-cyanomethylsulfanyl-5-trifluoromethylphenyl)acetamide(0.42 g) in dioxane (2.50 ml) was added dropwise to a stirred solution of sodium periodate (0.69 g) in a mixture of water (6 ml) and dioxane (1.50 ml) at ambient temperature. An additional amount of dioxane (2.50 ml) was added. The mixture was stirred at 40° C. for 6½ h, then at room temperature overnight. A precipitate was removed by filtration and washed on the filter with dichlorometane (20 ml). The two phases of the filtrate were shaken and separated. The aqueous phase was extracted with dichloromethane (2×10 ml). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The more polar component of the residue was isolated by flash chromatography on silica gel eluted with 1) ether and 2) ethyl acetate to give a slowly crystallizing oil. Trituration with petroleum ether and subsequent drying gave white crystals. Yield 0.16 g (38%); mp 149-151° C.; 1H-NMR(CDCl3) δ (ppm): 9.9 (br, 1H), 8.70 (d, J=2 Hz, 1H), 7.68-7.46 (d+dd, J=8Hz and 8 Hz/2 Hz, 1H+1H), ABX-system at 4.13 (d, J=16 Hz, 1H) and 3.98 (d, J=16 Hz, 1H), 2.25 (s, 3H); 13C-NMR (DMSO-d6) δ (ppm): 170.1, 141.3, 135.8, 132.7 (q, J=32 Hz), 127.0, 123.5 (CF3, J=273 Hz), 123.1 (J=3.6 Hz), 122.0 (J=3.6 Hz), 113.3 (C≡N), 42.6 (CH2), 23.2 (CH3); IR (KBr) ν (cm−1): 3220 (NH), 2252 (C≡N), 1691 (C═O), 1532, 1476, 1337, 1273, 1176, 1128, 1033, 888, 675.
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[F:5][C:6]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:7]=1[C:8]([Cl:10])=[O:9].[CH2:19]([NH:23][C:24]1[C:25](Cl)=[N:26][CH:27]=[CH:28][CH:29]=1)[CH2:20][CH2:21][CH3:22]>O1CCCC1>[ClH:10].[CH2:19]([N:23]1[C:24]2[C:25](=[N:26][CH:27]=[CH:28][CH:29]=2)[S:1]/[C:2]/1=[N:3]\[C:8](=[O:9])[C:7]1[CH:11]=[C:12]([C:15]([F:18])([F:17])[F:16])[CH:13]=[CH:14][C:6]=1[F:5])[CH2:20][CH2:21][CH3:22]
Reactant: O=C(Cl)c1cc(C(F)(F)F)ccc1F
Reactant: N#C[S-]
Reactant: CCCCNc1cccnc1Cl
Agent: [K+]
Solvent: C1CCOC1
Product: CCCCn1/c(=N/C(=O)c2cc(C(F)(F)F)ccc2F)sc2ncccc21
Product: Cl
Temperature: 50 °C
Reaction time: 48 h
Yield: 48.3 %

Procedure:
To a three-necked flask were charged potassium thiocyanate (5.0 g, 50.4 mmol), and tetrahydrofuran (110 mL). 2-Fluoro-5-(trifluoromethyl)benzoyl chloride (10.39 g, 41.7 mmol) was added into the flask slowly at room temperature. The reaction mixture was stirred at room temperature for 3 hours or until less than 1% of the acid chloride remains. The reaction mixture was filtered to remove potassium chloride by-product, and rinsed with tetrahydrofuran (10 mL). The combined solution of 2-fluoro-5-(trifluoromethyl)benzoyl isothiocyanate was charged back to the three-necked flask, followed by addition of N-butyl-2-chloropyridin-3-amine (6.91 g, 37.4 mmol) and tetrahydrofuran (100 mL). The reaction mixture was heated to approximately 50° C., and stirred vigorously for 2 days. The product suspension was then cooled to room temperature, and the product collected by filtration. The wet cake was washed with tetrahydrofuran (50 mL), and dried under vacuum at 50° C. to give the desired product (7.83 g, 48% isolated yield). MS-ESI: 398 (M+1); 1H-NMR (DMSO-d6) δ 0.96 (3H, t, J=7.4 Hz), 1.42 (2H, m), 1.81 (2H, m), 4.51 (2H, t, J=7.6 Hz), 7.53-7.64 (2H, m), 7.97-8.05 (1H, m), 8.21 (1H, dd, J=8.3, 1.2 Hz), 8.46 (1H, dd, J=6.7, 2.3 Hz), 8.52 (1H, dd, J=4.7, 1.2 Hz).
Reaction SMILES: C(O[CH2:7][C:8]1[CH:13]=[CH:12]C=[CH:10][CH:9]=1)(=O)C(C)=C.[C:14]([OH:18])(=O)[CH:15]=[CH2:16].S[CH2:20]CC(OC)=O.N(C(C1CC1)(C)C#N)=NC(C1CC1)(C)C#N.CCCCCCCCC(C)C.N(C(C)(C)C#N)=NC(C)(C)C#N>>[CH3:10][CH2:9][CH:8]([CH2:13][CH2:12][C:14]([OH:18])([CH2:15][CH3:16])[CH3:20])[CH3:7]
Reactant: C=C(C)C(=O)OCc1ccccc1
Reactant: COC(=O)CCS
Reactant: C=CC(=O)O
Agent: CC(C#N)(N=NC(C)(C#N)C1CC1)C1CC1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCCCCCCC(C)C
Product: CCC(C)CCC(C)(O)CC
Reaction time: 1 h

Procedure:
To the solution was dropwise added a mixed solution of 85.0 g of benzyl methacrylate, 15.0 g of acrylic acid, 2.0 g of methyl 3-mercaptopropionate, 1.2 g of 2,2'-azobis(2-cyclopropylpropionitrile) (abbreviated as ACPP) and 200 g of Isopar H over a period of one hour, followed by stirring for one hour. To the reaction mixture was added 0.8 g of ACPP, followed by reacting for 2 hours. Further, 0.5 g of 2,2'-azobis(isobutyronitrile) (abbreviated as AIBN) was added thereto, the reaction temperature was adjusted to 80° C., and the reaction was continued for 3 hours. After cooling, the reaction mixture was passed through a nylon cloth of 200 mesh to obtain a white dispersion which was a latex of good monodispersity with a polymerization ratio of 97% and an average grain diameter of 0.17 μm. The grain diameter was measured by CAPA-500 manufactured by Horiba Ltd. (hereinafter the same).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH3:15])[CH:12]=2)[NH:7][C:6](=[O:16])[CH:5]=1.[F:17][C:18]1[CH:31]=[CH:30][C:21]([C:22]([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[O:23])=[CH:20][CH:19]=1.C(=O)([O-])O.[Na+]>C(#N)C>[ClH:1].[F:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([CH:24]2[CH2:29][CH2:28][N:27]([CH2:2][CH2:3][C:4]3[C:13]4[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH3:15])[CH:12]=4)[NH:7][C:6](=[O:16])[CH:5]=3)[CH2:26][CH2:25]2)=[O:23])=[CH:30][CH:31]=1
Reactant: COc1ccc2[nH]c(=O)cc(CCCl)c2c1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: COc1ccc2[nH]c(=O)cc(CCN3CCC(C(=O)c4ccc(F)cc4)CC3)c2c1
Product: Cl

Procedure:
A mixture of 1.1 g (4.6 mmol) of 4-(2-chloroethyl)-6-methoxy-2(1H)-quinolone, 1.0 g (5.5 mmol) of 4-(4-fluorobenzoyl)piperidine and 0.38 g (4.6 mmol) of sodium hydrogen carbonate in 20 ml of acetonitrile is heated to reflux for 8.5 hours. The reaction medium is then evaporated to dryness and the crude product is purified by flash chromatography on silica, eluting with a methanol/dichloromethane (5:95) mixture containing traces of aqueous ammonia.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:17]([O:19][C:20](=[O:30])[CH:21]=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH2:29])[CH:24]=1)[CH3:18]>>[CH2:17]([O:19][C:20](=[O:30])[CH:21]=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH:29][C:14]([C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[N:13]=2)=[O:16])[CH:24]=1)[CH3:18]
Reactant: O=C(O)c1cccc(-c2ccc(Cl)cc2)n1
Reactant: CCOC(=O)C=Cc1cccc(N)c1
Product: CCOC(=O)C=Cc1cccc(NC(=O)c2cccc(-c3ccc(Cl)cc3)n2)c1

Procedure:
Carboxylic acid (149)(50 mg, 0.21 mmol) was coupled to aniline (60)(41 mg, 0.21 mmol) using Method C. The residue was purified by column chromatography eluting with 10% EtOAc in heptane to give the title compound.
Reaction SMILES: [OH:1][CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH2:3]1.S(OC)(O[CH3:22])(=O)=O>CC(O)=O.O=[Pt]=O.[Pd]>[OH:1][CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH3:22])[CH2:3]1
Reactant: OC1Cc2ccccc2C(c2ccccn2)C1
Reactant: COS(=O)(=O)OC
Agent: O=[Pt]=O
Agent: [Pd]
Solvent: CC(=O)O
Product: CN1CCCCC1C1CC(O)Cc2ccccc21

Procedure:
The 2-(3-hydroxy-1,2,3,4-tetrahydronaphthalenyl)-pyridine thus obtained is quaternized with dimethyl sulfate on the steam bath neat. After several hours, the salt is dissolved in HOAc and reduced over a mixture of PtO2 and Pd/C to yield 2-(3-hydroxy-1,2,3,4-tetrahydronaphthalenyl)-1-methyl piperidine.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]3[C:13]([C:20]4[CH:21]=[C:22]([CH3:26])[CH:23]=[CH:24][CH:25]=4)=[N:14][N:15]([CH2:17][CH:18]=[O:19])[CH:16]=3)=[CH:11][C:6]=2[N:5]([CH2:27][CH3:28])[C:4]1=[O:29])[CH3:2].C(I)C=C.[CH2:34]([NH:36][CH2:37]C)[CH3:35]>O>[CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]3[C:13]([C:20]4[CH:21]=[C:22]([CH3:26])[CH:23]=[CH:24][CH:25]=4)=[N:14][N:15]([CH2:17][CH:18]([OH:19])[CH2:37][NH:36][CH2:34][CH3:35])[CH:16]=3)=[CH:11][C:6]=2[N:5]([CH2:27][CH3:28])[C:4]1=[O:29])[CH3:2]
Reactant: CCn1c(=O)n(CC)c2cc(-c3cn(CC=O)nc3-c3cccc(C)c3)ccc21
Reactant: CCNCC
Agent: C=CCI
Solvent: O
Product: CCNCC(O)Cn1cc(-c2ccc3c(c2)n(CC)c(=O)n3CC)c(-c2cccc(C)c2)n1

Procedure:
1,3-Diethyl-5-(1-oxiranylmethyl-3-m-tolyl-1H-pyrazol-4-yl)-1,3-dihydro-benzoimidazol-2-one (obtained using a method similar to that for [4-(1,3-Diethyl-2-oxo-2,3-dihydro-1H-benzoimidazol-5-yl)-3-m-tolyl-pyrazol-1-yl]-acetaldehyde, substituting epibromohydrin for allyl iodide) (0.016 g) was diluted with diethylamine (0.3 mL, as a 70% solution in water) and stirred at 23° C. for 0.5 hours. Azeotropic removal of the water with toluene gave 1,3-Diethyl-5-[1-(3-ethylamino-2-hydroxy-propyl)-3-m-tolyl-1H-pyrazol-4-yl]-1,3-dihydro-benzoimidazol-2-one.