Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](C=O)=[N:2]1.NN1C=CC=C1.C(O)(=O)C>C(O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: O=Cc1n[nH]c2ccccc12
Agent: Nn1cccc1
Solvent: CC(=O)O
Solvent: CCO
Product: c1ccc2[nH]ncc2c1
Yield: 200.9 %

Procedure:
A solution of 6-pyridin-4-yl-1-(2-trimethylsilanyl)-ethoxymethyl)-1H-indazole-3-carbaldehyde (208 mg, 0.59 mmol), N-aminopyrrole (145 mg, 1.76 mmol), and acetic acid (5.8 μl) in ethanol (1 ml) was held at 95° C. for 16 h. The solution was then evaporated under reduced pressure, and purified by silica gel chromatography to give 1H-indazole as an oil (140 mg, 57%). 1H NMR (300 MHz, CDCl3) 9.08 (s, 1H), 8.71 (d, 2H, J=6.1 Hz), 8.46 (d, 1H, J=85 Hz), 834 (s, 1H), 7.85 (d, 2H, J=6.2 Hz), 7.80 (d, 1H, J=8.5 Hz), 7.56 (t, 2H, J=23 Hz), 6.25 (t, 2H, J=2.3 Hz), 5.93 (s, 1H), 5.74 (s, 2H), 3.64 (t, 2H, J=7.9 Hz), 0.86 (t, 2H, J=7.9 Hz), 0.00 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([OH:15])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(N(C(C)C)CC)(C)C.[CH2:25]([O:32][CH2:33][C:34](Cl)=[O:35])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>ClCCl>[CH2:25]([O:32][CH2:33][C:34]([N:12]1[CH2:11][CH2:10][C:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])([OH:15])[CH2:14][CH2:13]1)=[O:35])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)COCc1ccccc1
Reactant: OC1(c2ccc(Cl)cc2Cl)CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(COCc1ccccc1)N1CCC(O)(c2ccc(Cl)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(2,4-dichloro-phenyl)-piperidin-4-ol (0.10 g, 0.40 mmol) in dichloromethane (2 mL) was added diisopropyl ethylamine (0.073 mL, 0.42 mmol) followed by benzyloxy acetyl chloride (0.078 g, 0.42 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with dichloromethane (10 mL) and washed with saturated aqueous sodium bicarbonate (10 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residual oil was chromatographed on silica gel using dichloromethane/methanol from 100% to 97% dichloromethane in a gradient fashion, to give the title compound as a glassy solid. The material was used as is without further purification. 1H NMR (300 MHz, CDCl3): δ 7.35 (m, 8H), 4.58 (m, 3H), 4.22 (m, 2H), 3.86 (bm, 1H), 3.57 (bm, 1H), 3.13 (bm, 1H), 2.64 (s, 1H), 2.26 (m, 2H), 1.97 (m, 2H).
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([Cl:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:12][O:13][C:14]1(B(O)O)[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][NH:15]1>>[Cl:11][C:9]1[N:10]=[C:3]2[C:2]([C:19]3[C:14]([O:13][CH3:12])=[N:15][CH:16]=[C:17]([C:20]([F:23])([F:21])[F:22])[CH:18]=3)=[CH:7][CH:6]=[CH:5][N:4]2[N:8]=1
Reactant: Clc1nc2c(Br)cccn2n1
Reactant: COC1(B(O)O)C=CC(C(F)(F)F)=CN1
Product: COc1ncc(C(F)(F)F)cc1-c1cccn2nc(Cl)nc12

Procedure:
2-Chloro-8-(2-methoxy-5-trifluoromethyl-pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine and 2-methoxy-5-trifluoromethylpyridineboronic acid in a manner analogous to Example 2c (0.46 g, 65%). MP=183-185° C. MS=329 (MH)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[CH:8][C:9]([O:11][CH3:12])=[O:10])=[CH:3][CH:2]=1>[Pd].CO>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:3][CH:2]=1
Reactant: COC(=O)C=Cc1ccncc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCc1ccncc1

Procedure:
Methyl 3-(4-pyridinyl)propenoate (7.00 grams) and 10% palladium on carbon (1.00 gram) were vigorously stirred in methanol (70 mL) at room temperature under a hydrogen atmosphere for 5 hours. The catalyst was removed by filtration through a filter aide, and the filtrate was evaporated in vacuo. The crude product was purified by distillation in a kugelrohr apparatus. Yield: 5.14 grams (73%). Bp: 125° C. (oven temperature) at 0.6 mm Hg.
Reaction SMILES: [CH3:1][C:2]([OH:20])([CH3:19])[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-])=O)[CH:11]=2)[CH2:6][CH2:5]1.[H][H]>CO.[Pd]>[NH2:16][C:12]1[CH:11]=[C:10]([N:7]2[CH2:6][CH2:5][N:4]([CH2:3][C:2]([CH3:19])([OH:20])[CH3:1])[CH2:9][CH2:8]2)[CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(O)CN1CCN(c2cccc([N+](=O)[O-])c2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(O)CN1CCN(c2cccc(N)c2)CC1
Yield: 84 %

Procedure:
2-Methyl-1-[4-(3-nitro-phenyl)-piperazin-1-yl]-propan-2-ol (1.60 g, 0.00573 mol) was dissolved in Methanol (40 mL) and the solution was carefully added to a Parr vessel containing 10% Palladium on Carbon (90.10, carbon black. Palladium, 0.750 g, 0.0562 mol) under nitrogen. The reaction was then placed on a Parr apparatus and was allowed to shake until uptake of hydrogen ceased (overnight). Catalyst was filtered and the filtrate was reduced to provide 1.20 grams of 1-[4-(3-Amino-phenyl)-piperazin-1-yl]-2-methyl-propan-2-ol without further purification as a light purple solid. (M+H)=250.06.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH2:24]([O:31][CH2:32][CH2:33][CH2:34][O:35][C:36]1[CH:41]=[CH:40][C:39](B2OC(C)(C)C(C)(C)O2)=[CH:38][N:37]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([O:31][CH2:32][CH2:33][CH2:34][O:35][C:36]1[N:37]=[CH:38][C:39]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][C:6]4[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]5[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=5)[C:5]=4[C:4]=3[CH:3]=2)=[CH:40][CH:41]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: CC1(C)OB(c2ccc(OCCCOCc3ccccc3)nc2)OC1(C)C
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4ccc(OCCCOCc5ccccc5)nc4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 50 mg, 0.132 mmol) and 2-(3-benzyloxy-propoxy)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (Stage 20.1.1, 68 mg, 0.184 mmol) to give the title compound as an off-white solid. (HPLC: tR 3.22 min (Method A); M+H=535 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.95 (s, 1H), 8.31-8.26 (m, 1H), 8.15-8.05 (m, 2H), 7.93-7.86 (m, 1H), 7.79-7.73 (m, 1H), 7.50-7.45 (m, 1H), 7.35-7.22 (m, 5H), 6.93-6.87 (m, 1H), 4.55 (s, 2H), 4.36 (t, 2H), 3.91 (s, 3H), 3.60-3.55 (m, 5H), 2.05-1.97 (m, 2H), 1.95 (s, 3H))
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[CH2:17][CH2:18][O:19][C:20]1[C:29]2[C:24](=[CH:25][C:26]([Cl:40])=[C:27]([NH:30][C:31]([NH:33][C:34]3[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=3)=[O:32])[CH:28]=2)[NH:23][C:22](=[O:41])[C:21]=1[C:42]1[CH:47]=[C:46]([CH3:48])[CH:45]=[C:44]([CH3:49])[CH:43]=1)=O)C1C=CC=CC=1.Br>C(O)(=O)C>[Cl:40][C:26]1[CH:25]=[C:24]2[C:29]([C:20]([O:19][CH2:18][CH2:17][CH:12]3[CH2:13][CH2:14][CH2:15][CH2:16][NH:11]3)=[C:21]([C:42]3[CH:47]=[C:46]([CH3:48])[CH:45]=[C:44]([CH3:49])[CH:43]=3)[C:22](=[O:41])[NH:23]2)=[CH:28][C:27]=1[NH:30][C:31]([NH:33][C:34]1[CH:35]=[CH:36][N:37]=[CH:38][CH:39]=1)=[O:32]
Reactant: Cc1cc(C)cc(-c2c(OCCC3CCCCN3C(=O)OCc3ccccc3)c3cc(NC(=O)Nc4ccncc4)c(Cl)cc3[nH]c2=O)c1
Agent: Br
Solvent: CC(=O)O
Product: Cc1cc(C)cc(-c2c(OCCC3CCCCN3)c3cc(NC(=O)Nc4ccncc4)c(Cl)cc3[nH]c2=O)c1

Procedure:
A solution of 2-{2-[7-chloro-3-(3,5-dimethylphenyl)-2-oxo-6-(3-pyridin-4-yl-ureido)-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylic acid benzyl ester in 3 mL of a 30% solution of hydrobromic acid in acetic acid was stirred at room temperature for 3 hours then concentrated in vacuo. The residue was treated with saturated sodium bicarbonate and then extracted with ethyl acetate. Purification of the concentrate by flash chromatography on silica gel (methylene chloride:methanol:ammonium hydroxide, 96:3:1) gave the title compound.
Reaction SMILES: CC1C=CC(C)=CC=1.[C:9]([O:12][C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([O:22][C:23](=[O:25])[CH3:24])[CH:21]=1)[C:16](Cl)=O)(=[O:11])[CH3:10].[F:26][C:27]1[CH:34]=[CH:33][C:30]([CH:31]=C)=[CH:29][CH:28]=1.CN1CCOCC1>CC([O-])=O.CC([O-])=O.[Pd+2].[Cl-].C(C1C=CC=C(C(C)C)C=1[NH+]1CCN(C2C(C(C)C)=CC=CC=2C(C)C)C1)(C)C.CCOC(C)=O>[C:9]([O:12][C:13]1[CH:14]=[C:15]([CH:16]=[CH:31][C:30]2[CH:33]=[CH:34][C:27]([F:26])=[CH:28][CH:29]=2)[CH:19]=[C:20]([O:22][C:23](=[O:25])[CH3:24])[CH:21]=1)(=[O:11])[CH3:10]
Reactant: C=Cc1ccc(F)cc1
Reactant: CC(=O)Oc1cc(OC(C)=O)cc(C(=O)Cl)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cccc(C(C)C)c1N1CC[NH+](c2c(C(C)C)cccc2C(C)C)C1
Solvent: Cc1ccc(C)cc1
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: CC(=O)Oc1cc(C=Cc2ccc(F)cc2)cc(OC(C)=O)c1
Temperature: 120 °C
Reaction time: 3.5 h
Yield: 73.2 %

Procedure:
A 25 mL round bottom flask was charged with p-xylene (10 mL), Pd(OAc)2 (11.3 mg, 0.05 mmol), 1,3-bis-(2,6-diisopropylphenyl) imidazolinium chloride (21.4 mg, 0.05 mmol), 3,5-diacetoxybenzoyl chloride (1.28 g, 5 mmol), 4-fluorostyrene (0.73 g, 6 mmol), and N-methyl morpholine (0.69 g, 6 mmol). The mixture was stirred at 120° C. for 3.5 h under nitrogen atmosphere. Then it was cooled to room temperature and EtOAc was added and filtered. The filtrate was washed with brine and dried over Na2SO4. Then it was filtered and purified via flash chromatography and gave the product (1.15 g, 73%) as white solid. Data are: 1H NMR (CDCl3, 300 MHz) δ7.45 (dd, 2H), 7.11-6.91 (m, 6H), 6.82 (t, J=1.95 Hz, 1H).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10](=O)[CH3:11])=[CH:2]1.C([SiH](CC)CC)C>C(O)(C(F)(F)F)=O>[CH2:10]([C:3]1[C:4]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:1][CH:2]=1)[CH3:11]
Reactant: CC(=O)c1c[nH]c2ncccc12
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCc1c[nH]c2ncccc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.3 %

Procedure:
To a solution of 1-(1H-Pyrrolo[2,3-b]pyridin-3-yl)-ethanone (1.34 g, 8.38 mmol) in TFA (25 mL) is added triethylsilane (6.09 g, 52.4 mmol) and stirred at rt for 18 h. The mixture is concentrated, diluted with 2 N aqueous KOH solution and extracted three times with DCM. The combined organic layer is dried (Na2SO4), filtered and evaporated. The resulting residue is chromatographed through silica gel eluting with 10% MeOH in DCM to afford 3-ethyl-1H-pyrrolo[2,3-b]pyridine (0.91 g). MS: 147 (M+H); 1H NMR (300 MHz, CDCl3): δ 9.23 (broad s, 1H), 8.32 (d, 1H), 7.94 (s, 1H), 7.05-7.14 (m, 2H), 2.80 (q, 2H), 1.35 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:15][C:14](=[O:16])[O:13][C:11](=[O:12])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].CC[N:19]([CH2:22]C)[CH2:20][CH3:21]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:10][C:11]([N:19]([CH2:20][C:21]2[CH:3]=[CH:4][CH:9]=[CH:10][C:11]=2[O:13][CH3:14])[CH3:22])=[O:12])[CH2:15][C:14]([OH:13])=[O:16])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCN(CC)CC
Reactant: O=C1CC(c2ccc(Cl)c(Cl)c2)CC(=O)O1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1ccccc1CN(C)C(=O)CC(CC(=O)O)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Sequentially treat the product of Step 3 (5.9 g) in CH2Cl2 (80 mL) at 0° C. with N-methyl-N-[2-(methoxyphenyl)methyl]amine (3.8 g), Et3N (3.5 mL) and DMAP (278 mg). Stir the mixture at 0° C. for 2 h, allow to warm to room temperature and stir for 20 h. Wash the reaction mixture with 1N HCl (1×100 mL) and brine (1×100 mL), dry the organic layers over MgSO4, filter and concentrate to afford 3,4-dichloro-β-[2-[[(2-methoxy-phenyl)methyl]-methylamino]-2-oxoethyl] benzenepropanoic acid (9.3 g).
Reaction SMILES: CO[C:3]([C@@:5]1([CH3:25])[C@H:9]([O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[CH2:8][CH2:7][N:6]1[C:18](OC(C)(C)C)=[O:19])=[O:4].CCN(C(C)C)C(C)C.[Cl:35][C:36]1[C:43]([CH3:44])=[C:42]([N:45]=C=O)[CH:41]=[CH:40][C:37]=1[C:38]#[N:39].C1CCN2C(=NCCC2)CC1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[Si:11]([O:10][C@H:9]1[C@@:5]2([CH3:25])[N:6]([C:18](=[O:19])[N:45]([C:42]3[CH:41]=[CH:40][C:37]([C:38]#[N:39])=[C:36]([Cl:35])[C:43]=3[CH3:44])[C:3]2=[O:4])[CH2:7][CH2:8]1)([C:14]([CH3:15])([CH3:17])[CH3:16])([CH3:13])[CH3:12]
Reactant: COC(=O)[C@@]1(C)[C@H](O[Si](C)(C)C(C)(C)C)CCN1C(=O)OC(C)(C)C
Reactant: Cc1c(N=C=O)ccc(C#N)c1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1c(N2C(=O)N3CC[C@@H](O[Si](C)(C)C(C)(C)C)[C@]3(C)C2=O)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 88.9 %

Procedure:
A solution of (2R,3R)-3-(tert-Butyldimethylsilanyloxy)-2-methyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester-2-methyl ester (60A) (52 mg, 0.14 mmol) in CH2Cl2 (1.5 mL) and TFA (0.5 mL) was stirred at rt for 2 h. The reaction was concentrated under reduced pressure and dried under vacuum. The residue was dissolved in CH2Cl2 (1.5 mL) and Hunig's base (60 μL, 0.35 mmol) was added. After stirring at rt for 10 min, 2-chloro-4-isocyanato-3-methylbenzonitrile (34 mg, 0.18 mmol) was added and the reaction was stirred at rt overnight. The reaction was treated with DBU (40 μL, 0.27 mmol) and was stirred for 4 h at rt then concentrated under reduced pressure. The residue was purified via chromatography (silica gel) eluting with 30% EtOAc in hexane to provide the title compound (54 mg). LC/MS m/z 434 [M+H]+.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:9])[CH2:4][O:5][CH2:6][CH2:7][OH:8].[CH2:10](Br)[C:11]#[CH:12].C(OCC)(=O)C>C1COCC1>[CH2:12]([O:9][CH2:3][CH2:4][O:5][CH2:6][CH2:7][OH:8])[C:11]#[CH:10]
Reactant: OCCOCCO
Reactant: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C#CCOCCOCCO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of sodium hydride (60% dispersion in mineral oil) (23 mmol) in dry THF (20 mL) at 0° C. under nitrogen was added a THF solution (100 mL) of diethylene glycol (110 mmol) over 0.5 h. The resultant reaction mixture was allowed to stir at room temperature for 1 h. This was followed by the addition of propargyl bromide (21 mmol). The reaction mixture was then heated under reflux for 8 h. Following this, the reaction was cooled, concentrated in vacuo and diluted with water (30 mL). The mixture was then extracted with ethyl acetate (3×50 mL). The organics were combined, dried over sodium sulfate and the concentrated under vacuum to furnish a crude residue. This was subjected to column chromatography using hexanes and ethyl acetate to afford 22 as a clear oil. Yield 2.1 g (71%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O.[CH:17]1([C:21](=O)[CH2:22][C:23]#[N:24])[CH2:20][CH2:19][CH2:18]1>>[Cl:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[N:1]=[C:21]([CH:17]1[CH2:20][CH2:19][CH2:18]1)[C:22]([C:23]#[N:24])=[C:9]2[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: N#CCC(=O)C1CCC1
Product: N#Cc1c(C2CCC2)nc2ccc(Cl)cc2c1-c1ccccc1

Procedure:
The title compound was prepared in analogy to example 101 step B from (2-amino-5-chlorophenyl)(phenyl)methanone and 3-cyclobutyl-3-oxo-propionitrile. Light yellow powder. MS (ESI): 319.3 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]([N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:15]#[C:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH:11]=2)[CH2:6]1)=[O:4].C(C1C=C2C(=CC=1)CN(C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C2)#CCCCCCC>>[F:24][C:2]([F:1])([F:23])[C:3]([N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH:11]=2)[CH2:6]1)=[O:4]
Reactant: CCCCCCC#Cc1ccc2c(c1)CCN(C(=O)C(F)(F)F)C2
Agent: CCCCCCC#Cc1ccc2c(c1)CN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C2
Product: CCCCCCCCc1ccc2c(c1)CCN(C(=O)C(F)(F)F)C2
Yield: 75 %

Procedure:
When the product of Step C is substituted for 5-(oct-1-ynyl)-2-tritylisoindoline in Example 2, Step E, the identical process afforded the title compound in 75% yield after purification of the crude product by FCC (SiO2; EtOAc/hexane, 3:7)., as a colourless foam. 1H-NMR (CDCl3) 0.86 (tr, 3H, J=6.9 Hz); 1.28 (m, 10H); 1.56 (m, 2H); 2.55 (tr, 2H, J=6.9 Hz); 2.87-2.93 (m, 2H); 3.79-3.88 (m, 2H); 4.6-4.8 (m, 2H); 6.8-7.16 (m, 3H).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29][CH3:30])=[CH:23][CH:22]=3)=[CH:17][N:16]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.C(N(CC)CC)C.C(O)C>[Pd].C(OCC)(=O)C>[CH2:27]([C:24]1[CH:23]=[CH:22][C:21]([C:18]2[CH:19]=[N:20][C:15]([C:12]3[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=3)=[N:16][CH:17]=2)=[CH:26][CH:25]=1)[CH2:28][CH2:29][CH3:30]
Reactant: CCCCc1ccc(-c2cnc(-c3ccc(OCc4ccccc4)cc3)nc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCCCc1ccc(-c2cnc(-c3ccc(O)cc3)nc2)cc1

Procedure:
A mixture of 120g of 2-(4-benzyloxyphenyl)-5-(4-butylpheny)pyrimidine, 13 g of palladium active carbon, 85 g of triethylamine, four liters of ethanol and one liter of ethyl acetate was stirred under a hydrogen atmosphere. After the palladium active carbon was removed and the solvent was distilled away, the residue was recrystallized by using a mixture of n-heptane and toluene, and 86 g of 5-(4-butylphenyl)-2-(4-hydroxylphenyl)pyrimidine was obtained. This compound showed melting points of 172.5°-173.3° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([C:10]=1[CH3:11])[C:7]([OH:9])=O.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH3:29])[CH:19]=[C:20]([O:27][CH3:28])[C:21]=1[O:22][C:23](=[O:26])[CH2:24][CH3:25].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([C:10]=1[CH3:11])[C:7]([C:19]1[C:18]([CH3:29])=[CH:17][C:16]([O:15][CH3:14])=[C:21]([O:22][C:23](=[O:26])[CH2:24][CH3:25])[C:20]=1[O:27][CH3:28])=[O:9]
Reactant: CCC(=O)Oc1c(OC)cc(C)cc1OC
Reactant: COc1ccc(Cl)c(C)c1C(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCl
Product: CCC(=O)Oc1c(OC)cc(C)c(C(=O)c2c(OC)ccc(Cl)c2C)c1OC

Procedure:
5-Chloro-2-methoxy-6-methylbenzoic acid (6.00 g, 0.03 mol) is reacted with 3,5-dimethoxy-4-propionyloxytoluene (6.73 g; 0.03 mol) in the presence of P2O5 (18.0 g) and dichloromethane (200 ml) as described in Example 6 yielding white crystals, 6.65 g (56.4% ), mp 150-151° C.
Reaction SMILES: [NH:1]1[C:5]2[C:6]3[C:11]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=4[C:4]=2[N:3]=[C:2]1[C:18]1[C:25]([C:26]#[N:27])=[CH:24][CH:23]=[CH:22][C:19]=1[C:20]#[N:21])=[CH:10][CH:9]=[CH:8][CH:7]=3.C(=O)([O-])[O-].[Cs+].[Cs+].O.C(OCC)(=O)C.[Cl:41][CH2:42]I>>[Cl:41][CH2:42][N:1]1[C:5]2[C:6]3[C:11]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=4[C:4]=2[N:3]=[C:2]1[C:18]1[C:25]([C:26]#[N:27])=[CH:24][CH:23]=[CH:22][C:19]=1[C:20]#[N:21])=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: ClCI
Reactant: N#Cc1cccc(C#N)c1-c1nc2c3ccccc3c3ccccc3c2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1cccc(C#N)c1-c1nc2c3ccccc3c3ccccc3c2n1CCl
Temperature: 80 °C
Yield: 31 %

Procedure:
2-(1H-phenanthro[9,10-d]imidazol-2-yl)isophthalonitrile from Step 2 (1 g, 2.91 mmol) was mixed with cesium carbonate (1.14 g, 3.49 mmol) in chloroiodomethane (10 mL). The mixture was heated to 80° C. overnight. The reaction was cooled to room temperature and poured into 200 mL water and 500 mL ethyl acetate. The layers were separated, and the organic layer washed with 200 mL water, 200 mL saturated aqueous sodium bicarbonate solution, 100 mL brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The crude solid was purified by flash column chromatography using 40% ethyl acetate in hexane to give 357 mg of 2-[1-(chloromethyl)-1H-phenanthro[9,10-d]imidazol-2-yl]isophthalonitrile (31%) plus 650 mg of a mixture of product and starting material.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14](S(C)(=O)=O)=[N:15][CH:16]=2)[N:11]([CH3:23])[C:10]1=[O:24].[CH3:25][O:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1>Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14]([NH:31][C:30]3[CH:32]=[CH:33][C:27]([O:26][CH3:25])=[CH:28][CH:29]=3)=[N:15][CH:16]=2)[N:11]([CH3:23])[C:10]1=[O:24]
Reactant: CN1C(=O)N(c2c(Cl)cccc2Cl)Cc2cnc(S(C)(=O)=O)nc21
Reactant: COc1ccc(N)cc1
Agent: Cl
Product: COc1ccc(Nc2ncc3c(n2)N(C)C(=O)N(c2c(Cl)cccc2Cl)C3)cc1
Temperature: 60 °C
Yield: 40.2 %

Procedure:
A mixture of 100 mg (0.26 mmol) of 3-(2,6-dichlorophenyl)-7-methane-sulfonyl-3,4-dihydro-1-methylpyrimido[4,5-d]pyrimidin-2(1H)-one and 0.32 ml (2.6 mmol) of 4-methoxyaniline was heated at 60° C. for 4 hours and then cooled. 10 ml of 2M aqueous hydrochloric acid were added to the residue. The precipitated yellow solid was filtered off, washed in sequence with 2M aqueous hydrochloric acid, water and diethyl ether and then dried to give 45 mg (40%) of 3-(2,6-dichlorophenyl)-3,4-dihydro-7-(4-methoxyanilino)-1-methylpyrimido[4,5-d]pyrimidin-2(1H)-one as a yellow solid of melting point 175° C. (decomposition).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.[Cl:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15][NH2:16].C(N(CC)CC)C>C(O)CCC>[Cl:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15][NH:16][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2
Reactant: NCc1cccc(Cl)c1
Reactant: Clc1ncnc2nc[nH]c12
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: Clc1cccc(CNc2ncnc3nc[nH]c23)c1
Temperature: 90 °C
Yield: 95 %

Procedure:
3 mmol of 6-chloropurine were dissolved in 15 ml of butanol. Subsequently, 4 mmol of 3-chlorobenzylamine and 5 mmol triethylamine were added and the mixture was heated at 90° C. for 4 hours. After cooling, the precipitated product was filtered off, washed with cold water and n-butanol and crystallised from ethanol or dimethylformamide. M.p.=252° C., TLC (CHCl3:MeOH:conc. NH4OH (8:2:0.2, v/v/v)): single spot; HPLC: purity>98%. Yield 95%.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=[C:4](SCC)[N:3]=1.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>>[NH2:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:3]=1
Reactant: C1COCCN1
Reactant: CCSc1ncc(C(=O)O)c(N)n1
Product: Nc1nc(N2CCOCC2)ncc1C(=O)O
Temperature: 80 °C
Yield: 8.4 %

Procedure:
A mixture of 4-amino-5-carboxy-2-ethylmercaptopyrimidine (0.35 g, 1.8 mmol) and morpholine (0.5 mL, 10 mmol) was warmed at 80° C. for 4 d and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 4×7.5 cm, eluted with 97.25/2.5/0.25 acetonitrile/water/acetic acid) to yield the product as a white solid (34 mg, 30%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][N:4]1[C:8]([CH2:9]O)=[CH:7][C:6]([N+:11]([O-:13])=[O:12])=[N:5]1.P(Br)(Br)[Br:15].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.ClCCl>[Br:1][CH2:2][CH2:3][N:4]1[C:8]([CH2:9][Br:15])=[CH:7][C:6]([N+:11]([O-:13])=[O:12])=[N:5]1
Reactant: O=[N+]([O-])c1cc(CO)n(CCBr)n1
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(CBr)n(CCBr)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.3 %

Procedure:
To as solution of (1-(2-bromoethyl)-3-nitro-1H-pyrazol-5-yl)methanol (4.24 g, 17 mmol) in chloroform (100 mL), cooled to 0° C., was added phosphorus tribromide (4.59 g, 1.6 mL, 17 mmol) drop wise. The resulting solution was warmed to room temperature and stirred for 2 h. The resulting solution was cooled to 0° C. and diluted with dichloromethane (50 ml). The resulting solution was made basic (pH 8.5) with saturated aqueous sodium bicarbonate was (20 mL). The layers were separated, and the aqueous layer was extracted with dichloromethane (3×50 mL). The combined organic layers were washed with brine (30 mL), dried over magnesium sulfate. The resulting mixture was filtered and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, SF40-240 g, 15% to 40% EtOAc in hexanes) to give 1-(2-bromoethyl)-5-(bromomethyl)-3-nitro-1H-pyrazole (3.58 g, 67%) as a white solid. 1H NMR (300 MHz, DMSO-d6) 8 ppm 3.92 (t, J=6.23 Hz, 2 H) 4.69 (t, J=6.23 Hz, 2 H) 4.89 (s, 2 H) 7.19 (s, 1 H).