Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7]1([CH2:14][CH2:13][CH2:12][CH2:11]1)[CH2:6][C:5]2=[O:15].[C:16](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH3:16][O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7]1([CH2:14][CH2:13][CH2:12][CH2:11]1)[CH2:6][C:5]2=[O:15]
Reactant: O=C1CC2(CCCC2)c2ccc(O)cc21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1ccc2c(c1)C(=O)CC21CCCC1

Procedure:
A mixture of 5'-hydroxy-spiro(cyclopentane-1,1'-indan)-3'-one (20.2 g; 0.1 mole), acetone (1000 ml), anhydrous potassium carbonate (37.5 g) and methyl iodide (50 ml) is refluxed for 5-6 hours. The mixture is evaporated to dryness, after which the residue is taken up in water and trichloroethylene. The trichloroetylene solution is extracted with 2×150 ml of 2 N sodium hydroxide and dried with anhydrous magnesium sulphate. The solvent is distilled off and a yellow oil is obtained, which soon crystallizes, yield 16 g (74%). After recrystallization from n-hexane the substance melts at 80° C.
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([NH:12][CH2:13][C:14]([O:16]C(C)(C)C)=[O:15])=[O:11])[N:5]=[CH:4][C:3]=1[NH:21][C@@H:22]1[CH2:27][C@@H:26]2[CH2:28][C@@H:24]([C:25]2([CH3:30])[CH3:29])[C@H:23]1[CH3:31].FC(F)(F)C(O)=O>ClCCl>[Br:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([NH:12][CH2:13][C:14]([OH:16])=[O:15])=[O:11])[N:5]=[CH:4][C:3]=1[NH:21][C@@H:22]1[CH2:27][C@@H:26]2[CH2:28][C@@H:24]([C:25]2([CH3:30])[CH3:29])[C@H:23]1[CH3:31]
Reactant: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cnn(CC(=O)NCC(=O)OC(C)(C)C)c(=O)c1Br)C2(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cnn(CC(=O)NCC(=O)O)c(=O)c1Br)C2(C)C
Yield: 94.4 %

Procedure:
tert-Butyl 2-(2-{5-bromo-6-oxo-4-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-yl}acetamido)acetate (18 mg, 0.036 mmol) prepared in Synthetic Example 10 in dichloromethane (1 mL) was stirred with trifluoroacetic acid (0.1 mL) at room temperature. After completion of the reaction, the reaction solution was concentrated to give the desired product (15 mg, 94% yield).
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][C:17]3[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:24][N:25]([CH3:30])[S:26](Cl)(=[O:28])=[O:27]>>[CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][C:17]3[CH:22]=[CH:21][C:20]([NH:23][S:26](=[O:28])(=[O:27])[N:25]([CH3:30])[CH3:24])=[CH:19][CH:18]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CN(C)S(=O)(=O)Cl
Reactant: Nc1ccc(C=C2c3ccccc3CCc3ccccc32)cc1
Product: CN(C)S(=O)(=O)Nc1ccc(C=C2c3ccccc3CCc3ccccc32)cc1
Yield: 61.1 %

Procedure:
Following procedures essentially as described in Example 90, 4-(10,11-dihydro-dibenzo[a,d]cyclohepten-5-ylidenemethyl)-phenylamine (100 mg, 0.336 mmol) and dimethylsulfamoyl chloride (144 mg, 1.01 mmol) affords 83 mg (61%) of the title compound as a white solid. MS (ES) 427 (M+Na), 403 (M−H); HPLC shows 87% purity.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].[F:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32]Br)=[CH:30][CH:29]=1>>[F:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][N:22]2[CH2:21][CH2:20][N:16]3[C:17]4[CH:18]=[CH:19][C:11]([O:10][CH:7]5[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]5)=[CH:12][C:13]=4[CH:14]=[C:15]3[C:23]2=[O:24])=[CH:30][CH:29]=1
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCNC2=O)CC1
Reactant: Fc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCN(Cc3ccc(F)cc3)C2=O)CC1
Yield: 69 %

Procedure:
The title compound was synthesized in analogy to example 17, from 8-(1-isopropyl-piperidin-4-yloxy)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 1), sodium hydride and 4-fluorobenzyl bromide, to give the desired product as a white solid (69%).
Reaction SMILES: CC(C)([O-])C.[K+].CC1C=CC(S([CH2:17][N+:18]#[C-])(=O)=O)=CC=1.[O:20]1[CH2:24][CH2:23][O:22][CH:21]1[C:25]1[CH:29]=[CH:28][S:27][C:26]=1[CH:30]=O.[Cl-].[NH4+]>CO.C1COCC1>[O:22]1[CH2:23][CH2:24][O:20][CH:21]1[C:25]1[CH:29]=[CH:28][S:27][C:26]=1[CH2:30][C:17]#[N:18]
Reactant: O=Cc1sccc1C1OCCO1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: N#CCc1sccc1C1OCCO1
Reaction time: 0.67 h
Yield: 36.6 %

Procedure:
20 ml of a THF solution of 4.49 g (40.0 mmol) of potassium tert-butoxide was cooled to −45 to −30° C., and 20 ml of a THF solution of 3.90 g (20.0 mmol) of TOSmic and 20 ml of a THF solution of 3.68 g (20.0 mmol) of 3-(1,3-dioxolan-2-yl)-2-thiophenecarboaldehyde were successively added thereto. After 40 minutes, 60 ml of methanol was added at −15° C. After heating under reflux for 15 minutes, an aqueous saturated ammonium chloride was added, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, to give a crude product. The crude product was subjected to Cromatorex NH silica gel (ethyl acetate:hexane=1:4), to give 1.43 g (7.32 mmol, 36.6%) of the title compound as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=O.FC1C=C2C(=CC=1)C=[N:17][CH:16]=[CH:15]2>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:7]([CH:15]=[CH:16][N:17]=[CH:5]2)=[CH:8][C:9]=1[F:10]
Reactant: Fc1ccc2cnccc2c1
Reactant: O=Cc1ccc(F)c(Cl)c1
Product: Fc1cc2ccncc2cc1Cl

Procedure:
Starting from 3-chloro-4-fluoro-benzaldehyde, the title compound was prepared by the same reaction sequence as 6-fluoro-isoquinoline (5). Rt=0.77 min (Method #2). Detected mass: 182.1/184.1 (M+H+).
Reaction SMILES: [O:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6]2)[CH3:2].[CH:13]([C:15]1[CH:23]=[C:22]2[C:18]([C:19](/[CH:24]=[CH:25]/[C:26]3[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=3)=[N:20][NH:21]2)=[CH:17][CH:16]=1)=O>>[CH3:2][O:1][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])/[C:6]/2=[CH:13]/[C:15]1[CH:23]=[C:22]2[C:18]([C:19](/[CH:24]=[CH:25]/[C:26]3[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=3)=[N:20][NH:21]2)=[CH:17][CH:16]=1
Reactant: O=Cc1ccc2c(/C=C/c3ccc(C(=O)O)cc3)n[nH]c2c1
Reactant: COc1ccc2c(c1)CC(=O)N2
Product: COc1ccc2c(c1)/C(=C\c1ccc3c(/C=C/c4ccc(C(=O)O)cc4)n[nH]c3c1)C(=O)N2
Yield: 22.9 %

Procedure:
The title compound (20 mg, 23%) was synthesized as an orange red solid according to the method described for Example A67 (oil temp 75° C., reflux 90 min) using 5-methoxylindolin-2-one (32.6 mg, 0.2 mmol) and (E)-4-(2-(6-formyl-1H-indazol-3-yl)vinyl)benzoic acid (58.4 mg, 0.2 mmol). 1H NMR (400 MHz, DMSO-d6) δ 13.50 (s, 1H), 12.90 (s, br, 1H), 10.45 (s, 1H), 8.37 (d, J=8.4 Hz, 1H), 7.96 (d, J=8.0 Hz, 2H), 7.92 (s, 1H), 7.86 (d, J=8.0 Hz, 2H), 7.79 (s, 1H), 7.74 (d, J=16.8 Hz, 1H), 7.63 (d, J=16.4 Hz, 1H), 7.54 (d, J=8.4 Hz, 1H), 7.19 (s, 1H), 6.86 (dd, J=8.8 Hz, J=2.4 Hz, 1H), 6.80 (d, J=8.4 Hz, 1H), 3.60 (s, 3H); MS ESI 438.2 [M+H]+, calcd for [C26H19N3O4+H]+ 438.1.
Reaction SMILES: O1CCCC1.[NH:6]1[CH:10]=[CH:9][N:8]=[C:7]1[CH2:11][CH:12]([CH2:43][C:44]1[NH:45][CH:46]=[CH:47][N:48]=1)[CH2:13][NH:14][C:15]([C:17]1[CH:42]=[CH:41][C:20]([CH2:21][N:22]2[CH:26]([C:27]([O:29]CC)=[O:28])[CH2:25][C:24]3([CH2:36][CH2:35][N:34]([CH2:37][CH:38]([CH3:40])[CH3:39])[CH2:33][CH2:32]3)[CH2:23]2)=[CH:19][CH:18]=1)=[O:16].[OH-].[Na+].Cl>CO>[NH:6]1[CH:10]=[CH:9][N:8]=[C:7]1[CH2:11][CH:12]([CH2:43][C:44]1[NH:45][CH:46]=[CH:47][N:48]=1)[CH2:13][NH:14][C:15]([C:17]1[CH:18]=[CH:19][C:20]([CH2:21][N:22]2[CH:26]([C:27]([OH:29])=[O:28])[CH2:25][C:24]3([CH2:32][CH2:33][N:34]([CH2:37][CH:38]([CH3:39])[CH3:40])[CH2:35][CH2:36]3)[CH2:23]2)=[CH:41][CH:42]=1)=[O:16]
Reactant: CCOC(=O)C1CC2(CCN(CC(C)C)CC2)CN1Cc1ccc(C(=O)NCC(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)CN1CCC2(CC1)CC(C(=O)O)N(Cc1ccc(C(=O)NCC(Cc3ncc[nH]3)Cc3ncc[nH]3)cc1)C2
Temperature: 50 °C
Reaction time: 3 h
Yield: 72.1 %

Procedure:
To a tetrahydrofuran (2 mL)-methanol (2 mL) solution of the compound (51 mg) produced in Example 80(3), an aqueous 2N sodium hydroxide solution (0.5 mL) was added. The reaction solution was stirred at 50° C. for 3 hours. To the reaction solution, 1N hydrochloric acid was added so as to adjust the pH to about 5. The reaction solution was concentrated under reduced pressure. The residue was washed with ethanol. An insoluble salt was removed by filtration, and then the filtrate was concentrated. The residue was purified by silica gel chromatography (dichloromethane:methanol: 28% aqueous ammonia=8:2:0.5) to obtain the title compound (35 mg) having the following physical properties.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](Cl)=[O:8])([O-:3])=[O:2].[CH3:13][O:14][C:15]1[CH:30]=[CH:29][C:18]([C:19]([NH:21][C:22]2[C:23]([NH2:28])=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:20])=[CH:17][CH:16]=1>>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([NH:28][C:23]1[C:22]([NH:21][C:19](=[O:20])[C:18]2[CH:17]=[CH:16][C:15]([O:14][CH3:13])=[CH:30][CH:29]=2)=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:8])([O-:3])=[O:2]
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: COc1ccc(C(=O)Nc2ccccc2N)cc1
Product: COc1ccc(C(=O)Nc2ccccc2NC(=O)c2cccc([N+](=O)[O-])c2)cc1
Yield: 86.1 %

Procedure:
Using the procedure described in Example 93, Part A, 3-nitrobenzoyl chloride (2.3 mmol) and N1-(4-methoxybenzoyl)-1,2-benzenediamine (2.1 mmol) yielded 708 mg (86%) of the title compound.
Reaction SMILES: C1([C@@H]([N:9]2[C@@H:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C@H:13]3[CH2:20][CH2:21][C@@H:10]2[CH:11]=[CH:12]3)C)C=CC=CC=1>C(OCC)(=O)C.[OH-].[OH-].[Pd+2]>[CH:10]12[CH2:11][CH2:12][CH:13]([CH2:20][CH2:21]1)[C@H:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[NH:9]2
Reactant: CCOC(=O)[C@H]1[C@@H]2C=C[C@@H](CC2)N1[C@@H](C)c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H]1NC2CCC1CC2
Temperature: 45 °C
Reaction time: 14 h
Yield: 47.4 %

Procedure:
To a solution of ethyl (1R, 3R, 4S)-2-[(S)-1-phenylethyl]-2-azabicyclo[2.2.2]oct-5-ene-3-carboxylate (1.20 g, 4.17 mmol) in ethyl acetate (52 ml) was added 20 wt % Pd(OH)2 (0.878 g), and the mixture was stirred under a hydrogen atmosphere at 45° C. for 14 hours. After a filtration through Celite, the solvent was concentrated. The residue was purified by silica gel column chromatography (1%–5% methanol/chloroform), to give ethyl (3R)-2-azabicyclo [2.2.2]octane-3-carboxylate (0.362 g, 47%).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[CH2:10][CH2:9][CH:8]([C:11]3[C:12]([Cl:35])=[C:13]([NH:19][C:20]4[N:25]=[C:24]([NH:26][CH:27]5[CH2:29][CH2:28]5)[C:23]5=[N:30][CH:31]=[C:32]([C:33]#[N:34])[N:22]5[N:21]=4)[CH:14]=[C:15]([C:17]#[N:18])[CH:16]=3)[CH2:7][CH2:6]2)[CH2:2]1.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>>[Cl:35][C:12]1[C:11]([CH:8]2[CH2:7][CH2:6][N:5]([CH:3]3[CH2:2][N:1]([S:37]([CH3:36])(=[O:39])=[O:38])[CH2:4]3)[CH2:10][CH2:9]2)=[CH:16][C:15]([C:17]#[N:18])=[CH:14][C:13]=1[NH:19][C:20]1[N:25]=[C:24]([NH:26][CH:27]2[CH2:28][CH2:29]2)[C:23]2=[N:30][CH:31]=[C:32]([C:33]#[N:34])[N:22]2[N:21]=1
Reactant: N#Cc1cc(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c(Cl)c(C2CCN(C3CNC3)CC2)c1
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)N1CC(N2CCC(c3cc(C#N)cc(Nc4nc(NC5CC5)c5ncc(C#N)n5n4)c3Cl)CC2)C1

Procedure:
The title compound was prepared from 2-((3-(1-(azetidin-3-yl)piperidin-4-yl)-2-chloro-5-cyanophenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Example 318) and methanesulfonyl chloride using a method analogous to that used to prepare Example 319 HPLC Rt 3.020 min
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[O:10][C:8](=O)[C:7]2=[CH:13][CH:14]=1)([O-:3])=[O:2].[N+:15]([C:18]1[CH:25]=[C:22]([C:23]#[N:24])[C:21]([NH2:26])=[CH:20][CH:19]=1)([O-:17])=[O:16].CN(C)C=O.CC(N(C)C)=O>CS(C)=O>[C:23]([C:22]1[CH:25]=[C:18]([N+:15]([O-:17])=[O:16])[CH:19]=[CH:20][C:21]=1[N:26]1[C:11](=[O:12])[C:6]2=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:14][CH:13]=[C:7]2[C:8]1=[O:10])#[N:24]
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])ccc21
Reactant: N#Cc1cc([N+](=O)[O-])ccc1N
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: N#Cc1cc([N+](=O)[O-])ccc1N1C(=O)c2ccc([N+](=O)[O-])cc2C1=O

Procedure:
Equimolar quantities of 4-nitrophthalic anhydride and 5-nitroanthranilonitrile (Aldrich Chemical Co.) can be heated in a solvent such as dimethylformamide, dimethylacetamide or dimethyl sulfoxide to give N-(2'-cyano-4'-nitrophenyl)-4-nitrophthalimide, which can be isolated and purified by recrystallization. An alternative method of synthesis for this intermediate is the reaction of 2-chloro-5-nitrobenzonitrile with the potassium salt of 4-nitrophthalimide, using one of the solvents listed above.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1>CC1C=CC=CC=1C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][O:7][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Cl)cc1
Solvent: Cc1ccccc1C
Product: O=Cc1ccc(OCc2ccc(Cl)cc2)cc1
Temperature: 80 °C
Yield: 122.7 %

Procedure:
In a 200-ml eggplant-type flask, 5.3 g (37.0 mmol) of 4-chlorobenzyl alcohol were weighed. After 80 ml of o-xylene, a nonpolar solvent, were added to form a solution, 28.0 g (37.0 mmol) of tetrakis[tris(dimethylamino)phosphoranilideneamino]phosphonium hydroxide was added to form a homogeneous solution. The solution was heated to 80° C., at which it was then maintained at 5 mmHg for 1 hour. Its pressure was allowed to rise back to normal pressure by nitrogen, followed by cooling to room temperature. Further, 50 ml of o-xylene and 5.20 g (37.0 mmol) of 4-chlorobenzaldehyde were added, followed by heating at 130° C. for 96 hours. The reaction mixture was washed four times with 100-ml portions of 1 N hydrochloric acid. The organic layer was separated and then concentrated to dryness. The residue was recrystallized from ethanol, whereby 5.6 g of 4-(4-chlorobenzyloxy)benzaldehyde were obtained as colorless crystals. Its isolation yield was 61%.
Reaction SMILES: [CH:1]1[C:10]2[C:9](=[O:11])[CH:8]=[CH:7][C:6](=[O:12])[C:5]=2[CH:4]=[N:3][N:2]=1.[CH3:13][O:14][C:15]1[CH:24]=[CH:23][C:18]([CH2:19][N:20]=[N+:21]=[N-:22])=[CH:17][CH:16]=1>C(OCC)(=O)C>[CH3:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][N:20]2[C:7]3[C:6](=[O:12])[C:5]4[CH:4]=[N:3][N:2]=[CH:1][C:10]=4[C:9](=[O:11])[C:8]=3[N:22]=[N:21]2)=[CH:23][CH:24]=1
Reactant: COc1ccc(CN=[N+]=[N-])cc1
Reactant: O=C1C=CC(=O)c2cnncc21
Solvent: CCOC(C)=O
Product: COc1ccc(Cn2nnc3c2C(=O)c2cnncc2C3=O)cc1
Yield: 62 %

Procedure:
333 mg (2.07 mmol) of phthalazin-5,8-dione (1.00 g, 6.20 mmol) and 4-methoxybenzyl azide were dissolved in 60 ml of ethyl acetate, and then refluxed overnight. The solvent was removed under reduced pressure and residue was separated and purified by using column chromatography (ethyl acetate). 415 mg of brown powder was obtained and the yield was 62%.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:28]=[C:29]([NH:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH:30]=[CH:31][C:32]=2[F:33])[CH2:23][CH2:22]1>>[C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([NH:17][CH2:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27]3[CH:28]=[C:29]([NH:34][C:35](=[O:39])[CH:36]([CH3:37])[CH3:38])[CH:30]=[CH:31][C:32]=3[F:33])[CH2:23][CH2:22]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)C(=O)Nc1ccc(F)c(C2CCN(CCCN)CC2)c1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Product: CC(C)C(=O)Nc1ccc(F)c(C2CCN(CCCNC(=O)C(c3ccccc3)c3ccccc3)CC2)c1

Procedure:
Example 24 was prepared from diphenylacetyl chloride and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-fluorophenyl}-2-methylpropanamide according to the procedures described in Scheme 8: 1H NMR (400 MHz, CDCl3) δ 7.95 (s, 1H), 7.47 (dd, 1H, J=2.4, 6.4 Hz), 7.34–7.21 (m, 11H), 7.06 (t, 1H, J=4.8 Hz), 6.91 (t, 1H, J=10.0 Hz), 4.90 (s, 1H), 3.38 (dd, 2H, J=6.0, 11.6 Hz), 2.90–2.87 (m, 2H), 2.74 (m, 1H), 2.50 (m, 1H), 2.36 (t, 2H, J=6.8 Hz), 1.96 (dt, 2H, J=2.8, 12.0 Hz), 1.73–1.62 (m, 6H), 1.20 (d, 6H, J=6.8 Hz); ESMS m/e: 516.3 (M+H)+.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[OH:19].[O:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:31]=[CH:30][C:29](OB(O)O)=[CH:28][CH:27]=2)[CH2:22][CH2:21]1>>[OH:18][C:14]1[CH:13]=[C:12]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[C:4]([C:29]2[CH:28]=[CH:27][C:26]([N:23]4[CH2:22][CH2:21][O:20][CH2:25][CH2:24]4)=[CH:31][CH:30]=2)=[C:3]([OH:19])[CH:2]=[CH:11]3)[CH:17]=[CH:16][CH:15]=1
Reactant: OB(O)Oc1ccc(N2CCOCC2)cc1
Reactant: Oc1cccc(-c2ccc3c(Br)c(O)ccc3c2)c1
Product: Oc1cccc(-c2ccc3c(-c4ccc(N5CCOCC5)cc4)c(O)ccc3c2)c1
Reaction time: 21 h
Yield: 7 %

Procedure:
The compound is prepared by the reaction of 1-bromo-6-(3-hydroxyphenyl)-naphthalene-2-ol (150 mg, 0.48 mmol, 1 eq) with 4-morpholinophenylboric acid (98.6 mg, 0.48 mmol, 1 eq) according to method A in 21 h. Purification by column chromatography with dichloromethane/methanol 99/1 yields the desired compound in a yield of 7%, 13 mg.
Reaction SMILES: O1CCC[CH2:2]1.[Br:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[C:9]([CH2:23][C:24]#[N:25])=[CH:10][N:11]2C(OC(C)(C)C)=O.C([N-]C(C)C)(C)C.[Li+].CI>O.CO>[Br:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[C:9]([CH:23]([CH3:2])[C:24]#[N:25])=[CH:10][NH:11]2
Reactant: CC(C)(C)OC(=O)n1cc(CC#N)c2c(Br)cccc21
Reactant: C1CCOC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: CO
Solvent: CI
Product: CC(C#N)c1c[nH]c2cccc(Br)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a tetrahydrofuran solution (10 mL) of 1, -dimethylethyl 4-bromo-3-(cyanomethyl)-1H-indole-1-carboxylate [CAS registration number 151726-05-5, Organic Letters 2003, 5(19), 3519-3522] (1.0 g), lithium diisopropylamide (2M tetrahydrofuran solution; 3.4 mL) was added dropwise at −78° C. and the mixture was stirred at the same temperature for one hour. To the mixture, methyl iodide (0.5 mL) was added, followed by stirring for one hour. The mixture was gradually heated to room temperature and methanol (2 mL) was added. The mixture was stirred overnight at room temperature and water was added under ice cooling, followed by extraction with ethyl acetate. The organic layer was washed in turn with water and saturated saline, dried over anhydrous magnesium sulfate and then concentrated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=80:20 y 70:30) to obtain the titled compound having the following physical properties (0.35 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[C:5]([OH:8])=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH:17](Br)[CH3:18]>CC(C)=O.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8][CH:17]([CH3:18])[O:9][C:4]=2[CH:3]=1
Reactant: Oc1ccc(Br)cc1O
Reactant: CC(Br)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CC1Oc2ccc(Br)cc2O1

Procedure:
To a solution of 4-bromobenzene-1,2-diol (500 mg, 2.65 mmol) in acetone (4 mL) was added cesium carbonate (1.90 g, 5.82 mmol) and 1,1-dibromoethane (1.09 g, 5.82 mmol). The mixture was microwaved to 120° C. for 3 h. After cooling, the reaction mixture was diluted with EtOAc, extracted with H2O, brine, dried over Na2SO4, filtered and concentrated and purified by flash column chromatography (silica gel, 0 to 10% ethyl acetate/hexanes) to give the product. 1H-NMR: 400 MHz, (CDCl3) δ 6.93-6.89 (m, 2H), 6.63 (d, J=8 Hz, 1H), 6.27 (q, J=9.6 Hz, 1H), 1.67 (d, J=4.4 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8][CH3:9])=[C:6](Cl)[N:5]=[C:4]([NH:11][CH2:12][CH2:13][CH2:14][O:15][CH:16]([CH3:18])[CH3:17])[N:3]=1.[NH3:19]>CO>[NH2:19][C:6]1[C:7]([S:8][CH3:9])=[C:2]([Cl:1])[N:3]=[C:4]([NH:11][CH2:12][CH2:13][CH2:14][O:15][CH:16]([CH3:18])[CH3:17])[N:5]=1
Reactant: CSc1c(Cl)nc(NCCCOC(C)C)nc1Cl
Reactant: N
Solvent: CO
Product: CSc1c(N)nc(NCCCOC(C)C)nc1Cl
Yield: 87 %

Procedure:
100 g (0.322 mole) of 4,6-dichloro-2-(3-isopropoxypropylamino)-5-methylthio-pyrimidine are dissolved in 400 ml of methanol and the solution is heated at 100° C. with 500 ml of ammonia in an autoclave for 3 hours. The undissolved residue is filtered off. After the methanol phase has been concentrated, the residue which remains is taken up in methylene chloride, the mixture is washed with water and the resulting organic phase is dried. After removal of the solvent, the resulting oil is stirred with petroleum ether. The crystals thereby obtained are filtered off with suction. 81 g (87% of theory) of the desired pyrimidine, melting point: 76° C., are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][N:3]=1.[NH:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)[N+:11]([O-:13])=[O:12].C(N(CC)CC)C>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]2=[N:10][N+:11]([O-:13])=[O:12])=[CH:4][N:3]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: O=[N+]([O-])Nc1ccccn1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=[N+]([O-])N=c1ccccn1Cc1ccc(Cl)nc1
Temperature: 25 °C
Yield: 43.5 %

Procedure:
2-Chloro-5-chloromethylpyridine (3.24 g) and 2-nitraminopyridine (2.78 g) were dissolved in anhydrous ethanol (50 ml), and triethylamine (4.04 g) was added to the solution. The mixture was stirred at room temperature for a while. Then, it was heated under reflux conditions for 8 hours. The reaction mixture was cooled to room temperature, and poured into ice water. The precipitated crystals were collected by filtration, and recrystallized from ethanol to give pale yellow 1-(2-chloro-5-pyridylmethyl)-2-nitroimino-1,2-dihydropyridine (2.3 g) as the desired compound. mp. 209-212° C.
Reaction SMILES: [OH-].[Li+].[Si:3]([O:10][C@@H:11]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35]1[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=1)[CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:28]=[CH:27][C:21]([C:22]([O:24]CC)=[O:23])=[CH:20][CH:19]=2)[CH2:14][CH2:13]1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4]>C1COCC1.CO.O>[Si:3]([O:10][C@@H:11]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35]1[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=1)[CH:12]1[CH2:13][CH2:14][N:15]([C:18]2[CH:28]=[CH:27][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=2)[CH2:16][CH2:17]1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4]
Reactant: CCOC(=O)c1ccc(N2CCC([C@@H](O[Si](C)(C)C(C)(C)C)c3ccccc3-c3ccc(Cl)cc3)CC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)O[C@@H](c1ccccc1-c1ccc(Cl)cc1)C1CCN(c2ccc(C(=O)O)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.1 %

Procedure:
Lithium hydroxide (1.42 g, 59.29 mmol) was added to a mixture of (R)-ethyl 4-(4-((tert-butyldimethylsilyloxy)(4′-chlorobiphenyl-2-yl)methyl)piperidin-1-yl)benzoate (INTERMEDIATE 12, 3.83 g, 6.78 mmol) in THF (27 ml), MeOH (9 ml) and water (1 ml). The resulting mixture was stirred at room temperature overnight and then the volatiles were removed under reduced pressure. The concentrate was purified by column chromatography (ISCO, 80 g silica column, eluting with 0→80% EtOAc/hexanes) to give the title product (3.24 g, yield: 89%).