Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:14]([NH:15][CH3:16])=[CH:13][C:5]([CH:6](O)CS(C)(=O)=O)=[CH:4][C:3]=1[N:17]([CH3:19])[CH3:18].C[O-].[Na+].[NH:23]([CH2:30][CH2:31][C:32]#[N:33])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CS(C)=O>[NH:23]([CH:30]=[C:31]([CH2:6][C:5]1[CH:13]=[C:14]([NH:15][CH3:16])[C:2]([Cl:1])=[C:3]([N:17]([CH3:19])[CH3:18])[CH:4]=1)[C:32]#[N:33])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CNc1cc(C(O)CS(C)(=O)=O)cc(N(C)C)c1Cl
Reactant: N#CCCNc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CNc1cc(CC(C#N)=CNc2ccccc2)cc(N(C)C)c1Cl

Procedure:
A mixture of 9.48 g. of 4-chloro-3-dimethylamino-5-methylamino-α-[(methylsulfonyl)methyl]benzyl alcohol, 1.8 g. of sodium methylate and 4.8 g. of β-anilinopropionitrile in 20 ml. of dimethylsulfoxide was stirred with the exclusion of moisture for 5 hours at 50° C. The mixture was cooled, poured into 200 ml. of water, the precipitated oil extracted with ethyl acetate, the ethyl acetate solution dried over sodium sulfate and evaporated. By purification of the product over aluminum oxide with benzene and recrystallization from ethanol, there was obtained α-(anilinomethylene)-4-chloro-3-dimethylamino-5-methylaminohydrocinnamonitrile, having a melting point of 173°-174° C.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=[C:13]([C:15]([NH:17][NH2:18])=O)[O:12][N:11]=2)=[CH:6][CH:5]=1.Cl.[C:22](=N)([NH2:24])[CH3:23].[OH-].[Na+].CCOC(C)=O>C1COCC1>[CH3:23][C:22]1[NH:18][N:17]=[C:15]([C:13]2[O:12][N:11]=[C:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:20])([F:19])[F:1])=[CH:5][CH:6]=3)[N:14]=2)[N:24]=1
Reactant: CC(=N)N
Reactant: NNC(=O)c1nc(-c2ccc(OC(F)(F)F)cc2)no1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)n[nH]1
Temperature: 180 °C
Reaction time: 0.25 h
Yield: 45.8 %

Procedure:
To a solution of 3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole-5-carbohydrazide (9.7 g, 33.7 mmol) and acetimidamide hydrochloride (4.8 g, 50.5 mmol) in dry THF (300 mL), NaOH (2.0 g, 50.5 mmol) was added at RT. The mixture was refluxed overnight. The solution was cooled, concentrated and ethane-1,2-diol (100 mL) was added. The resulting mixture was heated at 180° C. for 3 h, cooled to RT, diluted with H2O (800 mL), and extracted with EtOAc (3×400 mL). The combined organic layers were washed with H2O (300 mL) and brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to afford the crude solid product, which was treated with EtOAc (150 mL). The resulting suspension was stirred at RT for 15 min, and then filtered to afford 4.8 g of the pure desired compound. The remaining filtrate was concentrated and purified by silica gel column chromatography (Petroleum ether:EtOAc=1:1) to afford 1.4 g of another batch of 5-(5-methyl-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole as a white solid-overall 6.2 g, yield 59%. MS (ES+) C12H8F3N5O2 requires: 311. found: 312 [M+H]+.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10](Br)=[CH:11][CH:12]=2)[C@H:7]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[CH2:6][C@@H:5]1[CH3:28])(=[O:3])[CH3:2].[CH:29]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)([CH3:31])[CH3:30].C(O[Na])(C)(C)C>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([N:35]3[CH2:36][CH2:37][N:32]([CH:29]([CH3:31])[CH3:30])[CH2:33][CH2:34]3)=[CH:11][CH:12]=2)[CH:7]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[CH2:6][CH:5]1[CH3:28])(=[O:3])[CH3:2]
Reactant: CC(C)N1CCNCC1
Reactant: CC(=O)N1c2ccc(Br)cc2[C@H](Nc2ccc(N3CCOCC3)cc2)C[C@@H]1C
Agent: [Pd]
Agent: CC(C)(C)O[Na]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(=O)N1c2ccc(N3CCN(C(C)C)CC3)cc2C(Nc2ccc(N3CCOCC3)cc2)CC1C

Procedure:
88.9 mg of (2S,4R)-1-acetyl-6-bromo-2-methyl-4-[(4-morpholinophenyl)amino]-1,2,3,4-tetrahydroquinoline was dissolved in 4 mL of toluene, and 142.5 μL of 1-isopropylpiperazine, 9.2 mg of tris(dibenzylideneacetone)dipalladium(0), 6.0 mg of (2-biphenyl)-di-tert-butylphosphine, and 38.4 mg of tert-butoxysodium were sequentially added to the solution. The mixture was heated to reflux for 12 hours. The reaction liquid was cooled, and then was filtered through Celite. The filtrate was washed with chloroform, water was added to the filtrate, and the mixture was extracted three times with chloroform. The extraction product was washed with saturated brine, dehydrated over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by using silica gel chromatography (chloroform:methanol=10:1), and then was recrystallized from ethyl acetate-hexane. Thus, 22.0 mg (22.4%, cis:trans=9:1) of the title compound was obtained as a pale yellow crystalline powder.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([O:9][CH2:10][C:11]([OH:13])=O)=[CH:5][CH:4]=[N:3]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(CC)CC.[OH:43][CH:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1>CN(C=O)C>[OH:43][CH:44]1[CH2:49][CH2:48][N:47]([C:11](=[O:13])[CH2:10][O:9][C:6]2[C:7](=[O:8])[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=2)[CH2:46][CH2:45]1
Reactant: OC1CCNCC1
Reactant: Cn1nccc(OCC(=O)O)c1=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1nccc(OCC(=O)N2CCC(O)CC2)c1=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 63 %

Procedure:
11.1 g (60.2 mmoles) of intermediate 4i are placed in 250 mL of DMF under nitrogen. At 0° C., 21.3 g (66.3 mmoles) of TBTU then 16.8 mL (120 mmoles) of Et3N then 6.1 g (60.2 mmoles) of 4-hydroxypiperidine are added. The reaction medium is agitated for 20 h at ambient temperature then concentrated to dryness. The residue obtained is purified by silica gel flash chromatography (CH2Cl2-MeOH, gradient 100:0 to 90:10 in 40 min). 10.14 g of intermediate 5c are thus obtained in the form of a yellow solid (yield 63%). TLC silica gel 60 F 254 Merck, CH2Cl2-MeOH: 80:20, Rf=0.59.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:28](C1N=C(Cl)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.N1CCC[C@H]1CO>>[C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:23][CH2:24][CH2:28][C@H:27]2[CH2:26][OH:25])[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Agent: OC[C@@H]1CCCN1
Product: CC(C)(C)c1nc(N2CCC[C@H]2CO)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and (S)-pyrrolidin-2-ylmethanol and isolated as light-yellow gum (14.6 mg, 77%). MS (m/e): 401.4 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][CH:3]=1.Cl.[CH3:12][NH:13][O:14][CH3:15].CCN=C=NCCCN(C)C.C(N(C(C)C)CC)(C)C>ClCCl>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:13]([O:14][CH3:15])[CH3:12])=[O:7])=[CH:4][CH:3]=1
Reactant: CNOC
Reactant: O=C(O)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.3 %

Procedure:
To a solution of 4-fluorobenzoic acid (200 g, 1.43 mol), N,O-dimethylhydroxylamine hydrochloride (207 g, 2.14 mol) and EDCI (407 g, 2.14 mol) in dichloromethane (2 L) was added diisopropylethylamine (553 g, 4.28 mol) at 0° C. and the mixture was stirred at RT overnight. The reaction mixture was then washed with aqueous HCl (1 N, 1 L*4), water (1 L) and brine (1 L) sequentially. The organic layer was dried over MgSO4, filtered and concentrated in vacuo to give the title compound (150 g, yield 57%). MS (ES+) C9H10FNO2 requires: 183. found 184 [M+H]+; purity: 90% (UV254).
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:41])[C:6]([N:26]1[C@H:29]([SH:30])[C@@H:28]([C@H:31]([O:33][C:34]([O:36][CH2:37][CH:38]=[CH2:39])=[O:35])[CH3:32])[C:27]1=[O:40])=[P:7]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH:2]=[CH2:3].Cl.[CH3:43][C:44]1[CH:52]=[CH:51][C:47]([C:48](Cl)=[O:49])=[CH:46][N:45]=1>[Ag]>[CH2:1]([O:4][C:5](=[O:41])[C:6]([N:26]1[C@H:29]([S:30][C:48](=[O:49])[C:47]2[CH:51]=[CH:52][C:44]([CH3:43])=[N:45][CH:46]=2)[C@@H:28]([C@H:31]([O:33][C:34]([O:36][CH2:37][CH:38]=[CH2:39])=[O:35])[CH3:32])[C:27]1=[O:40])=[P:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N(C(C(=O)OCC=C)=P(c2ccccc2)(c2ccccc2)c2ccccc2)[C@@H]1S
Reactant: Cc1ccc(C(=O)Cl)cn1
Agent: [Ag]
Agent: Cl
Product: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N(C(C(=O)OCC=C)=P(c2ccccc2)(c2ccccc2)c2ccccc2)[C@@H]1SC(=O)c1ccc(C)nc1

Procedure:
0.415 g of the silver salt of 2-[(3S,4R)-3-[(1R)-1-allyloxycarbonyloxyethyl]-4-mercapto-2-oxo-azetidin-1-yl]-2-triphenylphosphoranylideneacetic acid allyl ester and 0.18 g of 6-methylnicotinoyl chloride hydrochloride are converted into the title compound analogously to Example 1.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[F:13][C:14]1[C:19]([CH3:20])=[CH:18][C:17](B2OC(C)(C)C(C)(C)O2)=[CH:16][C:15]=1[CH3:30].C(=O)([O-])[O-].[Na+].[Na+].C(COC)OC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([C:17]3[CH:18]=[C:19]([CH3:20])[C:14]([F:13])=[C:15]([CH3:30])[CH:16]=3)=[N:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C)c1F
Reactant: Clc1ccc2c(Cl)ncnc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1cc(-c2ncnc3cc(Cl)ccc23)cc(C)c1F
Yield: 71.1 %

Procedure:
4,7-dichloroquinazoline (4.0 g, 20.1 mmol), 2-(4-fluoro-3,5-dimethylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5.53 g, 22.1 mmol), sodium carbonate (5.33 g, 50.2 mmol), palladium tetrakis (0.70 g, 0.60 mmol), dimethoxyethane (“DME”) (160 mL), and water (40 mL) were combined in a three neck round bottom flask. A condenser was attached then the system was evacuated and purged with nitrogen three times. The reaction was heated to a vigorous reflux overnight. The reaction was diluted with ethyl acetate, water and brine. The aqueous was partitioned off and the organic was washed once with brine, dried with sodium sulfate, filtered then concentrated down to a yellow solid. The yellow solid was purified with silica gel using DCM to 85/15 DCM/ethyl acetate solvent system to get 4.1 g of light yellow solid for a 71% yield.
Reaction SMILES: [F:1][C:2]1[C:7](I)=[C:6]([F:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[O:12][CH3:13].[CH3:14][Si:15]([C:18]#[CH:19])([CH3:17])[CH3:16].C(N(CC)CC)C.CN(C)C=O>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:1][C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]([O:10][CH3:11])=[C:6]([F:9])[C:7]=1[C:19]#[C:18][Si:15]([CH3:17])([CH3:16])[CH3:14]
Reactant: C#C[Si](C)(C)C
Reactant: COc1cc(OC)c(F)c(I)c1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(OC)c(F)c(C#C[Si](C)(C)C)c1F
Temperature: 25 °C
Reaction time: 70 h
Yield: 94.3 %

Procedure:
To a stirred mixture of 2,4-difluoro-3-iodo-1,5-dimethoxybenzene (740 mg, 2.47 mmol), (trimethylsilyl)acetylene (0.697 mL, 4.93 mmol), copper(I) iodide (38 mg, 0.20 mmol), and triethylamine (0.52 mL, 3.7 mmol) in N,N-dimethylformamide (DMF) (4 mL, 50 mmol), bis(triphenylphosphine)palladium(II) chloride (86 mg, 0.12 mmol) was added. The reaction mixture was stirred at room temperature for 70 hours. The reaction was quenched with saturated aq. NH4Cl, then extracted with methylene chloride. The combined organic layers were dried over MgSO4, then concentrated. The residue was purified on silica gel (eluting with 0 to 30% EtOAc in hexanes) to give the desired product (630 mg, 94%).
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-:4])[CH3:3].[K+].[C:7]1([SH:13])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C1COCC1.CN(C)C=O>[C:7]1([S:13][CH2:12][CH2:7][CH2:8][CH2:9][CH2:1][C:2]([OH:4])([CH3:5])[CH3:3])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)(C)[O-]
Reactant: Sc1ccccc1
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(O)CCCCCSc1ccccc1

Procedure:
To a solution of 7-bromo-2-methyl-2-trimethylsilyloxyheptane (10) (14.0 g) in methanol (55 ml) at room temperature was added ethanolic hydrogen chloride (ca. 1M, 0.2 ml). After 10 minutes the solution was concentrated in vacuo (at room temperature) to constant weight. The residue was taken up in chloroform and reconcentrated to constant weight to give 7-bromo-2-methyl-2-heptanol (H, n=4, R1 =R2 =Me) as a chromatographically homogenous oil. The product was dissolved in THF (10 ml) and added to a premixed, stirred solution of potassium tert-butoxide (6.7 g) and thiophenol (3.6 ml) in N,N-dimethylformamide (50 ml) at room temperature. After a few minutes a precipitate started forming, and after 30 minutes the mixture was partitioned between ethyl acetate (300 ml) and water (200 ml). The organic layer was washed consecutively with 2N sodium hydroxide solution, water and brine. Drying and concentration in vacuo gave 6-hydroxy-6-methylheptyl phenyl sulphide as a chromatographically homogenous oil. This was dissolved in methanol (60 ml), and to the stirred solution was added sodium hydrogen carbonate (4.7 g), aqueous sodium tungstate solution (2%, 5 ml) and hydrogen peroxide (100 vol, 11.8 ml). The initial exothermic reaction which ensued was checked by momentary ice-cooling. The reaction mixture was then stirred at 50° C. for 1 hour. After cooling, the mixture was partitioned between dichloromethane (200 ml) and water. The aqueous layer was extracted with more dichloromethane, and the combined dichloromethane layers were washed with water, brine, and dried. Concentration in vacuo gave a crude product which was purified by chromatography (150 g silica gel; ether as eluant) to give the sulphone (13) as a viscous oil, δ (300 MHz) 1.18 (6H, s), 1.4 (7H, m), 1.75 (2H, m), 3.09 (2H, m), 7.5-7.75 (3H, m), 7.90 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[CH:6][C:7]=1[Cl:8].[F:11][C:12]([F:20])([C:16]([F:19])([F:18])[F:17])[C:13](O)=O.Cl.C(=O)(O)[O-].[Na+]>O.C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]2[NH:9][C:13]([C:12]([F:20])([F:11])[C:16]([F:19])([F:18])[F:17])=[N:10][C:4]=2[CH:3]=1
Reactant: Nc1cc(Cl)c(Cl)cc1N
Reactant: O=C(O)C(F)(F)C(F)(F)F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: FC(F)(F)C(F)(F)c1nc2cc(Cl)c(Cl)cc2[nH]1
Temperature: 108 °C

Procedure:
4,5-Dichloro-benzene-1,2-diamine (2.01 g; 11.4 mmoles) and 2,2,3,3,3-pentafluoro-propionic acid (1.80 mL; 17.3 mmoles) were suspended in 6N HCl (10 mL; 60 mmoles) under a nitrogen atmosphere. The reaction was stirred vigorously and heated to 108° C. for 18 hrs, then cooled to room temperature. The reaction was diluted with water (60 mL) and with ethyl acetate (60 mL), then sodium bicarbonate (7.59 g; 90.3 mmoles) was added slowly and in portions to quench the reaction. The aqueous layer was separated and extracted with ethyl acetate (3×30 mL). The extracts were combined, washed with water (30 mL) and brine (30 mL), then dried over Na2SO4. The filtrate was concentrated in vacuo to yield a crude brown solid which was then purified by column chromatography (SiO2; 100% CH2Cl2) to yield the title compound as a light tan solid.
Reaction SMILES: [Cl:1][C:2]1[N:9]=[C:8]([N:10]([CH2:12][CH2:13][CH2:14][OH:15])[CH3:11])[C:7]([F:16])=[CH:6][C:3]=1[C:4]#[N:5].O[C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[C@H:23]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:22][CH2:21]2.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1COCC1>[Cl:1][C:2]1[N:9]=[C:8]([N:10]([CH3:11])[CH2:12][CH2:13][CH2:14][O:15][C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[C@H:23]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:22][CH2:21]3)[C:7]([F:16])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CN(CCCO)c1nc(Cl)c(C#N)cc1F
Reactant: CCOC(=O)C[C@@H]1CCc2cc(O)ccc21
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCCN(C)c3nc(Cl)c(C#N)cc3F)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.7 %

Procedure:
To a solution of 2-chloro-5-fluoro-6-[(3-ydroxypropyl)(methyl)amino]nicotinonitrile (Example 311) (0.50 g, 2.05 mmol) and ethyl [(1S)-5-hydroxy-2,3-dihydro-1H-inden-1-yl]acetate (Example 6, 0.25 g, 1.14 mmol) in THF (9 mL) were added PPh3 (0.54 g, 2.05 mmol) and ADDP (0.52 g, 2.05 mmol) under argon. The golden yellow mixture was stirred at rt for 18 h, and then concentrated under reduced pressure. The product (0.41 g, 81%) was isolated after silica gel flash chromatography (2:1 hexanes/EtOAc). 1H NMR (400 MHz, CD2Cl2) δ 7.29 (d, 1H), 7.04 (d, 1H), 6.73 (d, 1H), 6.66 (dd, 1H), 4.16 (q, 2H), 3.99 (t, 2H), 3.82 (t, 2H), 3.51 (qt, 1H), 3.25 (d, 3H), 2.95-2.78 (m, 2H), 2.70 (dd, 1H), 2.45-2.32 (m, 2H), 2.12 (qt, 2H), 1.82-1.72 (m, 1H), 1.29 (t, 3H).
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[N:14][CH:15]=[C:16]([Cl:18])[CH:17]=2)[CH2:7][CH2:6]1)=O.O.[NH2:20][NH2:21]>C(O)CCC>[Cl:18][C:16]1[CH:17]=[C:12]([O:11][C@H:8]2[CH2:9][CH2:10][C@H:5]([C:3]([NH:20][NH2:21])=[O:2])[CH2:6][CH2:7]2)[CH:13]=[N:14][CH:15]=1
Reactant: COC(=O)[C@H]1CC[C@H](Oc2cncc(Cl)c2)CC1
Reactant: NN
Solvent: O
Solvent: CCCCO
Product: NNC(=O)[C@H]1CC[C@H](Oc2cncc(Cl)c2)CC1
Temperature: 120 °C

Procedure:
A mixture of trans-4-(5-chloro-pyridin-3-yloxy)-cyclohexanecarboxylic acid methyl ester (0.19 g, 0.70 mmol) and hydrazine hydrate (0.14 ml, 2.8 mmol) in n-butanol (0.5 ml) was heated at 120° C. for 18 h. After cooling to room temperature the reaction mixture was triturated in toluene (100 ml). The product was collected by filtration and dried in vacuo to give the crude title compound (0.15 g, 79%) as white solid, which was used in the next step without further purification. MS m/e: 270 (M+H+)
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:14]([CH2:20][O:21][CH2:22][CH3:23])=[N:13][C:7]=3[C:8]([NH2:12])=[N:9][C:10]=2[CH:11]=1.[S:24]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25]1>>[CH2:22]([O:21][CH2:20][C:14]1[N:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:6]2[C:5]3[CH:4]=[CH:3][C:2]([C:26]4[CH:27]=[CH:28][S:24][CH:25]=4)=[CH:11][C:10]=3[N:9]=[C:8]([NH2:12])[C:7]=2[N:13]=1)[CH3:23]
Reactant: OB(O)c1ccsc1
Reactant: CCOCc1nc2c(N)nc3cc(Br)ccc3c2n1CC(C)C
Product: CCOCc1nc2c(N)nc3cc(-c4ccsc4)ccc3c2n1CC(C)C

Procedure:
7-Bromo-2-ethoxymethyl-1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine and thiophene-3-boronic acid were coupled according to the general procedure described in Part J of Example 1. Recrystallization from isopropanol followed by purification on silica gel (5% methanol in CH2Cl2 to 7% methanol in CH2Cl2 gradient) afforded 2-ethoxymethyl-1-isobutyl-7-(thiophen-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine as a pale yellow solid, m.p. 187–189° C.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH2:7]([S:9][C:10]1C=[CH:17][CH:16]=[CH:15][C:11]=1C(O)=O)[CH3:8].CN(C=O)C>C(Cl)Cl>[CH2:7]([S:9][C:10]1[CH:11]=[CH:15][CH:16]=[CH:17][C:1]=1[C:2]([Cl:4])=[O:3])[CH3:8]
Reactant: CCSc1ccccc1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCSc1ccccc1C(=O)Cl
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
Oxalyl chloride (113 μL, 1.3 mmol) was added slowly to a stirring suspension of 2-(ethylthio)benzoic acid (1-A) (182 mg, 1.0 mmol) and 3 μL DMF in methylene chloride (2 mL). After stirring for 3.5 h at room temperature, the mixture was concentrated in vacuo to give 2-(ethylthio)benzoyl chloride (1-B).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][NH:3][C:2]1=[O:7].CC(C)([O-])C.[K+].F[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=1[CH:24]([CH3:26])[CH3:25]>CS(C)=O.O>[CH:24]([C:16]1[CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=[CH:20][C:15]=1[N:1]1[CH2:6][CH2:5][CH2:4][NH:3][C:2]1=[O:7])([CH3:26])[CH3:25]
Reactant: O=C1NCCCN1
Reactant: CC(C)c1cc([N+](=O)[O-])ccc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)c1cc([N+](=O)[O-])ccc1N1CCCNC1=O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
347 mg (3.47 mmol) of tetrahydropyrimidinone in 21 ml of DMSO are admixed at RT with 584 mg (5.21 mmol) of potassium tert-butoxide, and the mixture is stirred at RT for 45 min. 700 mg (3.82 mmol) of 1-fluoro-2-isopropyl-4-nitrobenzene are added and the mixture is stirred at 60° C. After 18 h, it is cooled and diluted with 250 ml of water. It is extracted three times with ethyl acetate and the combined organic phases are dried over sodium sulfate. After filtration, the solvents are removed under reduced pressure and the residue is purified by chromatography on silica gel (1:5→1:10 cyclohexane/ethyl acetate). This affords 140 mg (14% of theory) of the desired compound.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:6]#[N:7].C1C(=O)N([Br:21])C(=O)C1>CN(C=O)C.CC(N=NC(C#N)(C)C)(C#N)C.O>[Br:21][C:8]1[CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:3]([NH:2][CH3:1])=[CH:4][C:5]=1[C:6]#[N:7]
Reactant: O=C1CCC(=O)N1Br
Reactant: CNc1cc(C#N)ccc1[N+](=O)[O-]
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: O
Solvent: CN(C)C=O
Product: CNc1cc(C#N)c(Br)cc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 3-(methylamino)-4-nitrobenzonitrile (0.9 g, 0.005 mol) and NBS (0.9 g, 0.005 mol) in DMF (15 ml), AIBN (catalytic) was carefully added and the resulting solution was stirred at 80° C. for 3 h. The reaction was diluted with H2O and extracted with dichloromethane (3×30 ml). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under vacuum to afford the title compound 2-bromo-5-(methylamino)-4-nitrobenzonitrile as a yellow solid. 1H NMR (400 MHz, CDCl3), δ: 8.44 (s, 1H), 8.04 (bs, 1H), 7.18 (s, 1H), 3.05 (s, 3H). MS (M+1): 256.12.