Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:12]=[C:11]([CH2:13][N:14]2[C:18]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([N:26]4[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]4=[O:33])=[N:24][CH:25]=3)=[CH:17][N:16]=[CH:15]2)[CH:10]=[CH:9][C:6]=1[C:7]#[N:8].[C:34](OC(=O)C)(=[O:36])[CH3:35].CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:32][C:30]1[CH:29]=[CH:28][C:27](=[O:33])[N:26]([C:23]2[CH:22]=[CH:21][C:20]([CH2:19][C:18]3[N:14]([CH2:13][C:11]4[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([CH:12]=4)[O:4][CH2:3][CH2:2][NH:1][C:34](=[O:36])[CH3:35])[CH:15]=[N:16][CH:17]=3)=[CH:25][N:24]=2)[CH:31]=1
Reactant: N#Cc1ccc(Cn2cncc2Cc2ccc(-n3cc(Cl)ccc3=O)nc2)cc1OCCN
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)NCCOc1cc(Cn2cncc2Cc2ccc(-n3cc(Cl)ccc3=O)nc2)ccc1C#N
Reaction time: 2 h

Procedure:
2-(2-Amino-ethoxy)-4-[5-(5-chloro-2-oxo-2H-[1,2']bipyridinyl-5'-ylmethyl)-imidazol-1-ylmethyl]-benzonitrile (L-824,459, 50 mg, 0.11 mmol) was dissolved in CH2Cl2 (550 , μl) and treated with acetic anhydride (208 μl, 0.22 mmol). DIEA was then added until pH=7-8. The reaction mixture was stirred at room temp. for 2 hours. Saturated NaHCO3 was added (10 mL) and the solution was extracted with CH2Cl2 (2×10 mL). The organic layer was washed with brine, dried (MgSO4), filtered, and concentrated to yield the final product.
Reaction SMILES: [N+:1]([C:4]1[C:13]2[O:12][CH2:11][CH2:10][O:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.C1C2C(=C(N[C:24](=[O:26])[CH3:25])C=CC=2)CC1.C1(NC(=O)C)C2CCCCC=2C=CC=1>>[O:9]1[C:8]2[CH:7]=[CH:6][CH:5]=[C:4]([NH:1][C:24](=[O:26])[CH3:25])[C:13]=2[O:12][CH2:11][CH2:10]1
Reactant: CC(=O)Nc1cccc2c1CCC2
Reactant: O=[N+]([O-])c1cccc2c1OCCO2
Agent: CC(=O)Nc1cccc2c1CCCC2
Product: CC(=O)Nc1cccc2c1OCCO2

Procedure:
Compound 8C was prepared from 8B by procedures analogous to those described in Experiment 3A and 2A.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].[CH2:7]([O:9][C:10](=[O:14])[CH:11]=[N+:12]=[N-:13])[CH3:8]>>[CH3:1][Si:2]([CH3:4])([CH3:3])[C:5]1[CH:6]=[C:11]([C:10]([O:9][CH2:7][CH3:8])=[O:14])[NH:12][N:13]=1
Reactant: C#C[Si](C)(C)C
Reactant: CCOC(=O)C=[N+]=[N-]
Product: CCOC(=O)c1cc([Si](C)(C)C)n[nH]1
Temperature: 95 °C

Procedure:
To a flame dried sealed tube equipped with a stir bar that was cooled under argon was added trimethylsilylacetylene (1.0 mL, 9.56 mmol) and ethyldiazoacetate (1.5 mL, 9.6 mmol). The tube was then sealed and heated to 95° C. over night. The next day the reaction was cooled to room temperature and the resulting mixture diluted with hexanes. It was then filtered. The precipitate was then washed with hexanes twice. It was then used without any further purification.
Reaction SMILES: C[O:2][C:3](=[O:32])[C:4](=[O:31])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[C:20]([CH:21]([CH3:23])[CH3:22])=[CH:19][CH:18]=[CH:17][C:16]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[CH:7][CH:6]=1.[OH-].[K+]>CO.O1CCCC1>[F:30][C:27]1[CH:28]=[CH:29][C:24]([C:16]2[CH:17]=[CH:18][CH:19]=[C:20]([CH:21]([CH3:23])[CH3:22])[C:15]=2[O:14][CH2:13][CH2:12][O:11][C:8]2[CH:7]=[CH:6][C:5]([C:4](=[O:31])[C:3]([OH:32])=[O:2])=[CH:10][CH:9]=2)=[CH:25][CH:26]=1
Reactant: COC(=O)C(=O)c1ccc(OCCOc2c(-c3ccc(F)cc3)cccc2C(C)C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)c1cccc(-c2ccc(F)cc2)c1OCCOc1ccc(C(=O)C(=O)O)cc1
Yield: 66.7 %

Procedure:
As in Example 19, 4-[2-[4'-fluoro-3-(1-methylethyl)[1,1'-biphenyl]-2-yloxy]ethoxy]-alpha-oxobenzeneacetic acid methyl ester (0.186 g) in a mixture of methanol (2 mL) and tetrahydrofuran (1 mL) was treated with 1N potassium hydroxide (0.52 mL). The usual work up gave 0.17 g of a solid, which after crystallization from diethyl ether-hexane afforded 0.12 g of 4-[2-[4'-fluoro-3-(1-methylethyl)[1,1'-biphenyl]-2-yloxy]ethoxy]-alpha-oxobenzeneacetic acid, mp 123°-125° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12](=[O:14])[CH3:13])[CH:6]=[CH:5]2.[F:15][C:16]([Si](C)(C)C)([F:18])[F:17].Cl>[F-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([OH:14])([CH3:13])[C:16]([F:18])([F:17])[F:15])[CH:6]=[CH:5]2
Reactant: CC(=O)c1ccc2cc(Br)ccc2n1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: CN(C)C=O
Product: CC(O)(c1ccc2cc(Br)ccc2n1)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 105.1 %

Procedure:
A DMF (5 ml) solution of 1-(6-bromoquinolin-2-yl)ethanone (129 mg, 0.52 mmol), (trifluoromethyl)trimethylsilane (220 mg, 1.55 mmol) and tetrabutylammonium fluoride (13.5 mg, 0.052 mmol) was stirred at 100° C. for 2 hours. Then the mixture was cooled to room temperature and 1N-hydrochloride aqueous solution (2 ml) was added. After 4 hours, the mixture was quenched with saturated sodium bicarbonate aqueous solution, and the product was extracted with ethyl acetate which was dried over sodium sulfate. Then, filtration, evaporation and purification through silica gel column chromatography, eluting with hexane/ethyl acetate (4:1), furnished the title compound (175 mg, quant.) as a white solid. 1H NMR (300 MHz, CDCl3) δ 1.81 (3H, s), 6.51 (1H, s), 7.64 (1H, d, J=8.1 Hz), 7.66-7.89 (1H, m), 8.00-8.12 (2H, m), 8.21 (1H, d, J=8.8 Hz). MS (ESI): m/z 320, 322 (M+H)+.
Reaction SMILES: C(OC([N:8]1[C:12]2=[N:13][CH:14]=[C:15]([O:17][CH:18]3[CH2:23][CH2:22][N:21]([CH:24]([CH3:26])[CH3:25])[CH2:20][CH2:19]3)[CH:16]=[C:11]2[CH:10]=[C:9]1[C:27]([O-])=[O:28])=O)(C)(C)C.[Li+].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=[CH:42][CH:43]=[CH:44][C:39]=2[N:38]=N1.N1CCCC1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH:24]([N:21]1[CH2:22][CH2:23][CH:18]([O:17][C:15]2[CH:16]=[C:11]3[CH:10]=[C:9]([C:27]([N:38]4[CH2:39][CH2:44][CH2:43][CH2:42]4)=[O:28])[NH:8][C:12]3=[N:13][CH:14]=2)[CH2:19][CH2:20]1)([CH3:26])[CH3:25]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CC(C)N1CCC(Oc2cnc3c(c2)cc(C(=O)[O-])n3C(=O)OC(C)(C)C)CC1
Agent: F[B-](F)(F)F
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCNC1
Product: CC(C)N1CCC(Oc2cnc3[nH]c(C(=O)N4CCCC4)cc3c2)CC1
Yield: 33 %

Procedure:
The title compound was synthesized in analogy to example 9, intermediate a), from lithium 1-tert-butoxycarbonyl-5-(1-isopropyl-piperidin-4-yloxy)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate, pyrrolidine and N,N-diisopropylethylamine in DMF to give the desired product as a light yellow solid (33%).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N+:9]([O-:11])=[O:10].[H-].[Na+].[Cl:14][C:15]1[C:20](Cl)=[N:19][CH:18]=[CH:17][N:16]=1.C(OCC)(=O)C>CN(C)C=O>[CH3:1][N:2]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N+:9]([O-:11])=[O:10])[C:20]1[C:15]([Cl:14])=[N:16][CH:17]=[CH:18][N:19]=1
Reactant: Clc1nccnc1Cl
Reactant: CNc1ccccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(c1ccccc1[N+](=O)[O-])c1nccnc1Cl
Reaction time: 0.5 h
Yield: 22.2 %

Procedure:
To a solution of 1.52 g of N-methyl-2-nitroaniline in N,N-dimethylformamide (50 ml) was added in a nitrogen atmosphere 0.44 g of sodium hydride. After stirring for 30 minutes, 1.75 g of 2,3-dichloropyrazine was added thereto and the resulting mixture was stirred at room temperature for additional 6 hours. Then the reaction mixture was distributed into ethyl acetate and a saturated aqueous solution of sodium dihydrogenphosphate and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed successively with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluted with n-hexane/ethyl acetate) to thereby give 0.586 g of the title compound as an oily substance.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH:27]([F:29])[F:28])[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[C@@H:5]([CH3:36])[CH2:4]1.[CH3:37][O:38][CH2:39][C:40](Cl)=[O:41]>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[CH:24][C:25]([CH:27]([F:29])[F:28])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:35])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:40](=[O:41])[CH2:39][O:38][CH3:37])[CH2:4][C@@H:5]4[CH3:36])=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:34][CH2:33]1
Reactant: COCC(=O)Cl
Reactant: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@H](N)C[C@@H]1C
Agent: Cl
Product: COCC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C(F)F)ccc4OCC4CC4)ncnc23)[C@@H](C)C1

Procedure:
Starting from N-[(1S*,2S*,4S*)-4-amino-2-methylcyclohexyl]-4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f63) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]#[N:24])=[CH:13][CH:12]=2)[C:8](=[O:25])[C:7]2([CH2:29][CH2:28][CH2:27][CH2:26]2)[N:6]=1)[CH2:2][CH2:3][CH3:4].[N-:30]=[N+:31]=[N-:32].[Na+].Cl.C(N(CC)CC)C.[OH-].[Na+]>CN(C)C=O.O>[CH3:4][CH2:3][CH2:2][CH2:1][C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[N:32]=[N:31][NH:30][N:24]=3)=[CH:13][CH:12]=2)[C:8](=[O:25])[C:7]2([CH2:26][CH2:27][CH2:28][CH2:29]2)[N:6]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CCCCC1=NC2(CCCC2)C(=O)N1Cc1ccc(-c2ccccc2C#N)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCC1=NC2(CCCC2)C(=O)N1Cc1ccc(-c2ccccc2-c2nn[nH]n2)cc1
Temperature: 25 °C
Yield: 30.6 %

Procedure:
A mixture of 2-n-butyl-3-[(2′-cyanobiphenyl-4-yl)methyl]-1,3-diazaspiro-[4,4]-non-1-en-4-one (10 g), sodium azide (7.7 g) and triethylamine hydrochloride (7.1 g) in N,N-dimethylformamide (30 ml) was refluxed for 14 hours under stirring. The reaction was cooled to room temperature and 20 ml water was added. The reaction mixture was adjusted to pH of about 12 using 10% NaOH solution. The alkaline solution was washed with toluene (15 ml) and the aqueous phase was neutralized to pH of 6.5 using concentrated HCl. The resulting suspension was stirred for 3 hours at room temperature and filtered to obtain irbesartan (3.4 g, 95% purity by HPLC). Recrystallization of the product using ethanol results in 3.05 g of irbesartan with 99.2% purity and content of the impurity 2-n-butyl-3-[(2′-carboxamidobiphenyl-4-yl)methyl]-1,3-diazaspiro-[4,4]-non-1-en-4-one: 0.09%.
Reaction SMILES: N1C=CN=C1.[Cl:6][C:7]1[CH:14]=[C:13]([OH:15])[CH:12]=[CH:11][C:8]=1[CH:9]=[O:10].[C:16]([Si:20]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)Cl)([CH3:19])([CH3:18])[CH3:17].O>C(Cl)Cl>[Si:20]([O:15][C:13]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[C:7]([Cl:6])[CH:14]=1)([C:16]([CH3:19])([CH3:18])[CH3:17])([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(O)cc1Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)[Si](Oc1ccc(C=O)c(Cl)c1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 107.2 %

Procedure:
To a solution of imidazole (4.28 g, 62.89 mmol) and 2-chloro-4-hydroxybenzaldehyde (8.95 g, 57.16 mmol) in CH2Cl2 (500 ml)was added dropwise a solution of t-butyldiphenylchlorosilane (17.27 g, 62.86 mmol) in CH2Cl2, (200 mL). The solution was stirred overnight at ambient temperature. The mixture was then poured into H2O (500 mL) and the organic layer washed with NaHCO3, H2O, brine, and dried (MgSO4). The solvent was removed in vacuo to provide 24.2 g of the title compound.
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=O)[NH:8][CH:7]=[CH:6]2>O=P(Cl)(Cl)Cl>[CH:9]1[C:10]2[C:5](=[CH:4][CH:3]=[CH:12][CH:11]=2)[CH:6]=[CH:7][N:8]=1
Reactant: COc1ccc2c(=O)[nH]ccc2c1
Solvent: O=P(Cl)(Cl)Cl
Product: c1ccc2cnccc2c1
Yield: 120.2 %

Procedure:
6-Methoxy-2H-isoquinolin-1-one (5.0 g, 28.4 mmol) in POCl3 (10 mL) was heated to gentle reflux for 3 h the evaporated in vacuo (Nicolas Briet et al, Tetrahedron, 2002, 5761–5766). The residue was poured into iced water (20 mL) and neutralized to pH 10 with 10 M NaOH. Extracted with CHCl3. The organic layer was washed with brine, dried over MgSO4, filtered, evaporated. The residue was purified by flash chromatography (1:1 hexane-EtOAc) to afford 4.41 g (80%) of the desired product as a white solid.
Reaction SMILES: [CH:1](=[C:8]1[NH:12][C:11](=[O:13])[C:10]([N:14]=[O:15])=[C:9]1OC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:18]>CO>[NH2:18][C:9]1[C:8](=[CH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[NH:12][C:11](=[O:13])[C:10]=1[N:14]=[O:15]
Reactant: COC1=C(N=O)C(=O)NC1=Cc1ccccc1
Reactant: N
Solvent: CO
Product: NC1=C(N=O)C(=O)NC1=Cc1ccccc1
Yield: 45 %

Procedure:
A solution of 0.11 g (0.5 mmol) 5-benzylidene-4-methoxy-3-nitroso-1,5-dihydropyrrol-2-one (prepared by the method of H. Poschenrieder et al (Arch. Pharm. Pharm. Med. Chem. 1998, vol. 331, pp. 389-394) and Stachel et al (J. Heterocycl. Chem. 1980, vol. 17, pp. 1195-1199 and Liebigs Ann. Chem. 1985, pp. 1692-1696)) in methanol was boiled under reflux with 0.25 ml (0.25 mmol) of an aqueous ammonia solution for two minutes. The compound 4-amino-5-benzylidene-3-nitroso-1,5-dihydropyrrol-2-one was obtained in a yield of 45% after recrystallization from methanol. The compound decomposes at 260° C.
Reaction SMILES: C(OC([O:6][CH2:7][C:8]#[C:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)=[O:11])C)C.Cl>O1CCCC1>[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([C:10](=[O:11])[C:9]#[C:8][CH2:7][OH:6])=[CH:17][CH:16]=1
Reactant: CCOC(C)OCC#CC(=O)c1ccc(Cl)cc1
Agent: Cl
Solvent: C1CCOC1
Product: O=C(C#CCO)c1ccc(Cl)cc1
Reaction time: 0.5 h

Procedure:
A solution of 6.7 g (25 mmol) of 4-(1-ethoxyethoxy)-1-(4-chlorophenyl)-2-butyn-1-one in 90 ml of tetrahydrofuran was treated at room temperature with 25 ml of 2N hydrochloric acid, whereupon the mixture was stirred for 30 minutes. The reaction mixture was then extracted twice with ethyl acetate. The combined organic phases were washed in succession with saturated sodium carbonate solution and with water, dried over magnesium sulphate and concentrated. Crystallization of the residue from ethyl acetate/hexane yielded 1-(4-chlorophenyl)-4-hydroxy-2-butyn-1-one of melting point 74° -trimethoxyphenyl)-.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:12][CH:11]([C:13]3[N:17]([CH3:18])[C:16]4[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=4[N:14]=3)[CH2:10]2)[CH:3]=1.[CH3:23][C:24]1[C:29](B(O)O)=[CH:28][CH:27]=[CH:26][N:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:18][N:17]1[C:16]2[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=2[N:14]=[C:13]1[CH:11]1[CH2:12][N:9]([C:4]2[CH:3]=[C:2]([C:29]3[C:24]([CH3:23])=[N:25][CH:26]=[CH:27][CH:28]=3)[N:7]=[C:6]([CH3:8])[N:5]=2)[CH2:10]1
Reactant: Cc1ncccc1B(O)O
Reactant: Cc1nc(Cl)cc(N2CC(c3nc4ccccc4n3C)C2)n1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: Cc1nc(-c2cccnc2C)cc(N2CC(c3nc4ccccc4n3C)C2)n1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A solution of Intermediate 3 (0.015 g, 0.048 mmol), (2-methylpyridin-3-yl)boronic acid (9.9 mg, 0.072 mmol), and cesium carbonate (1 M, 0.12 mL, 0.12 mmol) in THF (0.5 mL) under an atmosphere of nitrogen was treated with bis(tri-tert-butylphosphine)palladium(0) (1.5 mg, 0.0029 mmol) and heated to 100° C. overnight. The mixture was cooled, stirred with Quadrapure for 3 h, filtered, and concentrated. The residue was purified by reverse phase HPLC to give Example 80. 1H NMR: (400 MHz, d6-DMSO) δ 8.68 (d, J=1.2 Hz, 1H), 7.91 (d, J=15.0 Hz, 1H), 7.68-7.63 (m, 2H), 7.51-7.48 (m, 1H), 7.35-7.27 (m, 2H), 6.83 (s, 1H), 4.79-4.74 (m, 2H), 4.65-4.56 (m, 3H), 3.80 (s, 3H), 2.56 (s, 3H), 2.53 (s, 3H). MS: m/z=371.4 (M+H).
Reaction SMILES: [NH2:1][CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[O:14][CH:15]=[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][N:21]=3)[CH:17]=2)=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].CCN(C(C)C)C(C)C.[CH3:36][C:37]1[CH:45]=[C:44]([CH3:46])[CH:43]=[C:42]([CH3:47])[C:38]=1[C:39](O)=[O:40]>CS(C)=O>[CH3:26][C:24]1[CH:23]=[CH:22][N:21]=[C:20]([NH:19][CH2:18][C:16]2[CH:17]=[C:13]([C:10]3[CH:9]=[CH:8][C:7]([CH2:6][CH:2]([NH:1][C:39](=[O:40])[C:38]4[C:42]([CH3:47])=[CH:43][C:44]([CH3:46])=[CH:45][C:37]=4[CH3:36])[C:3]([OH:5])=[O:4])=[CH:12][CH:11]=3)[O:14][CH:15]=2)[CH:25]=1
Reactant: Cc1ccnc(NCc2coc(-c3ccc(CC(N)C(=O)O)cc3)c2)c1
Reactant: Cc1cc(C)c(C(=O)O)c(C)c1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccnc(NCc2coc(-c3ccc(CC(NC(=O)c4c(C)cc(C)cc4C)C(=O)O)cc3)c2)c1
Reaction time: 12 h

Procedure:
50 mg of (11) as 2HCl salt and 1201l of DIPEA were dissolved in 1 ml of DMSO. 29 mg of the OAT ester of 2,4,6-trimethylbenzoic acid were added. The solution was stirred for 12 h and the product was purified by HPLC to give 10.8 mg of (12) as TFA salt.
Reaction SMILES: [ClH:1].[Cl:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[C:20]([CH:21]=1)=[N:19][C:18]1[C:13](=[CH:14][CH:15]=[C:16]([O:22][CH2:23][CH2:24][CH2:25][CH2:26]Cl)[CH:17]=1)[CH:12]=2.[CH2:28]([NH:30][CH2:31][CH3:32])[CH3:29]>>[ClH:2].[ClH:1].[ClH:2].[CH2:28]([N:30]([CH2:31][CH3:32])[CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[C:20]([CH:21]=1)=[N:19][C:18]1[C:13](=[CH:14][CH:15]=[C:16]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][N:19]([CH2:20][CH3:11])[CH2:18][CH3:17])[CH:17]=1)[CH:12]=2)[CH3:29]
Reactant: ClCCCCOc1ccc2cc3ccc(OCCCCCl)cc3nc2c1
Reactant: CCNCC
Agent: Cl
Product: CCN(CC)CCCCOc1ccc2cc3ccc(OCCCCN(CC)CC)cc3nc2c1

Procedure:
A mixture of 2.0 g. of 3,6-bis(4-chlorobutoxy) acridine hydrochloride and 150 ml. of diethylamine is heated in a steel bomb at 100° C. for 24 hours. The excess diethylamine is removed under reduced pressure. The residue is dissolved in 150 ml. of chloroform and this chloroform solution is washed with two 30 ml. portions of saturated aqueous sodium bicarbonate, then dried over sodium sulfate and filtered. The chlorofrom is evaporated and the residue is dissolved in 50 ml. of absolute ethanol. A 10 ml. portion of 6 N hydrochloric acid in isopropanol is added giving the desired product as yellow crystals.
Reaction SMILES: [OH-].[Na+].[NH2:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]1[NH:10][C:11]([NH:13][C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:21])=S.C1(C)C=CC(S(Cl)(=O)=O)=CC=1>O.C1COCC1>[Cl:21][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]([Cl:20])[C:14]=1[N:13]=[C:11]1[NH:10][CH:5]2[CH2:6][CH2:7][CH2:8][CH2:9][CH:4]2[NH:3]1
Reactant: NC1CCCCC1NC(=S)Nc1c(Cl)cccc1Cl
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Clc1cccc(Cl)c1N=C1NC2CCCCC2N1
Reaction time: 1 h
Yield: 98.6 %

Procedure:
A solution of sodium hydroxide (15.7 mg) and water (0.6 ml) was added under argon to a solution of 1-(2-aminocyclohexyl)-3-(2,6-dichlorophenyl)thiourea (50 mg) and THF (1.5 ml). Subsequently, a solution of p-toluenesulfonyl chloride (32.9 mg) and THF (0.5 ml) was added dropwise over fifteen minutes. After stirring for 60 minutes, the reaction mixture was added to water and extracted three times with ether. The combined organic phases were dried over magnesium sulfate, filtered and concentrated. 44 mg of the desired product were obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:26][C:6]2[N:7]=[C:8]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][C@@H:11]3[CH2:16][C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[NH:19][CH:18]=3)[S:9][C:5]=2[C:4](=[O:27])[CH2:3]1.C(N(CC)CC)C.[C:36](OC(=O)C)(=[O:38])[CH3:37]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:36]([N:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17]([CH2:16][C@H:11]2[CH2:12][O:13][CH2:14][CH2:15][N:10]2[C:8]2[S:9][C:5]3[C:4](=[O:27])[CH2:3][C:2]([CH3:28])([CH3:1])[CH2:26][C:6]=3[N:7]=2)=[CH:18]1)(=[O:38])[CH3:37]
Reactant: CC1(C)CC(=O)c2sc(N3CCOC[C@@H]3Cc3c[nH]c4ccccc34)nc2C1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)n1cc(C[C@H]2COCCN2c2nc3c(s2)C(=O)CC(C)(C)C3)c2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 45.7 %

Procedure:
To a stirred solution of Example 25 (0.10 g, 0.25 mmol) in DCM (10 mL) was added triethylamine (0.03 g, 0.04 mL, 0.28 mmol), acetic anhydride (0.03 g, 0.03 mL, 0.30 mmol) and a catalytic amount of DMAP. The reaction mixture was stirred at r.t. for 16 h before being diluted with DCM (50 mL) and washed with sat. NaHCO3 solution (2×25 mL) and sat. brine (25 mL). The organic fraction was dried over MgSO4 and concentrated in vacuo. Purification by column chromatography (SiO2, 45:55 EtOAc/hexanes) gave the title compound (0.05 g, 49%) as a white solid. δH(CDCl3) 8.37 (1H, d, J 7.1 Hz), 7.82 (1H, dd, J 6.7 and 2.5 Hz), 7.32 (3H, m), 4.35 (1H, bs), 4.02 (1H, m), 3.82 (1H, d, J 11.9 Hz), 3.48-3.69 (4H, m), 3.31 (1H, m), 3.00 (1H, m), 2.66 (2H, d, J 3.3 Hz), 2.55 (3H, s), 2.34 (2H, s), 1.08 (6H, s). LCMS (ES+) 438.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].Br[CH2:15][C:16](=[O:18])[CH3:17].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][C:7]=1[O:8][CH2:15][C:16](=[O:18])[CH3:17]
Reactant: COC(=O)Cc1ccc(O)c(Cl)c1
Reactant: CC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccc(OCC(C)=O)c(Cl)c1

Procedure:
Following a procedure similar to that described in Preparation 3, but using 20 g of methyl 3-chloro-4-hydroxyphenylacetate, 27 g of bromoacetone, 28 g of potassium carbonate and 300 ml of dimethylformamide, the title compound was obtained having an Rf=0.33 (thin layer chromatography over silica gel, using a 3:1 by volume mixture of hexane and ethyl acetate as the developing solvent).
Reaction SMILES: C(OC([N:8]1[CH2:15][CH2:14][N:13]([C:16]2[C:17]3[CH:24]=[CH:23][NH:22][C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:12][C:9]21[CH2:11][CH2:10]2)=O)(C)(C)C.Cl>C(OCC)C.O1CCOCC1>[CH2:11]1[C:9]2([CH2:12][N:13]([C:16]3[C:17]4[CH:24]=[CH:23][NH:22][C:18]=4[N:19]=[CH:20][N:21]=3)[CH2:14][CH2:15][NH:8]2)[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncnc3[nH]ccc23)CC12CC2
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: c1nc(N2CCNC3(CC3)C2)c2cc[nH]c2n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To 7-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4,7-diazaspiro[2.5]octane-4-carboxylic acid tert-butyl ester (intermediate 20) (0.5 g, mmol) dissolved in diethyl ether (20 ml) was added HCl in dioxane (ml, M) and the reaction mixture was stirred for 5 hours at room temperature. The precipitate was isolated by filtration, and washed with diethyl ether (2×5 ml). The precipitate was suspended in THF (50 ml) and stirred vigorously with K2CO3 (5 gram) for 3 hours. After filtration and evaporation of the solvent in vacuo, the product was obtained as an off-white compound.
Reaction SMILES: C([NH:14][C:15]1([CH:24]=[CH:23][CH:22]=[CH:21][CH2:20]1)[CH2:16][P:17]([OH:19])[OH:18])(C1C=CC=CC=1)C1C=CC=CC=1.C(NC(P(O)O)C(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>>[NH2:14][C:15]1([CH2:16][P:17]([OH:19])[OH:18])[CH:20]=[CH:21][CH:22]=[CH:23][CH2:24]1
Reactant: OP(O)CC1(NC(c2ccccc2)c2ccccc2)C=CC=CC1
Agent: CC(C)C(NC(c1ccccc1)c1ccccc1)P(O)O
Product: NC1(CP(O)O)C=CC=CC1

Procedure:
The procedure described in Example 1C was repeated using DL-1-benzhydrylaminobenzylphosphonous acid as starting material instead of DL-1-benzhydrylamino-2-methylpropanephosphonous acid to give DL-1-aminophenylmethanephosphonous acid of melting point 239°-240° (dec.).