Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1.Br[CH:17]([CH3:33])[C:18]([C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[C:25]([O:31][CH3:32])[C:26]=2[Cl:30])[CH:21]=1)=[O:19].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[ClH:3].[ClH:30].[Cl:3][C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][N:13]([CH:17]([C:18]([C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[C:25]([O:31][CH3:32])[C:26]=4[Cl:30])[CH:21]=3)=[O:19])[CH3:33])[CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1
Reactant: Clc1cccc(N2CCNCC2)c1
Reactant: COc1ccc2cc(C(=O)C(C)Br)ccc2c1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc2cc(C(=O)C(C)N3CCN(c4cccc(Cl)c4)CC3)ccc2c1Cl
Yield: 127.8 %

Procedure:
A mixture of N-(3-chlorophenyl) piperazine dihydrochloride (1.35 g, 5 mmol), 2-bromo-1-(5-chloro-6-methoxynaphthalen-2-yl)propan-1-one (1.96 g, 6 mmol) and K2CO3 (2.42 g, 17.5 mmol) in DMF (40 ml) was treated according to the general preparation 2 to obtain 1.65 g of N1-(3-chlorophenyl)-N4-[1-(5-chloro-6-methoxy-2-naphthoyl)ethyl] piperazine dihydrochloride, yield 64%. The above product was reduced with NaBH4 in methanol (50 ml) according to the general preparation 3 to obtain the title compound as white solid, yield 78%.
Reaction SMILES: [CH:1](=O)[C:2]1[C:3]([O:8][CH3:9])=[CH:4][CH:5]=[CH:6][CH:7]=1.[Br:11][C:12]1[CH:18]=[C:17]([N+:19]([O-])=O)[C:15]([NH2:16])=[C:14]([CH3:22])[CH:13]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+]>CCO>[Br:11][C:12]1[CH:13]=[C:14]([CH3:22])[C:15]2[NH:16][C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[O:8][CH3:9])=[N:19][C:17]=2[CH:18]=1
Reactant: COc1ccccc1C=O
Reactant: Cc1cc(Br)cc([N+](=O)[O-])c1N
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccccc1-c1nc2cc(Br)cc(C)c2[nH]1
Temperature: 80 °C
Yield: 79 %

Procedure:
o-Anisaldehyde (0.105 ml, 0.866 mmol) and 4-bromo-2-methyl-6-nitroaniline (0.2 g, 0.866 mmol) in EtOH (3.46 ml) were treated with solid sodium dithionite (0.535 g, 2.60 mmol) and the mixture was heated to 80° C. for 16 hours following the procedure of D. Yang et. al. (Synthesis 2005, 47-56). The reaction mixture was taken to dryness and partitioned between ethyl acetate and 2N NH4OH(aq). After the usual work-up the crude material was purified by silica gel chromatography (Biotage 25S, 20% -40% ethyl acetate in hexanes) to obtained 159 (0.217 g, 0.684 mmol, 79% yield) as yellow solid. LRMS (ESI): (calc.) 316.0 and 318.0 (found) 317.1 and 319.1 (MH)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[CH:7]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])([CH3:4])([CH3:3])[CH3:2].[Br:23]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[C:11]([O:10][C:8](=[O:9])[CH:7]([C:15]1[CH:20]=[CH:19][C:18]([CH2:21][Br:23])=[CH:17][CH:16]=1)[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:22])([CH3:13])([CH3:14])[CH3:12]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)C(C(=O)OC(C)(C)C)c1ccc(CBr)cc1
Temperature: 25 °C
Yield: 66.5 %

Procedure:
p-Tolyl-malonic acid di-tert-butyl ester (5.695 g, 16.6 mmol) was dissolved in 80 ml of CCl4. To the solution was added N-bromosuccinimide (3.309 g, 16.6 mmol, 1 equivalents) and benzoyl peroxide (220 mg), the reaction mixture was refluxed under argon overnight; the reaction mixture was then cooled to room temperature, and the precipitate that had formed was filtered and washed with hexanes. The combined organic portions was dried, and the residue obtained was purified by chromatography to give (4-bromomethylphenyl)-malonic acid di-tert-butyl ester 4.2559 g (59.5% yield) as white solid. 1H NMR (CDCl3) δ: 7.379 (4H, s), 4.493 (2H, s), 4.435 (1H, s), 1.473 (18H, s) ppm. FABMS (+Ve), m/z 387 [MH+, 81Br], 385 [MH+, 79Br], 331 [MH+—C4H8, 81Br], 329 [MH+—C4H8. 79Br], 275 [MH+—2C4H8, 81Br], 273 [MH+—2C4H8, 79Br]. Anal. calcd. for C18H25BrO4: C, 56.1; H,6.5; Br, 20.7. Found: C, 55.52; H, 6.38; Br, 21.85.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11](=O)[CH2:12][CH3:13])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[Cl:15][CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=2)=O)=[CH:21][CH:20]=1>>[Cl:15][CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22](/[C:25](/[C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=2)=[C:11](\[CH:8]2[CH2:7][CH2:6][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:10][CH2:9]2)/[CH2:12][CH3:13])=[CH:21][CH:20]=1
Reactant: CCC(=O)C1CCC2(CC1)OCCO2
Reactant: O=C(c1ccc(O)cc1)c1ccc(OCCCl)cc1
Product: CC/C(=C(\c1ccc(O)cc1)c1ccc(OCCCl)cc1)C1CCC2(CC1)OCCO2
Yield: 15.6 %

Procedure:
Following general procedure of McMurry reaction as described in example 1, step B, 1-(1,4-dioxaspiro[4.5]decan-8-yl)propan-1-one (259 mg, 1.3 mmol) was reacted with (4-(2-chloroethoxy)phenyl)(4-hydroxyphenyl)methanone (360 mg, 1.3 mmol) to give 90 mg title compound (Z-isomer, 16% yield) and 110 mg E-isomer (19% yield) as well.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=2)=[CH:9][S:8][C:7]=1[NH:18][C:19](=[O:23])[CH2:20][C:21]#[N:22])=[O:5])[CH3:2].S(Cl)([Cl:27])(=O)=O>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=2)=[C:9]([Cl:27])[S:8][C:7]=1[NH:18][C:19](=[O:23])[CH2:20][C:21]#[N:22])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(-c2ccc(Br)cc2)csc1NC(=O)CC#N
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)c1c(NC(=O)CC#N)sc(Cl)c1-c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a cold (0° C.) solution of 4-(4-bromophenyl)-2-(2-cyano-acetylamino)-thiophene-3-carboxylic acid ethyl ester (4.0 g, 10.18 mmol) in methylene chloride (34 mL) was added sulfuryl chloride (0.82 mL, 10.2 mmol). The cold bath was removed, and the reaction was stirred at room temperature for 4 h. Saturated aqueous sodium bicarbonate solution was then added (30 mL) to the reaction. The layers were separated, and the aqueous was extracted with additional methylene chloride (3×15 mL). The combined organic layers were dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the titled compound as a solid. MS (DCI/NH3) m/e 446 (M+NH3)+, NMR (300 MHz, CDCl3): δ ppm 12.1 (br s, 1H), 7.53 d, 2H), 7.09 (d, 2H), 4.08 (q, 2H), 3.67 (s, 2H), and 0.91 (t, 3H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[N:54]([C:57]1[CH:61]=[CH:60][S:59][CH:58]=1)=[C:55]=[O:56]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][CH2:46][CH:47]1[CH2:48][CH2:49][N:50]([C:55]([NH:54][C:57]2[CH:61]=[CH:60][S:59][CH:58]=2)=[O:56])[CH2:51][CH2:52]1
Reactant: O=C=Nc1ccsc1
Reactant: Clc1cnc2nc1Nc1ccc(OCCC3CCNCC3)c(c1)CCc1cncc(c1)N2
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccsc1)N1CCC(CCOc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 30 %

Procedure:
The desired compound was prepared according to the procedure of Example D41 using 6-chloro-12-(2-piperidin-4-ylethoxy)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate) and 3-isocyanatothiophene as the starting materials in 30% yield. LCMS for C29H31ClN7O2S (M+H)+: m/z=576.0.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH3:8][C:9]1[CH:10]=[C:11]([NH:16][C:17]([C:19]2[C:20]([S:25][CH2:26][C:27]3[CH:32]=[CH:31][N:30]=[C:29](F)[CH:28]=3)=[N:21][CH:22]=[CH:23][CH:24]=2)=[O:18])[CH:12]=[C:13]([CH3:15])[CH:14]=1>C(OCC)(=O)C>[CH3:8][C:9]1[CH:10]=[C:11]([NH:16][C:17]([C:19]2[C:20]([S:25][CH2:26][C:27]3[CH:32]=[CH:31][N:30]=[C:29]([N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)[CH:28]=3)=[N:21][CH:22]=[CH:23][CH:24]=2)=[O:18])[CH:12]=[C:13]([CH3:15])[CH:14]=1
Reactant: CN1CCNCC1
Reactant: Cc1cc(C)cc(NC(=O)c2cccnc2SCc2ccnc(F)c2)c1
Solvent: CCOC(C)=O
Product: Cc1cc(C)cc(NC(=O)c2cccnc2SCc2ccnc(N3CCN(C)CC3)c2)c1
Temperature: 150 °C
Reaction time: 3 h
Yield: 32 %

Procedure:
N-Methylpiperazine (2.0 mL) was added to N-(3,5-dimethylphenyl)-2-(2-fluoropyridin-4-ylmethylthio)pyridine-3-carboxamide (Reference compound No. 3-1, 100 mg, 0.27 mmol) at room temperature, then the vessel was sealed and the reaction mixture was stirred for 3 hours at 150° C. The mixture was cooled to room temperature, ethyl acetate (20 mL) was added to the reaction mixture, and then the whole was washed with brine (20 mL) and dried over anhydrous magnesium sulfate. The organic layer was evaporated under reduced pressure, and the resulting solid was filtered off with ethyl acetate to give 39 mg of the target compound as a colorless crystal. (Yield 32%)
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([C:16]#[N:17])=[C:4](Cl)[N:3]=1.CC(C)([O-])C.[K+].[OH:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1>>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([C:16]#[N:17])=[C:4]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)[N:3]=1
Reactant: N#Cc1c(N)nc(Cl)c(C#N)c1-c1ccccc1
Reactant: OCc1ccccn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: N#Cc1c(N)nc(OCc2ccccn2)c(C#N)c1-c1ccccc1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
102 mg (0.4 mmol) of 2-amino-6-chloro-4-phenyl-3,5-pyridinedicarbonitrile [Quintela et al., Heterocycles 38, 1299-1305 (1994)] and 54 mg (0.48 mmol) of potassium tert-butoxide are dissolved together in 1.696 g (=1.5 ml, 15.55 mmol) of 2-hydroxymethylpyridine, and the mixture is stirred at 60° C. for about 16 h. The product which crystallizes out is filtered off with suction, washed with water and dried under reduced pressure.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[CH2:7][N:8]=C(C1C=CC=CC=1)C1C=CC=CC=1)([CH3:4])([CH3:3])[CH3:2].C[Si](C)(C)N[Si](C)(C)C.[Li].Br[CH2:34][C:35]1[CH:36]=[CH:37][C:38]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[N:39][CH:40]=1>C1COCC1>[NH2:8][CH:7]([CH2:34][C:35]1[CH:40]=[N:39][C:38]([NH:41][C:42]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:48])=[CH:37][CH:36]=1)[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:22]
Reactant: CC(C)(C)OC(=O)CN=C(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(CBr)cn1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(CC(N)C(=O)OC(C)(C)C)cn1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 79.7 %

Procedure:
660 mg of N-(diphenylmethylene)glycine tert-butyl ester (2.23 mmol, 1.0 equiv.) were dissolved in 15 ml of dry THF and cooled to 0° C. under argon. Then 2.23 ml of 1 M lithium hexamethyldisilazane (LiHMDS) solution in THF were added dropwise, and the mixture was stirred at 0° C. for 15 min. Subsequently, 642 mg of tert-butyl (5-bromomethylpyridin-2-yl)-carbamate (2.23 mmol, 1.0 equiv.) were added, and the mixture was stirred at 0° C. for 2 h. The mixture was quenched with 18 ml of sat. citric acid and stirred at RT for 1 h. The mixture was extracted with ethyl acetate (2×30 ml), and the organic phases were washed with 50 ml of 1 M HCl. The aqueous phases were combined and adjusted to pH 10 with 2M NaOH and then extracted 3× with ethyl acetate. The combined organic phases were dried over Na2SO4 and concentrated. The residue was purified by flash chromatography on silica gel with heptane/ethyl acetate mixtures as eluent. 600 mg (80% yield) of the title compound were obtained as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:41])[C:14]2[CH:13]=[C:12]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:23]=[CH:24][C:25]5[N:26]([C:35]6[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=6)[C:27]6[C:32]([C:33]=5[CH:34]=4)=[CH:31][CH:30]=[CH:29][CH:28]=6)=[CH:18][CH:17]=3)[CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[Br:42][C:43]1[CH:48]=[CH:47][C:46]([C:49]2[CH:54]=[CH:53][C:52](I)=[CH:51][CH:50]=2)=[CH:45][CH:44]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[Br:42][C:43]1[CH:44]=[CH:45][C:46]([C:49]2[CH:54]=[CH:53][C:52]([N:15]([C:12]3[CH:11]=[CH:10][C:9]4[C:8]5[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=5)[C:2]([CH3:41])([CH3:1])[C:14]=4[CH:13]=3)[C:16]3[CH:17]=[CH:18][C:19]([C:22]4[CH:23]=[CH:24][C:25]5[N:26]([C:35]6[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=6)[C:27]6[C:32]([C:33]=5[CH:34]=4)=[CH:31][CH:30]=[CH:29][CH:28]=6)=[CH:20][CH:21]=3)=[CH:51][CH:50]=2)=[CH:47][CH:48]=1
Reactant: CC1(C)c2ccccc2-c2ccc(Nc3ccc(-c4ccc5c(c4)c4ccccc4n5-c4ccccc4)cc3)cc21
Reactant: Brc1ccc(-c2ccc(I)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC1(C)c2ccccc2-c2ccc(N(c3ccc(-c4ccc(Br)cc4)cc3)c3ccc(-c4ccc5c(c4)c4ccccc4n5-c4ccccc4)cc3)cc21
Temperature: 25 °C
Yield: 66.7 %

Procedure:
30 g (57 mmol) (9,9-dimethyl-9H-fluoren-2-yl)-[4-(9-phenyl-9H-carbazol-3-yl)-phenyl]-amine and 20 g (57 mmol) 4-bromo-4′-iodo-biphenyl [105946-82-5] are dissolved in 200 ml toluene and treated with 100 ml of a 2 M solution of sodium carbonate. The reaction mixture is carefully degassed and 200 mg tetrakistriphenylphosphine palladiume are added and refluxed for 20 h. The reaction mixture is then cooled to room temperature and 250 ml water is added. The layers are separated. The water phase is then extracted three times with toluene. The organic layers are then washed twice with water, dried over magnesium sulphate, filtrated and the solvent is then removed under vacuum. The residue is recrystallized from butanole/toluene, to yield 29 g (38 mmol) (67%) of a white solid with a purity of 99.3%.
Reaction SMILES: [S:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[S:3].[CH:8]([C:11]1[CH:25]=[CH:24][CH:23]=[CH:22][C:12]=1[O:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1)([CH3:10])[CH3:9]>>[CH:8]([C:11]1[CH:25]=[CH:24][CH:23]=[CH:22][C:12]=1[O:13][C:14]1[CH:15]=[CH:16][C:17]([CH:18]=[C:7]2[S:1][C:2](=[S:3])[NH:4][C:5]2=[O:6])=[CH:20][CH:21]=1)([CH3:10])[CH3:9]
Reactant: O=C1CSC(=S)N1
Reactant: CC(C)c1ccccc1Oc1ccc(C=O)cc1
Product: CC(C)c1ccccc1Oc1ccc(C=C2SC(=S)NC2=O)cc1

Procedure:
The title compound was prepared using rhodanine and 4-(2-Isopropyl-phenoxy)-benzaldehyde according to General Procedure B.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[C:14](=[O:16])[CH2:13][CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[OH-].[K+].[CH3:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22]Br.C(Br)C1C=CC=CC=1>CCOCC.O>[CH3:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22][NH:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[C:14](=[O:16])[CH2:13][CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2
Reactant: Cc1ccccc1CBr
Reactant: Nc1c2c(nc3ccccc13)CCCC2=O
Agent: BrCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: Cc1ccccc1CNc1c2c(nc3ccccc13)CCCC2=O
Reaction time: 0.5 h
Yield: 63.4 %

Procedure:
9-amino-3,4-dihydroacridin-1(2H)-one (7.63 g) was suspended in 75 ml of dimethylsufoxide and 5 g of pulverized 85% potassium hydroxide was added. After 45 minutes a homogeneous solution was obtained to which was added 7.0 g of 2-methylbenzyl bromide. The reaction mixture was stirred for 30 minutes and then additional 2.0 g of the benzyl bromide was added. After 60 more minutes 300 ml of water and 30 ml of ether were added to the reaction. The precipitated product was filtered off and washed with additional ether, then flushed over a short magnesium silicate column with ethyl acetate. After evaporating the solvent, the product was again washed with cold ether to give 7.21 g of product.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[C:11]([NH2:20])[C:10]=2[N:9]=[C:8]1[CH2:21][CH3:22].[C:23]1([N:29]=[C:30]=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[NH2:20][C:11]1[C:10]2[N:9]=[C:8]([CH2:21][CH3:22])[N:7]([CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:1][C:30]([NH:29][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:31])[C:19]=2[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1
Reactant: CCc1nc2c(N)nc3ccccc3c2n1CCOCCN
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Product: CCc1nc2c(N)nc3ccccc3c2n1CCOCCNC(=O)Nc1ccccc1
Reaction time: 18 h
Yield: 50 %

Procedure:
A solution of the compound of Example 46, 1-[2-(2-aminoethoxy)ethyl]-2-ethyl-1H-imidazo[4,5-c]quinolin-4-amine (800 mg, 2.67 mmol) in 30 mL of CH2Cl2 was stirred vigorously and treated with phenyl isocyanate (0.290 mL, 2.67 mmol). After 18 h, the reaction was concentrated to yield an off white solid. Purification by column chromatography (SiO2, 95:5:0.5 CHCl3:MeOH:NH4OH) gave 559 mg of N-{2-[2-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethyl}-N′-phenylurea as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([NH2:16])=[O:15])=[CH:12][N:11]=[CH:10][CH:9]=2)=[C:4](F)[CH:3]=1.[H-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[C:13](=[CH:12][N:11]=[CH:10][CH:9]=3)[C:14](=[O:15])[NH:16][C:4]=2[CH:3]=1
Reactant: NC(=O)c1cnccc1-c1ccc(Cl)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=c1[nH]c2cc(Cl)ccc2c2ccncc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 96.7 %

Procedure:
To a solution of 4-(4-chloro-2-fluorophenyl)nicotinamide (0.9 g, 3.59 mmol) in THF (20 mL) at 0° C. was added sodium hydride (0.258 g, 10.77 mmol) and the reaction mixture was stirred at 0° C. for 1 h and then warmed to room temperature and stirred overnight (14 h). The reaction mixture was then quenched with ice and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with brine (1×100 mL), dried (Na2SO4) and concentrated under reduced pressure to afford crude 8-chlorobenzo[c][2,7]naphthyridin-5(6H)-one (0.80 g, 3.47 mmol, 97% yield). LC/MS (ESI) m/e 231.2 [(M+H)+, calcd for C12H8ClN2O 231]; LC/MS retention time (method D): tR=0.61 min.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([OH:9])=[O:8].O=S(Cl)Cl.[CH3:14]O>>[CH3:14][O:8][C:7]([C:3]1[S:4][CH:5]=[CH:6][C:2]=1[Br:1])=[O:9]
Reactant: CO
Reactant: O=C(O)c1sccc1Br
Solvent: O=S(Cl)Cl
Product: COC(=O)c1sccc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Bromothiophene-2-carboxylic acid (5.0 g, 24 mmol, 1 eq.) was dissolved in MeOH (100 mL) and the mixture was degassed and purged with nitrogen (2×). SOCl2 (15 mL, 0.2 mol, 8.3 eq.) was added dropwise and the resulting mixture was stirred overnight at room temperature. The mixture was then concentrated and DCM (150 mL) was added. Saturated NaHCO3 (20 mL) was added, and the resulting mixture was stirred at room temperature for 15 minutes. The organic layer was washed with saturated NaHCO3 (20 mL), water (20 mL), and saturated aqueous NaCl (20 mL), then dried over Na2SO4, filtered and concentrated to yield 3-bromothiophene-2-carboxylic acid methyl ester (4.0 g) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([NH2:18])(Cl)[C:5]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][S:8][C:6]=2[N:7]=1.N[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1.C(O)C>O>[CH3:1][C:2]1[N:3]=[C:4]([NH:18][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[C:5]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][S:8][C:6]=2[N:7]=1
Reactant: NCc1ccccn1
Reactant: CC1=Nc2scc(-c3ccccc3)c2C(N)(Cl)N1
Solvent: CCO
Solvent: O
Product: Cc1nc(NCc2ccccn2)c2c(-c3ccccc3)csc2n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 842.3 %

Procedure:
In a 10 ml glass tube were placed 2-methyl-4-chloro-5-phenylthieno[2,3-d]pyrimidin-4-ylamine (0.076 g, 0.293 mmol), 2-(aminomethyl)pyridine (0.0364 g, 0.03 mmol) and ethanol (2.5 ml). The vessel was sealed with a septum and placed in the microwave cavity. Microwave irradiation of 200 W was used, the temperature being ramped from room temperature to 150° C. Once 150° C. was reached, the reaction mixture was held at this temperature for 10 minutes. After cooling to ambient temperature, water (4 ml) was added and the mixture stirred for 2.5 hours. The resulting solid was collected by filtration, washed with water and dried in vacuo to give 2-methyl-N-(2-pyridyl)methyl-5-phenylthieno[2,3-d]pyrimidin-4-ylamine (0.084 g) as an off white solid, m.pt. 110-112° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])([CH3:4])([CH3:3])[CH3:2].Br[C:20]1[CH:33]=[CH:32][C:23]([C:24]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[O:25])=[CH:22][CH:21]=1>>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:20]1[CH:21]=[CH:22][C:23]([C:24]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[O:25])=[CH:32][CH:33]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(c1ccc(Br)cc1)N1CCOCC1
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)COc1ccc(Cl)cc1C#Cc1ccc(C(=O)N2CCOCC2)cc1

Procedure:
Following the general method as outlined in Intermediate 20, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and 4-(4-bromobenzoyl)morpholine (Intermediate 174), the title compound was obtained as a brown sticky solid after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([N:8]([C:16]1[S:17][C@H:18]2[O:24][C@H:23]([CH2:25][OH:26])[C@@H:22]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)[C@H:21]([O:37][CH2:38][C:39]3[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=3)[C@H:19]2[N:20]=1)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH3:7]>N1C=CC=CC=1.C(Cl)Cl>[CH3:1][S:2]([O:26][CH2:25][C@H:23]1[O:24][C@H:18]2[C@H:19]([N:20]=[C:16]([N:8]([C:9]([O:10][C:11]([CH3:13])([CH3:14])[CH3:12])=[O:15])[CH2:6][CH3:7])[S:17]2)[C@@H:21]([O:37][CH2:38][C:39]2[CH:40]=[CH:41][C:42]([O:45][CH3:46])=[CH:43][CH:44]=2)[C@@H:22]1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)(=[O:4])=[O:3]
Reactant: CCN(C(=O)OC(C)(C)C)C1=N[C@@H]2[C@@H](OCc3ccc(OC)cc3)[C@H](OCc3ccc(OC)cc3)[C@@H](CO)O[C@@H]2S1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCN(C(=O)OC(C)(C)C)C1=N[C@@H]2[C@@H](OCc3ccc(OC)cc3)[C@H](OCc3ccc(OC)cc3)[C@@H](COS(C)(=O)=O)O[C@@H]2S1
Reaction time: 3 h
Yield: 99.8 %

Procedure:
Methanesulfonyl chloride (0.038 mL, 0.495 mmol) was added in portions to a stirred solution of tert-butyl ethyl(-(3aR,5R,6S,7R,7aR)-5-(hydroxymethyl)-6,7-bis((4-methoxybenzyl)oxy)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)carbamate (0.190 g, 0.323 mmol) in dry pyridine (5 mL) at −20° C. After 3 h, the reaction mixture was diluted with DCM (20 mL) and the DCM extract was washed with satd. NaHCO3, brine, dried over Na2SO4 and concentrated. Residual pyridine was removed by co-evaporation with hexanes. The crude product was purified by silica gel column chromatography (3:7 EtOAc/hexanes) to give (-(3aR,5R,6S,7R,7aR)-2-((tert-butoxycarbonyl)(ethyl)amino)-6,7-bis((4-methoxybenzyl)oxy)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-5-yl)methyl methanesulfonate (0.215 g, 99.6%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.32 (d, J=8.5 Hz, 2H), 7.17 (d, J=8.5 Hz, 2H), 6.91-6.83 (m, 4H), 6.01 (d, J=6.88 Hz, 1H), 4.66 (d, J=11.6 Hz, 1H), 4.60 (d, J=11.6 Hz, 1H), 4.52 (d, J=11.1 Hz, 1H), 4.42-4.36 (m, 2H), 4.27-4.23 (m, 3H), 3.96-3.84 (m, 2H), 3.8 (s, 3H), 3.79 (s, 3H), 3.55 (m, 2H), 2.98 (s, 3H), 1.52 (s, 9H), 1.20 (t, J=6.9 Hz, 3H).