Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[ClH:17].[C:18]1([CH2:24][C:25](=[NH:29])OCC)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C.C(Cl)(Cl)Cl>[ClH:17].[F:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][O:8][C:7]2[C:2]([NH:1][C:25](=[NH:29])[CH2:24][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:3][CH:4]=[CH:5][CH:6]=2)=[CH:11][CH:12]=1
Reactant: CCOC(=N)Cc1ccccc1
Reactant: Nc1ncccc1OCc1ccc(F)cc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: N=C(Cc1ccccc1)Nc1ncccc1OCc1ccc(F)cc1
Yield: 9.4 %

Procedure:
A mixture of 2-amino-3-(4-fluorobenzyloxy)pyridine (5.42 g, 24.2 mmol) and ethyl phenylacetimidate hydrochloride (6.28 g, 26.7 mmol) in ethanol (80 ml) was heated under reflux for 2 hours. Evaporation of the solvent gave an oil which was taken up in chloroform, filtered to remove an insoluble white solid, and purified by flash chromatography (chloroform/methanol) to obtain the product (0.85 g), m.p. 175°-178° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH:4]([NH:10][C:11]([C:13]1[C:14](=[O:28])[N:15]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[C:22]([F:27])[CH:21]=2)[CH:16]=[CH:17][CH:18]=1)=[O:12])[C:5]1[S:6][CH:7]=[CH:8][CH:9]=1.CN(C)C=O.[Br:35]N1C(=O)CCC1=O>>[CH3:1][O:2][C:3](=[O:29])[CH:4]([C:5]1[S:6][C:7]([Br:35])=[CH:8][CH:9]=1)[NH:10][C:11]([C:13]1[C:14](=[O:28])[N:15]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[C:22]([F:27])[CH:21]=2)[CH:16]=[CH:17][CH:18]=1)=[O:12]
Reactant: COC(=O)C(NC(=O)c1cccn(Cc2ccc(F)c(F)c2)c1=O)c1cccs1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: COC(=O)C(NC(=O)c1cccn(Cc2ccc(F)c(F)c2)c1=O)c1ccc(Br)s1
Temperature: 25 °C

Procedure:
{[1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carbonyl]-amino}-thiophen-2-yl-acetic acid methyl ester (0.190 g, 0.000454 mol;) was dissolved in N,N-Dimethylformamide (6 mL, 0.07 mol;) and N-Bromosuccinimide (0.089 g, 0.00050 mol;) was added. The reaction was allowed to stir at room temperature o/n. LC-MS showed the formation of product at 1.89 498.45. The reaction was concentrated and dissolved in ethyl acetate. The reaction was then washed 1× with saturated bicarbonate and 1× with brine before drying with magnesium sulfate and concentrating. The crude was then dissolved in methylene chloride and injected onto the combiflash and eluted using a 0-100% hexanes ethyl acetate gradient. The pure fractions were combined and concentrated to give the product. ES (+) MS m/e=498.45
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[F:11][C:12]1[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[C:13]=1[CH2:14][N:15]1[C:20]([CH3:21])=[C:19]([C:22](OCC)=[O:23])[C:18](=[O:27])[C:17]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[C:30]=2[F:37])(Br)[CH:16]1[CH3:38].CC(C[AlH]CC(C)C)C.CO>C1COCC1.C(Cl)Cl>[F:11][C:12]1[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[C:13]=1[CH2:14][N:15]1[C:20]([CH3:21])=[C:19]([CH:22]=[O:23])[C:18](=[O:27])[C:17]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[C:30]=2[F:37])=[C:16]1[CH3:38]
Reactant: CCOC(=O)C1=C(C)N(Cc2c(F)cccc2F)C(C)C(Br)(c2cccc(OC)c2F)C1=O
Agent: CC(C)C[Al+]CC(C)C
Agent: CC(C)C[AlH]CC(C)C
Agent: [H-]
Solvent: CO
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1cccc(-c2c(C)n(Cc3c(F)cccc3F)c(C)c(C=O)c2=O)c1F
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Diisobutylaluminum hydride (3.75 mmol, 3.75 ml of a 1.0M solution in hexanes ) was added dropwise to a stirring solution of 1-(2,6-difluorobenzyl)-2,6-dimethyl-3-(2-fluoro-3-methoxyphenyl)-3-bromo-5-ethoxycarbonyl-4-pyridone (1.12 g, 2.5 mmol) in THF/DCM (30 mL/ 12 mL), at −78° C. under N2. A suspension was formed at the end of the addition. After 1 hour, an additional aliquot of DIBAL-H (2.5 mmol, 2.5 mL of a 1.0 M solution in hexanes) was added. The reaction was stirred for 1 hour at −78° C. MeOH (50 mL) was carefully added to quench any unreacted DIBAL-H. The solution was concentrated, then partitioned between EtOAc and 1 M HCl. The organic layer was concentrated and purified using flash silica gel chromatography (100% hexanes to EtOAc/hexanes 3/2). The fourth spot which eluted was evaporated to give product as a cream colored solid. 1H NMR (CDCl3, 300 MHz) δ 10.55 (s, 1H), 6.80-7.75 (m, 6H), 5.36 (s, 2H), 3.90 (s, 3H), 2.79 (s, 3H), 2.27 (s, 3H); LCMS=402 (MH+).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C@:9]1([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH2:14][CH2:13][N:12]([C@H:15]([C:17]2[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=2)[CH3:16])[C:11](=[O:24])[NH:10]1)(=O)=O.[CH3:32][S:33]([NH2:36])(=[O:35])=[O:34].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Br:23][C:20]1[CH:21]=[CH:22][C:17]([C@@H:15]([N:12]2[CH2:13][CH2:14][C@:9]([CH2:8][CH2:7][CH2:6][NH:36][S:33]([CH3:32])(=[O:35])=[O:34])([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[NH:10][C:11]2=[O:24])[CH3:16])=[CH:18][CH:19]=1
Reactant: CS(N)(=O)=O
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCOS(C)(=O)=O)(c2ccc(F)cc2)NC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCNS(C)(=O)=O)(c2ccc(F)cc2)NC1=O
Yield: 14.2 %

Procedure:
To a solution of 3-((R)-1-((S)-1-(4-bromophenyl)ethyl)-4-(4-fluorophenyl)-2-oxohexa hydropyrimidin-4-yl)propyl methanesulfonate (58 mg, 0.11 mmol) and methanesulfonamide (105 mg, 1.10 mmol) in acetone (10 mL) was added K2CO3 (31 mg, 0.22 mmol), and the mixture was refluxed overnight. The reaction was quenched with water, and the mixture was extracted with EtOAc. After removal of the solvent, the mixture was extracted with EtOAc, and the organic solution was washed with brine, dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by preparative TLC and preparative HPLC to give N-(3-((R)-1-((S)-1-(4-bromophenyl)ethyl)-4-(4-fluorophenyl)-2-oxohexahydropyrimidin-4-yl)propyl)methanesulfonamide (8 mg, 14%). 1H NMR (CDCl3): 1.18□m, 1H), 1.45 (d, 3H), 1.50 (m, 1H), 1.88-2.16 (m, 5H), 2.84 (m, 4H), 3.02 (m, 2H), 4.70 (s, 1H), 5.63 (m, 1H), 6.88-6.98 (m, 4H), 7.12 (m, 2H), 7.30 (m, 2H). LC-MS Method 1 tR=1.146 min, m/z=512.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]([O:9][C:10]([NH:12][C@@H:13]1[CH2:18][CH2:17][CH2:16][N:15]([C:19]2[N:27]([CH2:28][C:29]3[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=3[Cl:36])[C:26]3[C:25](=[O:37])[N:24](CC4C=CC(OC)=CC=4)[C:23](=[O:47])[N:22]([CH3:48])[C:21]=3[C:20]=2[C:49]([O:51][CH3:52])=[O:50])[CH2:14]1)=[O:11])([CH3:8])([CH3:7])[CH3:6].Cl>C1(OC)C=CC=CC=1>[C:5]([O:9][C:10]([NH:12][C@@H:13]1[CH2:18][CH2:17][CH2:16][N:15]([C:19]2[N:27]([CH2:28][C:29]3[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=3[Cl:36])[C:26]3[C:25](=[O:37])[NH:24][C:23](=[O:47])[N:22]([CH3:48])[C:21]=3[C:20]=2[C:49]([O:51][CH3:52])=[O:50])[CH2:14]1)=[O:11])([CH3:8])([CH3:7])[CH3:6]
Reactant: COC(=O)c1c(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)n(Cc2cc(F)ccc2Cl)c2c(=O)n(Cc3ccc(OC)cc3)c(=O)n(C)c12
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: COc1ccccc1
Product: COC(=O)c1c(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)n(Cc2cc(F)ccc2Cl)c2c(=O)[nH]c(=O)n(C)c12
Temperature: 65 °C
Reaction time: 4 h
Yield: 56.5 %

Procedure:
Under a nitrogen atmosphere, a solution of aluminum chloride (395 mg) in anisole (1.5 ml) was added to methyl 6-{(3R)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}-5-(2-chloro-5-fluorobenzyl)-3-(4-methoxybenzyl)-1-methyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidine-7-carboxylate (260 mg), and the resulting mixture was stirred at 65° C. for 4 hours. After the reaction solution was cooled to 25° C., 1N hydrochloric acid was added thereto and the aqueous layer was washed with ethyl acetate. The aqueous layer was neutralized with a 1N aqueous sodium hydroxide solution and extracted with chloroform. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and then filtered and the filtrate was concentrated under reduced pressure. To the resulting residue were added di-tert-butyl dicarbonate (415 mg), 1,4-dioxane (4 ml) and a saturated aqueous sodium hydrogencarbonate solution (4 ml) and the resulting mixture was stirred at 25° C. for 16 hours. Water was added to the reaction solution, followed by extraction with chloroform. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and then filtered and the filtrate was concentrated under reduced pressure. To the resulting residue was added diethyl ether/hexane and the resulting mixture was filtered and then washed with hexane to obtain the title compound (121 mg) as a light-yellow solid.
Reaction SMILES: [NH:1]1[CH2:10][CH2:9][CH2:8][C:7]2[N:6]=[CH:5][C:4]3[CH:11]=[CH:12][CH:13]=[CH:14][C:3]=3[C:2]1=2.[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>[OH-].[K+]>[C:15]([N:1]1[CH2:10][CH2:9][CH2:8][C:7]2[N:6]=[CH:5][C:4]3[CH:11]=[CH:12][CH:13]=[CH:14][C:3]=3[C:2]1=2)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: c1ccc2c3c(ncc2c1)CCCN3
Agent: [K+]
Agent: [OH-]
Product: O=C(c1ccccc1)N1CCCc2ncc3ccccc3c21
Yield: 86.8 %

Procedure:
A stirred solution of 1,2,3,4-tetrahydrobenzo[c]-1,5-naphthyridine (4.6 g) and KOH-dried pyridine (50 ml) was treated dropwise over one minute with benzoyl chloride (8.4 g). A crystalline precipitate formed. The stirred suspension was heated (steam bath) for 1.25 hours and the resultant solution was then stirred overnight at ambient temperature during which a crystalline precipitate formed. The mixture was decanted into water (200 ml), basified with 10% sodium hydroxide solution and extracted with dichloromethane. The dried (Na2SO4) organic phase was filtered and evaporated to dryness (7.47 g of crystalline solid). Recrystallization from toluene afforded 6.25 g of crystals, m.p. 208.5°-210.5° C. An aliquot of the material (4.81 g) was further purified by preparative HPLC (silica gel, eluted with ethyl acetate). The appropriate fractions were concentrated and the residue was recrystallized from toluene (100 ml) to give 4.14 g of crystals, m.p. 208°-210° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[N:7]([CH3:20])[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH3:16])=[C:10]([N+:17]([O-])=O)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2]>CCOC(C)=O.[Pd]>[C:1]([O:5][C:6](=[O:21])[N:7]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH3:16])=[C:10]([NH2:17])[CH:9]=1)[CH3:20])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCCc1ccc(N(C)C(=O)OC(C)(C)C)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCc1ccc(N(C)C(=O)OC(C)(C)C)cc1N
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of methyl-(3-nitro-4-propyl-phenyl)-carbamic acid tert-butyl ester (110 mg, 0.37 mmol) in EtOAc (10 ml) was added 10% Pd—C (100 mg). The resulting suspension was stirred at room temperature under H2 (1 atm) for 2 days. The progress of the reaction was monitored by TLC. Upon completion, the reaction mixture was filtered through a pad of Celite. The filtrate was concentrated in vacuo to afford (3-Amino-4-propyl-phenyl)-methyl-carbamic acid tert-butyl ester (D-15) as a colorless crystalline compound (80 mg, 81%). ESI-MS 265.3 m/z (MH+).
Reaction SMILES: C([O:4][CH:5]([C:9]1[CH:14]=C[C:12](C)=[CH:11][CH:10]=1)C(C)=C)C=C.[C:16]1([C:18](=[CH:20][C:21](=[CH:23][CH:24]=1)[CH3:22])C)[CH3:17]>>[CH3:14][CH:9]([CH2:10]/[C:11](/[CH3:12])=[CH:17]/[C:16]1[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:18]=1)[CH:5]=[O:4]
Reactant: Cc1ccc(C)c(C)c1
Reactant: C=CCOC(C(=C)C)c1ccc(C)cc1
Product: C/C(=C\c1ccc(C)cc1)CC(C)C=O

Procedure:
The 1-[1-(allyloxy)-2-methyl-2-propenyl]-4-methylbenzene (24 g, 0.116 mol) and [RuCl2(PPh3)3] (200 mg) were heated in the presence of BHT (50 mg) in pseudo-cumene (50 ml) at 170-180° C. (reflux) for 4 hours.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9][CH2:10][CH2:11][NH:12][CH2:13][C:14]2[CH:15]=[C:16]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH:17]=[CH:18][CH:19]=2)=[C:4]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[N:3]=1.[C:31]([O:38][CH3:39])(=[O:37])[CH2:32][CH2:33][C:34]([O-])=[O:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9][CH2:10][CH2:11][N:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH:15]=2)[C:34](=[O:35])[CH2:33][CH2:32][C:31]([O:38][CH3:39])=[O:37])=[C:4]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[N:3]=1
Reactant: CCCCCNc1nc(N)nc(C)c1CCCNCc1cccc(CC(=O)OC)c1
Reactant: COC(=O)CCC(=O)[O-]
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CCCCCNc1nc(N)nc(C)c1CCCN(Cc1cccc(CC(=O)OC)c1)C(=O)CCC(=O)OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 41.1 %

Procedure:
The product from Example 1 (61 mg), mono-methyl succinate (23.4 mg) and TEA (0.062 ml) were dissolved in DCM (15 ml) then HATU (61.7 mg) was added. The resulting solution was stirred at rt for 16 h. The solvents were evaporated, the residue was taken up in MeOH and the crude product was purified by RPHPLC to afford the title compound as a colorless gum 32 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1C=C[N:17]=[C:16]1[CH2:20][N:21]1C(=O)C2=CC=CC=C2C1=O.NN.[CH2:35](O)[CH3:36]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:15]2[CH:35]=[CH:36][N:17]=[C:16]2[CH2:20][N:21]=1
Reactant: CCO
Reactant: O=C(c1ccccc1Cl)c1ccccc1-n1ccnc1CN1C(=O)c2ccccc2C1=O
Agent: NN
Product: Clc1ccccc1C1=NCc2nccn2-c2ccccc21

Procedure:
In the manner given in Example 33, 2'-chloro-2-[2-(phthalimidomethyl)imidazol-1-yl]benzophenone in ethanol is heated with hydrazine to give 6-(o-chlorophenyl)-4H-imidazo[1,2-a][1,4]benzodiazepine.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[CH:7][N:6]=1)=[O:4].[OH-].[Na+].Cl>C(O)C>[C:11]([C:8]1[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[N:6][CH:7]=1)#[N:12]
Reactant: COC(=O)c1ccc(C#N)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: N#Cc1ccc(C(=O)O)nc1
Yield: 95.2 %

Procedure:
A solution of methyl-5-cyanopyridine-2-carboxylate (920 mg) and a 5 N NaOH solution (2.26 mL) in ethanol (30 mL) was stirred at RT for 10 min. 5 N hydrochloric acid (5.2 mL) was added to the reaction solution at RT, followed by extraction with EtOAc. The extract was dried over anhydrous MgSO4. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure to obtain the title compound (800 mg). 1H-NMR (400 MHz, DMSOd6) δ (ppm): 8.18 (d, J=8.0 Hz, 1H), 8.51 (dd, J=2.0, 8.0 Hz, 1H), 9.12-9.18 (m, 1H).
Reaction SMILES: F[C:2]1[C:7]([C:8]#[N:9])=[C:6]([F:10])[C:5]([C:11]#[N:12])=[C:4]([F:13])[C:3]=1[F:14].[CH3:15][C:16]([CH2:18][OH:19])=[CH2:17].[F-].[K+]>C(#N)C>[F:10][C:6]1[C:5]([C:11]#[N:12])=[C:4]([F:13])[C:3]([F:14])=[C:2]([O:19][CH2:18][C:16](=[CH2:15])[CH3:17])[C:7]=1[C:8]#[N:9]
Reactant: N#Cc1c(F)c(F)c(F)c(C#N)c1F
Reactant: C=C(C)CO
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Product: C=C(C)COc1c(F)c(F)c(C#N)c(F)c1C#N
Temperature: 25 °C
Reaction time: 10 h

Procedure:
The mixture of 3.0 g of tetrafluoroisophthalonitrile, 1.2 g of β-methallyl alcohol and 1.8 g of potassium fluoride in 30 ml of acetonitrile was stirred at room temperature for 10 hours. The mixture was cooled and filtered. The filtrate was evaporated under reduced pressure. After 50 ml of water was added to the residue, the mixture was extracted with carbon tetrachloride, washed with water, and dried over sodium sulfate. After evaporating carbon tetrachloride, the residue of 2.9 g (crystal) was obtained.
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[N:10]=[CH:11][N:12]4[C:21]5[C:16](=[C:17](Cl)[CH:18]=[CH:19][CH:20]=5)[C:15](=[O:23])[N:14]([CH3:24])[C:13]=34)[N:5]=2)[CH2:3][CH2:2]1.[CH2:25]([OH:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[H-].[Na+].O>CN(C)C=O.CCOCC>[CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[N:10]=[CH:11][N:12]4[C:21]5[C:16](=[C:17]([O:32][CH2:25][C:26]6[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=6)[CH:18]=[CH:19][CH:20]=5)[C:15](=[O:23])[N:14]([CH3:24])[C:13]=34)[N:5]=2)[CH2:3][CH2:2]1
Reactant: OCc1ccccc1
Reactant: Cn1c(=O)c2c(Cl)cccc2n2cnc(-c3noc(C4CC4)n3)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: Cn1c(=O)c2c(OCc3ccccc3)cccc2n2cnc(-c3noc(C4CC4)n3)c12
Temperature: 110 °C
Reaction time: 5 h
Yield: 52.4 %

Procedure:
A mixture of (3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-methyl5-oxo-6-chloro-4,5-dihydro-imidazo(1,5-a)quinazoline (0.4 g, 1.2 mmol), benzyl alcohol (0.32 g, 3 mmol), and sodium hydride (55% dispension in oil, 0.13 g, 3 mmol) in 20 ml of dry DMF (dimethylformamide) was stirred for 5 h at 110° C., then cooled to room temperature and was thereafter poured into 30 ml of water and 5 ml of ether. The mixture was then stirred for 1 h at 0° C. and the precipitate was filtered off, rinsed with water and dried giving 0.26 g (53%) of 3-(5-cyclopropyl-1.2.4-oxadiazol-3-yl)-4-methyl-5-oxo-6-benzyloxy-4,5-dihydro-imidazo (1,5-a)quinazoline, M.p. 221°-224° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7]O)=[CH:5][C:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[N:3]1.S(Cl)([Cl:22])=O>C(Cl)(Cl)Cl>[Cl:22][CH2:7][C:6]1[N:2]([CH3:1])[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)[CH:5]=1
Reactant: Cn1nc(-c2ccc(OC(F)(F)F)cc2)cc1CO
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Cn1nc(-c2ccc(OC(F)(F)F)cc2)cc1CCl

Procedure:
In analogy to the procedure described for example 1 b], [2-methyl-5-(4-trifluoromethoxy-phenyl)-2H-pyrazol-3-yl]-methanol (example 11 d]) was reacted with thionyl chloride in chloroform to yield 5-chloromethyl-1-methyl-3-(4-trifluoromethoxy-phenyl)-1H-pyrazole as colorless oil.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([CH2:16][CH3:17])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]1=[O:15].[Cl:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[Cl:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[N:26]1[CH2:27][CH2:28][N:29]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]2([CH2:16][CH3:17])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]2=[O:15])[CH2:30][CH2:31]1
Reactant: CCC1(CCCCCl)C(=O)Nc2ccccc21
Reactant: Fc1ccc(N2CCNCC2)c(Cl)c1
Product: CCC1(CCCCN2CCN(c3ccc(F)cc3Cl)CC2)C(=O)Nc2ccccc21

Procedure:
The title compound is prepared according to process H by applying processing method 1 from 3-(4-chlorobutyl)-3-ethyl-1,3-dihydro-2H-indol-2-one and 1-(2-chloro-4-fluorophenyl)-piperazine.
Reaction SMILES: [OH:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:10]1[C:18]2[C:17]([NH:19][C@H:20]([C:22]3[N:27]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:26](=[O:34])[C:25]4=[C:35]([CH3:38])[CH:36]=[CH:37][N:24]4[N:23]=3)[CH3:21])=[N:16][CH:15]=[N:14][C:13]=2[N:12](COCC[Si](C)(C)C)[CH:11]=1.FC(F)(F)C(O)=O.N>>[OH:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:10]1[C:18]2[C:17]([NH:19][C@H:20]([C:22]3[N:27]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:26](=[O:34])[C:25]4=[C:35]([CH3:38])[CH:36]=[CH:37][N:24]4[N:23]=3)[CH3:21])=[N:16][CH:15]=[N:14][C:13]=2[NH:12][CH:11]=1
Reactant: COc1cccc(-c2cn(COCC[Si](C)(C)C)c3ncnc(N[C@@H](C)c4nn5ccc(C)c5c(=O)n4-c4ccccc4)c23)c1O
Agent: N
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc(-c2c[nH]c3ncnc(N[C@@H](C)c4nn5ccc(C)c5c(=O)n4-c4ccccc4)c23)c1O
Yield: 48 %

Procedure:
(S)-2-(1-((5-(2-Hydroxy-3-methoxyphenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (71 mg, 0.08 mmol) was treated with trifluoroacetic acid (2 mL, 25.96 mmol) and a solution of ammonia (7N in methanol, 2 mL, 14 mmol) according to the method described in Example 27 to give 19.5 mg (48% yield) of the title compound. Purity 94%.
Reaction SMILES: BrC1C2C=NC([N+]([O-])=O)=C(O)C=2OC=1.ClC1C=CC=C(Cl)C=1C(O)C.ClC1C(F)=CC=C(Cl)C=1[C@H](OC1C2OC=CC=2C=NC=1[N+]([O-])=O)C.[Br:50][C:51]1[C:55]2[CH:56]=[N:57][C:58]([N+:71]([O-])=O)=[C:59]([O:60][CH:61]([C:63]3[C:68]([Cl:69])=[CH:67][CH:66]=[CH:65][C:64]=3[Cl:70])[CH3:62])[C:54]=2[O:53][CH:52]=1>[Fe].Cl>[Br:50][C:51]1[C:55]2[CH:56]=[N:57][C:58]([NH2:71])=[C:59]([O:60][CH:61]([C:63]3[C:64]([Cl:70])=[CH:65][CH:66]=[CH:67][C:68]=3[Cl:69])[CH3:62])[C:54]=2[O:53][CH:52]=1
Reactant: CC(Oc1c([N+](=O)[O-])ncc2c(Br)coc12)c1c(Cl)cccc1Cl
Agent: [Fe]
Agent: CC(O)c1c(Cl)cccc1Cl
Agent: C[C@@H](Oc1c([N+](=O)[O-])ncc2ccoc12)c1c(Cl)ccc(F)c1Cl
Product: CC(Oc1c(N)ncc2c(Br)coc12)c1c(Cl)cccc1Cl

Procedure:
3-Bromo-6-nitrofuro[3,2-c]pyridin-7-ol (Intermediate 10) was reacted with racemic 1-(2,6-dichlorophenyl)ethanol following the procedure described for Intermediate 8. The resulting 3-Bromo-7-[1-(2,6-dichlorophenyl)ethoxy]-6-nitrofuro[3,2-c]pyridine was reacted with iron/HCl as described in Example 2 to give 3-Bromo-7-[1-(2,6-dichlorophenyl)ethoxy]furo[3,2-c]pyridin-6-ylamine. Suzuki coupling with 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyrazol-1-yl]piperidine-1-carboxylic acid tert-butyl ester and Boc removal with HCl as described for Example 333 gave the title compound as HCl salt. 1H NMR (400 MHz, CD3OD): δ=1.86 (d, J=6.8 Hz, 3H), 1.91-2.03 (m, 2H), 2.11 (dd, J=12.0, 2.2 Hz, 2H), 2.75 (td, J=12.8, 2.5 Hz, 2H), 3.13-3.23 (m, 2H), 4.26-4.39 (m, 1H), 6.59 (q, J=6.8 Hz, 1H), 7.23 (d, J=7.8 Hz, 1H), 7.31-7.39 (m, 2H), 7.77 (s, 1H), 7.82 (s, 1H), 8.07 (s, 1H), 8.13 (s, 1H). MS (ES+): m/z 472.00/474.00 [MH+]. HPLC: tR=2.38 min (ZQ3, polar—5 min).
Reaction SMILES: CC(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-].[CH2:14]([CH:17]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][C:18]1=[O:29])[CH:15]=[CH2:16].CC(C)=O>C(O)(C)C>[CH2:14]([CH:17]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH:18]1[OH:29])[CH:15]=[CH2:16]
Reactant: C=CCC1CCCCCCCCCCC1=O
Agent: CC(C)[O-]
Agent: [Al+3]
Solvent: CC(C)=O
Solvent: CC(C)O
Product: C=CCC1CCCCCCCCCCC1O
Yield: 95 %

Procedure:
0.1 mole of aluminum isopropoxide in 500 ml of isopropanol is placed in a three-necked flask provided with a stirrer and a Vigreux column. The mixture is refluxed. A 25% by weight solution of 2-(2-propenyl)-cyclododecanone in isopropanol is added dropwise to the boiling reaction mixture, over a period of 12 hours. The acetone produced, which serves at the same time as indicator for the progress of the reaction, is collected at the top of the column. After approximately a further hour of refluxing, the reaction is complete. After the isopropanol has been drawn off, the reaction mixture is hydrolyzed with 6N hydrochloric acid. Extraction is then carried out with 200 ml of toluene and the organic phase is worked up by distillation. Finally, 2-(2-propenyl)-cyclododecanol is obtained as a colorless liquid in a yield of 95% of the theoretical yield at a boiling range of from 172° to 175° C. at 12 torr.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][C:6]=1[CH2:7][OH:8]>ClCCl.[O-2].[O-2].[Mn+4]>[Br:1][C:2]1[S:3][C:4]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][C:6]=1[CH:7]=[O:8]
Reactant: OCc1cc(-c2ccccc2)sc1Br
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=Cc1cc(-c2ccccc2)sc1Br
Yield: 80.7 %

Procedure:
A solution of (2-bromo-5-phenylthiophen-3-yl)methanol (11e) (220 mg, 0.83 mmol) and manganese dioxide (720 mg, 8.3 mmol) in dichloromethane (3 mL) was stirred at room temperature for 160 minutes. The reaction mixture was filtered over Celite® and the filtrate was evaporated to dryness to provide the desired aldehyde (11f) (180 mg, 0.67 mmol, 81%), which was used without further purification.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([I:14])=[CH:10][C:9]=1[NH2:15])(C)(C)C.CC1(C)O[C:22](=[O:24])[CH:21]=[C:20]([C:25]2[S:26][CH:27]=[CH:28][CH:29]=2)O1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[I:14][C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:20]([C:25]3[S:26][CH:27]=[CH:28][CH:29]=3)[CH2:21][C:22](=[O:24])[NH:15][C:9]=2[CH:10]=1
Reactant: CC1(C)OC(=O)C=C(c2cccs2)O1
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)cc1N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2cccs2)=Nc2ccc(I)cc2N1

Procedure:
Prepared from (2-amino-4-iodo-phenyl)-carbamic acid tert.-butyl ester (Example G1) and 2,2-dimethyl-6-thiophen-2-yl-[1,3]dioxin-4-one (Example J1) according to the general procedure K. The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a yellow solid (30 mg).