Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2]C1C(C2C=CC=CC=2C)=C(Cl)C=CC=1.Br.[H-].[Na+].C(Br)C=C.C(OCC=C)C=C.[CH2:31]([C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[C:36]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[CH3:47])[C:35]=1[OH:48])[CH:32]=[CH2:33].ClC1C=C(C=CC=1)C(OO)=O.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=C(C)C=C(C)C=1>[CH3:47][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=1[C:36]1[C:35]2[O:48][CH:32]([CH2:33][OH:2])[CH2:31][C:34]=2[CH:39]=[CH:38][C:37]=1[Cl:40]
Reactant: COc1cccc(Cl)c1-c1ccccc1C
Reactant: C=CCc1ccc(Cl)c(-c2ccccc2C)c1O
Agent: Br
Agent: C=CCOCC=C
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: Cc1cc(C)cc(C)c1
Solvent: C=CCBr
Product: Cc1ccccc1-c1c(Cl)ccc2c1OC(CO)C2
Yield: 52 %

Procedure:
Treatment of 1-bromo-2-methylbenzene (5.0 g, 26.88 mmol) with (2-chloro-6-methyoxyphenyl)boronic acid (13.8 g, 80.6 mol) generally according to the procedure described for Intermediate 37 afforded 3.85 g (62%) of 6-chloro-2′-methylbiphenyl-2-yl methyl ether. Treatment of 6-chloro-2′-methylbiphenyl-2-yl methyl ether with hydrogen bromide (100 mL, 30 wt. % in acetic acid) generally according to the procedure described for Example 395 afforded brown oil. The oil was reacted with sodium hydride (0.61 g, 25.38 mmol) and allyl bromide (3.07 g, 25.38 mmol) followed by refluxing the resultant allyl ether in mesitylene generally according to the procedure described for Intermediate 8 provided 3-allyl-6-chloro-2′-methylbiphenyl-2-ol. Treatment of 3-allyl-6-chloro-2′-methylbiphenyl-2-ol (4.38 g, 16.92 mmol) with m-chloroperoxybenzoic acid (4.38 g, 25.38 mmol, 77%) and potassium carbonate (2.81 g, 20.30 mmol) generally according to the procedure described for Intermediate 9 afforded 2.4 g (52%) of (±)-[7-(2-methylphenyl)-6-chloro-2,3-dihydro-1-benzofuran-2-yl]methanol. Treatment (±)-[7-(2-methylphenyl)-6-chloro-2,3-dihydro-1-benzofuran-2-yl]methanol (2.4 g, 8.73 mmol) with p-toluenesulfonyl chloride (2.50 g, 13.1 mmol) generally according to the procedure described for Intermediate 10 gave 3.2 g (85%) of (±)-[6-chloro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a colorless oil. Treatment of (±)-[6-chloro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.21 g, 0.49 mmol) with sodium azide (0.35 g, 5.38 mmol) generally according to the procedure described for Intermediate 98 afforded 0.14 g, (99%) of (±)-2-(azidomethyl)-7-(2-methylphenyl)-6-chloro-2,3-dihydro-1-benzofuran. Treatment of (±)-2-(azidomethyl)-7-(2-methylphenyl)-6-chloro-2,3-dihydro-1-benzofuran (0.14 g, 0.468 mmol) in tetrahydrofuran (10 m]L) with polymer-supported triphenylphosphine (0.24 g, 0.936 mmol) generally according to the procedure described for Example 154 provided 0.028 g (18%) of (±)-{[6-chloro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine as a white solid, hydrochloride salt. mp 204-206° C.
Reaction SMILES: CS(O[C@H:6]1[C:23]2[C@:18]([CH3:25])([CH:19]=[CH:20][C:21](=[O:24])[CH:22]=2)[C@@H:17]2[C@H:8]([C@H:9]3[C@@:13]([CH2:15][CH2:16]2)([CH3:14])[C:12](=[O:26])[CH2:11][CH2:10]3)[C@H:7]1OS(C)(=O)=O)(=O)=O.[N-:32]=[N+:33]=[N-:34].[Na+]>CN(C)C=O>[N:32]([C:6]1[C:23]2[C@:18]([CH3:25])([CH:19]=[CH:20][C:21](=[O:24])[CH:22]=2)[C@@H:17]2[C@H:8]([C@H:9]3[C@@:13]([CH2:15][CH2:16]2)([CH3:14])[C:12](=[O:26])[CH2:11][CH2:10]3)[CH:7]=1)=[N+:33]=[N-:34]
Reactant: [N-]=[N+]=[N-]
Reactant: C[C@]12C=CC(=O)C=C1[C@H](OS(C)(=O)=O)[C@H](OS(C)(=O)=O)[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@]12C=CC(=O)C=C1C(N=[N+]=[N-])=C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12

Procedure:
In a manner similar to that described in Example 1D, treat 6β,7β-dimethanesulfonyloxy-1,4-androstadiene-3,17-dione with sodium azide in dimethylformamide. Isolate and purify the resultant product in a manner similar to that described to obtain 6-azido-1,4,6-androstatriene-3,17-dione.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:39][CH3:40])=[C:17]([O:20][CH2:21][CH2:22][CH2:23][N:24]4[CH2:28][CH:27]5[CH2:29][N:30](C(OC(C)(C)C)=O)[CH2:31][CH:26]5[CH2:25]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1)#[CH:2].Cl>C(Cl)Cl.CCOC(C)=O>[C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:39][CH3:40])=[C:17]([O:20][CH2:21][CH2:22][CH2:23][N:24]4[CH2:25][CH:26]5[CH:27]([CH2:29][NH:30][CH2:31]5)[CH2:28]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1)#[CH:2]
Reactant: C#Cc1cccc(Nc2ncnc3cc(OC)c(OCCCN4CC5CN(C(=O)OC(C)(C)C)CC5C4)cc23)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C#Cc1cccc(Nc2ncnc3cc(OC)c(OCCCN4CC5CNCC5C4)cc23)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 91.4 %

Procedure:
To a solution of tert-butyl 5-(3-((4-((3-ethynylphenyl)amino)-7-methoxyquinazolin-6-yl)oxy) propyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (1.22 g) in DCM (30 mL) was added a solution of HCl in EtOAc at room temperature. The reaction mixture was stirred for 6 h at room temperature and filtered to give crude product. The crude product was recrystallized from a mixture of MeOH and EA to give the title compound as a white solid (0.91 g, 90.50%), HPLC: 94.65%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 444.2 (M+1); 1H NMR (400 MHz, CDCl3) δ: 1.84-1.89 (m, 4H), 2.38-2.44 (m, 6H), 2.69-2.76 (m, 4H), 3.95 (s, 3H), 4.03 (s, 1H), 4.14 (t, J=7.2 Hz, 2H), 7.13 (s, 1H), 7.25 (s, 1H), 7.43 (s, 1H), 7.55-7.60 (m, 1H), 7.90-7.93 (m, 1H), 8.68 (s, 1H) ppm.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1)=[CH2:2]>CO.C(O)(=O)C.[Pd]>[CH2:1]([C:3]1[CH:4]=[C:5]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1)[CH3:2]
Reactant: C=Cc1cc(CC(=O)OC)ccc1OCc1ccc2ccccc2n1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: CCc1cc(CC(=O)OC)ccc1OCc1ccc2ccccc2n1

Procedure:
14.3 g (0.0429 mol) of the compound from Example XXXII are dissolved in 150 ml of methanol and 15 ml of glacial acetic acid, 1.5 g of 5% strength Pd-C are added, and the reaction mixture is heated to 30°-35° C. and hydrogenated. It is filtered through silica gel, the filtrate is concentrated in vacuo and the residue is recrystallised from isopropanol.
Reaction SMILES: C(O)(=O)C.[Br:5][C:6]1[CH:7]=[N:8][N:9]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:10]=1.C(O[C:20]1(O[Si](C)(C)C)[CH2:22][CH2:21]1)C.C([BH3-])#N.[Na+]>CO>[Br:5][C:6]1[CH:7]=[N:8][N:9]([CH:11]2[CH2:16][CH2:15][N:14]([CH:20]3[CH2:22][CH2:21]3)[CH2:13][CH2:12]2)[CH:10]=1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Reactant: Brc1cnn(C2CCNCC2)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Brc1cnn(C2CCN(C3CC3)CC2)c1
Temperature: 60 °C

Procedure:
Acetic acid (1.258 ml, 21.98 mmol) is added dropwise, under stirring at RT, to a solution of 4-(4-Bromo-pyrazol-1-yl)-piperidine (as obtained in preparation 89, 1.686 g, 7.327 mmol) and [(1-ethoxy-1-cyclopropyl)oxy]trimethylsilane (2.210 ml, 10.99 mmol) in MeOH (20 ml). Sodium cyanoborohydride (775 mg, 11.7) is then added in one portion at RT. The mixture is then heated at 60° C. for 3 h. After cooling, the reaction mixture is concentrated in vacuo and the residue dissolved in EtOAc and diluted with saturated NaHCO3. After separation, the aqueous phase is re-extracted 3× with EtOAc. The combined organic layers are washed with brine, dried over Na2SO4, filtered and the filtrate is concentrated in vacuo. The residue is used without further purification in the next step, and afford the title compound as colorless solid, Rt=0.618 min (Acquity HPLC BEH C18, 2.1×50 mm, 1.7 micron, detection 215 nM, 0.1 min 2% CH3CN in H2O, 2% to 100% CH3CN in H2O in 1.5 min, 0.4 min 100% CH3CN+0.1% TFA, flow rate 1.0 ml/min); MS: 270 (M+1, 79Br)+
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:8])([CH3:7])[CH2:5][CH2:4][C:3]=1[CH2:9][C:10]([OH:12])=[O:11].[C:13]1(C)C=CC(S(O)(=O)=O)=C[CH:14]=1>C(O)C>[CH2:13]([O:11][C:10](=[O:12])[CH2:9][C:3]1[CH2:4][CH2:5][C:6]([CH3:7])([CH3:8])[C:2]=1[CH3:1])[CH3:14]
Reactant: CC1=C(CC(=O)O)CCC1(C)C
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCOC(=O)CC1=C(C)C(C)(C)CC1
Temperature: 78 °C
Yield: 745.7 %

Procedure:
A solution of β-campholenic acid (10 g) and p-toluene-sulfonic acid (1 g) in ethanol (500 ml) was kept at reflux (78° C.) for 5 hours, while the condensate was perculated through a layer of molecular sieves (3 Å) (40 g). The alcohol was then removed, the residue taken up in CH2Cl2 (500 ml) and the solution extracted with ice cold 5% aqueous sodium hydroxide (500 ml) and water (2×500 ml). Concentration of the dried CH2Cl2 solution gave a crude oil (12 g) which was distilled through a 3" Vigreux column to give 8.5 g of a colorless liquid; bp 58° C. @ 0.8 mm Hg; analysis: (CW 20M fused silica column, 120°-190° C.; 5° C./min.) 96% ethyl β-campholenate; odor: fruity, berry, resinous; flavor: fruity, woody, winey, berry.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:8]2[CH:9]=[C:10]([C:13]3[NH:17][C:16]([C:18]#[N:19])=[CH:15][CH:14]=3)[CH:11]=[CH:12][C:7]=2[NH:6][C:5](=O)[CH2:4][O:3]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:31])=CC=1>C1(C)C=CC=CC=1.C1COCC1>[CH3:1][C:2]1([CH3:21])[C:8]2[CH:9]=[C:10]([C:13]3[NH:17][C:16]([C:18]#[N:19])=[CH:15][CH:14]=3)[CH:11]=[CH:12][C:7]=2[NH:6][C:5](=[S:31])[CH2:4][O:3]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC1(C)OCC(=O)Nc2ccc(-c3ccc(C#N)[nH]3)cc21
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC1(C)OCC(=S)Nc2ccc(-c3ccc(C#N)[nH]3)cc21
Temperature: 100 °C
Yield: 118.4 %

Procedure:
To a solution of 5-(5,5-dimethyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-7-yl)-1H-pyrrole-2-carbonitrile (0.4 g, 1.4 mmol) in a mixture of toluene (20 mL) and THF (10 mL, help to dissolve the starting material) was added at rt under nitrogen the Lawesson's reagent (0.29 g, 0.71 mmol). The mixture was heated at 100° C. for 10 minutes, cooled to rt, and concentrated. The residue was purified by a flash chromatography on silica gel column (hexane:THF/4:1) to give the title compound as a yellowish solid (0.25 g, 60%). 1H-NMR (DMSO-d6) δ 12.66 (s, 1H), 11.96 (s, 1H), 7.69 (d, J=1.49 Hz, 1H), 7.64 (dd, J=1.48, 8.44 Hz, 1H), 7.35 (d, J=8.51 Hz, 1H), 7.01 (m, 1H), 6.79 (m, 1H), 4.49 (s, 2H), 1.60 (s, 6H); MS (FI) m/z 296 ([M−H]−, 100%)
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:4]([O:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2.C([O-])([O-])=O.[Cs+].[Cs+].Cl[CH2:35][CH2:36][O:37][CH2:38][CH2:39][OH:40]>CN(C=O)C>[CH3:1][C:2]1[C:3]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:4]([O:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:35][CH2:36][O:37][CH2:38][CH2:39][OH:40])=[CH:17][CH:16]=2)[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2
Reactant: OCCOCCCl
Reactant: COc1ccc2c(Oc3ccc(O)cc3)c(-c3ccccc3)c(C)cc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc2c(Oc3ccc(OCCOCCO)cc3)c(-c3ccccc3)c(C)cc2c1
Temperature: 25 °C
Yield: 100 %

Procedure:
The O-alkylation procedure described for Example 63 (Step 2) was employed with 4-{[3-methyl-6-(methyloxy)-2-phenyl-1-naphthalenyl]oxy}phenol (233) (0.605 g, 1.697 mmol), Cs2CO3 (1.658 g, 5.09 mmol), anhydrous DMF (8 mL), and 2-[(2-chloroethyl)oxy]ethanol (0.604 mL, 8.49 mmol) under N2. The reaction mixture was refluxed for 15 h and then cooled to room temperature. Standard work-up followed by column chromatography gave 0.754 g (˜100%) of the title compound (290) as a colorless oil. 1H NMR (400 MHz, DMSO-d6): δ 7.65 (s, 1H), 7.58 (d, J=8.8 Hz, 1H), 7.31 (d, J=2.4 Hz, 1H), 7.29 (d, J=7.6 Hz, 2H), 7.24 (m, 1H), 7.16 (d, J=8.4 Hz, 2H), 7.05 and 7.03 (dd, J1=9.2 Hz, J2=2.4 Hz, 1H), 6.67 (d, J=9.2 Hz, 2H), 6.47 (d, J=9.2 Hz, 2H), 4.58 (t, J=5.6 Hz, 1H), 3.91 (t, J=4.8 Hz, 2H), 3.85 (s, 3H), 3.63 (t, J=4.8 Hz, 2H), 3.45 (t, J=5.2 Hz, 2H), 3.43 (t, J=4.4 Hz, 2H), 2.17 (s, 3H). LCMS (ESI) m/z 445.27 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH2:11])=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4].Br[C:13]1[CH:14]=[N:15][CH:16]=[N:17][CH:18]=1>>[CH3:1][O:2][C:3]([C:5]1[C:10]([NH:11][C:13]2[CH:14]=[N:15][CH:16]=[N:17][CH:18]=2)=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1nccnc1N
Reactant: Brc1cncnc1
Product: COC(=O)c1nccnc1Nc1cncnc1

Procedure:
The title compound, MS: m/e=232.1 (M+H+), was prepared in accordance with the general method of example 4, step 2 from 3-aminopyrazine-2-carboxylic acid methyl ester and 5-bromopyrimidine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8](C(OC(C)(C)C)=O)[C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([Br:20])[C:18]=1[Cl:19])[C:12]([O:14][CH3:15])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:20][C:17]1[CH:16]=[C:11]([CH:10]=[C:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:18]=1[Cl:19])[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1cc(Br)c(Cl)c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1cc(Br)c(Cl)c(NC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 97.1 %

Procedure:
Methyl 3-(bis(tert-butoxycarbonyl)amino)-5-bromo-4-chlorobenzoate (3.06 g, 6.58 mmol) was dissolved in a solution of TFA (1.015 ml, 13.17 mmol) in CH2Cl2 (32.9 ml). The reaction was stirred at rt for 45 min, and then sat. NaHCO3 solution was added. The reaction mixture was diluted with a little more CH2Cl2 and washed 2× with sat. NaHCO3 to remove any residual TFA. The organic layer was dried over Na2SO4, filtered, and concentrated to provide methyl 3-bromo-5-(tert-butoxycarbonylamino)-4-chlorobenzoate (2.33 g) as a cream solid.
Reaction SMILES: [CH2:1]([C:4]1([C:21]([F:24])([F:23])[F:22])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([Cl:14])[CH:12]=2)[NH:7][C:6](=[O:15])[N:5]1[CH2:16][C:17]([F:20])([F:19])[F:18])[CH:2]=[CH2:3]>[Pd].C(OCC)(=O)C>[Cl:14][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:15])[N:5]([CH2:16][C:17]([F:20])([F:19])[F:18])[C:4]2([CH2:1][CH2:2][CH3:3])[C:21]([F:23])([F:24])[F:22]
Reactant: C=CCC1(C(F)(F)F)c2cc(Cl)ccc2NC(=O)N1CC(F)(F)F
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCC1(C(F)(F)F)c2cc(Cl)ccc2NC(=O)N1CC(F)(F)F
Reaction time: 8 h

Procedure:
A mixture of 4-allyl-6-chloro-3-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one (42 mg, 0.11 mmol), ethyl acetate (3.5 ml) and 10% Pd/C (10 mg) was placed under hydrogen atmosphere (1 atm) at room temperature and stirred overnight. After bubbling nitrogen through reaction mixture, the mixture was filtered through a Celite, washing with ethyl acetate. The collected filtrate was concentrated to give an oil which was purified by reverse phase prep HPLC to afford 6-chloro-4-propyl-3-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one as a white solid. 1H NMR (CD3OD, 400 MHz) δ 7.40 (s, 1H), 7.35 (dd, J=2.4 and 8.6 Hz, 1H), 6.86 (d, J=8.8 Hz 1H), 4.45 (m, 1H), 4.27 (m, 1H), 2.47 (m, 1H), 2.17 (m, 1H), 1.23 (m, 2H), 0.96 (t, J=7.2 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:21])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][N:9]2[CH:22]=1)=[O:4].[I:25]N1C(=O)CCC1=O>CC#N>[F:24][C:2]([F:1])([F:23])[C:3]([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:21])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][N:9]2[C:22]=1[I:25])=[O:4]
Reactant: O=C1CCC(=O)N1I
Reactant: O=C(c1ccccc1)c1ccc2nc(NC(=O)C(F)(F)F)cn2c1
Solvent: CC#N
Product: O=C(c1ccccc1)c1ccc2nc(NC(=O)C(F)(F)F)c(I)n2c1
Reaction time: 0.17 h
Yield: 94.4 %

Procedure:
To a solution of 2-trifluoroacetamido-6-benzoyl-imidazo[1,2-a]pyridine (2.0 g, 6.0 mmol) in 50 ml of dry CH3CN cooled at 0° C., was added N-iodosuccinimide (1.35 g, 6.0 mmol) portionwise. The mixture was stirred for 10 minutes. Acetonitrile was removed in vacuo and the residue was dissolved in EtOAc (250 ml), washed with NaHSO3 (40% p/v, 2×200 ml) and NaHCO3 (2×200 ml). The organic layer was dried (Na2SO4) and EtOAc was removed in vacuo to afford 2.60 g (95%) of product as a yellow solid. EIMS, NMR.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]([O:8][CH3:9])=[CH:6][S:5][CH:4]=1.[CH2:10](O)C(O)C>>[CH3:10][CH:1]1[O:2][C:3]2=[CH:4][S:5][CH:6]=[C:7]2[O:8][CH2:9]1
Reactant: CC(O)CO
Reactant: COc1cscc1OC
Product: CC1COc2cscc2O1

Procedure:
Racemic 2-methyl-2,3-dihydro-thieno[3,4-b][1,4]dioxine was synthesized by transetherification of 3,4-dimethoxythiophene with racemic 1,2-propanediol as described in COMPARATIVE EXAMPLE 1. It was characterized by GC-MS and H-NMR-spectroscopy, and exhibited no optical rotation.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[NH:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH2:13][C:14]2[C:18]3[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:17]=3[O:16][CH:15]=2)=[CH:8][C:7]=1[N+:24]([O-])=O)[CH3:2]>C(O)C.Cl.[Fe]>[CH2:1]([O:3][C:4](=[O:27])[NH:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH2:13][C:14]2[C:18]3[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:17]=3[O:16][CH:15]=2)=[CH:8][C:7]=1[NH2:24])[CH3:2]
Reactant: CCOC(=O)Nc1ccc(NCc2coc3ccc(F)cc23)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)Nc1ccc(NCc2coc3ccc(F)cc23)cc1N
Temperature: 60 °C
Yield: 65 %

Procedure:
{4-[(5-Fluoro-benzofuran-3-ylmethyl)-amino]-2-nitro-phenyl}-carbamic acid ethyl ester (4.50 g, 12.1 mmol) was dissolved in absolute ethanol (140 mL) whereto 6N aqueous HCl (38 mL) and iron powder (5.70 g, 0.10 mol) was added. The red mixture was heated at 60° C. until the intense colour disappeared (20 minutes). The solids were filtered off and the ethanol was removed from the filtrate by evaporation in vacuo. Aqueous ammonia (saturated) was added to the remanence, which was then extracted with ethyl acetate (3×100 mL). The combined organic fractions were washed with brine, dried (MgSO4) and concentrated in vacuo. The crude product was purified by chromatography on silica gel (eluent:ethyl acetate:heptane 1:1) to furnish 2.70 g (66%) of the title compound as a solid. M.p. 150-151° C. Calculated for C18H18FN3O3: C, 62.96; H, 5.28; N, 12.24. Found: C, 63.00; H, 5.38; N, 12.13. LC/MS (m/z) 344 (MH+); tR=2.00 min. 1H NMR (DMSO-d6): 1.19 (t, 3H); 4.03 (q, 2H); 4.26 (d, 2H); 4.55 (s, 2H, NH2); 5.79 (t, 1H); 5.91 (dd, 1H); 6.02 (d, 1H, NH); 6.72 (d, 1H); 7.13 (dt, 1H); 7.56 (m, 2H); 7.95 (s, 1H); 8.16 (b, 1H, NH).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH3:32])[C:7]2[C:16]3[CH:15]=[C:14]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=4)[CH:13]=[CH:12][C:11]=3[N+:10]([O-])=[CH:9][C:8]=2[N:31]=1)[CH2:2][CH2:3][CH3:4].C(C1[N:38](C)C2C3C=C(OCCCCCCOCCCCC4C=CC=CC=4)C=CC=3[N+]([O-])=CC=2N=1)CCC>>[CH2:1]([C:5]1[N:6]([CH3:32])[C:7]2[C:16]3[CH:15]=[C:14]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=4)[CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:38])[C:8]=2[N:31]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2c[n+]([O-])c3ccc(OCc4ccc(OC(F)(F)F)cc4)cc3c2n1C
Reactant: CCCCc1nc2c[n+]([O-])c3ccc(OCCCCCCOCCCCc4ccccc4)cc3c2n1C
Product: CCCCc1nc2c(N)nc3ccc(OCc4ccc(OC(F)(F)F)cc4)cc3c2n1C

Procedure:
The general method described in Example 61 was followed using 2-butyl-1-methyl-8-{[4-(trifluoromethoxy)benzyl]oxy}-5-oxido-1H-imidazo[4,5-c]quinoline (0.380 g, 0.853 mmol) in lieu of 2-butyl-1-methyl-5-oxido-8-{[6-(4-phenylbutoxy)hexyl]oxy}-1H-imidazo[4,5-c]quinoline. The crude product was purified by column chromatography on silica gel (eluting with 90:10 dichloromethane:methanol) to provide 93.9 mg of 2-butyl-1-methyl-8-{[4-(trifluoromethoxy)benzyl]oxy}-1H-imidazo[4,5-c]quinolin-4-amine as a white powder, mp 219.4-220.2° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH2:12][C:13]([C:15]2[CH:16]=[N:17][N:18]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:19]=2)=O)[CH:8]=[C:9]([CH3:11])[CH:10]=1)=O)C.C([O-])(=O)C.[NH4+:28].O>C(O)(=O)C>[C:20]([N:18]1[CH:19]=[C:15]([C:13]2[NH:28][C:4](=[O:3])[C:6]3[N:7]([CH:8]=[C:9]([CH3:11])[CH:10]=3)[CH:12]=2)[CH:16]=[N:17]1)([CH3:23])([CH3:22])[CH3:21]
Reactant: CCOC(=O)c1cc(C)cn1CC(=O)c1cnn(C(C)(C)C)c1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc2c(=O)[nH]c(-c3cnn(C(C)(C)C)c3)cn2c1
Temperature: 25 °C

Procedure:
A solution of 375 mg (1.18 mmol) 1-[2-(1-tert-butyl-1H-pyrazol-4-yl)-2-oxo-ethyl]-4-methyl-1H-pyrrole-2-carboxylic acid ethyl ester and 4.89 g (63.5 mmol) ammonium acetate in 4.15 ml acetic acid is stirred for 28 hours at 110° C. The reaction mixture is allowed to cool to room temperature and excess water is added. The resulting precipitate is filtered off, washed with water and dried. It is chromatographed on a silica gel column with cyclohexane/ethyl acetate as eluent to give 3-(1-tert-butyl-1H-pyrazol-4-yl)-7-methyl-2H-pyrrolo[1,2-a]pyrazin-1-one as light yellow solid; HPLC/MS 2.27 min (B), [M+H] 271;
Reaction SMILES: [OH-].[K+].[CH3:3][S:4]([NH:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[CH:11]2)(=[O:6])=[O:5].[CH3:17][N:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1>CO>[CH3:3][S:4]([NH:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[C:21]1[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH:20]=1)(=[O:5])=[O:6]
Reactant: CS(=O)(=O)Nc1ccc2[nH]ccc2c1
Reactant: CN1CCC(=O)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CN1CC=C(c2c[nH]c3ccc(NS(C)(=O)=O)cc23)CC1
Yield: 89.4 %

Procedure:
To a solution of 1.2 gm (21.4 mMol) potassium hydroxide in 12 mL methanol was added 1.0 gm (4.76 mMol) 5-methanesulfonylamino-1H-indole followed by 0.76 mL (6.2 mMol) 1-methyl-4-piperidone. The homogeneous solution was heated to reflux for 18 hours under nitrogen. The reaction mixture was then cooled and concentrated under reduced pressure. The residue was dissolved in water and the pH of the solution adjusted from 14 to 8-9 by the addition of acid. The precipitate that formed was filtered, washed with water and dried under vacuum to give 1.3 gm (89.6%) of the title compound as a tan solid.
Reaction SMILES: [N:1]([C:4]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[O:21])=[CH:16][CH:15]=2)=[N:12][C:11]([Br:28])=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])=[N+]=[N-]>ClC1C=CC=CC=1Cl>[Br:28][C:11]1[CH:10]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[C:4]2[NH:1][C:15]3[CH:16]=[C:17]([C:20]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[O:21])[CH:18]=[CH:19][C:14]=3[C:13]=2[N:12]=1
Reactant: COC(=O)c1cc(Br)nc(-c2ccc(C(=O)N3CCOCC3)cc2)c1N=[N+]=[N-]
Solvent: Clc1ccccc1Cl
Product: COC(=O)c1cc(Br)nc2c1[nH]c1cc(C(=O)N3CCOCC3)ccc12
Reaction time: 0.17 h
Yield: 44.8 %

Procedure:
A solution of methyl 3-azido-6-bromo-2-(4-(morpholine-4-carbonyl)phenyl)-isonicotinate (7.2 g, 16.1 mmol) in 1,2-dichlorobenzene (115 mL) was placed in a 180° C. oil bath and stirred for 10 minutes. The solvent was removed, the residue suspended in methylene chloride, and the solid collected by filtration. This was resuspended in methylene chloride and filtered to afford methyl 2-bromo-7-(morpholine-4-carbonyl)-5H-pyrido[3,2-b]indole-4-carboxylate (3.02 gm, 45% yield). Removal of the solvent from filtrate followed by flash silica gel chromatography (step gradient elution with methylene chloride containing 0 to 3% MeOH) afforded another 1.02 gm (15% yield) of product. MS (ESI) m/z 416 and 418 (M+H). 1H NMR (MeOD) δ ppm 8.39 (1H, d, J=7.94 Hz), 8.08 (1H, s), 7.78 (1H, s), 7.41 (1H, d, J=7.93 Hz), 4.12 (3H, s), 3.61-3.95 (6H, m), 3.46-3.61 (2H, m).