Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([CH3:8])([CH3:7])[CH2:3][C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[K+].[K+].F[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N+:22]([O-:24])=[O:23]>CCO>[CH3:7][C:2]([NH:1][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N+:22]([O-:24])=[O:23])([CH3:8])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: CC(C)(N)CC(=O)O
Reactant: O=[N+]([O-])c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(C)(CC(=O)O)Nc1ccccc1[N+](=O)[O-]
Yield: 78.5 %

Procedure:
A round bottomed flask was charged with 3-amino-3-methylbutanoic acid (1.452 g, 12.39 mmol), potassium carbonate (2.57 g, 18.59 mmol), and a stirbar. EtOH (20 mL, 0.5 M) was added, followed by 1-fluoro-2-nitrobenzene (2.84 ml, 15.49 mmol), and the solution was stirred at reflux overnight. The mixture was cooled, concentrated with celite, and purified by silica gel chromatography (eluting with methylene chloride/methanol/ammonium hydroxide) to yield 3-methyl-3-(2-nitrophenylamino)butanoic acid as a red solid (2.32 g, 9.73 mmol, 79%).
Reaction SMILES: [CH:1]([C:3]1[N:4]=[C:5]2[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:9][CH:8]=[N:7][N:6]2[C:17]=1[C:18]1[CH:30]=[CH:29][C:21]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:20][CH:19]=1)=[O:2].O1CCOCC1.CO.[BH4-].[Na+]>O>[OH:2][CH2:1][C:3]1[N:4]=[C:5]2[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:9][CH:8]=[N:7][N:6]2[C:17]=1[C:18]1[CH:30]=[CH:29][C:21]([C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2c(C=O)nc3c(N4CCOCC4)ccnn23)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)c1ccc(-c2c(CO)nc3c(N4CCOCC4)ccnn23)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Compound 5f (315 mg, 0.772 mmol) was placed in a 40 mL vial equipped with a stir bar and then dioxane (10 mL) and MeOH (10 mL) were added. NaBH4 (51.0 mg, 1.35 mmol) was added and then the reaction was stirred at rt for 18 h. The reaction was diluted with water (20 mL) and the mixture was extracted with DCM (3×25 mL). The organic extracts were combined, dried over Na2SO4, and filtered. The solvent was removed under reduced pressure to afford compound 34a. 1H-NMR (400 MHz, CDCl3) δ (ppm): 8.09-8.17 (m, 2H), 8.06 (d, J=5.6 Hz, 1H), 7.75-7.86 (m, 2H), 6.15 (d, J=5.6 Hz, 1H), 4.86 (d, J=5.6 Hz, 2H), 3.87-4.05 (m, 8H), 2.52 (t, J=5.6 Hz, 1H), 1.61 (s, 9H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C22H26N4O4: 411.2 (M+H). Found: 411.4.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH2:18][CH:19]1[O:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+]>C(O)(C)C>[OH:21][CH:19]([CH2:18][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[O:10][CH3:9])[CH2:20][N:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1
Reactant: COc1ccccc1OCC1CO1
Reactant: O=C1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: COc1ccccc1OCC(O)CN1CCC(=O)CC1
Temperature: 60 °C
Reaction time: 6 h

Procedure:
A mixture of 20 g of the hydrate of 4-piperidone-hydrochloride, 46.8 g of 1-(2-methoxyphenyloxy)-2,3-epoxy-propane, 18 g of potassium carbonate and 250 ml of isopropanol is stirred for 6 hours at a reaction temperature of 60° C. After cooling, the suspension is filtered and the filtrate is evaporated to dryness under reduced pressure. The residue is dissolved in 100 ml of 6N hydrochloric acid and washed with four 75 ml portions of ethyl acetate. The aqueous acid solution is adjusted with a 2N sodium carbonate solution to a pH of 10 and extracted with three 75 ml portions of ethyl acetate. The organic extracts are dried over sodium sulphate and concentrated under reduced pressure. The red residue is dissolved in methanol and the solution is boiled for 30 minutes with the addition of activated charcoal. The solution is filtered and the filtrate is concentrated under reduced pressure. The residue is treated with toluene and recrystallised from a mixture of ethyl acetate and petroleum ether to give 1-[2-hydroxy-(2-methoxyphenyloxy)-propyl]-piperidin-4-one with a melting point of 77°-78° C.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:8]O)=[N:4][N:5]([CH3:7])[CH:6]=1.S(Cl)([Cl:12])=O>C(Cl)Cl>[Cl:12][CH2:8][C:3]1[C:2]([F:1])=[CH:6][N:5]([CH3:7])[N:4]=1
Reactant: Cn1cc(F)c(CO)n1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cn1cc(F)c(CCl)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a 25 mL round-bottomed flask containing (4-fluoro-1-methyl-1H-pyrazol-3-yl)methanol (285 g, 2.2 mmol) in dry DCM (10 mL), was added thionyl chloride (0.3 mL, 4.4 mmol). The reaction mixture was stirred at RT for 2 h then concentrated to dryness to provide the title compound, which was carried forward without further purification.
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=2)=[C:5]([O:19][CH3:20])[CH:4]=1)=O.[O:21]1[CH2:26][CH2:25][CH:24]([CH2:27][CH2:28][NH2:29])[CH2:23][CH2:22]1>>[CH3:20][O:19][C:5]1[CH:4]=[C:3]([CH2:1][NH:29][CH2:28][CH2:27][CH:24]2[CH2:25][CH2:26][O:21][CH2:22][CH2:23]2)[CH:18]=[CH:17][C:6]=1[O:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=1
Reactant: NCCC1CCOCC1
Reactant: COc1cc(C=O)ccc1Oc1ccc(C(N)=O)cn1
Product: COc1cc(CNCCC2CCOCC2)ccc1Oc1ccc(C(N)=O)cn1
Yield: 76.8 %

Procedure:
Using a method similar to Example 405, a reaction of 6-(4-formyl-2-methoxyphenoxy)nicotinamide (Example 414, Part B) (0.050 g, 0.184 mmol) and 2-(tetrahydropyran-4-yl)ethylamine (0.0237 g, 0.184 mmol) gives the title compound (0.0545 g, 77.0%): TOF MS ES+ 386.2 (M+H)+, HRMS calcd for C21H28N3O4 386.2080 (M+H)+, found 386.2076, time 0.39 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 20-99% over 23 min], tR=4.3 min, 100% purity.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=O)[CH:8]=[CH:9][CH:10]=1.[Cl-].[CH2:16]([O:23][C:24]1[CH:49]=[CH:48][CH:47]=[CH:46][C:25]=1[CH2:26][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.N12CCCN=C1CCCCC2>C(#N)C>[CH2:16]([O:23][C:24]1[CH:49]=[CH:48][CH:47]=[CH:46][C:25]=1[CH:26]=[CH:13][CH:12]=[CH:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([O:4][CH2:3][O:2][CH3:1])[CH:6]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COCOc1cccc(C=CC=O)c1
Reactant: c1ccc(COc2ccccc2C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: COCOc1cccc(C=CC=Cc2ccccc2OCc2ccccc2)c1
Yield: 88.6 %

Procedure:
Following a procedure similar to that described in the first part of Preparation 3, 7.00 g of 3-(3-methoxymethoxyphenyl)-2-propenal and 18 g of 2-benzyloxybenzyltriphenylphosphonium chloride (prepared as described in Preparation 1) were dissolved in 200 ml of acetonitrile, with heating, and 5.54 g of 1,8-diazabicyclo[5,4,0]undec-7-ene were added to the mixture and reacted. The crude product, extracted as described in Preparation 3, was purified as described in Preparation 3, to give 12.0 g of 1-(2-benzyloxyphenyl)-4-(3-methoxymethoxyphenyl)butadiene as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[N:12]=[N:13][N:14]=[C:7]1[N:6]=[C:5]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[BH4-].[Na+].O>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[N:12]=[N:13][N:14]=[C:7]1[NH:6][CH:5]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Clc1ccc2c(c1)c(-c1ccccc1)nc1nnnn12
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Clc1ccc2c(c1)C(c1ccccc1)Nc1nnnn1-2
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.8 %

Procedure:
To a suspension of 1.3 g of 7-chloro-5-phenyltetrazolo[1,5-a]quinazoline in 100 ml of ethanol was added 0.2 g of sodium borohydride. The mixture was stirred at room temperature for 1 hour and then poured into 200 ml of water. The resulting precipitate was collected by filtration, washed with water and recrystallized from methanol to give 0.98 g of 7-chloro-4,5-dihydro-5-phenyltetrazolo[1,5-a]quinazoline as colorless needles, m.p. 260°-261° C. (decomp.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH2:4][C:5]([CH:7]1[CH2:9][CH2:8]1)=O.C([O:13][C:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH2:21])C.[C:23]1(C)C=CC=CC=1>C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:1]([O:2][C:3]([C:4]1[C:14](=[O:13])[C:15]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[NH:21][C:5]=1[CH:7]1[CH2:9][CH2:8]1)=[O:10])[CH3:23]
Reactant: CCOC(=O)c1ccccc1N
Reactant: COC(=O)CC(=O)C1CC1
Reactant: Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCOC(=O)c1c(C2CC2)[nH]c2ccccc2c1=O
Temperature: 120 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
A solution of 3-cyclopropyl-3-oxo-propionic acid methyl ester (6.2 g, 0.038 mols), 2-amino benzoic acid ethyl ester (4.95 g, 0.03 mols) and p-toluene sulfonic acid (0.04 g, 0.2 mmols) in toluene (25 ml) was heated at 125° C. for 2 h; 15 ml of solvent was then distilled. To the residual orange solution was added sodium ethoxide (2 M, 15 ml) in ethanol (reaction mixture turns red). This red mixture was stirred at 120° C. for 2 h; 15 ml of solvent was again distilled. The reaction mixture was left to cool to room temperature, diluted with ethyl acetate (1 litre), extracted with HCl 0.1 M and water. The combined organic extracts were dried over sodium sulfate and concentrated in vacuo to leave an orange residue which was washed once with cold ethyl acetate to yield 2-cyclopropyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid ethyl ester (3.87 g, 53%) as an off-white solid. LCMS m/z 244.14 [M+H]+ @ RT 0.78 min, 89%, m/z 230.11 [Acid+H]+ @ RT 1.27, 11%. δH (400 MHz, (CD3)2SO) 11.04 (1H, s), 8.06 (1H, dd, J1 1.1, J2 8.1), 7.76-7.66 (2H, m), 7.36 (1H, td, J1 1.1, J2 7.5), 3.89 (3H, s), 2.16 (1H, m), 1.18 (4H, d, J 7.0). Step 2 4-Chloro-2-cyclopropyl-quinoline-3-carboxylic acid ethyl ester
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[CH:4]([C:9]1[CH:10]=[C:11]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[CH:12]=[C:13](OS(C(F)(F)F)(=O)=O)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7].[NH:34]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH2:37][CH2:36][CH2:35]1>>[CH3:1][O:2][C:3](=[O:33])[CH:4]([C:9]1[CH:10]=[C:11]([C:23]2[CH:24]=[CH:25][C:26]([C:29]([F:32])([F:30])[F:31])=[CH:27][CH:28]=2)[CH:12]=[C:13]([N:34]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH2:37][CH2:36][CH2:35]2)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)C(CC(C)C)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: c1ccc2c(c1)CCCN2
Product: COC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(N2CCCc3ccccc32)c1
Yield: 25 %

Procedure:
The title compound was prepared in 25% yield from 4-methyl-2-(5-trifluoromethanesulfonyloxy-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid methyl ester and 1,2,3,4-tetrahydroquinoline under the conditions described in Example 24, steps (a).
Reaction SMILES: NC(N)=N.[CH:5](=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N)CC1C=CC=CC=1.[N+:22]([CH3:25])([O-:24])=[O:23]>>[N+:22]([CH2:25][CH:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:12])([O-:24])=[O:23]
Reactant: O=Cc1ccccc1
Reactant: C[N+](=O)[O-]
Agent: N=C(N)N
Agent: NCCc1ccccc1
Product: O=[N+]([O-])CC(O)c1ccccc1
Yield: 31 %

Procedure:
In recent years, attention has been paid to optically active guanidine compounds as base catalysts for asymmetric nucleophilic-type reactions, a representative of which is an asymmetric aldol-type reaction. However, all of the previously known optically active guanidine compounds have central chirality as a chiral element, and it cannot be said that molecular design based on only such the central chirality is sufficient to draw the potential usefulness of such optically active guanidine compounds. As one of the reactions using an optically active guanidine compound which is constructed based on central chirality as an asymmetric base catalyst, a nitroaldol reaction is reported (Non-Patent Literature 1: Tetrahedron: Asymmetry, 1994, 5, 1393; Non-Patent Literature 2: Tetrahedron Lett., 2003, 44, 8677). The Non-Patent Literature 1 disclosed that in the aldol condensation between benzaldehyde and nitromethane, optically active guanidines having a phenethylamine skeleton as an optically active site are used as an asymmetric catalyst, and 2-nitro-1-phenylethanol is obtained in a yield of 31% and an asymmetric yield of 33% ee.
Reaction SMILES: [O:1]=[C:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][NH:16][CH2:15][C:14]3=[O:19])=[CH:10][C:5]=2[CH2:4][O:3]1.Br[CH2:21][CH2:22][C:23]1[CH:32]=[CH:31][C:26]2[C:27](=[O:30])[O:28][CH2:29][C:25]=2[CH:24]=1>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[O:1]=[C:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][N:16]([CH2:21][CH2:22][C:23]4[CH:32]=[CH:31][C:26]5[C:27](=[O:30])[O:28][CH2:29][C:25]=5[CH:24]=4)[CH2:15][C:14]3=[O:19])=[CH:10][C:5]=2[CH2:4][O:3]1
Reactant: O=C1OCc2cc(CCN3CCNCC3=O)ccc21
Reactant: O=C1OCc2cc(CCBr)ccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Product: O=C1OCc2cc(CCN3CCN(CCc4ccc5c(c4)COC5=O)C(=O)C3)ccc21
Temperature: 55 °C

Procedure:
To a solution of 1-[2-(1-Oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-2-one (30 mg, 0.12 mmol) and 5-(2-Bromoethyl)-2-benzofuran-1(3H)-one (56 mg, 0.23 mmol) in DMF (2 ml) was added TEA (0.048 ml, 0.35 mmol) and tetrabutylammonium iodide (4.3 mg, 0.012 mmol). The mixture was heated to 55° C. for 16 hours. LC showed formation of the desired product, which was purified by mass-directed reverse phase HPLC (AcCN-Water with 0.1% TFA). LC-MS (IE, m/z): 421 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([F:11])[C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:12])[CH:3]=1.S(Cl)(Cl)=O.[CH3:17]N(C=O)C.Cl>C(Cl)Cl.CO>[CH3:17][O:7][C:6](=[O:8])[C:5]1[C:4]([F:12])=[CH:3][C:2]([Br:1])=[CH:10][C:9]=1[F:11]
Reactant: O=C(O)c1c(F)cc(Br)cc1F
Reactant: CN(C)C=O
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1c(F)cc(Br)cc1F
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a suspension of 4-Bromo-2,6-difluoro-benzoic acid (5 g, 21 mmol) in DCM (10 mL) is added thionyl chloride (15 mL) and DMF (0.5 mL). The mixture is stirred at room temperature for 2.5 h. It is then cooled to 0° C. and MeOH (20 mL) is added carefully causing vigorous HCl evolution. After stirring for an additional 0.5 h, the clear solution is partitioned between DCM (50 mL) and water (50 mL). The organic layer is washed with saturated NaHCO3, brine, dried over MgSO4 and the solvent is removed under vacuum to afford the title compound as a pale yellow oil which is used without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]1[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8]1.[CH3:17][O:18][NH:19][C:20](=O)[O:21]C1C=CC([N+]([O-])=O)=CC=1.C(N(CC)C(C)C)(C)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl.O>[CH3:17][O:18][NH:19][C:20]([N:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:15][CH2:16][CH:7]1[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)=[O:21]
Reactant: CONC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: c1ccc(C2CCc3ccccc3N2)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: CONC(=O)N1c2ccccc2CCC1c1ccccn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 94.7 %

Procedure:
A solution of 2-pyridin-2-yl-1,2,3,4-tetrahydroquinoline (0.723 g, 3.44 mmol) in methylene chloride (10.3 mL) was treated with 4-nitrophenyl methoxycarbamate (0.948 g, 4.47 mmol) (Org. Process Res. Dev. 2012, 16, 109-116) followed by the dropwise addition of N,N-diisopropylethylamine (1.20 mL, 6.88 mmol), and the resulting mixture was stirred at room temperature for 1.5 h. The reaction mixture was then poured over water (25 mL) and saturated sodium bicarbonate (25 mL) and extracted with dichloromethane (2×50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give a crude oily solid. Purification by flash column chromatography (100% hexanes to 20% ethyl acetate/hexanes [the ethyl acetate contained 5% methanol]) gave the desired product (0.923 g, 95%) as a racemic mixture. LCMS calculated for C16H18N3O2 (M+H)+: m/z=284.1. found: 284.0.
Reaction SMILES: [CH2:1]([N:4]([CH2:16][CH:17]=[CH2:18])[C:5]1[C:6]2[S:14][CH:13]=[C:12]([CH3:15])[C:7]=2[N:8]=[C:9]([Cl:11])[N:10]=1)[CH:2]=[CH2:3].[CH2:19]([NH2:22])[CH:20]=[CH2:21].C(=O)([O-])O.[Na+]>>[ClH:11].[CH2:19]([NH:22][C:9]1[N:10]=[C:5]([N:4]([CH2:16][CH:17]=[CH2:18])[CH2:1][CH:2]=[CH2:3])[C:6]2[S:14][CH:13]=[C:12]([CH3:15])[C:7]=2[N:8]=1)[CH:20]=[CH2:21]
Reactant: C=CCN(CC=C)c1nc(Cl)nc2c(C)csc12
Reactant: C=CCN
Agent: O=C([O-])O
Agent: [Na+]
Product: C=CCNc1nc(N(CC=C)CC=C)c2scc(C)c2n1
Product: Cl

Procedure:
In a sealed tube were heated 335 mg (1.2 mmol) of 4-diallylamino-2-chloro-7-methylthieno[3,2-d]pyrimidine and 1.10 g (19.2 mmol) of allylamine at 140° C. for 16 hours. After completion of the reaction, the reaction mixture was allowed to resume room temperature, and a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with ethyl acetate (50 ml×2). The organic layer was washed with brine and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate-hexane=1/4) to give 277 mg (yield: 77.0%) of a free base compound of the title compound.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:27])=[C:5]([C:23]([O:25][CH3:26])=[O:24])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:18][O:19]C(=O)C)[C:7]=1[C:8]([O:10][CH3:11])=[O:9].CO.C(=O)([O-])[O-].[K+].[K+]>CCOCC>[CH3:1][C:2]1[NH:3][C:4]([CH3:27])=[C:5]([C:23]([O:25][CH3:26])=[O:24])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:18][OH:19])[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1ccccc1COC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CO
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1ccccc1CO
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a 100 ml round bottomed flask with a magnetic stirring bar was added the compound (1d) (1.27 g, 3.40 mmol) methanol (50 ml), and powdered anhydrous potassium carbonate (14 mg, 1 mmol). The mixture was stirred for 5 hours at room temperature. The reaction mixture was then diluted with ether (200 ml) and was washed with water (2×75 ml) and brine (1×100 ml). Drying (MgSO4), filtration and removal of the solvent in vacuo. Recrystallization of the residue from boiling ethyl acetate-hexanes gave the compound (1e) as white crystals: mp 218°-220° C. 'H NMR (CDCl3) δ2.25 (s, 6H), 3.55 (s, 6H), 4.35 (br d, 1H, J=6 Hz), 4.85 (d, 2H, J=6 Hz), 5.13 (s, 1H), 5.93 (br s, 1H), 7.00-7.40 (m, 4H). Anal. Calcd. for C18H21NO5 : C, 65.24; H, 6.39; N, 4.23. Found: C, 65.44; H, 6.41; N, 4.41.
Reaction SMILES: Cl.O1CCOCC1.C(OC(=O)[NH:14][CH:15]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH2:29][C:30]2[O:34][N:33]=[C:32]([C:35]3[CH:40]=[CH:39][C:38]([CH2:41][CH:42]4[O:46][CH2:45][CH2:44][O:43]4)=[CH:37][CH:36]=3)[N:31]=2)[CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(C)(C)C>CO>[CH3:45][O:46][CH:42]([O:43][CH3:44])[CH2:41][C:38]1[CH:37]=[CH:36][C:35]([C:32]2[N:31]=[C:30]([CH2:29][O:28][C:24]3[CH:23]=[C:22]([CH:15]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[NH2:14])[CH:27]=[CH:26][CH:25]=3)[O:34][N:33]=2)=[CH:40][CH:39]=1
Reactant: CC(C)(C)OC(=O)NC(c1ccccc1)c1cccc(OCc2nc(-c3ccc(CC4OCCO4)cc3)no2)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COC(Cc1ccc(-c2noc(COc3cccc(C(N)c4ccccc4)c3)n2)cc1)OC
Yield: 96.6 %

Procedure:
Hydrogen chloride in dioxan (4.0 M, 5 mL, 24 mmol) was added to a solution of tert-butyl((3-((3-(4-((1,3-dioxolan-2-yl)methyl)phenyl)-1,2,4-oxadiazol-5-yl)methoxy)phenyl)(phenyl)methyl)carbamate (1.01 g, 1.85 mmol) in methanol (5 mL), and the resultant solution was stirred at ambient temperature for 2 hours. The solvent was evaporated at reduced pressure, and the residue was loaded onto an SCX-2 cartridge. The cartridge was eluted with methanol (eight column volumes) followed by ammonia/methanol. Fractions containing the product were combined and evaporated at reduced pressure to afford the title compound (0.796 g, 96%).
Reaction SMILES: [CH2:1]([N:17]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]#[N:42])[CH:36]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[O:43]1CCO[CH2:45][CH2:44]1.[ClH:49]>C(O)C.C1C=CC=CC=1>[ClH:49].[ClH:49].[CH2:44]([O:43][C:41](=[NH:42])[C:37]1[CH:38]=[CH:39][CH:40]=[C:35]([CH2:34][N:17]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:36]=1)[CH3:45]
Reactant: C1COCCO1
Reactant: CCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCC)Cc1cccc(C#N)c1
Agent: Cl
Solvent: CCO
Solvent: c1ccccc1
Product: CCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCC)Cc1cccc(C(=N)OCC)c1
Reaction time: 8 h
Yield: 100 %

Procedure:
A mixture of α-[N,N-di(n-hexadecyl)amino]-m-toluonitrile (29.0 g., 0.05 mole), ethanol (40 ml., 0.67 mole) and dioxane (100 ml.) was saturated with dry hydrogen chloride gas for 40 minutes at 15°-25° C. It was then stoppered and held overnight at room temperature. Thin layer chromatography analysis (4:1, benzene:ethanol on silica gel) indicated complete reaction of the nitrile. The mixture was evaporated in vacuo yielding the named product quantitatively as a foam [35.0 g., ~ 100% yield, Rf .87 (4:1, benzene: ethanol on silica gel)].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:18][NH2:19])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[CH:12]=[N:13][C:14]([CH3:17])=[CH:15][CH:16]=1.Cl[C:21]1[C:26]([N+:27]([O-:29])=[O:28])=[CH:25][C:24]([I:30])=[CH:23][N:22]=1.C(N(CC)C(C)C)(C)C>C(#N)C.O>[I:30][C:24]1[CH:25]=[C:26]([N+:27]([O-:29])=[O:28])[C:21]([NH:19][CH2:18][C:5]2[CH:6]=[CH:7][C:8]([O:9][CH2:10][C:11]3[CH:12]=[N:13][C:14]([CH3:17])=[CH:15][CH:16]=3)=[C:3]([O:2][CH3:1])[CH:4]=2)=[N:22][CH:23]=1
Reactant: COc1cc(CN)ccc1OCc1ccc(C)nc1
Reactant: O=[N+]([O-])c1cc(I)cnc1Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1cc(CNc2ncc(I)cc2[N+](=O)[O-])ccc1OCc1ccc(C)nc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 94.8 %

Procedure:
To a stirred solution of (3-methoxy-4-((6-methylpyridin-3-yl)methoxy)phenyl)methanamine (7.30 g, 28.26 mmol) in acetonitrile (200 mL) was added 2-chloro-5-iodo-3-nitropyridine (8.44 g, 29.67 mmol) and N,N-diisopropylethylamine (5.48 g, 42.39 mmol). The brown mixture was heated to reflux. After 5 h, the brown mixture was allowed to cool to room temperature and was diluted with water (600 mL). The resulting precipitate was isolated by filtration and washed with water (200 mL). The moist solids were dissolved in ethyl acetate (300 mL), and this solution was washed with water (100 mL). The organic phase was dried over magnesium sulfate, filtered, and concentrated to provide 13.57 g (95%) of 5-iodo-N-(3-methoxy-4-((6-methylpyridin-3-yl)methoxy)benzyl)-3-nitropyridin-2-amine as a bright yellow solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH:13]([F:15])[F:14])[CH:10]=2)[C:5]([CH2:16][C:17]2[C:22]([Cl:23])=[CH:21][N:20]=[CH:19][C:18]=2[Cl:24])=[N:4][N:3]=1.[OH2:25]>N1CCOCC1>[Cl:23][C:22]1[CH:21]=[N:20][CH:19]=[C:18]([Cl:24])[C:17]=1[CH2:16][C:5]1[C:6]2[C:11](=[CH:10][C:9]([O:12][CH:13]([F:14])[F:15])=[CH:8][CH:7]=2)[C:2]([N:20]2[CH2:21][CH2:22][O:25][CH2:18][CH2:19]2)=[N:3][N:4]=1
Reactant: FC(F)Oc1ccc2c(Cc3c(Cl)cncc3Cl)nnc(Cl)c2c1
Reactant: O
Solvent: C1COCCN1
Product: FC(F)Oc1ccc2c(Cc3c(Cl)cncc3Cl)nnc(N3CCOCC3)c2c1
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 96 %

Procedure:
A suspension under N2 of 4-chloro-1-(3,5-dichloro-pyridin-4-ylmethyl)-6-difluoromethoxy-phthalazine (5.5 g, 14.1 mmoles), prepared as described in example 99, in morpholine (11 ml) was heated at 100° C. for 1 hour, then cooled and poured into water (150 ml). A solid formed and was stirred for 15 minutes, then filtered, washed with water, dried over P2O5 at 50° C. under high vacuum. There were obtained 6 g of the title compound (yield: 96%). m.p.: 128.6-130.6° C.