Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[CH:13]=[C:12]([CH:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[S:11][C:10]=2[CH2:20][CH3:21])O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:24])=O.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[Cl:24][CH:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:9]1[CH:13]=[C:12]([CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[S:11][C:10]=1[CH2:20][CH3:21]
Reactant: CCc1sc(C2CCOCC2)cc1C(O)C1CCCCC1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCc1sc(C2CCOCC2)cc1C(Cl)C1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
To a solution of cyclohexyl[2-ethyl-5-(tetrahydro-2H-pyran-4-yl)thiophen-3-yl]methanol (737 mg) synthesized above in toluene (10 mL) was added thionyl chloride (209 μL), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into ice-cooled saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (725 mg, 93%) as a pale-yellow oil.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:16])[NH:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([NH2:14])=[CH:9][C:8]=1[CH3:15])[CH2:2][CH3:3].[CH3:17][C:18]1[C:23]([CH:24]=O)=[CH:22][N:21]=[C:20]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:19]=1.C([BH3-])#N.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CO.C(O)(=O)C>[CH2:1]([O:4][C:5](=[O:16])[NH:6][C:7]1[C:8]([CH3:15])=[CH:9][C:10]([NH:14][CH2:24][C:23]2[C:18]([CH3:17])=[N:19][C:20]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[N:21][CH:22]=2)=[CH:11][C:12]=1[CH3:13])[CH2:2][CH3:3]
Reactant: Cc1nc(-c2ccccc2)ncc1C=O
Reactant: CCCOC(=O)Nc1c(C)cc(N)cc1C
Agent: O=C([O-])[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCCOC(=O)Nc1c(C)cc(NCc2cnc(-c3ccccc3)nc2C)cc1C
Temperature: 170 °C
Yield: 16.5 %

Procedure:
(4-Amino-2,6-dimethyl-phenyl)-carbamic acid propyl ester (22 mg) and 4-methyl-2-phenyl-5-pyrimidinecarbaldehyde (20 mg) were dissolved in methanol (0.5 mL) and heated to 170° C. for 10 minutes in a sealed microwave process vial. Sodium cyanoborohydride (2 M in methanol, 250 uL) and acetic acid (100 uL) were added and the reaction mixture was heated to 50° C. for 2 hours. Aqueous sodium carbonate (10%, 1 mL) was added, the product was extracted with ethyl acetate (2×1 mL), and the combined organic phases were concentrated in vacuo. The crude product was redissolved in dimethyl sulfoxide (0.5 mL) of which 0.25 mL was subjected to preparative LC-MS purification to furnish 6.6 mg (33% yield) of the title compound as an oil. LC-MS (m/z) 405 (MH+); tR=3.12, (UV, ELSD) 84%, 99%.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]([CH3:69])([O:10]/[N:11]=[C:12](/[C:44]1[N:45]=[C:46]([NH:49][C:50]([C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[S:47][CH:48]=1)\[C:13]([NH:15][CH:16]1[C:42](=[O:43])[N:18]2[C:19]([C:26]([O:28][CH:29]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:27])=[C:20]([CH2:24]Cl)[CH2:21][S:22](=[O:23])[C@H:17]12)=[O:14])[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[I-:70].[Na+].C(OCC)(=O)C.S([O-])([O-])(=O)=S.[Na+].[Na+]>CC(C)=O>[C:1]([O:5][C:6]([C:8]([CH3:69])([O:10]/[N:11]=[C:12](/[C:44]1[N:45]=[C:46]([NH:49][C:50]([C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[S:47][CH:48]=1)\[C:13]([NH:15][CH:16]1[C:42](=[O:43])[N:18]2[C:19]([C:26]([O:28][CH:29]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:27])=[C:20]([CH2:24][I:70])[CH2:21][S:22](=[O:23])[C@H:17]12)=[O:14])[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)C(C)(C)O/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS(=O)[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: [I-]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)C(C)(C)O/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CI)CS(=O)[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
The compound obtained in (A) was dissolved in 200 ml of acetone, and 3.38 g (22.5 mmol) of sodium iodide was added. The mixture was stirred at room temperature for 30 minutes. To the reaction solution, 600 ml of ethyl acetate and 200 ml of a 10% sodium thiosulfate aqueous solution were added for extraction. Then, the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by slica gel flush column chromatography (ethyl acetate/n-hexane=1/2), and concentrated under reduced pressure. Then, diisopropyl ether was added thereto, and 7.0 g (yield: 63.0%) of a powder of the above-identified compound was collected by filtration.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:8]=[C:9]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH3:20])[C:15]1[C:14]3[CH:21]=[CH:22][CH:23]=[CH:24][C:13]=3[O:12][CH2:11][C:10]2=1.[C:25](=[O:27])=[O:26]>C1COCC1>[CH3:20][N:16]1[C:15]2[C:14]3[CH:21]=[CH:22][CH:23]=[CH:24][C:13]=3[O:12][CH2:11][C:10]=2[C:9]2[C:17]1=[CH:18][CH:19]=[C:7]([C:25]([OH:27])=[O:26])[CH:8]=2
Reactant: O=C=O
Reactant: Cn1c2c(c3cc(Br)ccc31)COc1ccccc1-2
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1c2c(c3cc(C(=O)O)ccc31)COc1ccccc1-2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
n-BuLi was added dropwise into 8-bromo-11-methyl-6,11-dihydro-5-oxa-11-aza-benzo[a]fluorene (420 mg, 1.338 mmoL) in THF (5 mL) at −78° C. After an additional 30 minutes, the reaction mixture was transferred into dry ice (˜10 g). The reaction mixture was then slowly warmed to room temperature. The solvent was removed and the residue was partitioned between EtOAc and 1 N NaOH solution. The aqueous layer was then acidified to a pH of about 2 using 1N HCl and extracted three times with EtOAc. The organic phase of each extraction was combined, washed with water, brine, dried over anhydrous Na2SO4, filtered and concentrated to yield a clear oil. The oil was then purified by column chromatography (silica gel, hexanes:EtOAc 1:1 as eluent) to yield the title compound as a white solid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([OH:11])=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1O.O=P(Cl)(Cl)[Cl:15]>>[Cl:15][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[C:7]([OH:11])[CH:6]=2)[N:1]=1
Reactant: Oc1ccc2nc(O)ccc2c1
Reactant: O=P(Cl)(Cl)Cl
Product: Oc1ccc2nc(Cl)ccc2c1

Procedure:
As set forth in reaction Scheme C, quinoline2,6-diol is chlorinated with POCl3 to obtain 2-chloroquinolin-6-ol, which is reacted with a desired amine substituent, in this case 4-bromo-3-methylaniline, and to obtain the amine substituted quinolinol. A mixture of the alcohol and potassium bis(trimethylsilyl)amide in dimethylformamide is reacted with a desired substituent at the alcohol group, in this case dimethylformamide, to obtain the desire product, in this case (4-{2-[(4-bromo-3-methylphenyl)amino](6-quinolyloxy)}(2-pyridyl))-N-methylcarboxamide.
Reaction SMILES: [C:1]([C:6](=[CH:12][NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]([OH:22])[CH3:21])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:5])[CH2:2][CH2:3][CH3:4].N1C=CC=CC=1.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>ClCCl>[C:1]([C:6](=[CH:12][NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]([O:22][C:29](=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH3:21])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCC(=O)C(=CNc1ccccc1C(C)O)C(=O)OCC
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCC(=O)C(=CNc1ccccc1C(C)OC(=O)c1ccccc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of ethyl 2-butyryl-3-(2-(1-hydroxyethyl)-phenylamino)acrylate (63 g, 0.2 mol) and pyridine (50 ml) in dichloromethane (400 ml) were stirred at 0° C. and treated with benzoyl chloride (50 ml) in dichloromethane (100 ml) added at such a rate to keep the reaction temperature below 10° C. The cooling bath was removed and the mixture was stirred at ambient temperature for 2 hours. The solution was washed with 2M hydrochloric acid (x2), saturated sodium hydrogen carbonate solution, water and brine, dried (anhyd. MgSO4), filtered and evaporated to an orange oil (70 g, 83%).
Reaction SMILES: CO[C:3]1[N:4]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:5]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=2)[C:6]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:7]([CH3:9])[N:8]=1.Cl.[CH3:30][NH2:31].C([O-])(=O)C.[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH3:9][C:7]1[N:8]=[C:3]([NH:31][CH3:30])[N:4]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:5]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=2)[C:6]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CN
Reactant: CCOC(=O)C1=C(C)N=C(OC)N(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C1=C(C)N=C(NC)N(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 51.6 %

Procedure:
A solution of 2-methoxy-4-methyl-6-(3-nitrophenyl)-1,5(6H)-pyrimidinedicarboxylic acid, diethyl ester (3.71 g crude) in dimethylformamide (15 ml) was treated with methylamine hydrochloride (1.01 g, 15.0 mmoles) and sodium acetate (1.49 g, 17.0 mmoles). The reaction was allowed to stir at room temperature for 48 hours. It was then diluted with ethyl acetate and filtered. The filtrate was washed with water, sodium bicarbonate, brine and was dried over anhydrous magnesium sulfate. Solvent was evaporated under reduced pressure and the residue was purified by flash chromatography (5-7% ethyl acetate, dichloromethane). The product was crystallized from dichloromethane-isopropyl ether-hexanes to provide the title compound as yellow crystals (1.91 g), melting point 112.5°-114.5° C.
Reaction SMILES: C(O[C:4](=[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=2)[NH:13][C:12]1=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)C.[N:24]1([CH2:28][C:29]2[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=2)[CH2:27][CH2:26][CH2:25]1>>[N:24]1([CH2:28][C:29]2[CH:35]=[CH:34][C:32]([NH:33]/[C:4](=[C:11]3\[C:12](=[O:23])[NH:13][C:14]4[C:19]\3=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=4)/[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=3)=[CH:31][CH:30]=2)[CH2:25][CH2:26][CH2:27]1
Reactant: CCOC(=C1C(=O)Nc2ccc([N+](=O)[O-])cc21)c1ccccc1
Reactant: Nc1ccc(CN2CCC2)cc1
Product: O=C1Nc2ccc([N+](=O)[O-])cc2/C1=C(/Nc1ccc(CN2CCC2)cc1)c1ccccc1

Procedure:
Prepared analogously to Example 89 by reacting 3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone with 4-(azetidin-1-yl-methyl)-aniline.
Reaction SMILES: [C:1]1([C:7]2([CH2:13][O:14][CH:15]([C:17]3[CH:18]=[C:19]([C:26]([F:29])([F:28])[F:27])[CH:20]=[C:21]4[C:25]=3[NH:24][N:23]=[CH:22]4)[CH3:16])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:30]([BH3-])#N.[Na+].C=O.C(O)(=O)C>C(#N)C.C(O)(=O)C>[CH3:30][N:10]1[CH2:11][CH2:12][C:7]([CH2:13][O:14][CH:15]([C:17]2[CH:18]=[C:19]([C:26]([F:28])([F:27])[F:29])[CH:20]=[C:21]3[C:25]=2[NH:24][N:23]=[CH:22]3)[CH3:16])([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][CH2:9]1
Reactant: [BH3-]C#N
Reactant: CC(OCC1(c2ccccc2)CCNCC1)c1cc(C(F)(F)F)cc2cn[nH]c12
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CC(OCC1(c2ccccc2)CCN(C)CC1)c1cc(C(F)(F)F)cc2cn[nH]c12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of (±)-7-(1-((4-phenylpiperidin-4-yl)methoxy)ethyl)-5-(trifluoromethyl)-1H-indazole (35 mg, 0.087 mmol) and sodium cyanoborohydride (5.5 mg, 0.087 mmol) in acetonitrile (1 mL) at room temperature was added formalin (25 μL). To this was added 1 drop of acetic acid. After 5 min, a second drop of acetic acid was added and the reaction stirred at room temperature for 15 min. The reaction was concentrated and loaded onto a strong cation exchange cartridge in methanol. The cartridge was washed with several volumes of methanol which were discarded. The product was eluted with 2 M ammonia in methanol and concentrated to give 21 mg (58%). 1H-NMR (CDCl3, 500 MHz) δ 9.78 (bs, 1H), 8.02 (s, 1H), 7.90 (s, 1H), 7.28-7.49 (m, 5H), 7.21 (s, 1H), 4.62 (q, J=6.7 Hz, 1H), 3.48 (s, 3H), 3.45-3.51 (m, 3H), 3.31 (d, J=8.9 Hz, 1H), 2.62 (m, 2H), 2.39 (m, 1H), 2.12-2.31 (m, 7H), 2.06 (m, 1H), 1.95 (m, 1H), 1.44 (d, J=6.7 Hz, 3H); 13C-NMR (CDCl3, 126 MHz) δ 138.1, 135.2, 128.9, 127.5, 127.1, 126.9, 124.7 (q, J=272 Hz), 123.3, 119.8 (q, J=2.9 Hz), 118.1 (q, J=3.8 Hz), 79.0 (br), 78.4, 52.0, 51.8, 50.8, 46.1, 40.7, 32.5, 32.3, 22.2. Mass spec.: 418.18 (MH)+. Accurate mass spec.: m/z 418.2101 [MH]+, Δ=1.2 ppm.
Reaction SMILES: [CH:1]1([CH2:7][NH:8][C:9]2[CH:17]=[CH:16][C:12]3[N:13]=[CH:14][NH:15][C:11]=3[CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:18][S:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1.C([O-])([O-])=O.[K+].[K+]>>[CH3:18][S:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][N:8]([CH2:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:9]2[CH:17]=[CH:16][C:12]3[NH:13][CH:14]=[N:15][C:11]=3[CH:10]=2)=[CH:22][CH:21]=1
Reactant: CSc1ccc(CBr)cc1
Reactant: c1nc2ccc(NCC3CCCCC3)cc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CSc1ccc(CN(CC2CCCCC2)c2ccc3[nH]cnc3c2)cc1

Procedure:
The compound was synthesized starting from N-cyclohexylmethyl-benzimidazol-5-amine (115 mg; 0.5 mmol; 1 eq.), 4-methylthiobenzylbromide (120 mg; 0.55 mmol; 1.1 eq.) and K2CO3 (76 mg; 0.55 mmol; 1.1 eq.) according to method 6; Yield: 0.068 g (37.3%); MS m/z: 366.4 [M+H]+; 1H-NMR (400 MHz, DMSO d6): δ 0.90-1.00 (m, 2H); 1.13-1.23 (m, 3H); 1.61-1.76 (m, 6H); 2.41 (s, 3H); 3.24 (d, 2H, 3J=6.6 Hz); 4.52 (s, 2H); 6.67-6.69 (m, 2H); 7.12-7.18 (m, 4H); 7.32-7.34 (m, 1H); 7.89 (s, 1H); 11.84 (br s, 1H); HPLC (METHOD [A]): rt 18.51 min (97.8%)
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][CH:17]=1)[O:7][C:8]1[CH:9]=[N+:10]([O-])[CH:11]=[CH:12][CH:13]=1)[CH3:2].COS(OC)(=O)=O.C(OC1C=C(C=CC=1)OC1[CH:33]=[N+:34](OC)C=CC=1)C.[Na]>O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][CH:17]=1)[O:7][C:8]1[C:9]([C:33]#[N:34])=[N:10][CH:11]=[CH:12][CH:13]=1)[CH3:2]
Reactant: CCOc1cccc(Oc2ccc[n+]([O-])c2)c1
Reactant: CCOc1cccc(Oc2ccc[n+](OC)c2)c1
Agent: [Na]
Solvent: COS(=O)(=O)OC
Solvent: O
Product: CCOc1cccc(Oc2cccnc2C#N)c1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A mixture of 68 g of 3-(3-ethoxyphenoxy)pyridine 1-oxide and 40 g of dimethylsulfate is heated at 100° C. for 4 hours. The 3-(3-ethoxyphenoxy)-1-methoxy pyridinium methosulfate is dissolved in 200 ml of water and is added dropwise to a cooled, stirred solution of 75 g sodium cyamide in 200 ml of water at 0°-5° C. under a nitrogen atmosphere. The mixture is stirred 16 hours and is extracted with 500 ml of dichloromethane. The dichloromethane layer is washed with 100 ml of water, dried, concentrated and distilled to yield 3-(3-ethoxyphenoxy)-2-pyridinecarbonitrile, bp 145°-150° C. at 0.2 mM, mp 83°-84° C. after recrystallization from methanol.
Reaction SMILES: [CH2:1]([C:3]1[S:30][C:6]2[N:7]([CH2:13][C:14]3[C:19]([F:20])=[CH:18][C:17]([C:21]4[C:22]([C:27]#[N:28])=[CH:23][CH:24]=[CH:25][CH:26]=4)=[CH:16][C:15]=3[F:29])[C:8](=[O:12])[NH:9][C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].Br[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=1)=[O:34].CN(C)C=O.[H-].[Na+]>C(OCC)(=O)C>[CH2:1]([C:3]1[S:30][C:6]2[N:7]([CH2:13][C:14]3[C:15]([F:29])=[CH:16][C:17]([C:21]4[C:22]([C:27]#[N:28])=[CH:23][CH:24]=[CH:25][CH:26]=4)=[CH:18][C:19]=3[F:20])[C:8](=[O:12])[N:9]([CH2:32][C:33]([C:35]3[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=3)=[O:34])[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1cc2c(=O)[nH]c(=O)n(Cc3c(F)cc(-c4ccccc4C#N)cc3F)c2s1
Reactant: COc1ccc(C(=O)CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1cc2c(=O)n(CC(=O)c3ccc(OC)cc3)c(=O)n(Cc3c(F)cc(-c4ccccc4C#N)cc3F)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.3 %

Procedure:
To a mixture of 4′-[(6-ethyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl)methyl]-3′,5′-difluorobiphenyl-2-carbonitrile (1.5 g), 2-bromo-1-(4-methoxyphenyl)ethanone (0.96 g) and N,N-dimethylformamide (19 mL) was added 60% sodium hydride (0.21 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% potassium hydrogensulfate and then saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as colorless crystals (1.2 g, 59%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=O)=[CH:5][CH:4]=1.Cl.[NH2:20][OH:21]>C(O)C.N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[N:20][OH:21])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)c2ccc(OC)cc2)cc1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: COc1ccc(C(=NO)c2ccc(OC)cc2)cc1
Reaction time: 3 h

Procedure:
4,4′-Dimethoxybenzophenone (25 g, 103 mmol) is suspended in ethanol (150 ml) and pyridine (30 ml). Hydroxylamine hydrochloride (21.50 g, 310 mmol) is added and the reaction mixture is refluxed. The reaction is shown to be complete by TLC after 3 hours. The reaction mixture is allowed to cool and the solvent is removed in vacuo. The residue is partitioned between ethyl acetate (500 ml) and water (500 ml). The organic layer dried is over MgSO4, filtered and the solvent removed in vacuo. The title compound is obtained following crystallisation from ethylacetate/cyclohexane. 1H nmr (CDCl3, 400 MHz); 7.70(s, 1H), 7.40 (d of d, 4H), 6.95(d, 2H), 6.85(d, 2H), 3.85(s, 3H), 3.80(s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[CH2:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C@H:24]([NH2:31])[C@@H:23]1[OH:32]>CN(C)C=O.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH:17]([OH:18])[CH2:19][NH:31][C@@H:24]4[C:25]5[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH2:22][CH:23]4[OH:32])=[CH:13][CH:14]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: N[C@H]1c2ccccc2C[C@H]1O
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Solvent: CCO
Solvent: CN(C)C=O
Product: OC(CN[C@@H]1c2ccccc2CC1O)COc1ccc(-c2noc3cc(F)ccc23)cc1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and (1S, 2R)-(−)-cis-1-amino-2-indanol in ethanol, essentially as described above in Example 70. Purity by LC/MS=100%, [M+H]+=435.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[N:6]([CH2:19][CH2:20][O:21][CH2:22][CH2:23][NH:24][CH3:25])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:17])[C:8]=2[N:18]=1.CCN(CC)CC.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>C(Cl)Cl>[NH2:17][C:9]1[C:8]2[N:18]=[C:5]([CH2:4][CH2:3][O:2][CH3:1])[N:6]([CH2:19][CH2:20][O:21][CH2:22][CH2:23][N:24]([CH3:25])[S:34]([CH3:33])(=[O:36])=[O:35])[C:7]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: CS(=O)(=O)Cl
Reactant: CNCCOCCn1c(CCOC)nc2c(N)nc3ccccc3c21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCOCCN(C)S(C)(=O)=O
Temperature: 0 °C
Yield: 61.4 %

Procedure:
2-(2-Methoxyethyl)-1-{2-[2-(methylamino)ethoxy]ethyl}-1H-imidazo[4,5-c]quinolin-4-amine (1.00 g, 2.92 mmol) was dissolved in 30 mL of anhydrous CH2Cl2 and cooled to 0° C. under N2. To the stirred solution were added Et3N (0.81 mL, 5.81 mmol) and methanesulfonyl chloride (226 μL, 2.92 mmol) and the reaction was allowed to warm to room temperature overnight. The reaction mixture was then quenched by addition of saturated NaHCO3 solution (30 mL) and CH2Cl2 (30 mL). The organic layer was separated and washed with H2O and brine, dried over Na2SO4 and concentrated under reduced pressure. Crystallization of the residue from EtOAc and CH2Cl2 gave 756 mg of N-(2-{2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)-N-methylmethanesulfonamide as tan crystals. m.p. 145.0-146.5° C.;
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[Br-].[C:16]1([PH+](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Li]CCCC>>[CH2:16]=[C:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)C1
Reactant: c1ccc([PH+](c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Li]CCCC
Product: C=C1CCCN(C(=O)OC(C)(C)C)C1
Reaction time: 0.05 h

Procedure:
The title compound was prepared according to the procedure of Intermediate 71 starting from tert-butyl 3-oxopiperidine-1-carboxylate (1 g, 5.0 mmol), triphenylphosphonium bromide (2.69 g, 7.5 mmol) and n-BuLi (1.8 M; 4.2 mL, 7.5 mmol). Yield: 0.28 g (28%) after purification by flash chromatography with 10% isohexane in DCM as eluent. HPLC purity 95%, RT=2.43 min (System A; 10-97% MeCN over 3 min); 90%, RT=2.38 min (System B; 10-97% MeCN over 3 min). 1H NMR (400 MHz, CDCl3) δ ppm 1.41-1.48 (m, 9H) 1.56-1.65 (m, 2H) 2.20-2.30 (m, 2H) 3.38-3.47 (m, 2H) 3.86 (s, 2H) 4.74 (s, 1H) 4.80 (s, 1H). MS (ESI+) for C11H19NO2 m/z 142 (M-C4H8)+. *Previously reported in Tetrahedron 2002, 58, 7165-7175.
Reaction SMILES: [H-].[Na+].[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]1=[O:12].[Cl:13][CH2:14][CH2:15][CH2:16]Br.O>CN(C)C=O>[Cl:13][CH2:14][CH2:15][CH2:16][N:5]1[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[O:3][C:4]1=[O:12]
Reactant: ClCCCBr
Reactant: O=c1[nH]c2ccccc2o1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1oc2ccccc2n1CCCCl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred suspension of sodium hydride (7.8 g, 0.16 mol, ether-washed) in dimethylformamide (75 ml) was added dropwise under nitrogen, 2-benzoxazolinone (20.0 g, 0.15 mol) dissolved in dimethylformamide (150 ml). After complete addition the reaction was stirred at ambient temperature for 30 min. and then it was cooled to −5° C. with an ice-acetone bath. A solution of 3-chloro-1-bromopropane (46.6 g, 0.30 mol) in dimethylformamide (50 ml) was added dropwise (temperature never exceeded 0° C.). The reaction was allowed to reach ambient temperature and was stirred for 16 hours. The reaction was poured into water, and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate was washed with water, dried (MgSO4), and the extract concentrated from toluene-hexane to afford N-(3-chloropropyl)-2-benzoxazolinone as large needles, 15.6 g, m.p.=264°-266° C.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([NH:9][C:10](=[O:11])[C:5]=12)=[O:8].[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>C(OCC)C>[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH:17]1[CH2:2][CH2:3][C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([NH:9][C:10](=[O:11])[C:5]=12)=[O:8]
Reactant: O=C1NC(=O)c2c(CCBr)cccc21
Reactant: CN1CCNCC1
Solvent: CCOCC
Product: CN1CCNCC1CCc1cccc2c1C(=O)NC2=O

Procedure:
2-Bromoethylphthalimide (508 mg; 2.0 mmoles) and N-methylpiperazine (0.44 mg; 4.0 mmoles) were dissolved in anhydrous ethyl ether (5 ml). Reaction times and process as per Example 1.