Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I-:1].[Na+].CC1C=CC(S(O[CH2:14][CH2:15][CH2:16][C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=2)(=O)=O)=CC=1>CC(C)=O>[I:1][CH2:14][CH2:15][CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19][CH:18]=1
Reactant: [I-]
Reactant: Cc1ccc(S(=O)(=O)OCCCc2c[nH]c3ccccc23)cc1
Agent: [Na+]
Solvent: CC(C)=O
Product: ICCCc1c[nH]c2ccccc12
Yield: 100.3 %

Procedure:
Sodium iodide (827 mg, 5.52 mmol, 2 equiv) was added to a solution of 3-(1H-indol-3-yl)propyl 4-methylbenzenesulfonate (909 mg, 2.76 mmol, 1 equiv) in acetone, and the mixture was refluxed for 16 h. Upon cooling the reaction, it was evaporated under reduced pressure and the residue was taken into dichloromethane. The organic layer was washed with water, dried over MgSO4, filtered and concentrated in vacuo. The crude mixture was purified using the Biotage flash chromatography system (SNAP 50 g cartridge, Rf=0.7, gradient—5%-30% ethyl acetate in hexanes) to afford the title compound as an oil (789 mg, quant); 1H NMR (400 MHz, DMSO-d6): δ 2.07-2.14 (m, 2H); 2.78 (t, 2H, J=7.6 and 6.8 Hz); 3.29 (t, 2H, J=6.8 Hz); 6.95-6.99 (m, 1H); 7.04-7.08 (m, 1H); 7.14 (d, 1H, J=2 Hz); 7.32-7.34 (m, 1H); 7.52 (d, 1H, J=8 Hz); 10.81 (s, 1H); MS for C11H12IN m/z 285.12 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]2[N:13]3[N:14]=[C:15]([NH:18][C@@H:19]4[CH2:24][CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20]4)[CH:16]=[CH:17][C:12]3=[N:11][CH:10]=2)=[CH:7][CH:6]=[CH:5][N:4]=1.Cl>CO.C(=O)([O-])O.[Na+]>[CH3:1][O:2][C:3]1[C:8]([C:9]2[N:13]3[N:14]=[C:15]([NH:18][C@@H:19]4[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]4)[CH:16]=[CH:17][C:12]3=[N:11][CH:10]=2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: COc1ncccc1-c1cnc2ccc(N[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)nn12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COc1ncccc1-c1cnc2ccc(N[C@@H]3CCCNC3)nn12
Yield: 102.8 %

Procedure:
A mixture of tert-butyl (3R)-3-{[3-(2-methoxypyridin-3-yl)imidazo[1,2-b]pyridazin-6-yl]-amino}piperidine-1-carboxylate (Preparation 3a, 0.1 g, 0.24 mmol) and a solution of hydrogen chloride in methanol (1.25 N solution, 4 mL) was stirred at ambient temperature for 5 hours. The reaction mixture was then carefully diluted with aqueous saturated sodium hydrogencarbonate solution and extracted with dichloromethane (×3). The organic layer was dried eluting through a Phase Separator® membrane and the solvent removed under reduced pressure to yield the title compound (0.08 g, 98%) as a yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10](=[O:28])[N:11]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23](O)[CH:22]=2)[CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:14]=1)#[N:2].[CH2:29]([N:31](CC)CC)[CH3:30].CS(Cl)(=O)=O>O1CCCC1.C(=O)(O)[O-].[Na+]>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10](=[O:28])[N:11]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH2:30][C:29]#[N:31])[CH:22]=2)[CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:14]=1)#[N:2]
Reactant: N#Cc1ccccc1-c1cc(-c2ccccn2)cn(-c2cccc(O)c2)c1=O
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CCc1cccc(-n2cc(-c3ccccn3)cc(-c3ccccc3C#N)c2=O)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3-(2-Cyanophenyl)-5-(2-pyridyl)-1-(3-hydroxyphenyl)-1,2-dihydropyridin-2-one (53 mg) was dissolved in 2 ml of tetrahydrofuran, then 60 ml of triethylamine and 20 ml of methanesulfonyl chloride were added thereto with ice cooling and the mixture was stirred at room temperature for 3 hours. The reaction solution was diluted with an aqueous solution of sodium bicarbonate and extracted with ethyl acetate and the extract was dried over anhydrous magnesium sulfate. The drying agent was filtered off, the filtrate was concentrated in vacuo, the resulting residue was dissolved in 1 ml of dimethyl sulfoxide, 3 mg of sodium cyanide were added and the mixture was stirred at room temperature for 1 hour. The reaction solution was diluted with ethyl acetate, washed with an aqueous solution of sodium bicarbonate and a saturated saline solution and dried over anhydrous magnesium sulfate. The drying agent was filtered off, the filtrate was concentrated in vacuo and the resulting crude crystals were recrystallized from ethyl acetate-diethyl ether-hexane to give 12 mg of the title compound.
Reaction SMILES: [CH2:1]([C:13]1[CH:26]=[C:25]2[C:16]([N:17]=[C:18]3[C:23](=[C:24]2O)[CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:15][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].O=P(Cl)(Cl)[Cl:30]>>[Cl:30][C:24]1[C:25]2[C:16]([N:17]=[C:18]3[C:23]=1[CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:15][CH:14]=[C:13]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH:26]=2
Reactant: CCCCCCCCCCCCc1ccc2nc3c(c(O)c2c1)CCCC3
Reactant: O=P(Cl)(Cl)Cl
Product: CCCCCCCCCCCCc1ccc2nc3c(c(Cl)c2c1)CCCC3

Procedure:
Three grams of 7-dodecyl-9-hydroxy-1,2,3,4-tetrahydroacridine was refluxed for 30 minutes in 30 mL of POCl3. At the end of this time the POCl3 was evaporated and the residue distributed between aqueous NH3 and ethyl ether. The organic phase was dried and evaporated to give 9-chloro-7-dodecyl-1,2,3,4-tetrahydroacridine (3.0 g) as a solid. A small sample was recrystallized from methanol to give fine needles, mp 36°-38°.
Reaction SMILES: [CH2:1]([NH:13][CH:14]=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].P(Cl)(Cl)(Cl)(Cl)Cl.[CH:22]([NH:25][CH:26]([CH3:28])[CH3:27])([CH3:24])[CH3:23].[OH-].[Na+]>C1C=CC=CC=1.O>[CH:22]([N:25]([CH:26]([CH3:28])[CH3:27])[CH:14]=[N:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])([CH3:24])[CH3:23]
Reactant: CCCCCCCCCCCCNC=O
Reactant: CC(C)NC(C)C
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: O
Product: CCCCCCCCCCCCN=CN(C(C)C)C(C)C
Reaction time: 12 h

Procedure:
A solution of 213 g of dodecylformamide (1.0 mole) in 500 ml of anhydrous benzene is added dropwise at 20°-30° to a suspension of 208 g of phosphorus pentachloride (1.0 mole) in 750 ml of anhydrous benezne. After a further 12 hours of stirring at 30°, the reaction mixture is concentrated in vacuo to dryness. The residue is then dissolved in 100 ml of anhydrous benzene, and 202 g of di-isopropylamine (2.0 moles) added dropwise at 40°-50°. The whole is heated for 2 hours at 50°; water and ice are added, and the mixture rendered alkaline with aqueous sodium hydroxide solution. The organic layer is then separated and concentrated by evaporation. The N1,N 1 -diisopropyl-N2 -dodecyl-formamidine obtained as residue boils at 125°-128°C and 0.03 Torr.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]=1[C:13]([OH:15])=[O:14])([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]=1[C:13]([OH:15])=[O:14]
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(C(=O)O)c1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(C(=O)O)cc1C(=O)O
Reaction time: 4 h
Yield: 87 %

Procedure:
To a solution of 4-nitro isophthalic acid (98 g, 0.457 mol) in methanol (5 L) was added Pd/C (20%) and hydrogenated at RT for 4 h. The reaction mixture was filtered through celite and filtrate concentrated under vacuum to give 4-amino isophthalic acid (72 g, 87%) as a solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[C:6]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C:5]=1[CH3:21].[Br:23]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[CH3:1][O:2][C:3](=[O:22])[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[C:6]([O:13][Si:14]([C:17]([CH3:18])([CH3:19])[CH3:20])([CH3:15])[CH3:16])[C:5]=1[CH2:21][Br:23]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1c([N+](=O)[O-])ccc(O[Si](C)(C)C(C)(C)C)c1C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1c([N+](=O)[O-])ccc(O[Si](C)(C)C(C)(C)C)c1CBr
Temperature: 80 °C
Reaction time: 22 h
Yield: 124.2 %

Procedure:
To a solution of 3-(tert-butyl-dimethyl-silanyloxy)-2-methyl-6-nitro-benzoic acid methyl ester (8.9 g, 25.1 mmol) and N-bromosuccinimide (5.36 g, 30.1 mmol) in 50 mL of CCl4 is added 2,2′-azobisisobutyronitrile (412 mg, 2.5 mmol) at room temperature. The reaction mixture is stirred at 80° C. for 22 hours and then cooled to room temperature and then quenched by crushed ice. The mixture is extracted with dichloromethane and washed with aqueous NaHCO3 solution followed by brine, dried over Na2SO4, filtered and evaporated in vacuo to afford the 2-bromomethyl-3-(tert-butyl-dimethyl-silanyloxy)-6-nitro-benzoic acid methyl ester (12.6 g) as brown oil. 1H-NMR (400 MHz, δ, ppm) CDCl3: 0.37 (s, 6H), 1.07 (s, 9H), 4.0 (s, 3H), 4.49 (s, 2H), 6.94 (d, 1H), 8.09 (d, 1H).
Reaction SMILES: [C:1]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:13])[CH2:2][C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].[H-].[Na+].[CH3:24][O:25][CH2:26][CH2:27]Br.O>O1CCCC1>[CH2:6]([O:5][C:3](=[O:4])[CH:2]([CH2:27][CH2:26][O:25][CH3:24])[C:1]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(CC(=O)OCc1ccccc1)OCc1ccccc1
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCCC(C(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.6 %

Procedure:
Dibenzyl malonate (28.43 g, 0.1 mole) was added dropwise over 1 hour to a stirred suspension of sodium hydride (3.15 g, 80% dispersion in oil; 0.105 mole) in dry tetrahydrofuran (100 ml) under nitrogen, the temperature being allowed to rise to 40° C. 2-Methoxyethyl bromide (13.9 g, 0.1 mole) was added to the resulting clear solution, which was stirred at room temperature for two hours, and then refluxed overnight. Water was added, and the mixture extracted with methylene chloride. The organic extract on washing with water, drying (MgSO4) and evaporation under vacuum gave a crude liquid (30.94 g). Chromatography on silica gel (700 g) eluting with a mixture of ether and hexane (2:8 by volume) gave 2-methoxyethyl-malonic acid dibenzyl ester as a colourless liquid (15.6 g). This was dissolved in dioxan (150 ml) and a solution of potassium hydroxide (2.55 g, 45.44 mmole) in water (40 ml) added at 0° C. with stirring. The mixture was stirred overnight at room temperature and the solvent was evaporated under vacuum. Water was added and the mixture was extracted with ether to remove unreacted diester. The aqueous phase was then acidified with 2N hydrochloric acid (50 ml) and extracted with ether. The organic extract on washing with water, drying (MgSO4) and evaporation under vacuum gave the mono-ester as a colourless oil (8.95 g, 78%).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5](N)=[C:4]([CH3:9])[CH:3]=1.[C:10]1([O:16][CH3:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(O[N+]([O-])=O)CC(C)C>>[CH3:9][C:4]1[CH:3]=[C:2]([F:1])[CH:8]=[CH:7][C:5]=1[C:13]1[CH:14]=[CH:15][C:10]([O:16][CH3:17])=[CH:11][CH:12]=1
Reactant: COc1ccccc1
Reactant: Cc1cc(F)ccc1N
Agent: CC(C)CCO[N+](=O)[O-]
Product: COc1ccc(-c2ccc(F)cc2C)cc1

Procedure:
A mixture of 9.0 grams of 4-fluoro-2-methyl-aniline, 200 ml. of anisole, and 9.0 grams of iso-amyl-nitrate, is warmed on a steam bath until a vigorous reaction with evolution of gas sets in. This evolution is allowed to proceed without heating until it has subsided, and the mixture is then heated on the steam bath for an additional 3 hours. The excess anisole is removed in vacuo, and the residue is chromatographed on a silica gel column using petroleum-benzin as eluent to yield 4-(2'-methyl-4'-fluorophenyl)-anisole.
Reaction SMILES: [Na].[NH:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.[Cl:7][C:8]1[CH:9]=[C:10]([CH:27]=[CH:28][CH:29]=1)[O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2([CH2:25]Br)[O:22][CH:21]([CH2:23][CH3:24])[CH2:20][O:19]2)=[CH:14][CH:13]=1.[I-].[K+]>CN(C)C=O.O>[Cl:7][C:8]1[CH:9]=[C:10]([CH:27]=[CH:28][CH:29]=1)[O:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2([CH2:25][C:3]3[NH:2][CH:6]=[CH:5][N:4]=3)[O:22][CH:21]([CH2:23][CH3:24])[CH2:20][O:19]2)=[CH:16][CH:17]=1
Reactant: CCC1COC(CBr)(c2ccc(Oc3cccc(Cl)c3)cc2)O1
Reactant: c1c[nH]cn1
Agent: [I-]
Agent: [K+]
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: CCC1COC(Cc2ncc[nH]2)(c2ccc(Oc3cccc(Cl)c3)cc2)O1
Temperature: 25 °C

Procedure:
1.2 parts of imidazole sodium salt, 4 parts of 2-[p-(3chlorophenoxy)phenyl]-2-bromomethyl-4-ethyl-1,3-dioxolane and a catalytic amount of potassium iodide are stirred in 50 ml of dimethyl formamide for 17 hours at a temperature of 125° C. The brown reaction mixture is cooled to room temperature, diluted with 150 ml of water and extracted with three 50 ml portions of ethyl acetate. The combined extracts are washed with two 50 ml portions of water, and dried over sodium sulfate. The solvent is removed by evaporation and the crude product is chromatographed over a 35 cm column of silica gel with acetone/ethyl acetate (1:1). The eluant is removed by evaporation and the oily residue is crystallised from petroleum ether in the form of slightly yellowish crystals with a melting point of 69°-71° C.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH:6]([CH3:8])[CH2:5][N:4]([S:9]([C:12]2[CH:25]=[CH:24][C:23]3[N:22]([CH3:26])[C:21]4[C:16](=[CH:17][C:18]([S:27]([N:30]5[CH2:35][CH:34]([CH3:36])[CH2:33][CH:32]([CH3:37])[CH2:31]5)(=[O:29])=[O:28])=[CH:19][CH:20]=4)[C:15](=S)[C:14]=3[CH:13]=2)(=[O:11])=[O:10])[CH2:3]1.[CH3:39][N:40]([CH2:42][CH2:43][CH2:44][NH2:45])[CH3:41]>N1C=CC=CC=1>[CH3:36][CH:34]1[CH2:33][CH:32]([CH3:37])[CH2:31][N:30]([S:27]([C:18]2[CH:19]=[CH:20][C:21]3[N:22]([CH3:26])[C:23]4[C:14](=[CH:13][C:12]([S:9]([N:4]5[CH2:3][CH:2]([CH3:1])[CH2:7][CH:6]([CH3:8])[CH2:5]5)(=[O:11])=[O:10])=[CH:25][CH:24]=4)[C:15](=[N:45][CH2:44][CH2:43][CH2:42][N:40]([CH3:41])[CH3:39])[C:16]=3[CH:17]=2)(=[O:28])=[O:29])[CH2:35]1
Reactant: CC1CC(C)CN(S(=O)(=O)c2ccc3c(c2)c(=S)c2cc(S(=O)(=O)N4CC(C)CC(C)C4)ccc2n3C)C1
Reactant: CN(C)CCCN
Solvent: c1ccncc1
Product: CC1CC(C)CN(S(=O)(=O)c2ccc3c(c2)c(=NCCCN(C)C)c2cc(S(=O)(=O)N4CC(C)CC(C)C4)ccc2n3C)C1
Temperature: 100 °C
Reaction time: 4 h
Yield: 85.1 %

Procedure:
A mixture of 2,7-bis(3,5-dimethylpiperidin-1-ylsulfonyl)-10-methylacridine-9(10H) thione (145 mg, 0.25 mmole), pyridine (5 mL) and dimethylaminopropylamine (0.125 mL, 1 mmole) was stirred at 100° C. for 4 hrs. Solvent was partially evaporated and reaction product was precipitated by addition of methanol. Precipitate was collected by filtration, washed with methanol and dried to give 137 mg (85%) of the title compound. MS 644 (MH+).
Reaction SMILES: [F-].[K+].O[C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([F:15])[F:14])[CH:7]=[O:8].FC1C=CC=CC=1[N+]([O-])=O.O>CS(C)=O>[F:14][CH:13]([F:15])[O:12][C:11]1[CH:4]=[CH:5][C:6]([CH:7]=[O:8])=[CH:9][CH:10]=1
Reactant: O=Cc1ccc(OC(F)F)c(O)c1
Agent: O=[N+]([O-])c1ccccc1F
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=Cc1ccc(OC(F)F)cc1
Temperature: 140 °C
Reaction time: 3.5 h
Yield: 153.5 %

Procedure:
To a stirred suspension of potassium fluoride (372 mg, 6.4 mmol) in dry DMSO (10 ml) was added a solution of 3-hydroxy-4-difluoromethoxy benzaldehyde (1.0 gm, 5.3 mmol) in DMSO (10 ml). The reaction contents were heated at 140° C. for 10 min. A solution of 2-fluoronitrobenzene (747 mg, 5.3 mmol) in DMSO (5 ml) was added to the above suspension and the reaction mixture was stirred at 140° C. for 3.5 h. The reaction mixture was cooled to room temperature and the contents were poured into water (200 ml) and extracted with ethyl acetate (100 ml×3). The organic extracts were combined and washed with 1N sodium hydroxide (50 ml×2), water and brine and dried over anhydrous sodium sulfite. The dried organic layer was concentrated in vaccuo to obtain 3-2-nitrophenoxy)-4-difluoromethoxy benzaldehyde as a pale yellow solid (1.4 gm).
Reaction SMILES: [C:1]([Si:5]([CH3:23])([CH3:22])[O:6][C@H:7]1[CH2:16][CH2:15][CH2:14][C@@:13]2([CH3:17])[C@H:8]1[CH2:9][CH2:10][CH:11]=[C:12]2[C@H:18]([CH3:21])[CH2:19][OH:20])([CH3:4])([CH3:3])[CH3:2].C(=O)(O)[O-].[Na+]>C(OC(=O)C)C.[Pd]>[C:1]([Si:5]([CH3:23])([CH3:22])[O:6][C@H:7]1[CH2:16][CH2:15][CH2:14][C@@:13]2([CH3:17])[C@H:8]1[CH2:9][CH2:10][CH2:11][C@@H:12]2[C@H:18]([CH3:21])[CH2:19][OH:20])([CH3:3])([CH3:4])[CH3:2]
Reactant: C[C@H](CO)C1=CCC[C@H]2[C@@H](O[Si](C)(C)C(C)(C)C)CCC[C@]12C
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: C[C@H](CO)[C@H]1CCC[C@H]2[C@@H](O[Si](C)(C)C(C)(C)C)CCC[C@]12C
Reaction time: 8 h
Yield: 95.5 %

Procedure:
To a solution of 2.27 g (6.7mMol) of (S)-2-[(4aR,5S,8aS)-5-(tert-butyl-dimethyl-silanyloxy)-8a-methyl-3,4,4a,5,6,7,8,8a-octahydro-naphtalen-1-yl]-propan-1-ol in 22.7 ml of ethylacetate were added 227 mg of Pd/C 10% and 227 mg of sodium bicarbonate. The reaction mixture was stirred under hydrogen atmosphere overnight, filtered over Speedex using ethylacetate for washing thoroughly and the solvent evaporated in vacuo. The residue was chromatographed over a 250 g Lobar column with hexane/ethylacetate 9/1 to yield 2.18 g (95.5%) of (S)-2-[(1R,4aR,5S,8aR)-5-(tert-Butyl-dimethyl-silanyloxy)-8a-methyl-decahydro-naphtalen-1-yl]-propan-1-ol as an oily product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[NH:8][C:7](=O)[C:6]([CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[N:5]2.O=P(Cl)(Cl)[Cl:24]>CN(C)C1C=CN=CC=1>[Cl:24][C:7]1[C:6]([CH:14]=[CH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:5][C:4]2[C:9](=[CH:10][C:11]([F:12])=[C:2]([F:1])[CH:3]=2)[N:8]=1
Reactant: O=c1[nH]c2cc(F)c(F)cc2nc1C=Cc1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Agent: CN(C)c1ccncc1
Product: Fc1cc2nc(Cl)c(C=Cc3ccccc3)nc2cc1F
Yield: 56 %

Procedure:
The above 6,7-difluoro-3-styryl-1H-quinoxalin-2-one (2.65 g, 0.93 mmol) was mixed with 4-dimethylaminopyridine (0.27 g) and POCl3 (27 ml) and the mixture was refluxed for 30 minutes. After cooling, the mixture was poured onto ice (400 ml) and the solid was filtered, washed with water (3×) and dried in vacuo overnight. Column chromatography on silica gel, eluting with ethyl acetate:heptane 1:20 afforded 1.6 g (56%) of the title compound.
Reaction SMILES: O[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[CH:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].[Cl:16][C:17]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:18]=1[NH2:19]>>[Cl:16][C:17]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:18]=1[NH:19][C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[CH:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: Nc1cc(Cl)ccc1Cl
Reactant: CCOC(=O)c1cnc2ccnn2c1O
Product: CCOC(=O)c1cnc2ccnn2c1Nc1cc(Cl)ccc1Cl
Yield: 75.5 %

Procedure:
Using ethyl 7-hydroxypyrazolo[1,5-a]pyrimidine-6-carboxylate (7.50 g, 36.2 mmol) and 2,5-dichloroaniline (5.30 g, 32.6 mmol) instead of 4-fluoro-2-methylaniline, and in the same manner as in Example 1 step 1, the title compound (8.64 g, 68%) was obtained.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:10])([F:9])[C:5]([CH3:8])([OH:7])[CH3:6].[C:11](=O)([O:19]C1C=CC=CN=1)[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1>C1COCC1>[C:11](=[O:19])([O:7][C:5]([CH3:8])([CH3:6])[C:4]([F:10])([F:9])[F:3])[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1
Reactant: O=C(Oc1ccccn1)Oc1ccccn1
Reactant: CC(C)(O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(OC(=O)Oc1ccccn1)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a slurry of NaH (1.03 g, 25.8 mmol) in THF (70 mL) was added 1,1,1-trifluoro-2-methylpropan-2-ol (3 g, 23.42 mmol). The reaction was stirred at 0° C. for 20 min. A solution of dipyridin-2-yl carbonate (5.06 g, 23.42 mmol) in THF (30 mL) was then added to the mixture. The resulting solution was stirred at room temperature for overnight. Filtered the resulting solid byproducts and washed with EtOAc (2×20 mL). The combined organic layers was washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting white pyridin-2-yl (1,1,1-trifluoro-2-methylpropan-2-yl) carbonate (1.24 g, 21%) was directly used as a reagent.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][C:12]([C:14]#N)=[CH:13][C:8]=2[NH:7][C:6]1=[O:16].C(O)=[O:18]>O>[OH:1][CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][C:12]([CH:14]=[O:18])=[CH:13][C:8]=2[NH:7][C:6]1=[O:16]
Reactant: N#Cc1ccc2c(c1)[nH]c(=O)n2CCCO
Reactant: O=CO
Solvent: O
Product: O=Cc1ccc2c(c1)[nH]c(=O)n2CCCO
Temperature: 90 °C
Reaction time: 6.5 h
Yield: 96 %

Procedure:
A mixture of 930 mg (4.28 mmol) of 1-(3-hydroxypropyl)-2-oxo-2,3-dihydro-1H-benzimidazole-5-carbonitrile (Intermediate 13) and 949 mg of Ni—Al alloy 1:1 in 7.3 ml of 75% formic acid in water is stirred at 90° C. for 6.5 hr. After filtration, the residue is again dissolved in 7.3 ml of 75% formic acid, 949 mg of Ni—Al alloy are added and the system is stirred at 90° C. for 1 hr. After filtration, 5 ml of 2N NaOH and 5 ml of EtOH are added and the system is stirred at rt overnight. The pH is made 6-7 by addition of 2N HCl and the solution is concentrated. The residue is chromatographically purified over silicagel eluting with hexane/EtOH (100/0 to 0/100). 0.91 g of pure title compound are obtained (96% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7](Cl)=[N:8][OH:9].[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)#[CH:13].N>>[F:20][C:16]1[CH:15]=[C:14]([C:12]2[O:9][N:8]=[C:7]([C:6]3[CH:5]=[N:4][CH:3]=[C:2]([F:1])[CH:11]=3)[CH:13]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: C#Cc1cccc(F)c1
Reactant: ON=C(Cl)c1cncc(F)c1
Agent: N
Product: Fc1cncc(-c2cc(-c3cccc(F)c3)on2)c1

Procedure:
The titled compound was prepared according to Method CB using the product of Example 28B (88 mg, 0.5 mmol) and 1-ethynyl-3-fluorobenzene (Aldrich, 60 mg, 0.5 mmol). 1H NMR (300 MHz, MeOH-d4) δ 7.20-7.35 (m, 1H), 7.46 (s, 1 H), 7.58 (td, J=8.0, 5.8 Hz, 1H), 7.68 (ddd, J=9.7, 2.5, 1.7 Hz, 1H), 7.76 (dt, J=8.0, 1.1 Hz, 1H), 8.17 (ddd, J=9.4, 2.8, 1.7 Hz, 1H), 8.61 (d, J=2.7 Hz, 1H), 8.97 (t, J=1.5 Hz, 1H) ppm; MS (DCI/NH3) m/z 259 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[N:7]([CH2:9][CH2:10][O:11][C:12]1[CH:17]=[C:16]([NH:18][NH2:19])[N:15]=[C:14]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[N:13]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[N:27]([O-])=O.[Na+].C(OCC)(=O)C>C(O)(=O)C.O>[C:1]([O:5][C:6](=[O:26])[N:7]([CH2:9][CH2:10][O:11][C:12]1[CH:17]=[C:16]([N:18]=[N+:19]=[N-:27])[N:15]=[C:14]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[N:13]=1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=N[O-]
Reactant: CN(CCOc1cc(NN)nc(N2CCOCC2)n1)C(=O)OC(C)(C)C
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CN(CCOc1cc(N=[N+]=[N-])nc(N2CCOCC2)n1)C(=O)OC(C)(C)C

Procedure:
[2-(6-hydrazino-2-morpholin-4-yl-pyrimidin-4-yloxy)-ethyl]-methyl-carbamic acid tert-butyl ester was dissolved in glacial acetic acid (30 mL). To this solution was added a solution of sodium nitrite (1.3 g) in water (4 mL). The reaction was stirred for ten minutes, and poured into ethyl acetate (100 mL). The organic layer was then washed with water (100 mL) and 10% sodium carbonate (2×100 mL). The organic layer was dried over magnesium sulfate and evaporated to give [2-(6-azido-2-morpholin-4-yl-pyrimidin-4-yloxy)-ethyl]-methyl-carbamic acid tert-butyl ester, which was used without purification in the next reaction.
Reaction SMILES: [N:1]([C:4]1[N:5]=[CH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:2]=S.Cl.Cl.[NH2:16][CH2:17][C@@:18]1([OH:25])[C@@H:23]2[CH2:24][N:20]([CH2:21][CH2:22]2)[CH2:19]1>>[CH:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:13]=[C:4]([NH:1][C:2]2[O:25][C@@:18]3([C@@H:23]4[CH2:24][N:20]([CH2:21][CH2:22]4)[CH2:19]3)[CH2:17][N:16]=2)[N:5]=1
Reactant: NC[C@]1(O)CN2CC[C@H]1C2
Reactant: S=C=Nc1cc2ccccc2cn1
Agent: Cl
Product: c1ccc2cc(NC3=NC[C@@]4(CN5CC[C@H]4C5)O3)ncc2c1
Yield: 26 %

Procedure:
3-Isothiocyanatoisoquinoline and (3S*,4S*)-3-(aminomethyl)-1-azabicyclo[2.2.1]heptan-3-ol dihydrochloride were reacted according to the method of EXAMPLE 6, STEP B to afford (3R*,4S*)—N-(isoquinolin-3-yl)-4′H-1-azaspiro[bicyclo[2.2.1]heptane-3,5′-oxazol]-2′-amine (80 mg, 0.27 mmol, 26% yield).