Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:21]1([N:31]=[C:32]=[O:33])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1.O.[CH2:35]1COCC1>>[CH2:18]([O:17][C:15](=[O:16])[C:14]1[CH:13]=[CH:12][C:11]([N:7]2[C:8]([NH:10][C:32]([NH:31][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=[CH:23][CH:22]=3)=[O:33])=[CH:9][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[N:6]2)=[CH:20][CH:19]=1)[CH3:35]
Reactant: O=C=Nc1cccc2ccccc12
Reactant: C1CCOC1
Reactant: COC(=O)c1ccc(-n2nc(C(C)(C)C)cc2N)cc1
Solvent: O
Product: CCOC(=O)c1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2cccc3ccccc23)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of Example X (2.9 g, 10 mmol) in THF (50 mL) was added a solution of 1-naphthyl isocyanate (1.7 g, 10 mmol) in THF (20 mL) at 0° C. The mixture was stirred at RT for 1 h and heated until all solids dissolved. The mixture was then stirred at RT for 3 h and poured into water (200 mL). The precipitate was filtered, washed with diluted HCl and H2O, dried under vacuum to give 4.3 g of 4-[3-t-butyl-5-(3-naphthalen-1-yl-ureido)-pyrazol-1-yl]-benzoic acid ethyl ester, which was used without further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([CH2:12][O:13][CH2:14][C:15]2([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)[N:3]=1.[CH3:29]B1OB(C)OB(C)O1.[OH-].[K+].C(O)(C(F)(F)F)=O>O1CCCC1.C(OCC)(=O)C>[F:28][C:25]1[CH:26]=[CH:27][C:22]([C:15]2([CH2:14][O:13][CH2:12][C:4]3[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=[C:2]([CH3:29])[N:3]=3)[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)=[CH:23][CH:24]=1
Reactant: CN1CCC(COCc2cc(C(F)(F)F)cc(Cl)n2)(c2ccc(F)cc2)CC1
Reactant: CB1OB(C)OB(C)O1
Agent: [K+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(C(F)(F)F)cc(COCC2(c3ccc(F)cc3)CCN(C)CC2)n1
Temperature: 100 °C
Yield: 39.6 %

Procedure:
2-chloro-6-(((4-(4-fluorophenyl)-1-methylpiperidin-4-yl)methoxy)methyl)-4-(trifluoromethyl)pyridine (80 mg, 0.192 mmol), tetrakis(triphenylphsophine)palladium(O) (22.18 mg, 0.019 mmol), and 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (72.3 mg, 0.576 mmol) were combined in tetrahydrofuran (1.5 mL). The reaction was then treated with potassium hydroxide (0.392 ml, 0.392 mmol) and heated to 100° C. for 2 hours. After cooling, the solution was diluted with ethyl acetate (25 mL), washed with water (10 mL) and brine (10 mL). The organics were dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified via preparatory HPLC to yield the desired product (30.23 mg, 0.076 mmol, 39.7%) as the TFA salt. 1H-NMR (CDCl3, 400 MHz) δ 10.02 (s, 1H), 8.09 (s, 1H), 7.93 (s, 1H). LC: Tr=1.920 min, HPLC Method 1. Mass spec.: 397.03 (MH)+.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([N:6]2[CH2:15][CH2:14][N:13]3[CH:8]([CH2:9][O:10][CH2:11][C:12]3=[O:16])[CH2:7]2)[CH2:3]1.Cl.Cl.[Br:19][C:20]1[CH:21]=[C:22]([CH:53]=[C:54]([C:56]([F:59])([F:58])[F:57])[CH:55]=1)[C:23]([N:25]([CH2:27][C@H:28]([C:46]1[CH:51]=[CH:50][C:49]([F:52])=[CH:48][CH:47]=1)[CH2:29][CH2:30]N1CC(N2CCN3C(=O)CCCC3C2)C1)[CH3:26])=[O:24]>CO.O.C(O)(=O)C>[Br:19][C:20]1[CH:21]=[C:22]([CH:53]=[C:54]([C:56]([F:59])([F:57])[F:58])[CH:55]=1)[C:23]([N:25]([CH2:27][C@H:28]([C:46]1[CH:47]=[CH:48][C:49]([F:52])=[CH:50][CH:51]=1)[CH2:29][CH2:30][N:2]1[CH2:5][CH:4]([N:6]2[CH2:15][CH2:14][N:13]3[CH:8]([CH2:9][O:10][CH2:11][C:12]3=[O:16])[CH2:7]2)[CH2:3]1)[CH3:26])=[O:24]
Reactant: CN(C[C@@H](CCN1CC(N2CCN3C(=O)CCCC3C2)C1)c1ccc(F)cc1)C(=O)c1cc(Br)cc(C(F)(F)F)c1
Reactant: O=C1COCC2CN(C3CNC3)CCN12
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: CN(C[C@@H](CCN1CC(N2CCN3C(=O)COCC3C2)C1)c1ccc(F)cc1)C(=O)c1cc(Br)cc(C(F)(F)F)c1
Temperature: 120 °C
Yield: 45.8 %

Procedure:
8-Azetidin-3-ylhexahydropyrazino[2,1-c][1,4]oxazin-4(3H)-one hydrochloride (see Method 8; 43 mg, 0.17 mmol) was dissolved in methanol (3 mL) together with a few drops of water and acetic acid (0.2 mL). 3-Bromo-N-[(2S)-2-(4-fluorophenyl)-4-oxobutyl]-N-methyl-5-(trifluoromethyl)benzamide (see Method 3; 80 mg, 0.18 mmol) dissolved in methanol (1 mL) was added to the former solution together with (polystyrylmethyl)-trimethylammonium cyanoborohydride (4.2 mmol/g, 47 mg, 0.25 mmol). The reaction mixture was heated to 120° C. for 5 min using microwave single node heating. The resin was filtered off and washed with methanol. The filtrate was concentrated by evaporation. The product was purified by reversed phase chromatography (acetonitrile-aqueous solution of ammonium formate 0.1M and formic acid 0.1M, 10% to 50%). The solvent of the collected fractions was removed by evaporation followed by freeze-drying. The residue was partitioned between methylene chloride and aqueous NaHCO3. The two phases were separated by means of a phase separator column and then the solvent of the organic solution was removed by evaporation. There was obtained 50 mg (44%) of the title compound. 1H NMR (500 MHz, CD3OD): 1.5-1.7 (b, 1H), 1.7-2.0 (cm, 3H), 2.2-4.2 (cm, 21H), 4.5 (d, 1H), 7.0-7.6 (cm, 6H), 7.9 (d, 1H); LCMS: m/z 642 (M+1)+.
Reaction SMILES: NC1N(C(OC(C)(C)C)=O)N=C(C2C=CC(OCC3C=CC(C4SC(N5CCC6C(=C(C(=O)N(C7SC8C=CC=CC=8N=7)[CH2:43][O:44][CH2:45][CH2:46][Si:47]([CH3:50])([CH3:49])[CH3:48])C=CC=6)C5)=NC=4C(OCC)=O)=CC=3)=CC=2)C=1C#N.NC1N(C(OC(C)(C)C)=O)N=C(C2C=CC(O)=CC=2)C=1C#N.[OH:92][CH2:93][CH2:94][CH2:95][C:96]1[C:97]([C:132]([O:134][C:135]([CH3:138])([CH3:137])[CH3:136])=[O:133])=[N:98][C:99]([N:102]2[CH2:111][CH2:110][C:109]3[C:104](=[C:105]([C:112](=[O:131])/[N:113]=[C:114]4\[S:115][C:116]5[CH:130]=[CH:129][CH:128]=[CH:127][C:117]=5[N:118]\4COCC[Si](C)(C)C)[CH:106]=[CH:107][CH:108]=3)[CH2:103]2)=[CH:100][CH:101]=1.[CH3:139][N:140]1[CH2:145][CH2:144][N:143]([C:146]2[CH:151]=[CH:150][C:149](O)=[CH:148][CH:147]=2)[CH2:142][CH2:141]1>>[S:115]1[C:116]2[CH:130]=[CH:129][CH:128]=[CH:127][C:117]=2[N:118]=[C:114]1[N:113]([CH2:43][O:44][CH2:45][CH2:46][Si:47]([CH3:50])([CH3:49])[CH3:48])[C:112]([C:105]1[CH:106]=[CH:107][CH:108]=[C:109]2[C:104]=1[CH2:103][N:102]([C:99]1[N:98]=[C:97]([C:132]([O:134][C:135]([CH3:137])([CH3:136])[CH3:138])=[O:133])[C:96]([CH2:95][CH2:94][CH2:93][O:92][C:149]3[CH:150]=[CH:151][C:146]([N:143]4[CH2:144][CH2:145][N:140]([CH3:139])[CH2:141][CH2:142]4)=[CH:147][CH:148]=3)=[CH:101][CH:100]=1)[CH2:111][CH2:110]2)=[O:131]
Reactant: CN1CCN(c2ccc(O)cc2)CC1
Reactant: CCOC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1-c1ccc(COc2ccc(-c3nn(C(=O)OC(C)(C)C)c(N)c3C#N)cc2)cc1
Reactant: CC(C)(C)OC(=O)c1nc(N2CCc3cccc(C(=O)/N=c4\sc5ccccc5n4COCC[Si](C)(C)C)c3C2)ccc1CCCO
Agent: CC(C)(C)OC(=O)n1nc(-c2ccc(O)cc2)c(C#N)c1N
Product: CN1CCN(c2ccc(OCCCc3ccc(N4CCc5cccc(C(=O)N(COCC[Si](C)(C)C)c6nc7ccccc7s6)c5C4)nc3C(=O)OC(C)(C)C)cc2)CC1

Procedure:
The title compound 94G was prepared in a similar manner to the synthesis of compound 35A by substituting compound 34D and compound 31F with compound 94F and compound 82A, respectively: ESI (+)LC/MS: 849 (M+H2O—NH4)+.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[C:2]1=[C:11]1[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[O:14][C:13]([C:21]3[CH:26]=[CH:25][C:24]([O:27]C)=[CH:23][CH:22]=3)=[N:12]1)[CH2:8]2.B(I)(I)I.O>C(Cl)Cl>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[C:2]1=[C:11]1[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[O:14][C:13]([C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=3)=[N:12]1)[CH2:8]2
Reactant: COc1ccc(C2=NC(=C3C4CC5CC(C4)CC3C5)c3ccccc3O2)cc1
Agent: IB(I)I
Solvent: ClCCl
Solvent: O
Product: Oc1ccc(C2=NC(=C3C4CC5CC(C4)CC3C5)c3ccccc3O2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 6 mmol 4-adamantylidene-2-(4'-methoxyphenyl)-4H-1,3-benzoxazine in 20 ml absolute methylene chloride is added dropwise to a solution of 12 mmol boron triiodide while stirring at -25° C. with the exclusion of air and water. The mixture is heated to room temperature within one hour and stirred for a further 4 hours. After admixing with 50 ml water the organic phase is separated and dried over sodium sulfate. The solvent is removed by distillation. The oily residue is separated by column chromatography (silica gel: ethyl acetate/petroleum ether 1:3).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.C(N(CC)CC)C.Cl[C:15]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C)C=O>[CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:6]=1
Reactant: Cc1c[nH]cn1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reaction time: 3.5 h

Procedure:
1 equivalent (i.e. 36.53 mmol, 1 eq.) of 4-methyl-1H-imidazole (1) was dissolved in 120 mL of dimethylformamide, triethylamine (73.06 mmol, 2 eq.) and chlorotriphenylmethane (40.1 mmol, 1.1 eq) where added. The mixture was stirred for 3.5 h. The precipitate filtered off and was washed by means of ice-cooled dimethylformamide (2×50 mL) and water (2×50 mL). After removal of the solvent the remaining product was dried over P4O10.
Reaction SMILES: [CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[NH:10][C:9]([C:14]3[CH:15]=[N:16][N:17]([CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=4)[CH:18]=3)=[N:8][C:7]=2[NH:6][C:5]1=[O:30])[CH2:2][CH3:3].[F:31][CH:32]([F:37])C(OCl)=O.[Na].C([O-])([O-])=O.[Cs+].[Cs+].CN(C=O)C>O>[F:31][CH:32]([F:37])[O:30][C:5]1[N:4]([CH2:1][CH2:2][CH3:3])[C:12](=[O:13])[C:11]2[NH:10][C:9]([C:14]3[CH:15]=[N:16][N:17]([CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:27])([F:29])[F:28])[CH:21]=4)[CH:18]=3)=[N:8][C:7]=2[N:6]=1
Reactant: O=C(OCl)C(F)F
Reactant: CCCn1c(=O)[nH]c2nc(-c3cnn(Cc4cccc(C(F)(F)F)c4)c3)[nH]c2c1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: CCCn1c(OC(F)F)nc2nc(-c3cnn(Cc4cccc(C(F)(F)F)c4)c3)[nH]c2c1=O
Temperature: 60 °C
Reaction time: 18 h

Procedure:
A mixture of 1-Propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-3,7-dihydro-purine-2,6-dione (100 mg, 0.24 mmol), Sodium chloro difluoroacetate (47 mg, 0.31 mmol), Cs2CO3 (117 mg, 0.36 mmol) and DMF (2 ml) were stirred at 60° C. for 18 hours. Reaction mixture was cooled and diluted with water (10 ml), solid materials were filtered off and it was purified by preparative HPLC to obtain 2-Difluoromethoxy-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one as off white solid (1 mg, 10%) and
Reaction SMILES: [CH2:1]([C:3]1[O:7][C:6]([CH2:8][CH2:9][NH:10]C(=O)OC(C)(C)C)=[N:5][N:4]=1)[CH3:2].FC(F)(F)C(O)=O>ClCCl>[CH2:1]([C:3]1[O:7][C:6]([CH2:8][CH2:9][NH2:10])=[N:5][N:4]=1)[CH3:2]
Reactant: CCc1nnc(CCNC(=O)OC(C)(C)C)o1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1nnc(CCN)o1

Procedure:
2.95 g (12.23 mmol) tert-butyl [2-(5-ethyl-[1,3,4]oxadiazol-2-yl)-ethyl]-carbamate and 10 ml trifluoroacetic acid are stirred in 100 ml dichloromethane for 24 hours at ambient temperature. Then the mixture is evaporated down, the residue is made basic and extracted with ethyl acetate. The organic phase is dried and evaporated to dryness.
Reaction SMILES: [C:1]1([NH2:8])[C:2]([NH2:7])=[CH:3][CH:4]=[CH:5][CH:6]=1.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][C@@H:19]([NH:22][C:23]([NH:25][C:26]2[CH:27]=[N:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=2)=[O:24])[CH2:18][C@@H:17]1[C:36](O)=[O:37])=[O:15])([CH3:12])([CH3:11])[CH3:10].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[NH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[NH:8][C:36]([C@H:17]1[CH2:18][C@H:19]([NH:22][C:23]([NH:25][C:26]2[CH:27]=[N:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=2)=[O:24])[CH2:20][CH2:21][N:16]1[C:14]([O:13][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:15])=[O:37]
Reactant: Nc1ccccc1N
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)Nc2ccc(C(F)(F)F)nc2)C[C@@H]1C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)Nc2ccc(C(F)(F)F)nc2)C[C@@H]1C(=O)Nc1ccccc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.7 %

Procedure:
Benzene-1,2-diamine (131 mg, 1.21 mmol) was added to a mixture of (2R,4R)-1-(tert-butoxycarbonyl)-4-(3-(6-(trifluoromethyl)pyridin-3-yl)ureido)piperidine-2-carboxylic acid (500 mg, 1.16 mmol), BOP (563 mg, 1.27 mmol) and DIEA (0.403 mL, 2.31 mmol) in DMF (5 mL), and the resulting solution was stirred at room temperature for 8 hours. Water (20 mL) was added to the reaction mixture and then extracted with ethyl acetate (2×30 mL). The organic layers were dried over MgSO4 and concentrated to give a red solid. Purification was done by Companion (ReadySep, 40 g, silica gel packed) with methanol/methylenechloride from 1-5% to give the title compound as a white solid 550 mg (91%). LC-MS: 523.3, 521.3; (t=2.3 min).
Reaction SMILES: CS(O)(=O)=O.[NH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH:18]1[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]1=[O:25])[CH2:11]2.[CH2:26]([N:29]=[C:30]=[O:31])[CH2:27][CH3:28].C(N(CC)CC)C.Cl>C(#N)C>[O:25]=[C:19]1[CH:18]([N:12]2[CH2:11][C:10]3[C:14](=[CH:15][CH:16]=[C:8]([CH2:7][NH:6][C:30]([NH:29][CH2:26][CH2:27][CH3:28])=[O:31])[CH:9]=3)[C:13]2=[O:17])[CH2:23][CH2:22][C:21](=[O:24])[NH:20]1
Reactant: CCCN=C=O
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCNC(=O)NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Reaction time: 2 h
Yield: 55.8 %

Procedure:
To a stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione methane sulfonate (0.37 g, 1.0 mmol) and propylisocyanate (0.09 mL, 1.0 mmol) in acetonitrile (10 mL), was added triethylamine (0.28 mL, 2.0 mmol) at room temperature under nitrogen. After 2 h, 1 N aq. HCl (15 mL) was added and the solids were isolated by filtration, washed with water (2×20 mL). The product was extracted with EtOAc (3×50 mL) and CH2Cl2 (3×50 mL). The organic layers were combined, concentrated and the residue was triturated in Et2O (20 mL). The product was isolated by filtration and dried in vacuo to give 1-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-3-propyl-urea as a white solid (0.20 g, 53% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 to 90/10 CH3CN/0.1% H3PO4 gradient over 15 mins, 5.84 min (98.91%); mp: 250-252° C.; 1H NMR (DMSO-d6) δ 0.84 (t, J=7.4 Hz, 3H, CH3), 1.22-1.59 (m, 2H, CH2), 1.85-2.10 (m, 1H, CHH), 2.25-2.47 (m, 1H, CHH), 2.60 (d, J=17.4 Hz, 1H, CHH), 2.78-3.10 (m, 3H, CH2, CHH), 4.21-4.37 (m, 3H, CH2, CHH), 4.44 (d, J=17.4 Hz, 1H, CHH), 5.11 (dd, J=5.1, 13.2 Hz, 1H, CH), 5.99 (t, J=5.7 Hz, 1H, NH), 6.40 (t, J=5.9 Hz, 1H, NH), 7.38 (d, J=7.7 Hz, 1H, Ar), 7.45 (s, 1H, Ar), 7.67 (d, J=7.9 Hz, 1H, Ar), 10.98 (s, 1H, NH); 13C NMR (DMSO-d6) δ 11.32, 22.49, 23.19, 31.20, 41.18, 42.92, 47.09, 51.55, 121.73, 122.83, 126.78, 130.11, 142.29, 145.55, 158.02, 167.98, 171.01, 172.86; LCMS: MH=359; Anal Calcd for C18H22N4O4: C, 60.32; H, 6.19; N, 15.63. Found: C, 60.21; H, 6.15; N, 15.51.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[C:13]([O:16][CH3:17])(=[O:15])[CH3:14].[C:18]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:23]=[CH:22][C:21]([CH2:24][CH:25]=[O:26])=[CH:20][CH:19]=1>C1COCC1>[C:18]1([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:19]=[CH:20][C:21]([CH2:24][CH:25]([OH:26])[CH2:14][C:13]([O:16][CH3:17])=[O:15])=[CH:22][CH:23]=1
Reactant: COC(C)=O
Reactant: O=CCc1ccc(-c2ccccc2)cc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)CC(O)Cc1ccc(-c2ccccc2)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 58.5 %

Procedure:
A solution of diisopropylamine (0.241 mL, 1.72 mmol) in anhydrous THF (1.5 mL) was treated with n-BuLi (1.6 M in hexane, 0.7 mL, 1.72 mmol) at −78° C. The mixture was kept at this temperature for 1 h, and then a solution of methyl acetate (0.137 mL, 1.72 mmol) in anhydrous THF (1 mL) was added at −78° C. The reaction mixture was stirred for 1 h at −78° C., and a solution of 2-(biphenyl-4-yl)acetaldehyde (S90, 282 mg, 1.43 mmol) in anhydrous THF (2 mL) was added. The reaction mixture was stirred for another hour, then quenched by the addition of saturated aqueous NH4Cl, which was extracted with EtOAc. The combined extracts were dried over Na2SO4 and the solvent was removed under reduced pressure. Flash chromatography (SiO2, 50% Et2O-hexanes) yielded the title compound (226 mg, 58%) as a white solid: 1H NMR (CDCl3, 400 MHz) δ 7.64 (dd, 2H, J=7.2 Hz), 7.58 (dd, 2H, J=8.0 Hz), 7.49 (t, 2H, J=7.6 Hz), 7.38 (t, 1H, J=7.0 Hz), 7.34 (d, 2H, J=8.0 Hz), 4.38-4.34 (m, 1H), 3.71 (s, 3H), 3.35 (s, 1H(—OH)), 2.97-2.82 (m, 2H), 2.61-2.43 (m, 2H); 13C NMR (CDCl3, 75 MHz) δ 172.7, 140.5, 139.1, 136.6, 129.6, 128.5, 126.9, 126.7, 68.7, 51.4, 42.3, 40.3.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:13][CH2:14][CH2:15][CH2:16][CH:17]([O:20][CH3:21])[O:18][CH3:19])=[C:7]([NH2:12])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.C(O[CH:25](OCC)[CH2:26][CH2:27][CH2:28]NC1C2C(=CC=CC=2)N=C(N)C=1)C.C(OC)(OC)(OC)CCC.S(C1C=CC(C)=CC=1)([O-])(=O)=O.[NH+]1C=CC=CC=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:13]([CH2:14][CH2:15][CH2:16][CH:17]([O:20][CH3:21])[O:18][CH3:19])[C:25]([CH2:26][CH2:27][CH3:28])=[N:12][C:7]=3[CH:8]=[N:9][C:10]=2[CH:11]=1
Reactant: COC(CCCNc1c(N)cnc2cc(Br)ccc12)OC
Reactant: CCOC(CCCNc1cc(N)nc2ccccc12)OCC
Agent: CCCC(OC)(OC)OC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Product: CCCc1nc2cnc3cc(Br)ccc3c2n1CCCC(OC)OC
Reaction time: 8 h

Procedure:
A modification of the general method of Part B of Example 6 was followed using 7-bromo-N4-(4,4-dimethoxybutyl)quinoline-3,4 diamine (59.3 g, 167.39 mmol) in lieu of N4-(4,4-diethoxybutyl)quinoline-2,4 diamine. The reaction was incomplete after running overnight. Trimethyl orthobutyrate (5 mL) was added to the reaction mixture and heated to reflux for an additional 2 hours, upon which an additional amount of trimethyl orthobutyrate (5 mL) and pyridinium tosylate (5 mL) were added. After 2 hours of heating to reflux, the mixture was concentrated under reduced pressure, diluted in dichloromethane (300 mL) and methanol (45 mL), washed with saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, and the mixture was concentrated under reduced pressure to afford 57.0 g of 7-bromo-1-(4,4-dimethoxybutyl)-2-propyl-1H-imidazo[4,5-c]quinoline as a brown solid.
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.ClCCl.[N:21]1([C:27]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][C:28]=2[NH2:29])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>O>[N:21]1([C:27]2[CH:33]=[CH:32][C:31]([C:34]([F:36])([F:37])[F:35])=[CH:30][C:28]=2[NH:29][C:2](=[O:9])[C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: O=C(Cl)c1ccncc1
Reactant: Nc1cc(C(F)(F)F)ccc1N1CCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=C(Nc1cc(C(F)(F)F)ccc1N1CCCCC1)c1ccncc1
Yield: 86.3 %

Procedure:
Isonicotinoyl chloride hydrochloride (6.48 g, 36.4 mmol, commercially available product) and triethylamine (5.57 ml, 54.6 mmol) were sequentially added at 0° C. to a dichloromethane (10 ml) solution of 2-(1-piperidinyl)-5-(trifluoromethyl)aniline (4.45 g, 18.2 mmol) obtained as described in Referential Example 1-2B. The mixture was stirred for half an hour. Water was added to the mixture, and the resulting mixture was extracted three times with ethyl acetate. The obtained organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (200 g, hexane/ethyl acetate=1/1) and recrystallization. Thus, N-[2-(1-piperidinyl)-5-(trifluoromethyl)phenyl]isonicotinamide (SRPIN-1, GIF-0340) (5.49 g, 86.3%) was yielded as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([N:6]([CH3:17])[S:7]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[N+:20]([O-])([OH:22])=[O:21].O.C(OCC)C>C(O)(=O)C>[F:1][C:2]1[CH:19]=[CH:18][C:5]([N:6]([CH3:17])[S:7]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)(=[O:9])=[O:8])=[C:4]([N+:20]([O-:22])=[O:21])[CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(S(=O)(=O)N(C)c2ccc(F)cc2)cc1
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc(S(=O)(=O)N(C)c2ccc(F)cc2[N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 70 %

Procedure:
4′-Fluoro-N-methyl-p-toluenesulfonanilide (1.00 g (3.58 mmol) was dissolved in 5.0 ml of acetic acid. To this, was added with stirring at room temperature, 97% fuming nitric acid (0.35 ml (8.19 mmol)) dropwise, and the mixture was stirred at 100° C. for one hour, poured into water and extracted with ethyl acetate. The extract was washed with saturated aqueous solution of sodium bicarbonate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give crude crystals. Diethyl ether was added to these crystals. The crystals were filtered and washed to give 0.81 g (70%) of the title compound as yellow crystals.
Reaction SMILES: Cl[CH:2]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:3](=[O:5])[CH3:4].[S-:10][C:11]#[N:12].[Na+]>C(C(C)=O)C>[CH3:8][CH:7]([CH3:9])[CH2:6][CH:2]([S:10][C:11]#[N:12])[C:3](=[O:5])[CH3:4]
Reactant: N#C[S-]
Reactant: CC(=O)C(Cl)CC(C)C
Agent: [Na+]
Solvent: CCC(C)=O
Product: CC(=O)C(CC(C)C)SC#N

Procedure:
17.91 g (120.5 mmol) of 3-chloro-5-methylhexan-2-one were dissolved in 120 ml of methyl ethyl ketone, 10.0 g (123.4 mmol) of sodium thiocyanate were added and the reaction mixture was heated under reflux for 1 h. After cooling, the reaction mixture was filtered, the residue was washed with methyl ethyl ketone and the combined filtrates were concentrated on a rotary evaporator. The oily residue was taken up in about 400 ml of dichloromethane and washed three times with in each case 100 ml of water. The organic phase was dried over sodium sulfate and the solvent was removed on a rotary evaporator. This gave 20.07 g of the crude product, which was reacted further as such.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5]=[C:6]([CH3:14])[CH:7]=[CH:8][CH:9]=[C:10]([CH3:13])[CH2:11]O)[CH3:2].CCOCC.P(Br)(Br)[Br:22]>N1C=CC=CC=1.CCCCCC>[CH2:1]([O:3][C:4](=[O:15])[CH:5]=[C:6]([CH3:14])[CH:7]=[CH:8][CH:9]=[C:10]([CH3:13])[CH2:11][Br:22])[CH3:2]
Reactant: CCOC(=O)C=C(C)C=CC=C(C)CO
Reactant: BrP(Br)Br
Solvent: CCCCCC
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCOC(=O)C=C(C)C=CC=C(C)CBr
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
36.5 G. of 8-hydroxy-3,7-dimethyl-octa-2,4,6-trien-1-oic acid ethyl ester are dissolved in 380 ml. of ether. The solution is cooled to 0° C., and after the addition of 3 drops of pyridine treated dropwise with 28.6 g. of phosphorous tribromide in 120 ml. of hexane. The mixture is stirred for 20 minutes at 0° C., then poured onto ice water and extracted with ether. The ether extract is washed successively with water, a saturated aqueous sodium bicarbonate solution and again with water, dried over sodium sulfate and evaporated. There is obtained 8-bromo-3,7-dimethyl-octa-2,4,6-trien-1-oic acid ethyl ester.