Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:9]=2)=[CH:4][CH:3]=1.CN(C)C=O.[I-:24].[K+].II>N.O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:9]=2)=[CH:6][C:7]=1[I:24]
Reactant: CCOC(=O)c1cccc(-c2ccc(O)cc2)c1
Reactant: [I-]
Agent: II
Agent: N
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc(-c2ccc(O)c(I)c2)c1
Reaction time: 1 h

Procedure:
The product from Example 143A (7.71 g, 31.8 mmol) was dissolved into N,N-dimethylformamide (30 mL), diluted with concentrated aqueous ammonia (320 mL), and treated with a solution of potassium iodide (27.72 g, 167 mmol) and iodine (8.48 g, 33.4 mmol) in water (100 mL) all at once. After the mixture was stirred for one hour, the ammonia was removed under reduced pressure on a rotary evaporator. The remaining solution was neutralized to pH 7 with aqueous hydrochloric acid, diluted with EtOAc (200 mL), worked up as usual, dried (Na2SO4), concentrated, and chromatographed on silica with a 33 to 100% gradient of CH2Cl2/hexanes to provide the title compound as a white microcrystalline solid (37% yield). 1HNMR (300 MHz, d6-DMSO) δ 1.35 (t, 3 H), 4.35 (q, 2H), 7.00 (d, 1 H), 7.53-7.60 (m, 2 H), 7.84-7.91 (m, 2 H), 7.97 (d, 1 H), 8.08 (dd, 1 H), 10.55 (bs, 1 H).
Reaction SMILES: [CH:1]1([NH2:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.C(N(CC)CC)C.[C:16](Cl)(=[O:19])[CH2:17][CH3:18].Cl>C(Cl)(Cl)Cl>[CH:1]1([NH:8][C:16](=[O:19])[CH2:17][CH3:18])[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1
Reactant: CCC(=O)Cl
Reactant: NC1C=CCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCC(=O)NC1C=CCCCC1
Temperature: 20 °C
Reaction time: 3 h
Yield: 89.7 %

Procedure:
To a mixture of 2-cycloheptenylamine (1.11 g, 10 mmoles), triethylamine (1.01 g, 10 mmoles) and chloroform (10 ml), propionyl chloride (0.93 g, 10 mmoles) was added dropwise at 0° to 5° C. After stirring at 20° C. for 3 hours, the reaction mixture was poured into a 1N hydrochloric acid, and the separated organic layer was washed with a saturated aqueous sodium chloride solution and concentrated to obtain 1.50 g of N-(2-cycloheptenyl)propionamide [Compound (51)].
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=O)[CH2:3][CH2:4][C:5]([OH:7])=[O:6].C1(C)C(S(O)(=O)=O)=CC=CC=1.[CH2:22]([O:29][C:30](=[O:39])[CH2:31][NH:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N1CCOCC1)C.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl.CN(C=O)C.ClCCl>[CH2:22]([O:29][C:30](=[O:39])[CH2:31][N:32]([C:8](=[O:10])[C@H:2]([CH2:3][CH2:4][C:5](=[O:6])[OH:7])[NH2:1])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=C(CNc1ccccc1)OCc1ccccc1
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN1CCOCC1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N[C@@H](CCC(=O)O)C(=O)N(CC(=O)OCc1ccccc1)c1ccccc1

Procedure:
A solution of 20 mmoles of pyro-L-glutamic acid and 20 mmoles phenylglycine benzyl ester toluene sulfonic acid, neutrallized with N-ethyl morpholine, in dichloromethane:DMF (4:1) is cooled in an ice bath with stirring. A solution of 20 mmoles of dicyclohexylcarbodiimide in dichloromethane is added to the above reaction mixture. The reaction mixture is stirred in an ice water bath for 1 hour and then at room temperature overnight. Dicyclohexylurea is removed by filtration and the product is washed in ethyl acetate. Solvents of the combined filtrates are removed under reduced pressure with a rotary evaporator at 40° C. Ethyl acetate is added to the residue and the organic solution is washed until neutral. The organic phase is dried over anhydrous MgSO4, filtered and then the solvent is removed with a rotary evaporator. The material is crystallized from isopropanol and ether yielding the named product.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([S:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]3[C:19](=[O:20])[CH2:18][S:17][C:16]3=[O:21])=[CH:8][CH:7]=[CH:6][C:5]=12.[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][CH2:30][CH:31]=O.N1CCCCC1>C(O)C>[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][CH2:30][CH:31]=[C:18]1[S:17][C:16](=[O:21])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][S:10][C:9]2[N:4]3[CH:3]=[CH:2][N:1]=[C:5]3[CH:6]=[CH:7][CH:8]=2)[C:19]1=[O:20]
Reactant: O=CCCc1ccccc1F
Reactant: O=C1CSC(=O)N1CCCCSc1cccc2nccn12
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1SC(=CCCc2ccccc2F)C(=O)N1CCCCSc1cccc2nccn12

Procedure:
To a solution of 964 mg (3.0 mmol) of 3-[4-(imidazo[1,2-a]pyridin-5-ylthio)butyl]thiazolidine-2,4-dione and 609 mg (4.0 mmol) of 3-(2-fluorophenyl)-1-propanal in 20 ml of ethanol, 26 mg (0.3 mmol) of piperidine was added, followed by refluxing for 4.5 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in dichloromethane, washed with purified water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, chloroform/methanol=50/1) to yield 1.11 g (81.5%, yellow oily substance) of the desired product.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([O:9][C:10]2[CH:11]=[C:12]([CH3:26])[C:13]3[CH:17]([CH2:18][C:19]([O:21]CC)=[O:20])[O:16][B:15]([OH:24])[C:14]=3[CH:25]=2)[CH:4]=1)#[N:2].[OH-].[Na+]>CO.C1COCC1>[C:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([O:9][C:10]2[CH:11]=[C:12]([CH3:26])[C:13]3[CH:17]([CH2:18][C:19]([OH:21])=[O:20])[O:16][B:15]([OH:24])[C:14]=3[CH:25]=2)[CH:4]=1)#[N:2]
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3cc(C#N)ccn3)cc(C)c21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(Oc2cc(C#N)ccn2)cc2c1C(CC(=O)O)OB2O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 2-(6-(4-cyanopyridin-2-yloxy)-1-hydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (1.18 g, 3.31 mmol) in MeOH/THF (12 mL, 1:1) was added aqueous NaOH solution (250 mg in 3 mL of water). After stirring at room temperature for two hours, the reaction mixture was evaporated and then acidified to pH 5 using 1 N HCl and then concentrated. HPLC purification gave desired product as a white powder. 1H NMR (400 MHz, DMSO-d6) δ 12.2 (b, 1H), 9.24 (b, 1H), 8.30 (d, J=5.2 Hz, 1H), 7.57 (s, 1H), 7.50 (dd, J=5.2, 1.2 Hz, 1H), 7.17 (d, J=2 Hz, 1H), 7.01 (d, J=1.6 Hz, 1H), 5.45 (dd, J=9.6, 2 Hz, 1H), 3.02 (dd, J=15.6, 2.4 Hz, 1H), 2.46 (s, 3H), 2.08 (dd, J=16, 10 Hz, 1H). MS (ESI) m/z=323 [M−H]+.
Reaction SMILES: [SH:1][CH2:2][CH2:3][OH:4].C([O-])(=O)C.[Na+].Cl[C:11]1[CH:16]=[CH:15][C:14]([S:17]([NH2:20])(=[O:19])=[O:18])=[CH:13][C:12]=1[N+:21]([O-:23])=[O:22].Cl>O>[OH:4][CH2:3][CH2:2][S:1][C:11]1[CH:16]=[CH:15][C:14]([S:17]([NH2:20])(=[O:19])=[O:18])=[CH:13][C:12]=1[N+:21]([O-:23])=[O:22]
Reactant: OCCS
Reactant: NS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NS(=O)(=O)c1ccc(SCCO)c([N+](=O)[O-])c1
Yield: 75.8 %

Procedure:
A mixture of 2-mercaptoethanol (1.66 g, 0.02 mol), anhydrous sodium acetate (2 g) and 4-chloro-3-nitrobenzenesulfonamide (2.37 g, 0.01 mol) was heated on the steam bath for about 5 hours. The reaction mixture was diluted with water, acidified with 6N hydrochloric acid and cooled. Filtration and drying gave 2.11 g of a yellow solid that was recrystallized from ethyl acetate, m.p. 150°-152° C.
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:21][CH2:22]OC)[CH2:11][CH2:10][N:9]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH2:8][CH2:7]1)=O)C.[Cl-].C[Al+]C.[NH2:29][C:30]1[N:31]=[N:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=1>CCCCCCC>[C:15]1([S:12]([N:9]2[CH2:8][CH2:7][C:6]3([C:4](=[O:3])[N:29]([C:30]4[N:31]=[N:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=4)[CH2:22][CH2:21]3)[CH2:11][CH2:10]2)(=[O:13])=[O:14])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COc1ccc(N)nn1
Reactant: CCOC(=O)C1(CCOC)CCN(S(=O)(=O)c2ccccc2)CC1
Agent: C[Al+]C
Agent: [Cl-]
Solvent: CCCCCCC
Product: COc1ccc(N2CCC3(CCN(S(=O)(=O)c4ccccc4)CC3)C2=O)nn1
Yield: 14.1 %

Procedure:
This material was prepared in analogy to example 1 step D) from 1-Benzenesulfonyl-4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (0.15 g), dimethylaluminium chloride in heptane (0.9 molar, 0.71 ml) and 3-amino-6-methoxypyridazine (0.069 g) to give the desired 8-benzenesulfonyl-2-(6-methoxy-pyridazin-3-yl)-2,8-diaza-spiro[4.5]decan-1-one (0.024 g) as a white solid. MS (ESI): 403.146 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:18])=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:11]=[N:12][C:13]([NH2:16])=[N:14][CH:15]=1)=[O:8].C(N(CC)CC)C.[F:26][C:27]([F:39])([F:38])[C:28]1[CH:29]=[C:30]([S:34](Cl)(=[O:36])=[O:35])[CH:31]=[CH:32][CH:33]=1>C(Cl)(Cl)Cl>[NH2:16][C:13]1[N:12]=[CH:11][C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:17]=[C:2]([NH:1][S:34]([C:30]3[CH:31]=[CH:32][CH:33]=[C:28]([C:27]([F:26])([F:38])[F:39])[CH:29]=3)(=[O:36])=[O:35])[CH:3]=[CH:4][C:5]=2[CH3:18])=[CH:15][N:14]=1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Reactant: Cc1ccc(N)cc1C(=O)Nc1cnc(N)nc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1ccc(NS(=O)(=O)c2cccc(C(F)(F)F)c2)cc1C(=O)Nc1cnc(N)nc1
Temperature: 25 °C

Procedure:
To a solution of 5-amino-N-(2-aminopyrimidin-5-yl)-2-methylbenzamide 28 (85 mg, 0.349 mmol) in CHCl3 (2 mL) was added triethylamine (0.453 mmol) and 3-(trifluoromethyl)benzene-1-sulfonyl chloride (0.064 mL, 0.401 mmol). The reaction mixture was heated to reflux for 12 h, cooled to rt and concentrated in vacuo. The crude residue was adsorbed on SiO2 and purified by flash chromatography (CH2Cl2/MeOH 99:1) on SiO2 to afford N-(2-aminopyrimidin-5-yl)-2-methyl-5-(3-(trifluoromethyl)phenylsulfonamido)benzamide 29. MS m/z found 452 [MH+]; calc. for C19H16F3N5O3S=451.09.
Reaction SMILES: [C:1]([N:8]1[CH2:15][CH2:14][CH2:13][C@@H:9]1[C:10]([NH2:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:25])=CC=1>C(Cl)Cl>[C:10]([C@H:9]1[CH2:13][CH2:14][CH2:15][N:8]1[C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])(=[S:25])[NH2:12]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(N)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1C(N)=S
Reaction time: 8 h
Yield: 170.5 %

Procedure:
To a stirred solution Boc-D-prolinamide (2.63 g, 12.3 mmol) in CH2Cl2 (25 mL) at rt was added Lawesson's reagent (2.73 g, 6.75 mmol). The mixture was stirred overnight and concentrated. The oily residue was purified by chromatography on a 40-g silica gel cartridge, eluted with a 0-20% MeOH in CH2Cl2 gradient, to afford (R)-tert-butyl 2-carbamothioylpyrrolidine-1-carboxylate (2.65 g, 94%) as a tan solid. LC-MS Method 1 tR=1.23 min, m/z=231, 173, 131.
Reaction SMILES: [CH2:1]1N2CN3CN(C2)CN1C3.[F:11][C:12]([F:21])([F:20])[C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1.[OH2:22].S(=O)(=O)(O)O>FC(F)(F)C(O)=O>[F:11][C:12]([F:20])([F:21])[C:13]1[CH:14]=[CH:15][C:16]([OH:19])=[C:17]([CH:18]=1)[CH:1]=[O:22]
Reactant: C1N2CN3CN1CN(C2)C3
Reactant: O
Reactant: Oc1ccc(C(F)(F)F)cc1
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Product: O=Cc1cc(C(F)(F)F)ccc1O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Hexamethylenetetramine (47.5 g) was added portionwise to a stirred solution of 4-trifluoromethylphenol (50 g) in trifluoroacetic acid (680 ml) and the mixture was heated at reflux temperature for 24 hours. After cooling, water (355 ml) was added followed by aqueous sulphuric acid (50% v/v, 190 ml) and the reaction was stirred at ambient temperature for 4 hours. The acidic aqueous phase was extracted with diethyl ether (3×500 ml). The combined organic extracts were washed with hydrochloric acid (5M, 3×500 ml) then water (500 ml) and dried over magnesium sulphate. The solvent was removed under reduced pressure and the residue purified by column chromatography on silica eluting with a 4:1 mixture of petroleum ether (b.p. 40-60° C.) and ethyl acetate. The appropriate fractions were combined and the solvent removed under reduced pressure to give 5-trifluoromethyl-2-hydroxybenzaldehyde (25 g) as a light pink solid.
Reaction SMILES: Cl[C:2]1[C:3]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:4][C:5]([F:8])=[N:6][CH:7]=1.[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1B(O)O.ClC1C=CC=CC=1C1C(C2C=CC(Cl)=CC=2)=CC2N(C(=O)N(CC3C=NC(C(F)(F)F)=CC=3)N=2)C=1C>>[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:2]1[C:3]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:4][C:5]([F:8])=[N:6][CH:7]=1
Reactant: Fc1cc(-c2ccc(Cl)cc2)c(Cl)cn1
Reactant: OB(O)c1ccccc1Cl
Agent: Cc1c(-c2ccccc2Cl)c(-c2ccc(Cl)cc2)cc2nn(Cc3ccc(C(F)(F)F)nc3)c(=O)n12
Product: Fc1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)cn1
Yield: 35.4 %

Procedure:
The title compound (0.33 g, 35% yield) as a white foam was prepared from 5-chloro-4-(4-chlorophenyl)-2-fluoropyridine (0.71 g, 2.93 mmol) and 2-chlorophenylboronic acid (0.55 g, 3.52 mmol) in a manner analogous to that in which 6-(2-chlorophenyl)-7-(4-chlorophenyl)-5-methyl-2-((6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one was prepared. HPLC/MS: retention time=4.03 min, [M+H]+=318.1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([Li])CCC.C([O:25][B:26](OC(C)C)[O:27]C(C)C)(C)C>O1CCCC1>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([B:26]([OH:27])[OH:25])=[C:3]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:4]=1
Reactant: Clc1ccc(Br)c(OCc2ccccc2)c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc(Cl)cc1OCc1ccccc1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
1-bromo-4-chloro-2-[(phenylmethyl)oxy]benzene (2.976 g, 10 mmol) in dry tetrahydrofuran (40 ml) was cooled to −100° C. n-Butyl lithium, 1.6M solution in hexanes (6.9 ml, 11 mmol) was added dropwise over 10 min under nitrogen. The reaction mixture was then allowed to warm to −70° C. for 1 h. Triisopropylborate (5.514, 30 mmol) was added dropwise under nitrogen. The cooling bath was then removed and the reaction mixture was allowed to warm to room temperature before being quenched with 2N hydrochloric acid (30 mL) and stirred vigorously at room temperature for 1 h. The product was then extracted with ether, dried over magnesium sulphate and evaporated down to an oil which was dissolved in iso-hexane and the solid which separated out was filtered off and dried. Yield 1.89 g.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[C:5]([Cl:7])[NH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:6]=[C:5]([Cl:7])[N:4]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:3]=1
Reactant: CCOC(=O)CBr
Reactant: Clc1cc(Cl)[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1nc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 94.1 %

Procedure:
A suspension of 3,5-dichloro-1H-pyrazole (690 mg, 5.0 mmol) (i.e. the product of Example 12, Step D), potassium carbonate (3 g, 21 mmol) in N,N-dimethylformamide (10 mL) was treated with ethyl bromoacetate (1.0 mL, 9.0 mmol) and stirred at ambient temperature for 12 h. The suspension was diluted with ethyl acetate, washed with water, and dried over MgSO4. The reaction mixture was then concentrated under reduced pressure giving 1.05 g of the title compound. This compound was of sufficient purity to use in subsequent reactions.
Reaction SMILES: CC1(C)[O:7][CH2:6][C:5]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][CH2:21][CH2:22][CH2:23][C:24]([CH3:33])([O:26]C4CCCCO4)[CH3:25])[CH:15]=3)[CH:10]=[CH:11][C:4]=2[O:3]1>C(O)(=O)C.C1COCC1.O>[OH:7][CH2:6][C:5]1[CH:8]=[C:9]([CH:12]=[CH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])([CH3:25])[CH3:33])[CH:15]=2)[CH:10]=[CH:11][C:4]=1[OH:3]
Reactant: CC(C)(CCCCc1cccc(C=Cc2ccc3c(c2)COC(C)(C)O3)c1)OC1CCCCO1
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(O)CCCCc1cccc(C=Cc2ccc(O)c(CO)c2)c1

Procedure:
In a manner similar to Example 8(k), by reacting 313 mg (0.67 mmol) of 2,2-dimethyl-6-(2-{3-[5-methyl-5-(tetrahydropyran-2-yloxy)hexyl]phenyl}vinyl)-4H-benzo[1.3]dioxin in 10 ml of acetic acid, 5 ml of THF and 2.5 ml of water, and after purification on a silica column (ethyl acetate 40-heptane 60), white crystals (m=91 mg; Y=40%) are obtained. m.p.=130-1° C.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:24])[C:13](=[O:23])[N:14]([C:15]4[C:16]([CH3:22])=[N:17][N:18]([CH3:21])[C:19]=4[CH3:20])[C:5]=3[C:4]=2[CH:3]=1.[CH2:25]([NH:27][C:28]1[C:29]([F:43])=[N:30][CH:31]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:33]=1)[CH3:26]>>[CH2:25]([NH:27][C:28]1[CH:33]=[C:32]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][C:6]4[N:12]([CH3:24])[C:13](=[O:23])[N:14]([C:15]5[C:16]([CH3:22])=[N:17][N:18]([CH3:21])[C:19]=5[CH3:20])[C:5]=4[C:4]=3[CH:3]=2)[CH:31]=[N:30][C:29]=1[F:43])[CH3:26]
Reactant: CCNc1cc(B2OC(C)(C)C(C)(C)O2)cnc1F
Reactant: Cc1nn(C)c(C)c1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: CCNc1cc(-c2ccc3ncc4c(c3c2)n(-c2c(C)nn(C)c2C)c(=O)n4C)cnc1F

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-3-methyl-1-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate H, 0.104 mmol) and ethyl-[2-fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-amine (stage 154.1.1) to give the title compound as a white solid. (HPLC: tR 2.63 min (Method A); M+H=446 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.97 (s, 1H), 8.11-8.07 (m, 1H), 7.96-7.91 (m, 1H), 7.55-7.52 (m, 1H), 7.48-7.45 (m, 1H), 7.00-6.95 (m, 1H), 5.96 (t, 1H), 3.78 (s, 3H), 3.59 (s, 3H), 3.20 (qt, 2H), 2.07 (s, 3H), 1.91 (s, 3H), 1.23 (t, 3H))
Reaction SMILES: [O:1]=[C:2]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])[C:3]([OH:5])=O.[CH2:11]([NH2:14])[CH2:12][CH3:13]>>[CH2:11]([NH:14][C:3](=[O:5])[C:2](=[O:1])[CH2:6][CH2:7][C:8]([OH:10])=[O:9])[CH2:12][CH3:13]
Reactant: O=C(O)CCC(=O)C(=O)O
Reactant: CCCN
Product: CCCNC(=O)C(=O)CCC(=O)O

Procedure:
Using 1.46 g of 2-oxoglutaric acid and 0.828 ml of n-propylamine, there was obtained 496 mg of the subject Compound (85), by conducting a reaction and treatment analogous to Example 83, as pale yellow crystals, m.p. 79°-81° C.
Reaction SMILES: [I:1][CH2:2][CH:3]1[CH2:7][CH2:6][CH2:5][CH2:4]1.[C:8]1([P:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(#N)C>[I-:1].[CH:3]1([CH2:2][P+:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: ICC1CCCC1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: [I-]
Product: c1ccc([P+](CC2CCCC2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Yield: 86.3 %

Procedure:
A solution of iodomethylcyclopentane (4.60 g, 21.89 mmol) and triphenylphosphine (5.74 g, 21.89 mmol) in acetonitrile (22 mL) was heated under reflux for 2 weeks. The reaction mixture was allowed to cool to 25° C. and then concentrated in vacuo to provide an orange solid. The orange solid was triturated with diethyl ether and then filtered. The solid was washed well with diethyl ether until the washings showed the absence of iodomethylcyclopentane and triphenylphosphine by thin layer chromatography. The solid was allowed to air dry to afford cyclopentylmethyl triphenylphosphonium iodide (8.92 g, 86%) as a light orange solid: mp 195-198° C.; FAB-HRMS m/e calcd for C24H26P (M+H)+ 345.1772, found 345.1784.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:9]([CH3:10])=[CH:8][C:7]([CH3:11])=[CH:6][C:5]=1[OH:12].[Cl:13][C:14]1[N:19]=[C:18](Cl)[C:17]([CH:21]([CH3:23])[CH3:22])=[C:16]([Cl:24])[N:15]=1.C(OCC)(=O)C>CN(C=O)C>[Cl:13][C:14]1[N:15]=[C:16]([Cl:24])[C:17]([CH:21]([CH3:23])[CH3:22])=[C:18]([O:12][C:5]2[CH:6]=[C:7]([CH3:11])[CH:8]=[C:9]([CH3:10])[C:4]=2[CH3:3])[N:19]=1
Reactant: CC(C)c1c(Cl)nc(Cl)nc1Cl
Reactant: Cc1cc(C)c(C)c(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(C)c(C)c(Oc2nc(Cl)nc(Cl)c2C(C)C)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 93.9 %

Procedure:
Sodium hydride (60%, 59 mg, 1.44 mmol. 1.1 eq.) was added to 2,3,5-trimethyl-phenol (179 mg, 1.31 mmol) in DMF (2 mL). The mixture was stirred at room temperature for 15 minutes and then added to 2,4,6-trichloro-5-isopropyl-pyrimidine (296 mg, 1.31 mmol) in 1 mL DMF. The reaction was stirred at room temperature for 4 hours. Ethyl acetate was added and washed with brine. The organic layer was concentrated down and purified (silica gel, 0-50% EtOAC/hexane) to give white solid (400 mg, 94%). LC-MS shows 325.2 (M+1). 1H NMR (300 MHz, CDCl3): δ 6.94 (s, 1H), 6.63 (s, 1H), 3.61 (m, 1H), 2.32 (s, 6H), 2.02 (s, 3H), 1.42 (d, 6H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][C:12](=[O:14])[NH:11][C:10]2[CH:15]=[C:16]([CH2:19]O)[CH:17]=[N:18][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-].C(C[P+](C)(C)C)#N.C(N(C(C)C)C(C)C)C.Cl.[Cl:39][C:40]1[CH:45]=[CH:44][C:43]([CH:46]2[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)=[CH:42][CH:41]=1>C(#N)CC>[CH2:1]([N:8]1[CH2:13][C:12](=[O:14])[NH:11][C:10]2[CH:15]=[C:16]([CH2:19][N:49]3[CH2:50][CH2:51][CH:46]([C:43]4[CH:42]=[CH:41][C:40]([Cl:39])=[CH:45][CH:44]=4)[CH2:47][CH2:48]3)[CH:17]=[N:18][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CN(Cc2ccccc2)c2ncc(CO)cc2N1
Reactant: Clc1ccc(C2CCNCC2)cc1
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CN(Cc2ccccc2)c2ncc(CN3CCC(c4ccc(Cl)cc4)CC3)cc2N1
Temperature: 90 °C
Reaction time: 2 h
Yield: 42.3 %

Procedure:
4-benzyl-7-(hydroxymethyl)-3,4-dihydropyrido[2,3-b]pyrazin-2(1H)-one (100 mg, 0.37 mmol) was suspended in propionitrile (1 mL) and (cyanomethyl)trimethylphosphonium iodide (123.0 mg, 0.51 mmol) was added followed by N-ethyl-N-isopropylpropan-2-amine (180 ul, 1.03 mmol). To the stirred mixture was then added 4-(4-chlorophenyl)piperidine hydrochloride (104.5 mg, 0.45 mmol). The reaction was heated to 90° C. with stirring for 2 h. The reaction was then cooled to room temperature and purified via HPLC (55-90% acetonitrile in water, ammonium bicarbonate buffer). The fractions were combined and concentrated until a white solid precipitated. The precipitate was filtered and dried in vacuum to afford the title compound (69.9 mg, 42%) as a white solid. 1H NMR (DMSO-d6) δ (ppm): 10.56 (s, 1H), 7.63 (d, J=2.0 Hz, 1H), 7.30-7.37 (m, 6H), 7.23-7.30 (m, 3H), 7.00 (d, J=2.0 Hz, 1H), 4.71 (s, 2H), 3.85 (s, 2H), 3.33 (s, 3H), 2.89 (d, J=11.4 Hz, 2H), 1.99 (t, J=10.6 Hz, 2H), 1.67-1.78 (m, 2H), 1.48-1.66 (m, 2H). [M+H] calc'd for C11H15Cl2N, 447; found, 447.
Reaction SMILES: [C:1]([NH:5][N:6]=[C:7]([CH2:9][CH:10]([CH3:12])[CH3:11])[CH3:8])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:20]Cl>CCCCC>[C:1]([N:5]=[N:6][C:7]([Cl:20])([CH2:9][CH:10]([CH3:12])[CH3:11])[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(CC(C)C)=NNC(C)(C)C
Reactant: ClCl
Solvent: CCN(CC)CC
Solvent: CCCCC
Product: CC(C)CC(C)(Cl)N=NC(C)(C)C
Temperature: -15 °C

Procedure:
Into a 5 liter, 4-neck round bottom flask equipped with a low temperature thermometer, a chlorine inlet tube, a mechanical stirrer, and a gas exit tube protected from the atmosphere with a CaCl2 tube, was added 510 grams (3.0 moles) of methyl isobutyl ketone t-butylhydrazone, 303.6 grams (3.0 moles) of triethylamine and 2400 ml of pentane. The contents were cooled to -15°C with a dry ice-isopropanol bath. Then with rapid stirring 213 grams (3.0 moles) of chlorine were passed into the reaction mixture as fast as it was possible to control the temperature at 5°C or below. After all of the chlorine had been added the reaction temperature was adjusted to -5°C to 0°C and the reaction mixture filtered to remove the triethylamine hydrochloride. The triethylamine hydrochloride filter cake was washed with fresh pentane and the filtrate added to the original pentane solution.