Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:11]=[C:5]2[CH:6]=[C:7]([Br:10])[CH:8]=[CH:9][N:4]2[N:3]=1.[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1>>[Br:10][C:7]1[CH:8]=[CH:9][N:4]2[N:3]=[C:2]([N:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[N:11]=[C:5]2[CH:6]=1
Reactant: Brc1ccn2nc(Br)nc2c1
Reactant: C1CCNC1
Product: Brc1ccn2nc(N3CCCC3)nc2c1
Yield: 51.6 %

Procedure:
A mixture of 2,7-dibromo-[1,2,4]triazolo[1,5-a]pyridine (770 mg, 2.78 mmol) and pyrrolidine (15 ml, 181 mmol) was refluxed for 3 hours under nitrogen atmosphere. The pyrrolidine was evaporated. The residue was diluted with ethyl acetate and washed with water and brine. The organic layer was separated, dried over magnesium sulfate, filtrated and evaporated. The crude material was applied on silicagel and purified by flash chromatography over a 50 g silicagel column using heptane/ethyl acetate 10-50% as eluent affording 7-bromo-2-pyrrolidin-1-yl-[1,2,4]triazolo[1,5-a]pyridine (383 mg, 51.5%) as an off-white solid. mp: 170-172° C., MS: m/z=266.9/269 (M+H+)
Reaction SMILES: Br[C:2]1[CH:15]=[C:14]2[C:5]([CH2:6][C:7]3([C:13]42[N:19]=[C:18]([NH2:20])[C:17]([CH3:21])=[N:16]4)[CH2:12][CH2:11][O:10][CH2:9][CH2:8]3)=[CH:4][CH:3]=1.[Cl:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][C:28]=1[F:29]>>[Cl:22][C:23]1[CH:24]=[C:25]([C:2]2[CH:15]=[C:14]3[C:5]([CH2:6][C:7]4([C:13]53[N:19]=[C:18]([NH2:20])[C:17]([CH3:21])=[N:16]5)[CH2:8][CH2:9][O:10][CH2:11][CH2:12]4)=[CH:4][CH:3]=2)[CH:26]=[CH:27][C:28]=1[F:29]
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: CC1=NC2(N=C1N)c1cc(Br)ccc1CC21CCOCC1
Product: CC1=NC2(N=C1N)c1cc(-c3ccc(F)c(Cl)c3)ccc1CC21CCOCC1
Yield: 42 %

Procedure:
The title compound was synthesized as described for Example 26a in 42% yield, starting from 6′-bromo-5-methyl-2″,3″,5″,6″-tetrahydro-3′H-dispiro[imidazole-2,1′-indene-2′,4″-pyran]-4-amine (Example 25, 75 mg, 0.22 mmol) and 3-chloro-4-fluorobenzeneboronic acid (45.1 mg, 0.26 mmol); 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.72 (dd, 1 H), 7.52 (m, 2 H), 7.42 (m, 2 H), 6.80 (d, 1 H), 6.60 (br. s, 1 H), 3.66 (m, 2 H), 3.48 (t, 1 H), 3.40 (m, 1 H), 3.20 (m, 1 H), 3.07 (m, 1 H), 2.19 (s, 3 H), 1.71 (td, 1 H), 1.23 (m, 3 H), MS (ES+) m/z 398 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1/[C:9](=[CH:14]\[O:15][CH3:16])/[C:10]([O:12][CH3:13])=[O:11].P([O-])([O-])(O)=[O:18].[Na+].[Na+].P([O-])([O-])(O)=O.[K+].[K+].O>CS(C)=O>[CH:2]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1/[C:9](=[CH:14]\[O:15][CH3:16])/[C:10]([O:12][CH3:13])=[O:11])=[O:18]
Reactant: CO/C=C(/C(=O)OC)c1ccccc1CBr
Reactant: O=P([O-])([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CO/C=C(/C(=O)OC)c1ccccc1C=O
Temperature: 80 °C
Yield: 35.9 %

Procedure:
A mixture of (E)-methyl 2-[2-(bromomethyl)phenyl]-3-methoxypropenoate (10.0 g, 90% pure), sodium hydrogen orthophosphate dibasic (Na2HPO4, 5.74 g) and potassium hydrogen monophosphate monobasic (KH2PO4, 0.55 g) in DMSO (20 ml) was heated at 80° C. for 1 hour and then at 110° C. for a further hour (compare J. H. Babler, M. J. Coghlan, M. Feng and P. Fries, J. Org. Chem., 1979, 44, 1716). After cooling, the reaction mixture was poured into water and extracted with ether. The extracts were washed with brine, dried, concentrated and chromatographed using ether as eluant to give (E) -methyl 2-(2-formylphenyl)-3-methoxypropenoate (2.77 g, 40% yield) as a white crystalline solid, m.p. 67°-69° C. IR (nujol): 1710, 1634 cm-1. 1H NMR: delta 3.72 (3H, s), 3.84 (3H, s), 7.30-7.65 (3H, m), 7.69 (1H, s), 7.9 (1H, m), 10.0 (1H, s) ppm.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].I[CH2:22][CH2:23][CH3:24].C(O)(=O)/C=C/C(O)=O>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:14])[CH2:13][CH2:12][N:11]([CH2:22][CH2:23][CH3:24])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: OC1(c2cc(F)cc(F)c2)CCNC1
Reactant: CCCI
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CCCN1CCC(O)(c2cc(F)cc(F)c2)C1

Procedure:
Preparation according to Example 8: 3-(3,5-difluorophenyl)pyrrolidin-3-ol (0.54 g, 2.7 mmol), acetonitrile (30 mL), sodium carbonate (0.38 g, 6.75 mmol), iodopropane (0.26 mL, 2.7 mmol). Yield: 0.22 g. The amine was converted to the fumaric acid salt: M.p. 136-137° C.; MS m/z (relative intensity, 70 eV) 241 (M+, 8), 213 (13), 212 (bp), 182 (34), 84 (60).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10](Cl)=[CH:9][C:8]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:7][N:6]=1)=[O:4].[CH2:20]([Sn](CCCC)(CCCC)CCCC)[CH:21]=[CH2:22]>C1(C)C=CC=CC=1.CCOC(C)=O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:10]([CH2:22][CH:21]=[CH2:20])=[CH:9][C:8]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:7][N:6]=1)=[O:4]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)c1ncc(COc2ccccc2)cc1Cl
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=CCc1cc(COc2ccccc2)cnc1C(=O)OC
Temperature: 125 °C
Reaction time: 20 h
Yield: 83.4 %

Procedure:
Tetrakis (triphenylphosphine) palladium (0) (54 mg, 0.046 mmol) was added to a stirred solution of 3-chloro-5-phenoxymethyl-pyridine-2-carboxylic acid methyl ester (130 mg, 0.47 mmol) and allyltri-n-butyltin (0.25 mL, 0.79 mmol) in degassed toluene (1.5 mL) under nitrogen. The mixture was stirred at 125° C. for 20 h. Then further tetrakis (triphenylphosphine) palladium (0) (54 mg, 0.046 mmol) and allyltri-n-butyltin (0.25 mL, 0.79 mmol) were added and the mixture was stirred at 125° C. for 16 h. The mixture was diluted with EtOAc, filtered through a diatomaceous earth pad. The filtrate was evaporated in vacuo. The crude product was purified by flash column chromatography (silica; EtOAc in DCM 0/100 to 100/0). The desired fractions were collected and the solvents evaporated in vacuo to yield 3-allyl-5-phenoxymethyl-pyridine-2-carboxylic acid methyl ester (111 mg, 84% yield) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH2:11])=[CH:5][CH:4]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH:11][C:12](=[O:14])[CH3:13])=[CH:5][CH:4]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(CCN)cc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1ccc(CCNC(C)=O)cc1
Temperature: 20 °C
Reaction time: 0.67 h
Yield: 175.3 %

Procedure:
To 100 g of 2-(4-methoxyphenyl)ethylamine in 500 mL of chloroform was slowly added 100 mL of triethylamine acetic anhydride (72 g), and this was stirred at 20° C. for 40 minutes. The mixture was then extracted twice with a dilute aqueous solution of HCl (0.4 N, 400 mL) followed by a saturated aqueous solution of NaHCO3 (2×400 mL). The solvent was removed by rotary evaporation, and the residue was dried in a vacuum oven (45° C.), resulting in an off-white powder, N-[2-(4-methoxyphenyl)ethyl]acetamide (120 g, 93.9% yield). 1HNMR (DMSO-d6) spectrum was consistent with the desired product.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([S:13]([NH2:16])(=[O:15])=[O:14])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1)([CH3:4])[CH3:3].CO[CH:19](OC)[N:20]([CH3:22])[CH3:21]>CN(C)C=O>[CH3:4][C:2]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([S:13]([N:16]=[CH:19][N:20]([CH3:22])[CH3:21])(=[O:15])=[O:14])[CH:6]=1)([CH3:1])[CH3:3]
Reactant: COc1ccc(C(C)(C)C)cc1S(N)(=O)=O
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: COc1ccc(C(C)(C)C)cc1S(=O)(=O)N=CN(C)C
Reaction time: 0.5 h

Procedure:
4.68 g (0.02 mol) of 3-(1,1-dimethylethyl)-6-methoxybenzenesulfonamide are dissolved in 50 ml of dimethylformamide, and 2.5 g (0.022 mol) of dimethylformamide dimethyl acetal are added. The mixture is left at room temperature for 30 minutes, then poured onto ice-water and filtered with suction.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:10][C:11](=[O:41])[CH2:12][C:13]1[CH:22]=[C:21]([C:23](=[O:39])[C:24]2[CH:29]=[CH:28][C:27]([S:30]([N:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)(=[O:32])=[O:31])=[CH:26][CH:25]=2)[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([F:40])[CH:19]=2)[CH:14]=1)[CH3:9].Cl[C:43]([O:45][CH2:46][CH3:47])=[O:44]>ClCCl>[CH2:46]([O:45][C:43]([N:36]1[CH2:37][CH2:38][N:33]([S:30]([C:27]2[CH:26]=[CH:25][C:24]([C:23]([C:21]3[C:20]4[C:15](=[CH:16][CH:17]=[C:18]([F:40])[CH:19]=4)[CH:14]=[C:13]([CH2:12][C:11]([O:10][CH2:8][CH3:9])=[O:41])[CH:22]=3)=[O:39])=[CH:29][CH:28]=2)(=[O:31])=[O:32])[CH2:34][CH2:35]1)=[O:44])[CH3:47]
Reactant: CCOC(=O)Cc1cc(C(=O)c2ccc(S(=O)(=O)N3CCNCC3)cc2)c2cc(F)ccc2c1
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1cc(C(=O)c2ccc(S(=O)(=O)N3CCN(C(=O)OCC)CC3)cc2)c2cc(F)ccc2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 41.9 %

Procedure:
Triethylamine (0.19 mL, 1.34 mmol) was added slowly at 0° C. to a stirred reaction mixture of {6-fluoro-4-[4-(piperazine-1-sulfonyl)-benzoyl]-naphthalen-2-yl}-acetic acid ethyl ester (0.200 g, 0.33 mmol, prepared as described above) in dichloromethane (7 mL). The reaction mixture was stirred at room temperature for 15 minutes. Ethyl chloroformate (0.07 mL, 0.73 mmol) was added slowly to the reaction mixture and stirring was continued for an additional 3 hours at room temperature. The mixture was diluted with dichloromethane (10 mL), then washed with a saturated solution of sodium bicarbonate (5 mL) and water (5 mL). The organic layer was collected, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel (100-200 mesh) column chromatography (1:3 ethyl acetate -hexane) to give 0.077 g (41.4%) of 4-[4-(3-ethoxycarbonylmethyl-7-fluoro-naphthalene-1-carbonyl)-benzenesulfonyl]-piperazine-1-carboxylic acid ethyl ester as a viscous yellow solid. MS cald. for C28H29FN2O7S ([M+H]+) 556, obsd. 557.2.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[N:16]=2)[CH2:10][CH:9]1[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:30][C:31]1[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[C:32]=1[C:33](Cl)=[O:34]>O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:33](=[O:34])[C:32]3[C:36]([F:40])=[CH:37][CH:38]=[CH:39][C:31]=3[Cl:30])[N:16]=2)[CH2:10][CH:9]1[CH3:22])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1CC(Oc2cccc(N)n2)CCN1C(=O)OC(C)(C)C
Reactant: O=C(Cl)c1c(F)cccc1Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC1CC(Oc2cccc(NC(=O)c3c(F)cccc3Cl)n2)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
Combine 4-(6-Amino-pyridin-2-yloxy)-2-methyl-piperidine-1-carboxylic acid tert-butyl ester cis isomer 1 (preparation 63, 0.286 g, 0.93 mmol), 1,4-dioxane (10 mL), triethylamine (0.16 mL, 1.12 mmol) and 2-chloro-6-fluorobenzoyl chloride (0.215 g, 1.12 mmol) with stirring at ambient temperature. After 2 hr., partition between water (50 mL) and 4:1 hexane:ethyl acetate (100 mL). Separate aqueous layer and wash with 4:1 hexane:ethyl acetate (50 mL). Combine organic layers, dry over sodium sulfate, filter and concentrate to obtain the title compound (0.53 g>100%). Mass spectrum (electrospray): m/z=462.3 (M−1); 1H NMR (CDCl3): 7.9 (m, 2H), 7.65 (dd, 1H), 7.4 (m, 1H), 7.25 (m, 1H), 7.1 (dd, 1H), 6.5 (d, 1H), 5.25 (m, 1H), 4.35 (m, 1H), 3.9 (m, 1H), 3.25 (m, 1H), 1.9 (m, 3H), 1.7 (m, 1H), 1.45 (s, 9H), 1.3 (d, 3H).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([N:12]([CH2:21][CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][CH:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=3)[CH2:26][CH2:25]2)[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(N(CC)CC)C.[C:45](Cl)(=[O:47])[CH3:46].[OH-].[Na+]>O1CCCC1>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([N:12]([CH2:21][CH2:22][CH2:23][N:24]2[CH2:25][CH2:26][CH:27]([CH2:30][C:31]3[CH:32]=[CH:33][C:34]([NH:37][C:45](=[O:47])[CH3:46])=[CH:35][CH:36]=3)[CH2:28][CH2:29]2)[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(C(=O)N(CCCN2CCC(Cc3ccc(N)cc3)CC2)c2ccc(Cl)c(Cl)c2)CC1
Reactant: CC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(CC2CCN(CCCN(C(=O)C3CCN(C(C)=O)CC3)c3ccc(Cl)c(Cl)c3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.9 %

Procedure:
1-Acetyl-N-(3-[4-(4-aminobenzyl)-1-piperidinyl]propyl}-N-(3,4-dichlorophenyl)-4-piperidinecarboxamide (Example 303) (18 mg, 0.033 mmol) was dissolved in tetrahydrofuran (0.3 mL). To the solution were added triethylamine (5.0 mg, 0.050 mmol) and acetyl chloride (3.4 mg, 0.043 mmol), and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added aqueous solution of 1N-sodium hydroxide (5 mL), and the mixture was extracted with ethyl acetate (5 mL×2). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The concentrate was subjected to alumina column chromatography (alumina 2 g, ethyl acetate), and the desired fraction was concentrated under reduced pressure to give the titled compound (18 mg, 0.031 mmol, Yield 93%) as a colorless oily substance.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH2:17][C:18]([O:20]CC)=O)=[CH:5][N:6]2[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[O:20]=[C:18]1[CH2:17][C:4]2=[CH:5][N:6]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]3[C:3]2=[C:2]([CH:10]=[CH:9][CH:8]=3)[NH:1]1
Reactant: CCOC(=O)Cc1cn(CC(=O)OCC)c2cccc(N)c12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)Cn1cc2c3c(cccc31)NC(=O)C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of diethyl 2,2′-(4-amino-1H-indole-1,3-diyl)diacetate from Step F (83 mg, 0.273 mmol) in toluene (8 mL) was added p-toluenesulfonic acid monohydrate (5 mg, 0.026 mmol) and the mixture was heated at reflux. After 2 h, the reaction was allowed to cool to ambient temperature and the mixture was partitioned between EtOAc (40 mL) and aqueous NaHCO3 (15 mL). The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:MeOH—100:0 to 92:8, to give the title compound. MS: m/z=259 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)[CH2:7][CH2:8][CH3:9].[N+](N[C:20]1[NH:25][C:24](=[O:26])[C:23]([CH2:27][C:28]2[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=2)=[CH:22][N:21]=1)([O-])=O>N1C=CC=CC=1.O>[CH2:7]([N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:20]1[NH:25][C:24](=[O:26])[C:23]([CH2:27][C:28]2[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=2)=[CH:22][N:21]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)[CH2:8][CH3:9]
Reactant: CCCN(CCCCN)c1ccccn1
Reactant: O=c1[nH]c(N[N+](=O)[O-])ncc1Cc1ccncc1
Solvent: c1ccncc1
Solvent: O
Product: CCCN(CCCCNc1ncc(Cc2ccncc2)c(=O)[nH]1)c1ccccn1

Procedure:
2-[N-(4-aminobutyl)-N-propylamino]pyridine (0.9 g) and 2-nitroamino-5-pyrid-4-ylmethylpyrimid-4-one (0.72 g) were heated together under reflux in pyridine (2.5 ml) for 21 hr. After stripping the residue was taken up in water, basified, and extracted with ether. The aqueous was acidified (pH 6.5), extracted with dichloromethane and stripped to give an oil which was crystallized from ethanol/water to give 2-[4-(N-propyl-N-pyrid-2-ylamino)butylamino]-5-pyrid-4-ylmethylpyrimid-4-one 1.2 H2O; 0.45 g (38%) m.p. 58°-60° C.
Reaction SMILES: [Li+].C[CH:3]([N-:5]C(C)C)C.[CH2:9]1[C:11]2([CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]2)[CH2:10]1.S(C#N)(C1C=CC(C)=CC=1)(=O)=O>C1COCC1>[O:17]=[C:14]1[CH2:15][CH2:16][C:11]2([CH2:10][CH2:9]2)[CH:12]=[C:13]1[C:3]#[N:5]
Reactant: CC(C)[N-]C(C)C
Reactant: O=C1CCC2(CC1)CC2
Agent: Cc1ccc(S(=O)(=O)C#N)cc1
Agent: [Li+]
Solvent: C1CCOC1
Product: N#CC1=CC2(CCC1=O)CC2
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
LDA (1.34 mL, 2.69 mmol, 2.0 M in hexanes) was combined with THF (2.4 mL) and cooled to −78° C. To this mixture was added a solution of spiro[2.5]octan-6-one (0.30 g, 2.4 mmol) in THF (2.4 mL). The resulting mixture was stirred at −78° C. for 20 mins then taken up in a syringe and added to a mixture of tosyl cyanide (0.88 g, 4.8 mmol) in THF (2.4 mL) at −78° C. The reaction mixture was allowed to stir at −78° C. for 45 mins then quenched with 0.5 M NaOH and extracted with EtOAc (2×) The combined organic extracts were washed with 1N aqueous HCl, brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by MPLC on silica gel (using a gradient elution of 0-50% EtOAc/hexanes). Desired fractions were identified, combined and concentrated in vacuo to afford the title compound.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][NH:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=2)=[O:11])[CH:5]=[CH:4][N:3]=[CH:2]1.C1CCCCC=1>[Pd].C(O)C>[N:1]1([CH2:6][CH2:7][CH2:8][NH:9][C:10]([C:12]2[CH:13]=[CH:14][C:15]([NH2:18])=[CH:16][CH:17]=2)=[O:11])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C(NCCCn1ccnc1)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CCO
Product: Nc1ccc(C(=O)NCCCn2ccnc2)cc1
Reaction time: 1 h
Yield: 67.3 %

Procedure:
A mixture of 4-{N-[3-(imidazol-1-yl)propyl]carbamoyl}nitrobenzene (Method 41; 2.0 g, 7.30 mmol), 10% palladium on carbon (100 mg) cyclohexene (40 ml) and ethanol (80 ml) was heated under reflux under an atmosphere of nitrogen for 4 hours. Two further portions of cyclohexene (40 ml) were added and heating was continued for 1 hour after each addition. The mixture was left to cool and the catalyst was removed by filtration. The filtrate was concentrated by evaporation and the residue was recrystallized from a mixture of ethanol and ether to give the product (1.2 g, 67%). NMR: 1.9-2.0 (m, 2H), 3.1-3.2 (m, 2H), 4.0 (t, 2H), 5.6 (br s 2H), 6.55 (d, 2H), 6.85 (s, 1H), 7.2 (s, 1H), 7.55 (d, 2H), 7.65 (s, 1H), 8.0 (br t, H).
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].Br[CH2:7][C:8]([O:10][CH3:11])=[O:9].C(OCC)(=O)C>C(N(CC)CC)C>[C:1]([O:5][CH2:7][C:8]([O:10][CH3:11])=[O:9])(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)O
Reactant: COC(=O)CBr
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C=CC(=O)OCC(=O)OC
Temperature: 15 °C
Reaction time: 8 h

Procedure:
Into a five-liter, three-necked, round-bottom flash (equipped with a mechanical stirrer, a thermometer and a one-liter dropping funnel topped with a drying tube) were placed 527.9 mls. of acrylic acid, 662.7 mls. of methyl bromoacetate and 1750 mls. of ethyl acetate. The resulting solution was cooled to about 15° C. and 1073.2 mls. of triethylamine were added over a period of about one hour. An exotherm was noted and reaction temperature was maintained between 15° and 25° C. with an ice/salt cooling bath. Upon completion of the triethylamine addition, the cooling bath was removed and the reaction mixture was stirred at room temperature (25° to 30° C.) overnight. The resulting thick slurry was poured into 1750 mls. of distilled water and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (two times, 500 mls. each) and the combined organic portions were washed successively with 500 mls. of 0.5N hydrochloric acid, 500 mls. of saturated aqueous sodium bicarbonate and, then, with 500 mls. of saturated aqueous sodium chloride. The organic solution (about 3.5 to 3.75 liters) was then dried (magnesium sulfate) and evaporated in vacuo (water aspirator) at ≤30° C. to provide a very pale-yellow product. The product was purified by addition of one gram of 2,6-di-tert-butyl-p-cresol as a free radical inhibitor and vacuum distilling through a distillation column. The purified product exhibited a boiling point of 50° C. (1.2 mm.) to 56° C. (1.9 mm.).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]1[C:11]2[CH:12]=[C:13]([N:16]3[C:21](=[O:22])[CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[NH:18][C:17]3=[O:27])[CH:14]=[CH:15][C:10]=2[S:9][N:8]=1.[C:28](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O>[CH3:28][N:18]1[C:19]([C:23]([F:26])([F:25])[F:24])=[CH:20][C:21](=[O:22])[N:16]([C:13]2[CH:14]=[CH:15][C:10]3[S:9][N:8]=[C:7]([C:3]4[N:2]([CH3:1])[CH:6]=[CH:5][CH:4]=4)[C:11]=3[CH:12]=2)[C:17]1=[O:27]
Reactant: Cn1cccc1-c1nsc2ccc(-n3c(=O)cc(C(F)(F)F)[nH]c3=O)cc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1cccc1-c1nsc2ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12
Temperature: 0 °C
Yield: 21.5 %

Procedure:
To a mixture of 3-[3-(1-methylpyrrol-2-yl)-1,2-benzisothiazol-5-yl]-6-(trifluoromethyl)uracil(1.35 g, 3.44 mmol), dry dimethylformamide and potassium carbonate (0.710 g, 5.14 mmol) is added iodomethane (0.730 g, 5.14 mmol). The resultant mixture is stirred overnight at room temperature and poured into ice water. Filtration and drying affords the title compound as a pink foam (0.300 g, 21.4%) which is identified by NMR spectral analysis.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][S:6]([C:9]1[N:13]=[CH:12][NH:11][N:10]=1)(=[O:8])=[O:7])[CH3:2].[CH2:14]([N:17]([CH2:21][CH:22]=[CH2:23])[C:18](Cl)=[O:19])[CH:15]=[CH2:16].C(N(CC)CC)C>O1CCCC1>[CH2:14]([N:17]([CH2:21][CH:22]=[CH2:23])[C:18]([N:11]1[CH:12]=[N:13][C:9]([S:6]([CH2:5][CH2:4][O:3][CH2:1][CH3:2])(=[O:8])=[O:7])=[N:10]1)=[O:19])[CH:15]=[CH2:16]
Reactant: C=CCN(CC=C)C(=O)Cl
Reactant: CCOCCS(=O)(=O)c1nc[nH]n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CCN(CC=C)C(=O)n1cnc(S(=O)(=O)CCOCC)n1

Procedure:
A solution of 4.1 g. 3-(2-ethoxyethylsulphonyl)-1,2,4-triazole, 3.5 g. diallylcarbamoyl chloride and 4 ml. triethylamine in 40 ml. dry tetrahydrofuran was refluxed under anhydrous conditions for 15 hours. The cooled reaction mixture was filtered to remove triethylamine hydrochloride and the filtrate was evaporated to remove solvent. The residue was triturated with petroleum ether (b.p. 40° - 60°C.) to give a solid product. This product was collected and recrystallised from ether/petroleum ether b.p. 40° - 60°C. to give 1-diallylcarbamoyl-3-(2-ethoxyethylsulphonyl)-1,2,4-triazole, m.p. 62° - 63°C. Elemental analysis satisfactory.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:14])([F:13])[F:12])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2.Cl[CH2:18][C:19]1[N:20]=[C:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[S:22][CH:23]=1>>[CH3:1][C:2]1[N:3]([CH2:18][C:19]2[N:20]=[C:21]([C:24]3[CH:25]=[CH:26][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:28][CH:29]=3)[S:22][CH:23]=2)[C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:12])([F:14])[F:13])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2
Reactant: FC(F)(F)c1ccc(-c2nc(CCl)cs2)cc1
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1csc(-c2ccc(C(F)(F)F)cc2)n1

Procedure:
Synthesized as described in Example 4 using 2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 120) and 4-(chloromethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole: MS (ES) m/z 466 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:9]=[C:8]([OH:10])[C:7]([C:11]#[N:12])=[CH:6][C:4]=1[OH:5])#[N:2].[CH2:13](Br)[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(=O)([O-])[O-].[K+].[K+].Cl>C(O)C.CN(C=O)C>[CH2:13]([O:10][C:8]1[C:7]([C:11]#[N:12])=[CH:6][C:4]([OH:5])=[C:3]([C:1]#[N:2])[CH:9]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCBr
Reactant: N#Cc1cc(O)c(C#N)cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCO
Product: CCCCCCOc1cc(C#N)c(O)cc1C#N
Temperature: 120 °C
Reaction time: 3 h
Yield: 23.3 %

Procedure:
In a 300 ml-reaction vessel, 35.0 g (2.19×10-1M) of 2,5-dicyanohydroquinone, 23.8 g (1.44×10-1M) of n-hexylbromide, 20.0 g (1.45×10-1M) of potassium carbonate and 180 ml of DMF were placed, followed by stirring for 3 hours at 120° C. After the reaction, the reaction mixture was cooled and poured into 500 ml of 4N-hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was washed with water and dried with anhydrous magnesium sulfate, followed by distilling-off of the solvent. The resultant residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=2/1) to obtain 17.6 g of a crude product. The crude product was dissolved in ethanol and treated with activated carbon, followed by recrystallization from ethanol to obtain 8.2 g of 4-hexyloxy-2,5-dicyanophenol (Yield: 22.9%).