Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[N:14]=[CH:13][C:12]([CH2:15][N:16]2[CH:20]=[C:19]([C:21]3[CH:22]=[C:23]([NH:28][C:29]4[N:34]=[C:33]([CH:35]([F:37])[F:36])[CH:32]=[CH:31][N:30]=4)[CH:24]=[C:25]([CH3:27])[CH:26]=3)[CH:18]=[N:17]2)=[CH:11][CH:10]=1)C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[F:37][CH:35]([F:36])[C:33]1[CH:32]=[CH:31][N:30]=[C:29]([NH:28][C:23]2[CH:22]=[C:21]([C:19]3[CH:18]=[N:17][N:16]([CH2:15][C:12]4[CH:11]=[CH:10][C:9](=[O:8])[NH:14][CH:13]=4)[CH:20]=3)[CH:26]=[C:25]([CH3:27])[CH:24]=2)[N:34]=1
Reactant: Cc1cc(Nc2nccc(C(F)F)n2)cc(-c2cnn(Cc3ccc(OCc4ccccc4)nc3)c2)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(Nc2nccc(C(F)F)n2)cc(-c2cnn(Cc3ccc(=O)[nH]c3)c2)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of N-[3-(1-{[6-(benzyloxy)pyridin-3-yl]methyl}-1H-pyrazol-4-yl)-5-methylphenyl]-4-(difluoromethyl)pyrimidin-2-amine (80 mg, 0.16 mmol) in methanol (20 mL) was added palladium hydroxide on carbon (20 wt %, 8 mg). The reaction mixture was stirred at 25° C. under a hydrogen atmosphere (1 atm) for 12 hours. The mixture was then filtered and concentrated under reduced pressure. The residue was purified by reverse phase HPLC to give the 5-{[4-(3-{[4-(difluoromethyl)pyrimidin-2-yl]amino}-5-methylphenyl)-1H-pyrazol-1-yl]methyl}pyridin-2(1H)-one. MS ESI calc'd. for C21H19F2N6O [M+H]+ 409. found 409.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[O:19][CH:20]=[CH:21][N:22]=3)=[CH:14][CH:13]=2)=[CH:7][CH:6]=1.[I-:23].[Na+]>CC(=O)CC>[I:23][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[O:19][CH:20]=[CH:21][N:22]=3)=[CH:14][CH:13]=2)=[CH:7][CH:6]=1
Reactant: [I-]
Reactant: ClCCOc1ccc(Cc2ccc(-c3ncco3)cc2)cc1
Agent: [Na+]
Solvent: CCC(C)=O
Product: ICCOc1ccc(Cc2ccc(-c3ncco3)cc2)cc1
Yield: 78.5 %

Procedure:
A solution of 2-[4-[[4-(2-chloroethoxy)phenyl]methyl]phenyl]oxazole (1.7 g, 4.4 mmol) in 2-butanone (18 mL) was stirred as sodium iodide (7 g, 44 mmol) was added. The reaction was heated at reflux for 2 days. The reaction was concentrated. The residue was dissolved in ethyl acetate and washed with water. The combined organic layers were dried and concentrated. The residue was recrystallized from methanol to give 1.4 g of 2-[4-[[4-(2-iodoethoxy)phenyl]methyl]phenyl]oxazole, 1H NMR (400 MHz, CDCl3) δ 7.97 (d, 2H), 7.68 (s, 1H), 7.27 (d, 2H), 7.21 (s, 1H), 7.13 (d, 2H), 6.82 (d, 2H), 4.22 (t, 2H), 3.96 (s, 2H), 3.39 (t, 2H).
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5]P(=O)(OCC)OCC)#[N:4].[Br:14][C:15]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[C:21]([O:27][CH3:28])=[C:20]2[C:16]=1[CH2:17][CH2:18][C:19]2=O.[Cl-].[NH4+]>O1CCCC1>[Br:14][C:15]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[C:21]([O:27][CH3:28])=[C:20]2[C:16]=1[CH2:17][CH2:18][C:19]2=[CH:5][C:3]#[N:4]
Reactant: COc1c([N+](=O)[O-])cc(Br)c2c1C(=O)CC2
Reactant: CCOP(=O)(CC#N)OCC
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1c([N+](=O)[O-])cc(Br)c2c1C(=CC#N)CC2
Reaction time: 0.25 h
Yield: 76.9 %

Procedure:
To a suspension of 60% sodium hydride (1.03 g, 25.6 mmol) in tetrahydrofuran (100 mL) was added diethyl cyanomethylphosphonate (4.52 mL, 28.0 mmol) under ice-cooling, and the mixture was stirred for 15 min. Thereto was added a solution of 4-bromo-7-methoxy-6-nitroindan-1-one (6.67 g, 23.3 mmol) in tetrahydrofuran (50 mL), and the mixture was further stirred for 30 min. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=10/90→40/60) to give the title compound (5.54 g, yield 77%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1[OH:10])[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Cl)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O.O>[CH2:18]([O:10][C:9]1[C:2]([F:1])=[CH:3][C:4]([CH:5]=[O:6])=[CH:7][C:8]=1[F:11])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=Cc1cc(F)c(O)c(F)c1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cc(F)c(OCc2ccccc2)c(F)c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a mixture of 3,5-difluoro-4-hydroxybenzaldehyde (6) (8.26 g, 52.2 mmol), and potassium carbonate (14.4 g, 104.4 mmol) in dimethylformamide (100 mL) was added benzyl chloride (7.2 mL, 62.7 mmol) and stirred overnight at 50° C. The reaction was diluted with water and extracted with ethyl acetate (3×75 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (0-100% EtOAc in hexanes) to afford 4-(benzyloxy)-3,5-difluorobenzaldehyde (7).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][C@H:9]1[C:16](=[O:17])[N:15]2[C@@H:11]([S:12][CH2:13][C@H:14]2[C:18]#[N:19])[CH2:10]1.C(O)(=O)C.[CH:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:24]([NH:8][C@H:9]1[C:16](=[O:17])[N:15]2[C@@H:11]([S:12][CH2:13][C@H:14]2[C:18]#[N:19])[CH2:10]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=Cc1ccccc1
Reactant: N#C[C@@H]1CS[C@H]2C[C@@H](N)C(=O)N12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: N#C[C@@H]1CS[C@H]2C[C@@H](NCc3ccccc3)C(=O)N12
Temperature: 45 °C

Procedure:
20 mg of (3R,6R,7aS)-6-amino-5-oxohexahydropyrrolo[2,1-b]thiazole-3-carbonitrile trifluoroacetate were dissolved in 1 ml of 1,2-dichloroethane. 2 μl of acetic acid, 7 μl of benzaldehyde and 29 mg of sodium triacetoxyborohydride were successively added. The mixture was heated at 45° C. for 2 h. The solvent was then removed in vacuo. The residue was purified by preparative HPLC (Merck RP18, acetonitrile/water (0.5% trifluoroacetic acid), linear gradient (0–>80% acetonitrile)).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:13])([CH3:12])[CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.[CH:14]([C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=1)=[CH2:15].C(=O)(O)[O-].[Na+].CCCCCC>O.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CCOC(C)=O.C(Cl)Cl>[CH3:12][C:6]1([CH3:13])[C:5]2[C:9](=[CH:10][C:2]([CH:15]=[CH:14][C:16]3[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=3)=[CH:3][CH:4]=2)[C:8](=[O:11])[CH2:7]1
Reactant: CC1(C)CC(=O)c2cc(Br)ccc21
Reactant: C=Cc1ccc(C(=O)OC)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: COC(=O)c1ccc(C=Cc2ccc3c(c2)C(=O)CC3(C)C)cc1
Yield: 69.6 %

Procedure:
6-Bromo-3,3-dimethyl-indan-1-one (1.20 g, 5.02 mmol), methyl 4-vinylbenzoate (1.63 g, 10.0 mmol), palladium acetate (56 mg, 0.25 mmol), tetrabutylammonium chloride hydrate (1.53 g, 5.52 mmol ), and sodium bicarbonate (1.05 g, 12.6 mmol) were stirred in 10 mL of anhydrous N,N-dimethylformamide at 80°-100° C. for 8 hours. The mixture was diluted with water (100 mL), extracted with methylene chloride (50 mL×3). The combined extracts were dried over magnesium sulfate and evaporated. The residue was purified by flash chromatography (CH2Cl2 :hexane=1:1 to 1:0, then CH2Cl2 :EtOAc=10:1) to give 1.12 g (70% yield) of the title compound as a yellow solid; 1H-NMR (CDCl3) δ1.45 (s, 6H), 2.64 (s, 2H), 5.30 (s, 3H), 7.18 (d, J=16.5 Hz, 1H), 7.26 (d, J=16.5 Hz, 1H), 7.52 (d, J=8.1 Hz, 1H), 7.58 (d, J=8.5 Hz, 2H), 7.78 (d, J=1.7, 8.1 Hz, 1H), 7.86 (d, J=1.7 Hz, 1H), 8.05 (d, J=8.5 Hz, 2H); MS m/e 321 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[N:4][C:3]=1[C:14](=O)[NH2:15].P(Cl)(Cl)(Cl)=O.Cl>CN(C)C=O>[NH2:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[N:4][C:3]=1[C:14]#[N:15]
Reactant: NC(=O)c1nnn(Cc2ccccc2)c1N
Agent: Cl
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1nnn(Cc2ccccc2)c1N
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
11 Parts of the 5-amino-1-benzyl-4-carbamoyl-1,2,3-triazole obtained are suspended in 50 parts dimethylformamide. At 0°, 15.3 parts phosphorus oxychloride are added dropwise thereto and the mixture is stirred for 15 minutes at room temperature and 15 minutes at 80°. After cooling to 25°, 50 parts 1 N hydrochloric acid are added thereto and the whole is heated to 100° for approximately 5 minutes. On cooling to room temperature the desired product precipitates which is then filtered and dried.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:20])[CH2:16][CH2:17][CH2:18]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:21]([C:28]1[CH:33]=[CH:32][C:31]([CH:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:20])[CH2:16][CH2:17][CH2:18][N:37]1[CH2:38][CH2:39][CH:34]([C:31]2[CH:32]=[CH:33][C:28]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:29][CH:30]=2)[CH2:35][CH2:36]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(Oc2ccc(C3CCNCC3)cc2)cc1
Reactant: O=C(CCCBr)Nc1ccccc1Cc1ccccc1
Product: O=C(CCCN1CCC(c2ccc(Oc3ccccc3)cc2)CC1)Nc1ccccc1Cc1ccccc1

Procedure:
The compound (11) synthesized in Reference Example 11 and the compound (4) synthesized in Reference Example 4 were used to produce the above compound in the same way as Example 1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][CH2:9][CH2:10][NH2:11])[N:2]=1.CS[C:14](=[NH:19])[NH:15][N+:16]([O-:18])=[O:17]>>[N+:16]([NH:15][C:14]([NH:11][CH2:10][CH2:9][NH:8][CH2:7][C:3]1[N:2]=[N:1][CH:6]=[CH:5][CH:4]=1)=[NH:19])([O-:18])=[O:17]
Reactant: CSC(=N)N[N+](=O)[O-]
Reactant: NCCNCc1cccnn1
Product: N=C(NCCNCc1cccnn1)N[N+](=O)[O-]

Procedure:
Reacting N-(3-pyridazinylmethyl)ethylenediamine with S-methyl-N-nitroisothiourea by the procedure of Example 2(ii) give N-nitro-N'-[2-(3-pyridazinylmethylamino)ethyl]guanidine. Treatment with hydrobromic acid gives the hydrobromide salt.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([C@@H:13]2[CH2:18][CH2:17][CH2:16][CH2:15][NH:14]2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[O:20]1[CH2:25][CH2:24][CH:23]([CH:26]=O)[CH2:22][CH2:21]1.C(O)(=O)C.S([O-])([O-])(=O)=O.[Na+].[Na+].C([BH3-])#N.[Na+]>CN(C=O)C.ClCCl>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([C@@H:13]2[CH2:18][CH2:17][CH2:16][CH2:15][N:14]2[CH2:26][CH:23]2[CH2:24][CH2:25][O:20][CH2:21][CH2:22]2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(NC(=O)[C@@H]2CCCCN2)no1
Reactant: O=CC1CCOCC1
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(NC(=O)[C@@H]2CCCCN2CC2CCOCC2)no1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (S)-Piperidine-2-carboxylic acid (5-tert-butyl-isoxazol-3-yl) amide; hydrochloride (110 mg; 0.382 mmol) in DMF (1.5 mL) is added tetrahydro-pyran-4-carbaldehyde (87.2 mg; 0.764 mmol), acetic acid (0.022 mL; 0.382 mmol) and sodium sulfate (5-10 equivalents). The mixture is stirred at room temperature for 30 minutes before adding sodium cyanoborohydride (24 mg; 0.382 mmol). The mixture is stirred at room temperature for 18 hours. The mixture is diluted with dichloromethane and washed with saturated NaHCO3 aqueous solution. The organic layer is dried over Na2SO4, filtered and concentrated in vacuo. Crude product is purified by preparative HPLC. Product fractions are pooled and concentrated in vacuo to afford the title compound, m/z 350 [M+H+].
Reaction SMILES: [NH2:1][C:2]1[C:12]([Br:13])=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([NH:6][CH2:7][CH3:8])=[O:5].Cl[C:15](Cl)([O:17]C(=O)OC(Cl)(Cl)Cl)Cl.CCN(C(C)C)C(C)C>C(Cl)Cl>[Br:13][C:12]1[CH:11]=[CH:10][CH:9]=[C:3]2[C:2]=1[NH:1][C:15](=[O:17])[N:6]([CH2:7][CH3:8])[C:4]2=[O:5]
Reactant: CCNC(=O)c1cccc(Br)c1N
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCn1c(=O)[nH]c2c(Br)cccc2c1=O
Temperature: 60 °C
Reaction time: 4 h
Yield: 97.7 %

Procedure:
A mixture of 2-amino-3-bromo-N-ethylbenzamide (2.0 g, 8.23 mmol, 481a), triphosgene (0.830 g, 2.80 mmol, Sigma Aldrich,), DCM (28.0 mL), and DIPEA (1.6 mL, 8.95 mmol) was set stirring at 60° C. with a condenser for 4 h. The mixture was concentrated under reduced pressure to a yellow residue. It was adsorbed onto silica and purified on 24 g SiO2 (eluent: 0-100% EtOAc/hexanes over 25 min, RediSep Gold). The product fractions were combined and concentrated under reduced pressure to give the product as a white solid (736 mg, 98%). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.52 (1H, s) 7.95 (1H, dd, J=7.82, 1.37 Hz) 7.98 (1H, dd, J=7.82, 1.37 Hz) 7.15 (1H, t, J=7.82 Hz) 3.93 (2H, q, J=7.04 Hz) 1.15 (3H, t, J=7.04 Hz). m/z (ESI, +ve) 268.9 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:29][C:30]([O:32]C)=[O:31])[CH:5]=[CH:6][C:7]=1[NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]2[C:17]([C:25]([F:28])([F:27])[F:26])=[N:18][O:19][C:20]=2[C:21]=1[CH2:22][CH2:23][CH3:24].[OH-].[Li+]>CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:29][C:30]([OH:32])=[O:31])[CH:5]=[CH:6][C:7]=1[NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]2[C:17]([C:25]([F:28])([F:26])[F:27])=[N:18][O:19][C:20]=2[C:21]=1[CH2:22][CH2:23][CH3:24]
Reactant: CCCc1c(OCCCNc2ccc(CC(=O)OC)cc2Cl)ccc2c(C(F)(F)F)noc12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCc1c(OCCCNc2ccc(CC(=O)O)cc2Cl)ccc2c(C(F)(F)F)noc12
Temperature: 0 °C

Procedure:
A solution of Methyl 3-chloro-4-(3-(3-trifluoromethyl-7-propyl-6-benz-[4,5]-isoxazoloxy)propylamino)-phenylacetate (Step C, 0.113 grams) in methanol (1.5 mL) was treated with a solution of lithium hydroxide in water (1.01 M; 0.362 mL). The reaction was refluxed 1 hour. The reaction mixture was partitioned between isopropyl acetate and 0.1N HCl. The organic was dried over magnesium sulfate, filtered and concentrated to a solid. The solid was suspended in methylene chloride/cyclohexane (1:1; 2 mL). The mixture was refluxed briefly and cooled to 0° C. The title compound was isolated by filtration.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.C([NH:29][CH:30]([C:60]1[CH:65]=[CH:64][C:63]([O:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH2:83][CH2:84][CH2:85][CH2:86][CH2:87][CH3:88])=[CH:62][CH:61]=1)[C:31]1[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])=[CH:33][CH:32]=1)(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O.Cl>ClCCl>[CH2:38]([O:37][C:34]1[CH:33]=[CH:32][C:31]([CH:30]([NH2:29])[C:60]2[CH:65]=[CH:64][C:63]([O:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH2:83][CH2:84][CH2:85][CH2:86][CH2:87][CH3:88])=[CH:62][CH:61]=2)=[CH:36][CH:35]=1)[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59]
Reactant: CCCCCCCCCCCCCCCCCCCCCCOc1ccc(C(NC(=O)OCC2c3ccccc3-c3ccccc32)c2ccc(OCCCCCCCCCCCCCCCCCCCCCC)cc2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCCCCCCCCCCCCCCCCCCCOc1ccc(C(N)c2ccc(OCCCCCCCCCCCCCCCCCCCCCC)cc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 86.1 %

Procedure:
To dichloromethane (10 ml) was added DBU (1,8-diazabicyclo[5,4,0]-7-undecene, 200 μl), and N-Fmoc-di(4-docosoxyphenyl)methylamine (500 mg, 474 μmol) obtained in Example 4 was added and the mixture was stirred at room temperature for 5 hr. 1N Hydrochloric acid (1.3 ml) was added dropwise and, after stirring, the solvent was evaporated and the residue was washed with acetonitrile (10 ml) to give di(4-docosoxyphenyl)methylamine (340 mg, 408 μmol, yield 86%).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH3:6][O:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:17][C:16]3([N:21]([CH3:22])[CH2:20][CH2:19][CH2:18]3)[CH2:15]2)[C:11]([NH2:23])=[CH:10][C:9]=1[NH:24][C:25]1[N:30]=[C:29]([C:31]2[CH:32]=[N:33][N:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=23)[CH:28]=[CH:27][N:26]=1>C(Cl)Cl.CO>[CH3:6][O:7][C:8]1[C:9]([NH:24][C:25]2[N:30]=[C:29]([C:31]3[CH:32]=[N:33][N:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=34)[CH:28]=[CH:27][N:26]=2)=[CH:10][C:11]([NH:23][C:1](=[O:4])[CH:2]=[CH2:3])=[C:12]([N:14]2[CH2:15][C:16]3([N:21]([CH3:22])[CH2:20][CH2:19][CH2:18]3)[CH2:17]2)[CH:13]=1
Reactant: C=CC(=O)Cl
Reactant: COc1cc(N2CC3(CCCN3C)C2)c(N)cc1Nc1nccc(-c2cnn3ccccc23)n1
Solvent: CO
Solvent: ClCCl
Product: C=CC(=O)Nc1cc(Nc2nccc(-c3cnn4ccccc34)n2)c(OC)cc1N1CC2(CCCN2C)C1
Reaction time: 0.5 h
Yield: 51.8 %

Procedure:
A solution of acryloyl chloride (0.766 mL, 0.77 mmol, 1.0 M in CH2Cl2) was added dropwise over 10 minutes to 4-methoxy-6-(8-methyl-2,8-diazaspiro[3.4]octan-2-yl)-N′-(4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)benzene-1,3-diamine (Intermediate 162, 333 mg, 0.73 mmol) in CH2Cl2 (6 mL), which was cooled in an ice/CH3OH bath. The mixture was then stirred for 0.5 h, then diluted with 10% CH3OH in CH2Cl2. The resulting solution was washed with sat. NaHCO3, dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 1-10% methanolic ammonia in CH2Cl2 gave the title compound (193 mg, 52%) as an beige solid after trituration with diethyl ether; 1H NMR: 1.69 (2H, dt), 2.03-2.08 (2H, m), 2.38 (3H, s), 2.63 (2H, t), 3.65 (2H, d), 3.83 (3H, s), 3.94 (2H, d), 5.68 (1H, dd), 6.19 (1H, dd), 6.25 (1H, s), 6.47 (1H, dd), 7.06 (1H, td), 7.19 (1H, d), 7.44 (1H, dd), 7.67 (1H, s), 7.98 (1H, s), 8.29 (1H, d), 8.47 (1H, d), 8.75 (1H, s), 8.78 (1H, d), 9.25 (1H, s); m/z: ES+ MH+ 511.34.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]3[CH2:15][CH:14]([CH2:16][CH2:17][CH2:18][CH2:19][CH:20]([OH:33])[C:21]4[C:30]5[C:25](=[CH:26][CH:27]=[C:28]([O:31][CH3:32])[N:29]=5)[N:24]=[CH:23][CH:22]=4)[O:13][C:12]3=[O:34])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1>C(Cl)Cl.O=[Mn]=O>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]3[CH2:15][CH:14]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]([C:21]4[C:30]5[C:25](=[CH:26][CH:27]=[C:28]([O:31][CH3:32])[N:29]=5)[N:24]=[CH:23][CH:22]=4)=[O:33])[O:13][C:12]3=[O:34])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: COc1ccc2nccc(C(O)CCCCC3CN(c4ccc5c(c4)OCCO5)C(=O)O3)c2n1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: COc1ccc2nccc(C(=O)CCCCC3CN(c4ccc5c(c4)OCCO5)C(=O)O3)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.9 %

Procedure:
A solution of the compound of Example 61 (0.55 g, 0.12 mmol) in DCM (5 mL) was treated with MnO2 (0.5 g, 50 eq.). The mixture was stirred at rt for 1 h, filtered over MgSO4 and concentrated. Chromatography on SiO2 (EA) gave the title compound as a colourless oil (0.025 g, 46% yield).
Reaction SMILES: [NH:1]([CH2:8][C:9]([N:11]1[CH:20]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12]1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].Cl.C(=O)(O)[O-].[Na+]>C1COCC1>[C:2]1([NH:1][CH2:8][CH2:9][N:11]2[CH:20]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12]2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CNc1ccccc1)N1Cc2ccccc2CC1Cc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Al+3]
Solvent: C1CCOC1
Product: c1ccc(CC2Cc3ccccc3CN2CCNc2ccccc2)cc1
Yield: 26 %

Procedure:
10 mg of 2-(2-anilinoacetyl)-3-benzyl-1,2,3,4-tetrahydroisoquinoline was dissolved in 1 mL of THF, and 1.1 mg of LAH was added thereto under an argon atmosphere, followed by stirring under ice-cooling 2 hours. After completion of the reaction, 2N hydrochloric acid was added thereto, and when foaming was stopped, a saturated aqueous sodium bicarbonate solution was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with brine and then dried over anhydrous sodium sulfate, and the solvent was removed by evaporation, followed by purification using PLC (chloroform:methanol=10:1) to obtain 2.5 mg (yield 26%) of a title compound as a pale yellow oily substance.
Reaction SMILES: [CH2:1]([N:5]1[CH2:12][CH:11]2[C:13]([CH3:15])([CH3:14])[CH:7]([CH2:8][N:9]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([NH:25]C(=O)C)=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH2:10]2)[CH2:6]1)[CH2:2][CH2:3][CH3:4].[OH-].[K+].O>C(O)C>[CH2:1]([N:5]1[CH2:6][CH:7]2[C:13]([CH3:14])([CH3:15])[CH:11]([CH2:10][N:9]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH2:8]2)[CH2:12]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1CC2CN(S(=O)(=O)c3ccc(NC(C)=O)cc3)CC(C1)C2(C)C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCN1CC2CN(S(=O)(=O)c3ccc(N)cc3)CC(C1)C2(C)C
Yield: 87.5 %

Procedure:
5.1 g of 7-(n-Butyl)-3-[(4-acetylaminophenyl)-sulfonyl]-9,9-dimethyl-3,7-diazabicyclo[3.3.1]nonane (for preparation see Example 2) and 1.5 g of potassium hydroxide were refluxed for 6 hours in 100 ml of ethanol. The reaction mixture was then cooled, water was added, and the mixture was extracted twice with diethyl ether. The combined ether extracts were dried with magnesium sulfate and concentrated. 4.0 g of 7-(n-butyl)-3-[(4-aminophenyl)-sulfonyl]-9,9-dimethyl-3,7-diazabicyclo[3.3.1]nonane were obtained, which were employed in the following reaction step without further purification.
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][C:13]=3[CH:14]=2)=[CH:6][CH:5]=1.Cl.N1C=CC=CC=1>O>[OH:19][C:16]1[CH:17]=[CH:18][C:12]2[O:11][C:10]([C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:21])=[O:2])=[CH:5][CH:6]=3)=[CH:14][C:13]=2[CH:15]=1
Reactant: COC(=O)c1ccc(-c2cc3cc(OC)ccc3o2)cc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: O=C(O)c1ccc(-c2cc3cc(O)ccc3o2)cc1
Temperature: 200 °C
Reaction time: 2 h
Yield: 45.9 %

Procedure:
A mixture of 4-(5-Methoxy-benzofuran-2-yl)-benzoic acid methyl ester (0.5 g, 1.8 mmol) and Pyridine HCl (5 g) was heated to 200° C. After 2 hr, the reaction was cooled and poured into water and extracted with EtOAc. The EtOAc layer was dried over MgSO4, concentrated and the product was purified by column chromatography on silica gel (75% EtOAc/hex) to give a solid (0.21 g, 47%): 1H NMR (DMSO-d6) δ 13.07 (br s, 1 H), 9.29 (br s, 1 H), 8.02 (d, 2 H, J=8.1 Hz), 7.97 (d, 2 H, J=8.7 Hz), 7.46 (m, 2 H), 6.97 (d, 1 H, J=2.9 Hz), 6.79 (dd, 1 H, J=9.3 Hz, 2.9 Hz); MS 253 (M−H)−
Reaction SMILES: C(OC([O:8][N:9]([CH2:17][C:18]1[CH:23]=[C:22]([I:24])[C:21]([O:25][C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)=[C:20]([I:33])[CH:19]=1)C(=O)OC(C)(C)C)=O)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[OH:8][NH:9][CH2:17][C:18]1[CH:19]=[C:20]([I:33])[C:21]([O:25][C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)=[C:22]([I:24])[CH:23]=1
Reactant: CC(C)(C)OC(=O)ON(Cc1cc(I)c(Oc2ccc(O)cc2)c(I)c1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: ONCc1cc(I)c(Oc2ccc(O)cc2)c(I)c1
Reaction time: 2 h

Procedure:
A solution containing tert-butyl N-(tert-butoxycarbonyloxy)-N-[3,5-diiodo-4-(4-hydroxyphenoxy)benzyl]carbamate (150 mg, 0.21 mmol) in 4 ml of 30% TFA in CH2Cl2 was stirred for 2 h and then evaporated to dryness to afford 4-(4-hydroxyaminomethyl-2,6-diiodophenoxy)phenol (M+1=484). This residue was then treated with triethylamine (0.5 ml) and the mixed anhydride (0.5 ml) [made from formic acid and acetic anhydride (1:2 v/v) at 50° C. for 1 h] in 2 ml of CH2Cl2 for 0.5 h. All volatiles were removed and the residue dissolved in methanol then treated with 10% NaOH for 0.5 h. This was diluted with ethyl acetate and water and adjusted to pH of 6. The layers were separated and the organic extract was evaporated in vacuo. Purification by preparative HPLC afforded the title compound (27 mg, 25%) as an off white solid. 1H NMR (400 MHz, CD3OD): δ 8.38, 8.18* (s, 1H); 7.89*, 7.86 (s, 2H); 6.69 (d, j=8.8 Hz, 2H); 6.55 (d, j=8.8 Hz, 2H),; 4.67, 4.63* (s, 2H). M+1=512. *: minor rotamer