Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:47])[C@@H:12]([NH:21][C:22](=[O:46])[C@H:23]([NH:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[C:24]2[CH:29]=[CH:28][C:27]([NH:30]C(OC(C)(C)C)=O)=[CH:26][CH:25]=2)[C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:14])[S:8][CH:9]=1)=[O:4].C(OC(OC(OC(C)(C)C)=O)=O)(C)(C)C>FC(F)(F)C(O)=O.ClCCl.O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:47])[C@@H:12]([NH:21][C:22](=[O:46])[C@@H:23]([C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=2)[NH:38][C:39]([O:41][C:42]([CH3:44])([CH3:45])[CH3:43])=[O:40])[C@H:13]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH3:14])[S:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1csc(NC(=O)[C@@H](NC(=O)[C@H](NC(=O)OC(C)(C)C)c2ccc(NC(=O)OC(C)(C)C)cc2)[C@@H](C)c2ccccc2)n1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)c1csc(NC(=O)[C@@H](NC(=O)[C@H](NC(=O)OC(C)(C)C)c2ccc(N)cc2)[C@@H](C)c2ccccc2)n1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 57.9 %

Procedure:
2-{(2S,3S)-2-[(R)-2-tert-butoxycarbonylamino-2-(4-tert-butoxycarbonylamino-phenyl)-acetylamino]-3-phenyl-butyrylamino}-thiazole-4-carboxylic acid methyl ester (510 mg, 0.76 mmol) was dissolved in 30% v/v trifluoroacetic acid in dichloromethane solution (10 mL) at 0° C. The mixture was stirred at 0° C. for 2.5 hours and then partitioned between ethyl acetate and saturated aqueous sodium carbonate. The aqueous layer was adjusted to pH=9 by the addition of solid sodium carbonate and the organic layer collected, dried over sodium sulfate, filtered and concentrated. The residue was without further purification dissolved in tetrahydrofuran (50 mL) and the resulting solution cooled to 0° C. A solution of di-tert-butyldicarbonate (167 mg, 0.76 mmol) in tetrahydrofuran (5 mL) was added dropwise and after stirring overnight the reaction mixture was evaporated and the residue was purified by chromatography over silica gel gradient eluted with 0 to 100% ethyl acetate in hexanes to afford 2-{(2S,3S)-2-[(R)-2-(4-amino-phenyl)-2-tert-butoxycarbonylamino-acetylamino]-3-phenyl-butyrylamino}-thiazole-4-carboxylic acid methyl ester as a white solid (250 mg, 58%).
Reaction SMILES: Br[C:2]1[C:3]([F:31])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18]4[N:22]([CH3:23])[N:21]=[C:20]([C:24]5[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=5)[N:19]=4)=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:30]=1.[CH3:32][C:33]([OH:37])([C:35]#[CH:36])[CH3:34]>>[F:31][C:3]1[C:2]([C:36]#[C:35][C:33]([OH:37])([CH3:34])[CH3:32])=[CH:30][C:6]2[C:7]3[N:8]([C:12]([C:18]4[N:22]([CH3:23])[N:21]=[C:20]([C:24]5[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=5)[N:19]=4)=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=3)[CH2:9][CH2:10][O:11][C:5]=2[CH:4]=1
Reactant: Cn1nc(-c2ccncc2)nc1-c1c(C(N)=O)nc2n1CCOc1cc(F)c(Br)cc1-2
Reactant: C#CC(C)(C)O
Product: Cn1nc(-c2ccncc2)nc1-c1c(C(N)=O)nc2n1CCOc1cc(F)c(C#CC(C)(C)O)cc1-2
Yield: 35.3 %

Procedure:
The title compound was prepared similarly according to Procedure E. 10-bromo-9-fluoro-3-(1-methyl-3-(pyridin-4-yl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with 2-methyl-3-butyn-2-ol to afford 35.3% yield of the titled product. 1H NMR (400 MHz, DMSO) δ 8.73-8.67 (m, 3H), 7.99 (br s, 1H), 7.97-7.93 (m, 2H), 7.47 (br s, 1H), 7.06 (d, J=10.5 Hz, 1H), 5.53 (s, 1H), 4.58-4.52 (m, 2H), 4.38-4.28 (m, 2H), 3.83 (s, 3H), 1.51 (s, 6H). M+H=488.2
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]([C:13]2[NH:14][C:15]([C@@H:18]3[CH2:22][CH2:21][CH2:20][O:19]3)=[CH:16][N:17]=2)=[CH:8][C:3]=1[C:4]([O:6]C)=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH:48]1[CH2:53][CH2:52][CH:51]([C:54]2[CH:61]=[CH:60][C:57]([C:58]#[N:59])=[CH:56][CH:55]=2)[CH2:50][CH2:49]1.CCN(C(C)C)C(C)C>CN(C)C=O>[CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]([C:13]2[NH:14][C:15]([C@@H:18]3[CH2:22][CH2:21][CH2:20][O:19]3)=[CH:16][N:17]=2)=[CH:8][C:3]=1[C:4]([N:48]1[CH2:53][CH2:52][CH:51]([C:54]2[CH:61]=[CH:60][C:57]([C:58]#[N:59])=[CH:56][CH:55]=2)[CH2:50][CH2:49]1)=[O:6]
Reactant: COC(=O)c1cc(-c2ncc([C@@H]3CCCO3)[nH]2)c(C)cc1C
Reactant: N#Cc1ccc(C2CCNCC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C)c(-c2ncc([C@@H]3CCCO3)[nH]2)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 15.2 %

Procedure:
To a round-bottom flask was added a solution of (S)-methyl 2,4-dimethyl-5-(5-(tetrahydrofuran-2-yl)-1H-imidazol-2-yl)benzoate (compound 257.4, 143 mg, 0.500 mmol, 1.00 equiv) in N,N-dimethylformamide (10 mL). HBTU (285 mg, 0.750 mmol, 1.50 equiv) was added to the reaction, and it was stiffed for 30 min at 25° C. To this was added 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 133 mg, 0.600 mmol, 1.20 equiv) and DIEA (390 mg, 3.02 mmol, 6.04 equiv) dropwise. The resulting solution was stirred for 30 min at 25° C., then quenched with 20 mL of water. The mixture was extracted with 3×25 mL of ethyl acetate and the combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified using silica gel column chromatography with methanol/ethyl acetate (1:30) as eluent. The product (˜100 mg) was further purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column, Xbridge Prep C18, 5 um, 19*150 mm; mobile phase, water with 0.03% NH3H2O and CH3CN (35% CH3CN up to 52% in 8 min, up to 100% in 1 min, down to 35% in 1 min); Detector, Waters 2489 254&220 nm. The fractions containing pure compound were combined and lyophilized to yield 34.6 mg (15%) of the title compound as a white solid. m/z (ES+) 455 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:27]2([CH3:28])[C@H:12]([C@H:13]3[C@H:24]([CH2:25][CH2:26]2)[C@:22]2([CH3:23])[C:16]([CH2:17][C@H:18]([CH2:20][CH2:21]2)O)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].CN(C)C1C=CC=CC=1.S(Br)([Br:40])=O>C(Cl)(Cl)Cl>[CH3:8][C@@H:7]([C@@H:9]1[C@@:27]2([CH3:28])[CH2:26][CH2:25][C@@H:24]3[C@@:22]4([CH3:23])[CH2:21][CH2:20][C@H:18]([Br:40])[CH2:17][C:16]4=[CH:15][CH2:14][C@H:13]3[C@@H:12]2[CH2:11][CH2:10]1)[CH2:6][CH2:5][CH2:4][CH:2]([CH3:3])[CH3:1]
Reactant: O=S(Br)Br
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: CN(C)c1ccccc1
Solvent: ClC(Cl)Cl
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](Br)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Cholesterol, (25 g, 64.6 mmol) was dissolved in 10 ml of dimethylaniline (78.9 mmol) and 5 ml of chloroform. While stirring on ice; small quantities of thionyl bromide (6 ml, 77.6 mmol) dissolved in 20 ml of cold chloroform was added slowly over a period of 15 minutes. After the addition of thionyl bromide was complete, the mixture was stirred for an additional 2 hours at room temperature. The resulting solution was poured into 200 ml of ice cold 95% ethanol and left on ice for 2 hour until crystallization was complete. The product was filtered and washed with 25 ml of ice cold 95% ethanol. A small amount of product was recovered from the filtrate with the addition of 75 ml distilled water followed by refrigeration. Finally, the product was recrystallized from 120 ml of acetone giving 21.8 g of cholesteryl bromide (yield, 75%) with a melting point of 93-95% C. (lit 97-98° C.). The identity of the product was confirmed with mass spectrometry (EI) which showed an intense peak with an m/z of 448, corresponding to the molecular ion (M+°) of cholesteryl bromide. Also, the bromide molecular weight pattern characteristic of the two different isotopes of bromine (79Br:81-Br,1:1) was observed.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26]O[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([C:32]1[N:33]=C(Cl)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.Cl.N1CCC[C@H]1C#N>>[C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][CH2:24][C@H:23]2[C:32]#[N:33])[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]
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Agent: Cl
Agent: N#C[C@@H]1CCCN1
Product: CC(C)(C)c1nc(N2CCC[C@H]2C#N)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)-pyrrolidine-2-carbonitrile hydrochloride and isolated as light-yellow solid (11.5 mg, 65%). MS (m/e): 396.4 (MH+).
Reaction SMILES: C(OP(CC=CCOC1C=CC=CC=1C(Cl)=O)(=O)OCC)C.[H-].[Na+].Cl.C(=O)([O-])[O-].[Na+].[Na+].C[O:33][C:34]1[CH:43]=[C:42]([O:44]C)[CH:41]=[C:40]2[C:35]=1[C:36](=[O:52])[CH:37]=[C:38]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[O:39]2>>[OH:33][C:34]1[CH:43]=[C:42]([OH:44])[CH:41]=[C:40]2[C:35]=1[C:36](=[O:52])[CH:37]=[C:38]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[O:39]2
Reactant: COc1cc(OC)c2c(=O)cc(-c3ccccc3)oc2c1
Agent: CCOP(=O)(CC=CCOc1ccccc1C(=O)Cl)OCC
Agent: Cl
Agent: O=C([O-])[O-]
Product: O=c1cc(-c2ccccc2)oc2cc(O)cc(O)c12

Procedure:
Condensation with [4-(2-chlorocarbonyl-phenoxy)-but-2-enyl]-phosphonic acid diethyl ester (synthesis below) is followed by successive treatment with sodium hydride, hydrochloric acid and sodium carbonate, generating the 5,7-dimethoxyflavone. Demethylation to provide the 5,7-dihydroxyflavone final product is achieved as in Scheme 27.2 (see Bioorg. Med. Chem. Lett., (2000), 10, 1037).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]2[CH2:8][C:9]3[C:21]4[NH:20][C:19]5[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=5)[C:13]=4[C:12]4[C:22](=[O:25])[NH:23][CH2:24][C:11]=4[C:10]=3[C:4]=2[CH:3]=1.[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C=O)C.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>[C:26]1([C:2]2[CH:7]=[CH:6][C:5]3[CH2:8][C:9]4[C:21]5[NH:20][C:19]6[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=6)[C:13]=5[C:12]5[C:22](=[O:25])[NH:23][CH2:24][C:11]=5[C:10]=4[C:4]=3[CH:3]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: OB(O)c1ccccc1
Reactant: O=C1NCc2c3c(c4[nH]c5ccccc5c4c21)Cc1ccc(Br)cc1-3
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: O=C1NCc2c3c(c4[nH]c5ccccc5c4c21)Cc1ccc(-c2ccccc2)cc1-3
Temperature: 25 °C
Yield: 76.6 %

Procedure:
A solution of 3-bromo-5H,6H,12H,13H-indeno[2,3-a]pyrrolo[3,4-c]carbazole-7(7H)-one (Compound I-9) (100 mg, 0.26 mmol), phenylboronic acid (35 mg, 0.29 mmol) and bis(triphenylphosphine)palladium(II) chloride (25 mg) in DMF (5 ml) was heated in a sealed reaction tube at 100°-110° C. for 24 hours. The mixture was cooled to ambient temperature, filtered through a pad of Celite® and concentrated at reduced pressure. The product was triturated with THF to give 77 mg of a brown solid which contained product and starting material. HPLC purification gave Compound I-27 as a tan solid. The melting point was greater than 300° C. The following NMR data were obtained: 1H NMR (DMSO-d6, 300 MHz): δ4.2 (s, 2H), 5.05 (s, 2H), 7.3-7.55 (m, 5H), 7.7 (d, 2H, J=8 Hz), 7.8-7.9 (m, 3H), 8.2 (s, 1H); 8.6 (s, 1H), 9.4 (d, 1H, J=9 Hz), 12.0 (s, 1H) MS(FAB): m/e 387 (m+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[CH:12]=[C:11](Br)[CH:10]=[CH:9][C:8]2=[O:14])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:25]2[CH:30]=[CH:29][C:28]([CH2:31][C:32]([OH:34])=[O:33])=[CH:27][CH:26]=2)O1>>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[C:8](=[O:14])[CH:9]=[CH:10][C:11]([C:25]3[CH:30]=[CH:29][C:28]([CH2:31][C:32]([OH:34])=[O:33])=[CH:27][CH:26]=3)=[CH:12]2)=[CH:4][CH:3]=1
Reactant: O=c1ccc(Br)cn1Cc1ccc(Cl)cc1
Reactant: CC1(C)OB(c2ccc(CC(=O)O)cc2)OC1(C)C
Product: O=C(O)Cc1ccc(-c2ccc(=O)n(Cc3ccc(Cl)cc3)c2)cc1
Yield: 101.2 %

Procedure:
According to Scheme 3 Method A: The title compound was prepared according to Example 2 Step 2, from 1-(4-chlorobenzyl)-5-bromopyridin-2(1H)-one (1 eq, 0.67 mmol, 0.20 g, Example 2 Step 1) and 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetic acid (1.5 eq, 1.00 mmol, 0.26 g). Reaction conditions: 4.5 hours at 90° C. The reaction mixture was made acidic then extracted with AcOEt. The organic layer washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography over silicagel (AIT Flashsmart prepacked column 25 g SiO2, AcOEt/MeOH 95/5), yielding the title compound (0.24 g, 100%) as a white solid. LC (XTerra RP18, 3.5 μm, 3.0×50 mm Column): RT=3.53 min; MS m/z (CI) [MH]+=354, 356.
Reaction SMILES: [C:1](Cl)(=[O:10])[O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl.[CH2:13]([O:20][CH2:21][CH:22]([NH2:25])[CH:23]=[CH2:24])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CCN(C(C)C)C(C)C>C(#N)C.O>[CH2:13]([O:20][CH2:21][CH:22]([NH:25][C:1](=[O:10])[O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH:23]=[CH2:24])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C=CC(N)COCc1ccccc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Solvent: CC#N
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(COCc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Benzyl carbonochloridate (4.7 g, 27.4 mmol) was added dropwise over a period of 30 minutes to a mixture of 1-(benzyloxy)but-3-en-2-amine hydrochloride (3.9 g, 18 mmol) and Hunig's base (10.0 mL, 54.8 mmol) in acetonitrile (100 mL) at 0° C. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford the crude product residue. The crude product residue was purified by silica gel chromatography (ethyl acetate/petroleum ether) to afford benzyl [1-(benzyloxy)but-3-en-2-yl]carbamate. MS ESI calc'd. for C19H22NO3 [M+H]+ 312. found 312. 1H NMR (300 MHz, CD3OD) δ 7.34-7.25 (m, 10H), 5.87-5.79 (m, 1H), 5.25-5.08 (m, 4H), 4.51 (s, 2H), 4.38-4.36 (m, 1H), 3.54-3.44 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][CH2:13]C(OC(C)(C)C)=O)[N:7]=1)[CH3:2].Cl.O1CCOCC1>O1CCOCC1>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][CH3:13])[N:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cccc(NCC(=O)OC(C)(C)C)n1
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)Cc1cccc(NC)n1
Temperature: 25 °C
Reaction time: 17 h
Yield: 119.9 %

Procedure:
A solution of ethyl-6-[(tert-butoxycarbonyl)methylamino]-2-pyridylacetate (10.72 g, 36.42 mmole) in anhydrous dioxane (91 mL) was cooled to the point of partial crystallization of the solvent, and 4 M HCl/dioxane (91 mL, 364.2 mmole) was added. The solution was warmed to RT and stirred for 17 hr, then was concentrated. The resulting light yellow solid was slurried with CH2Cl2/toluene and reconcentrated to leave the title compound (8.48 g, quantitative) as a light yellow powder: 1H NMR (250 MHz, CD3OD) δ7.84 (dd, J=9.0, 7.2 Hz, 1 H), 6.96 (d, J=9.0 Hz, 1 H), 6.78 (d, J=7.2 Hz, 1 H), 4.22 (q, J=7.1 Hz, 2 H), 3.93 (s, 2 H), 3.05 (s, 3 H), 1.27 (t, J=7.1 Hz, 3 H); MS (ES) m/e 195 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][CH2:10][N:11]1[C:23]2[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N:16]=[C:15]([NH2:24])[C:14]=2[N:13]=[C:12]1[CH2:25][CH2:26][CH2:27][CH3:28].[S:29](Cl)([C:32]1[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=1)(=[O:31])=[O:30].O>CN1CCCC1=O>[NH2:24][C:15]1[C:14]2[N:13]=[C:12]([CH2:25][CH2:26][CH2:27][CH3:28])[N:11]([CH2:10][CH2:9][NH:8][S:29]([C:32]3[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=3)(=[O:31])=[O:30])[C:23]=2[C:22]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N:16]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCN
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCNS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Yield: 84.1 %

Procedure:
Triethylamine (1.1 g, 15.9 mmol) was added to a cooled (0° C.) solution of 1-(2-aminoethyl)-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine (3.0 g, 10.6 mmol) in 1-methyl-2-pyrrolidinone (100 mL). A solution of tosyl chloride (2.11 g, 11.1 mmol) in 1-methyl-2-pyrrolidinone (20 mL) was slowly added in a dropwise fashion. The reaction was allowed to warm to ambient temperature and was maintained overnight. The reaction was poured into water (1500 mL) and adjusted to pH 9. A white precipitate was isolated by filtration and then recrystallized from acetonitrile (60 mL) to provide 3.9 g of N-[2-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]-4-methylbenzenesulfonamide, m.p. 187.0–188.0° C. Analysis: Calculated for C23H27N5O2S.0.3H2O: % C, 62.29; % H, 6.28; % N, 15.79. Found: % C, 62.52; % H, 6.36; % N, 15.88.
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([O:15][CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[CH:14]=1)[N:11]=[CH:10][CH:9]=[CH:8]2)[CH2:2][CH2:3][CH3:4].[S:22]1(=[O:28])(=[O:27])[CH:26]=[CH:25][CH2:24][CH2:23]1.CO>C1COCC1>[CH2:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([O:15][CH:16]3[CH2:17][CH2:18][N:19]([CH:24]4[CH2:25][CH2:26][S:22](=[O:28])(=[O:27])[CH2:23]4)[CH2:20][CH2:21]3)[CH:14]=1)[N:11]=[CH:10][CH:9]=[CH:8]2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cc(OC2CCNCC2)c2ncccc2c1
Reactant: O=S1(=O)C=CCC1
Solvent: C1CCOC1
Solvent: CO
Product: CCCCc1cc(OC2CCN(C3CCS(=O)(=O)C3)CC2)c2ncccc2c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 8 %

Procedure:
To a solution of 6-butyl-8-(4-piperidinyloxy)quinoline (for example, as prepared for Intermediate 4) (0.15 g, 0.53 mmol) in THF (5 ml) was added 2,3-dihydrothiophene 1,1-dioxide (commercially available, for example, from AKOS) (0.150 g, 1.27 mmol). The solution was heated to 80° C. for 2.5 h. To the solution at ambient temperature was added a further amount of 2,3-dihydrothiophene 1,1-dioxide (0.150 g, 1.27 mmol) and the solution stirred overnight at ambient temperature. The solution was heated to reflux for 2 h and then at ambient temperature for 7 days. The reaction was applied to an SCX-2 cartridge (20 g), preconditioned with methanol, and the cartridge washed with methanol (2 column volumes). The cartridge was eluted with 10% 0.880 s.g. ammonia in methanol (2 column volumes) and the basic fractions concentrated in vacuo. The residue was purified by MDAP and the appropriate fractions combined and evaporated. The combined fractions were applied to an SCX-2 cartridge (20 g), preconditioned with methanol, and the cartridge washed with methanol. The cartridge was eluted with 10% 0.88 s.g. ammonia in methanol (2 column volumes) and the basic fractions concentrated in vacuo to give the title compound (17 mg, 8%). LCMS RT=2.59 min, ES+ve m/z 403 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][CH2:10][C:11]#[CH:12].Cl[CH2:14][C:15]([N:17]1[CH2:36][CH2:35][C:20]2[N:21]=[C:22]([NH:25][CH:26]3[CH2:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH2:27]3)[N:23]=[CH:24][C:19]=2[CH2:18]1)=[O:16]>O1CCCC1>[CH2:9]([NH:8][CH2:14][C:15]([N:17]1[CH2:36][CH2:35][C:20]2[N:21]=[C:22]([NH:25][CH:26]3[CH2:27][C:28]4[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:34]3)[N:23]=[CH:24][C:19]=2[CH2:18]1)=[O:16])[CH2:10][C:11]#[CH:12]
Reactant: O=C(CCl)N1CCc2nc(NC3Cc4ccccc4C3)ncc2C1
Reactant: C#CCCN
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C#CCCNCC(=O)N1CCc2nc(NC3Cc4ccccc4C3)ncc2C1
Temperature: 55 °C

Procedure:
Add triethylamine (0.85 mL; 2.0 equiv; 6.13 mmoles) followed by 1-amino-3-butyne (0.38 mL; 1.5 equiv; 4.59 mmoles) to a solution of 2-chloro-1-[2-(2,3-dihydro-1H-inden-2-ylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl]ethanone (1.05 g; 1.0 equiv; 3.06 mmoles) in tetrahydrofuran (10.2 mL), and heat to 55° C. for 16 hours, then concentrate and use the 2-(but-3-ynylamino)-1-[2-(indan-2-ylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl]ethanone directly in the next step: MS (m/z): 376(M+1).
Reaction SMILES: [C:1]([C:3]1[O:7][C:6]([C:8](Cl)=[O:9])=[CH:5][CH:4]=1)#[N:2].[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[CH:22][C:21]([NH2:24])=[C:20]([C:25]3[C:29]([CH3:30])=[CH:28][S:27][CH:26]=3)[CH:19]=2)[CH2:14][CH2:13]1.CCN(C(C)C)C(C)C>>[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:8]([C:6]3[O:7][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)=[O:9])=[C:20]([C:25]3[C:29]([CH3:30])=[CH:28][S:27][CH:26]=3)[CH:19]=2)[CH2:14][CH2:13]1
Reactant: Cc1cscc1-c1cc(N2CCN(C)CC2)ccc1N
Reactant: N#Cc1ccc(C(=O)Cl)o1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cscc1-c1cc(N2CCN(C)CC2)ccc1NC(=O)c1ccc(C#N)o1
Yield: 24 %

Procedure:
Using a procedure similar to Example 9, step (c), 5-cyano-furan-2-carbonyl chloride (64 mg, 0.41 mmol, as prepared in Example 9, step (c)) was allowed to react with 4-(4-methyl-piperazin-1-yl)-2-(4-methyl-thiophen-3-yl)-phenylamine (80 mg, 0.27 mmol, as prepared in the previous step) in the presence of DIEA (0.10 mL, 0.59 mmol) to afford 25.8 mg (24%) of the title compound as a yellow solid. 1H-NMR (CDCl3; 400 MHz): δ 2.09 (s, 3H), 2.37 (s, 3H), 2.59-2.60 (m, 4H), 3.24-3.26 (m, 4H), 6.83 (d, 1H, J=2.9 Hz), 6.98-7.06 (m, 2H), 7.14-7.21 (m, 3H), 7.96 (s, 1H), 8.32 (d, 1H, J=9.0 Hz). Mass spectrum (ESI, m/z): Calcd. for C22H22N4O2S, 407.1 (M+H), found 407.1.
Reaction SMILES: Cl.Cl[C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH2:16][CH:17]3[CH2:22][CH2:21][CH2:20][N:19]([CH3:23])[CH2:18]3)=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[CH:5][N:4]=1.[NH2:24][C:25]1[CH:26]=[C:27]([NH:32][C:33]([C:35]2[CH:40]=[CH:39][N:38]=[C:37]([N:41]3[CH2:46][CH2:45][O:44][CH2:43][CH2:42]3)[CH:36]=2)=[O:34])[CH:28]=[CH:29][C:30]=1[CH3:31]>C(OCC)C>[CH3:14][O:13][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][C:9]=1[O:15][CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][N:19]([CH3:23])[CH2:18]1)[N:6]=[CH:5][N:4]=[C:3]2[NH:24][C:25]1[CH:26]=[C:27]([NH:32][C:33]([C:35]2[CH:40]=[CH:39][N:38]=[C:37]([N:41]3[CH2:46][CH2:45][O:44][CH2:43][CH2:42]3)[CH:36]=2)=[O:34])[CH:28]=[CH:29][C:30]=1[CH3:31]
Reactant: COc1cc2c(Cl)ncnc2cc1OCC1CCCN(C)C1
Reactant: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1N
Agent: Cl
Solvent: CCOCC
Product: COc1cc2c(Nc3cc(NC(=O)c4ccnc(N5CCOCC5)c4)ccc3C)ncnc2cc1OCC1CCCN(C)C1
Yield: 34 %

Procedure:
Using an analogous procedure to that described in Example 26 except that 3 equivalents of the 1M solution of hydrogen chloride in diethyl ether were used. 4-chloro-6-methoxy-7-(N-methylpiperidin-3-ylmethoxy)quinazoline was reacted with N-(3-amino-4-methylphenyl)-2-morpholinopyridine-4-carboxamide. The reaction product was purified by column chromatography on silica using an 89:10:1 mixture of methylene chloride, methanol and a saturated aqueous ammonium hydroxide solution as eluent. There was thus obtained the title compound in 34% yield; NMR: 1.12 (m, 1H), 1.52 (m, 1H), 1.65-2.05 (broad, 3H), 2.15 (s, 3H), 2.2 (s, 3H), 2.7 (m, 2H), 2.90 (m, 2H), 3.53 (m, 4H), 3.73 (m, 4H), 3.95 (s, 3H), 4.04 (d, 2H), 7.1 (m, 1H), 7.16 (s, 1H), 7.24 (m, 1H), 7.31 (m, 1H), 7.59 (m, 1H), 7.78 (m, 1H), 7.84 (s, 1H), 8.27 (m, 2H), 9.4 (s, 1H), 10.3 (s, 1H); m/s: M+H+ 598.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]=[O:8])=[C:5]([CH3:9])[CH:4]=[C:3]1[C:10]([O:12][CH3:13])=[O:11].[Mn]([O-])(=O)(=O)=[O:15].[K+].S([O-])([O-])=O.[Na+].[Na+].[Mn]([O-])(=O)(=O)=O>CC(C)=O.O.O.CC(C)=O>[C:7]([C:6]1[N:2]([CH3:1])[C:3]([C:10]([O:12][CH3:13])=[O:11])=[CH:4][C:5]=1[CH3:9])([OH:15])=[O:8]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: COC(=O)c1cc(C)c(C=O)n1C
Agent: O=S([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)c1cc(C)c(C(=O)O)n1C
Reaction time: 1.5 h
Yield: 61.3 %

Procedure:
To a solution of methyl 1,4-dimethyl-5-formylpyrrole-2-carboxylate (0.3 g, 0.0016 m) in acetone (10 ml) at room temperature was added over 15 minutes a solution of potassium permanganate (0.52 g, 0.0033 m) in 1:1 water-acetone (10 ml), and the resulting mixture allowed to stir for 1.5 hours. The reaction mixture was then diluted with water (100 ml), treated with enough sodium sulfite to reduce the excess permanganate, filtered, and the filtrate acidified with dilute hydrochloric acid. The resulting precipitate was filtered, washed well with water and dried to give 0.20 g (64%) of methyl 5-carboxy-1,4-dimethylpyrrole-2-carboxylate.