Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: IC1C=CC=CC=1N.FC1C=CC(B(O)O)=CC=1.[OH-].[Na+].[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[NH2:34])=[CH:24][CH:23]=1.N1C=CC=CC=1.[C:41](OC(=O)C)(=[O:43])[CH3:42]>O1CCCC1.ClCCl.CN(C1C=CN=CC=1)C>[F:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[NH:34][C:41](=[O:43])[CH3:42])=[CH:26][CH:27]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccccc1-c1ccc(F)cc1
Agent: CN(C)c1ccncc1
Agent: Nc1ccccc1I
Agent: OB(O)c1ccc(F)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)Nc1ccccc1-c1ccc(F)cc1
Temperature: 25 °C

Procedure:
A stirred solution of 2-iodoaniline (32.6 g, 149 mmol) and 4-fluorophenylboronic acid (20.8 g, 149 mmol) in tetrahydrofuran (1.5 L) was treated under nitrogen with [1,1 ′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (2.20 g, 2.69 mmol) and a 5 N sodium hydroxide solution (60 mL). The reaction mixture was heated at reflux for twelve hours, cooled to room temperature, and the solvent removed in vacuo. The residue was dissolved in ethyl acetate (250 mL) and extracted with a saturated, aqueous, sodium chloride solution (100 mL). The aqueous phase was further extracted with ethyl acetate (2×50 mL). The combined organic phase was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to a brown oil. The brown oil was filtered through a short column of silica gel, and eluted with a mixture of ethyl acetate-hexane (1:4). After evaporation of the solvent in vacuo, a solution of the crude 4′-fluoro-biphenyl-2-ylamine in dichloromethane (75 mL) was treated with pyridine (27.7 mL, 343 mmol), acetic anhydride (15.5 mL, 164 mmol), and 4-(N,N-dimethylamino)pyridine (0.55 g, 4.5 mmol). After stirring for twelve hours at room temperature, the reaction was quenched with a saturated, aqueous, ammonium. chloride solution (250 mL). The separated aqueous phase was extracted with dichloromethane (3×75 mL), and the combined organic phase washed sequentially with a 0.1 N hydrochloric acid solution (2×50 mL), and a saturated, aqueous, sodium bicarbonate solution (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to a second brown oil. After toluene was added and removed in vacuo (3×), the resulting brown solid was crystallized from ethyl acetate-hexane to yield a first crop of the desired product (19.0 g). The mother liquor was concentrated and purified by flash column chromatography on silica gel, eluting with ethyl acetate-hexane (1:4), to obtain a second crop (5.0 g). The combined crops afforded the title compound as a homogeneous, colorless, crystalline, solid (24.0 g, 70%). m.p. 123-124° C.; MS [(+ESI), m/z]: 230 [M+H]+;
Reaction SMILES: C[O:2][C:3](=[O:39])[C@H:4]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:25](=[O:38])[N:26]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:27]=[C:28]([Cl:30])[CH:29]=2)=[CH:20][CH:19]=1)[NH:5][C:6]([C:8]1([CH2:13][CH2:14][O:15][CH3:16])[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7].O.[OH-].[Li+]>C1COCC1.O.C(O)(=O)C>[Cl:30][C:28]1[CH:29]=[C:24]([C:21]2[CH:20]=[CH:19][C:18]([CH2:17][C@@H:4]([C:3]([OH:39])=[O:2])[NH:5][C:6]([C:8]3([CH2:13][CH2:14][O:15][CH3:16])[CH2:12][CH2:11][CH2:10][CH2:9]3)=[O:7])=[CH:23][CH:22]=2)[C:25](=[O:38])[N:26]([CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:27]=1
Reactant: COCCC1(C(=O)N[C@@H](Cc2ccc(-c3cc(Cl)cn(Cc4ccccc4)c3=O)cc2)C(=O)OC)CCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: COCCC1(C(=O)N[C@@H](Cc2ccc(-c3cc(Cl)cn(Cc4ccccc4)c3=O)cc2)C(=O)O)CCCC1
Reaction time: 1 h
Yield: 59 %

Procedure:
A solution of 4-(1-benzyl-5-chloro-2-oxo-3-pyridinyl)-N-[[1-(2-methoxyethyl)cyclopentyl]carbonyl]-L-phenylalanine methyl ester (78 mg, 0.142 mmol) in THF (3 mL) was treated with a solution of lithium hydroxide monohydrate (24 mg, 0.57 mmol) in water (1.0 mL). Sufficient THF was added to the mixture to effect solution. The mixture was stirred 1 hr and a few drops of acetic acid were added. The entire reaction mixture was applied to a 4×30 cm, C-18 reversed phase HPLC column and eluted with a gradient of acetonitrile in water of 5- to 95% over 35 min. The product containing fraction was lyophillyzed to give 4-(5-chloro-1-benzyl-2-oxo-3-pyridinyl)-N-[[1-(2-methoxyethyl)cyclopentyl]carbonyl]-L-phenylalanine (45 mg, 60%) as a white solid. LRMS-Electrospray: m/z positive ion 559 (M+Na), 554 (M+NH4), 537 (M+H (1 Cl)); negative ion 535 (M−H (1 Cl)). HRMS: obs. mass 537.2151. calcd. mass 537.2156 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[NH2:21])[C:5]([NH:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1)=[O:6].C[O:23][C:24](=[O:39])[C:25]([CH3:38])([CH3:37])[CH2:26][C:27]1[CH:32]=[C:31]([CH3:33])[C:30]([CH:34]=O)=[C:29]([CH3:36])[CH:28]=1>>[CH3:36][C:29]1[CH:28]=[C:27]([CH2:26][C:25]([CH3:38])([CH3:37])[C:24]([OH:39])=[O:23])[CH:32]=[C:31]([CH3:33])[C:30]=1[C:34]1[NH:1][C:2]2[CH:3]=[C:4]([C:5](=[O:6])[NH:7][C:8]3[CH:17]=[CH:16][C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[N:9]=3)[CH:18]=[CH:19][C:20]=2[N:21]=1
Reactant: Nc1ccc(C(=O)Nc2ccc3ccccc3n2)cc1N
Reactant: COC(=O)C(C)(C)Cc1cc(C)c(C=O)c(C)c1
Product: Cc1cc(CC(C)(C)C(=O)O)cc(C)c1-c1nc2ccc(C(=O)Nc3ccc4ccccc4n3)cc2[nH]1

Procedure:
The title compound was prepared from 3,4-diamino-N-quinolin-2-yl-benzamide (from Example 6-17) and 3-(4-formyl-3,5-dimethylphenyl)-2,2-dimethylpropionic acid methyl ester analogous to Example 6-26. 1H NMR (Methanol-d4, 400 MHz): δ 8.45 (d, 1H), 8.38 (d, 2H), 8.04 (dd, 1H), 7.93 (m, 2H), 7.77 (m, 2H), 7.55 (m, 1H), 7.06 (s, 2H), 2.89 (s, 2H), 2.16 (s, 6H), 1.2 (s, 6H). MS (m/z) 493.2 (M+1); Retention time: 1.25 min (Method 10).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]=2[O:2]1.[N+:15]([C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=1)([O-:17])=[O:16].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.C([O-])([O-])=O.[K+].[K+]>C(Cl)CCl.O>[CH2:1]1[O:2][C:3]2[C:8](=[CH:7][C:6]([C:22](=[O:23])[C:21]3[CH:20]=[CH:19][C:18]([N+:15]([O-:17])=[O:16])=[CH:26][CH:25]=3)=[C:5]([CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:4]=2)[O:9]1
Reactant: COC(=O)Cc1ccc2c(c1)OCO2
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [K+]
Solvent: ClCCCl
Solvent: O
Product: COC(=O)Cc1cc2c(cc1C(=O)c1ccc([N+](=O)[O-])cc1)OCO2
Temperature: 25 °C
Yield: 50 %

Procedure:
To a solution of methyl 3,4-methylenedioxyphenylacetate (5.4 g, 28 mmol) in ClCH2CH2Cl (100 mL) was added 4-nitrobenzoic acid (7.2 g, 43 mmol) and P2O5 (18 g) at room temperature under argon. The mixture was refluxed for 28 h, cooled to room temperature, then cold water was added slowly. The resulting mixture was carefully neutralized with solid K2CO3, and extracted with 1:1 hexane/EtOAc (2×300 mL). The combined extracts were washed with water and brine, and dried over Na2SO4. The solvent was removed in vacuo and the resulting residue was separated by chromatography (3:1 hexane/EtOAc) to afford the title compound as a yellow solid (4.7 g, 14 mmol, 50%). 1H NMR (CDCl3) 8.32 (d, 2H, J=8.5), 7.92 (d, 2H, J=8.5), 6.85 (s, 1H), 6.81 (s, 1H), 6.07 (s, 2H), 3.88 (s, 2H), 3.63 (s, 3H).
Reaction SMILES: O.C([O:9][C:10]1[CH:18]=[C:17]2[C:13]([C:14]([CH:25]([O:27][CH3:28])[CH3:26])=[N:15][N:16]2[CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)=[CH:12][CH:11]=1)C1C=CC=CC=1.[H][H]>[Pd].C1COCC1>[CH3:28][O:27][CH:25]([C:14]1[C:13]2[C:17](=[CH:18][C:10]([OH:9])=[CH:11][CH:12]=2)[N:16]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[N:15]=1)[CH3:26]
Reactant: [H][H]
Reactant: COC(C)c1nn(C2CCCCO2)c2cc(OCc3ccccc3)ccc12
Agent: [Pd]
Solvent: O
Solvent: C1CCOC1
Product: COC(C)c1nn(C2CCCCO2)c2cc(O)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 113.6 %

Procedure:
5% Palladium on carbon-STD-type-50% wet with water (79.5 mg; manufactured by N. E. Chemcat Corp.) and 6-(benzyloxy)-3-(1-methoxyethyl)-1-(tetrahydro-2H-pyran-2-yl)-indazole (195 mg) which can be prepared according to the method described in Reference example 25, etc. were dissolved in THF (5.6 mL; manufactured by Kanto Chemical Co., Inc.). After replacing the reaction system with hydrogen, it was stirred overnight at room temperature under hydrogen atmosphere. After replacing the reaction solution with nitrogen, the mixture was filtered and the filtrate was concentrated under reduced pressure to obtain the title compound (167 mg).
Reaction SMILES: [Na].Cl[C:3]1[C:8]([S:9]([NH2:12])(=[O:11])=[O:10])=[CH:7][CH:6]=[CH:5][N:4]=1.[CH3:13][O:14][CH2:15][CH2:16][OH:17]>>[CH3:13][O:14][CH2:15][CH2:16][O:17][C:3]1[C:8]([S:9]([NH2:12])(=[O:11])=[O:10])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: NS(=O)(=O)c1cccnc1Cl
Reactant: COCCO
Agent: [Na]
Product: COCCOc1ncccc1S(N)(=O)=O
Reaction time: 0.08 h

Procedure:
4.36 g of a 55% dispersion of sodium in oil is added in portions over 15 minutes and under nitrogen to 25 ml of methyl cellosolve. A solution of 9.6 g of 2-chloro-3-pyridylsulfonamide in 25 ml of methyl cellosolve is then added dropwise, with stirring, to the above dispersion over 5 minutes. The reaction mixture is then stirred for 1 hour at reflux temperature and concentrated in vacuo. The residue is acidified to pH 2 with about 25 ml of aqueous HCl at a temperature below 15° C., then stirred and filtered, affording 11.3 g of the desired 2-(2-methoxyethoxy)-3-pyridylsulfonamide, which is recrystallised from acetonitrile and has a melting point of 102°-103° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:10]2[CH:11]=[CH:12][C:13]([CH3:15])=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:16].C([O-])([O-])=O.[K+].[K+].[Na+].[I-].[CH2:25]([CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)[CH2:26][CH2:27][CH3:28]>CCCCCCC.CCOC(C)=O>[CH2:25]([CH:29]1[CH2:34][CH2:33][N:32]([CH2:2][CH2:3][CH2:4][N:5]2[C:10]3[CH:11]=[CH:12][C:13]([CH3:15])=[CH:14][C:9]=3[O:8][CH2:7][C:6]2=[O:16])[CH2:31][CH2:30]1)[CH2:26][CH2:27][CH3:28]
Reactant: Cc1ccc2c(c1)OCC(=O)N2CCCCl
Reactant: CCCCC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CCCCC1CCN(CCCN2C(=O)COc3cc(C)ccc32)CC1
Yield: 78.5 %

Procedure:
4-(3-Chloropropyl)-7-methyl-4H-benzo[1,4]oxazin-3-one (81MF2246b) (1.64 g, 6.84 mmol), K2CO3 (1.89 g, 13.68 mmol), NaI (2.05 g, 13.68 mmol) and 4-butylpiperidine (1.02 g, 7.18 mmol) were mixed according to GP11. CC (SiO2; Heptane/EtOAc 10:1-4) gave the title compound (81MF2246F) (1.85 g, 79%). 1H NMR (CDCl3) δ 6.97 (d, J=8.0 Hz, 1H), 6.82-6.78 (m, 2H), 4.54 (s, 2H), 3.94 (t, J=7.2 Hz, 2H), 2.86 (d, J=10.8 Hz, 2H), 2.37 (t, J=7.0 Hz, 2H), 2.28 (s, 3H), 1.92-1.79 (m, 4H), 1.66 (d, J=9.2 Hz, 2H), 1.31-1.18 (m, 9H), 0.88 (t, J=7.2 Hz, 3H) 13C NMR (CDCl3) δ 164.2, 145.3, 133.9, 126.3, 123.3, 117.7, 115.0, 67.8, 56.0, 54.3, 39.7, 36.5, 36.0, 32.7, 29.2, 24.9, 23.1, 20.8, 14.2.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]1[CH:13]=[C:12]([Cl:14])[N:11]=[CH:10][N:9]=1.[NH2:15][C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][C:19]([OH:25])=[CH:18][C:17]=1[CH3:26]>CN(C=O)C>[Cl:14][C:12]1[N:11]=[CH:10][N:9]=[C:8]([O:25][C:19]2[CH:20]=[C:21]([N+:22]([O-:24])=[O:23])[C:16]([NH2:15])=[C:17]([CH3:26])[CH:18]=2)[CH:13]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: Cc1cc(O)cc([N+](=O)[O-])c1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(Oc2cc(Cl)ncn2)cc([N+](=O)[O-])c1N
Temperature: 50 °C
Reaction time: 6 h

Procedure:
1.66 g (12.0 mmol) potassium carbonate were added to 0.922 g (6.00 mmol) 4,6-dichloropyrimidine and 1.11 g (6.60 mmol) 4-amino-3-methyl-5-nitro-phenol in 1.5 mL DMF and the mixture was stirred for 6 h at 50° C. Then the mixture was added to ice water and extracted several times with EtOAc. The combined organic phases were dried on sodium sulphate, evaporated down and purified by flash chromatography. The product-containing fractions were combined and evaporated down. The residue was triturated with EtOAc, suction filtered and dried under HV.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]([CH2:11][S+:12]([O-:24])[C:13]2[N-:14][C:15]3[CH:16]=[CH:17][C:18]([O:22][CH3:23])=[CH:19][C:20]=3[N:21]=2)=[C:6]([CH3:10])[C:7]=1[O:8][CH3:9].[K+].O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Mg+2:38]>CO>[CH3:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([CH3:10])[C:5]([CH2:11][S@@:12]([C:13]2[N-:14][C:15]3[CH:16]=[CH:17][C:18]([O:22][CH3:23])=[CH:19][C:20]=3[N:21]=2)=[O:24])=[N:4][CH:3]=1.[Mg+2:38]
Reactant: COc1ccc2[n-]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Agent: [Mg+2]
Solvent: O
Solvent: CO
Product: COc1ccc2[n-]c([S@@](=O)Cc3ncc(C)c(OC)c3C)nc2c1
Temperature: 2.5 °C
Reaction time: 1.75 h
Yield: 45 %

Procedure:
To a solution of esomeprazole potassium salt (100 g, 0.261 mole) in methanol (500 ml) kept in a round bottom flask, was added magnesium sulphate heptahydrate (64.1 g, 0.26 mole) at 25-30° C. and stirred for 1.5-2 hrs. The insoluble material formed was filtered off and the filtrate was passed through a 0.45 micron membrane filter. To the filtrate, water (1300 ml) was added and stirred at 25-30° C. for 1-1.5 hrs, cooled to 0-5° C., and stirred for a further period of 1-1.5 hrs. The solid formed was collected by filtration and washed with water and dried under reduced pressure at 40-45° C. to obtain the esomeprazole magnesium salt.
Reaction SMILES: O1CCCC1.[Br-].[O:7]1[CH2:12][CH2:11][CH2:10][O:9][CH:8]1[CH2:13][CH2:14][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[C:40]([C:42]1[CH:47]=[CH:46][C:45]([CH:48]2[CH2:53][CH2:52][CH:51]([CH2:54][CH:55]=O)[CH2:50][CH2:49]2)=[CH:44][CH:43]=1)#[N:41]>CCOCC>[O:9]1[CH2:10][CH2:11][CH2:12][O:7][CH:8]1[CH2:13][CH:14]=[CH:55][CH2:54][CH:51]1[CH2:50][CH2:49][CH:48]([C:45]2[CH:44]=[CH:43][C:42]([C:40]#[N:41])=[CH:47][CH:46]=2)[CH2:53][CH2:52]1
Reactant: c1ccc([P+](CCC2OCCCO2)(c2ccccc2)c2ccccc2)cc1
Reactant: N#Cc1ccc(C2CCC(CC=O)CC2)cc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: N#Cc1ccc(C2CCC(CC=CCC3OCCCO3)CC2)cc1
Reaction time: 1 h
Yield: 50 %

Procedure:
Tetrahydrofuran (100 ml) was added to 2-(1,3-dioxan-2-yl)ethyltriphenylphosphonium bromide (19.2 g, 42 mmols), followed by suspending, stirring under ice cooling till the liquid temperature reached 10° C. The reaction mixture was added potassium t-butoxide (4.7 g, 42 mmols), followed by elevating the temperature up to room temperature under ice cooling for one hour, stirring for one hour, dropwise adding a tetrahydrofuran (20 ml) solution of 2-(4-(4-cyanophenyl)cyclohexyl)acetaldehyde (9.0 g, 40 mmols) over 30 minutes from the dropping funnel, further stirring the reaction mixture for 5 hours after completion of the dropwise addition, adding ether (100 ml), allowing to stand for one hour, filtering off deposited insoluble substance, concentrating the filtrate under reduced pressure and isolating and purifying the resulting pale brown oil by means of silica gel column chromatography, to obtain white solids (6.8 g, 20 mmols) of 1-(4-(1,3-dioxan-2-yl)-2-butenyl)-4-(4-cyanophenyl)cyclohexane.
Reaction SMILES: Cl[C:2]1[N:3]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[N:26]=3)=[CH:21][CH:20]=2)[N:4]=[C:5]2[C:10]=1[C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[N:6]2[CH2:14][CH:15]([CH3:17])[CH3:16].C(=O)([O-])[O-].[Cs+].[Cs+].[CH:38]1([OH:43])[CH2:42][CH2:41][CH2:40][CH2:39]1>>[CH:38]1([O:43][C:2]2[N:3]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[N:26]=4)=[CH:21][CH:20]=3)[N:4]=[C:5]3[C:10]=2[C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[N:6]3[CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:42][CH2:41][CH2:40][CH2:39]1
Reactant: OC1CCCC1
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(Cl)n(Cc3ccc(-c4cccc(F)n4)cc3)nc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(OC3CCCC3)n(Cc3ccc(-c4cccc(F)n4)cc3)nc21
Temperature: 150 °C

Procedure:
3-chloro-2-(4-(6-fluoropyridin-2-yl)benzyl)-7-isobutyl-5-methyl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (20 mg, 0.045 mmol), cesium carbonate (22 mg, 0.068 mmol) and cyclopentanol (0.3 mL) are placed in a Biotage microwave vial. The vial is sealed, and then heated in a Biotage microwave instrument at 150° C. for 4 h. The reaction mixture is purified with a semi-preparative HPLC to give 10.4 mg of pure product as pale yellow solids (Purity: 97.7%). MS (ESI) m/z 492.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=3[CH3:21])=[CH:7][C:6]=2[C:5]2[CH:22]=[CH:23][C:24]([CH3:26])=[CH:25][C:4]=2[N:3]=1.Br[CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][CH2:36][P:37](=[O:44])([O:41][CH2:42][CH3:43])[O:38][CH2:39][CH3:40]>>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][CH2:36][P:37](=[O:44])([O:41][CH2:42][CH3:43])[O:38][CH2:39][CH3:40])=[CH:16][C:15]=3[CH3:21])=[CH:7][C:6]=2[C:5]2[CH:22]=[CH:23][C:24]([CH3:26])=[CH:25][C:4]=2[N:3]=1
Reactant: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(O)cc3C)cc12
Reactant: CCOP(=O)(CCCOCCOCCBr)OCC
Product: CCOP(=O)(CCCOCCOCCOc1ccc(CCc2cnc3c(N)nc4cc(C)ccc4c3c2)c(C)c1)OCC

Procedure:
Diethyl 3-(2-(2-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)ethoxy)ethoxy)propylphosphonate was prepared from following the procedure described for Example 139, but using 4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenol (from Example148) and diethyl 3-(2-(2-bromoethoxy)ethoxy)propylphosphonate. 1H NMR (Acetone-d6): δ 8.75 (s, 1H), 8.70 (s, 1H), 8.26 (d, 1H), 7.42 (s, 1H), 7.16 (d, 1H), 7.09 (d, 1H), 6.77 (s, 1H), 6.71 (d, 1H), 6.58 (br, 2H), 3.95-4.11 (m, 6H), 3.76-3.80 (m, 2H), 3.63-3.67 (m, 2H), 3.55-3.58 (m, 2H), 3.57-3.51 (m, 2H), 3.14-3.18 (m, 2H), 3.04-3.05 (m, 2H), 2.46 (s, 3H), 2.29 (s, 3H), 1.71-1.87 (m, 4H), 1.22-1.29 (m, 8H). LRMS [M+H]=610.3.
Reaction SMILES: [OH-].[K+].[CH3:3][CH:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6][C:5]1=O.[CH:15]([C:17]([CH3:19])=[O:18])=[CH2:16].Cl>O.CO>[CH3:3][C:4]12[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7][CH2:6][C:5]1=[CH:19][C:17](=[O:18])[CH2:15][CH2:16]2
Reactant: C=CC(C)=O
Reactant: CC1C(=O)CCc2ccccc21
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC12CCC(=O)C=C1CCc1ccccc12
Temperature: -15 °C
Reaction time: 6 h
Yield: 90.3 %

Procedure:
Potassium hydroxide in the amount of 2.25 g (40 mmol) was dissolved in 4.5 g of water in 100-ml three-necked flask, and the obtained solution was then cooled with ice under agitation in a stream of nitrogen gas. A methanol solution (8 ml) containing 4.8 g (30 mmol) of 1-methyl-2-tetralone was added dropwisely to the above obtained solution. The reaction vessel was cooled to -15° C., then, 2.1 g (30 mmol) of methyl vinyl ketone was added dropwisely to the reaction vessel and 2 ml of methanol was further added thereto. The resulted mixture was agitated under cooling with ice for 1 hour and then at room temperature for 6 hours in a stream of nitrogen-gas. Then, the mixture had been allowed to react at 70° C. for 6 hours. The reaction mixture was then poured into iced water, made acidic with hydrochloric acid and extracted with ether. The ether layer was removed and washed with water, and then dried with sodium sulfate. The ether was distilled off to obtain 5.75 g of oily yellowish orange residue. A part of this residue was crystallized and resulted crystals were recrystallized twice from cyclohexane to obtain 2.8 g of colorless plate-like crystals. The oily portion was further allowed to crystallize to obtain 1.9 g of crystals. The total yield was 4.7 g.
Reaction SMILES: [C:1]([C@H:5]1[C:32](=[O:33])[N:31]2[CH2:34][C@@H:28]([CH2:29][C@H:30]2[C:35]([O:37][CH3:38])=[O:36])[O:27][C:17]2=[N:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[C:25]([OH:26])=[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[CH2:39][C@H:9]2[O:8][C:7](=[O:40])[NH:6]1)([CH3:4])([CH3:3])[CH3:2].[C:41]([N:48]1[CH2:53][CH2:52][CH:51](O)[CH2:50][CH2:49]1)([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42]>>[C:44]([O:43][C:41]([N:48]1[CH2:53][CH2:52][CH:51]([O:26][C:25]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:18]=[C:17]3[O:27][C@H:28]4[CH2:34][N:31]([C:32](=[O:33])[C@H:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[NH:6][C:7](=[O:40])[O:8][C@@H:9]5[CH2:39][C@H:10]5[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]=23)[C@H:30]([C:35]([O:37][CH3:38])=[O:36])[CH2:29]4)[CH2:50][CH2:49]1)=[O:42])([CH3:47])([CH3:45])[CH3:46]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: COC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C(C)(C)C)NC(=O)O[C@@H]1C[C@H]1CCCCCc1c(nc3ccccc3c1O)O2
Product: COC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C(C)(C)C)NC(=O)O[C@@H]1C[C@H]1CCCCCc1c(nc3ccccc3c1OC1CCN(C(=O)OC(C)(C)C)CC1)O2

Procedure:
The title compound was prepared using the same method as described in Example 210, Step 1 with methyl (1aR,5S,8S,10R,22aR)-5-tert-butyl-17-hydroxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoline-8-carboxylate (Example 113, Step 5) and 1-Boc-4-hydroxypiperidine. LRMS (ES+) m/z 737.5 (M+H)+.
Reaction SMILES: [C:1]1([S:7]([NH:10][CH:11]([CH2:25][C:26]2[CH:34]=[C:33]([Cl:35])[C:32]([O:36]C)=[C:31]3[C:27]=2[CH:28]=[N:29][NH:30]3)[C:12]([NH:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:13])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH+]1C=CC=CC=1>>[C:1]1([S:7]([NH:10][CH:11]([CH2:25][C:26]2[CH:34]=[C:33]([Cl:35])[C:32]([OH:36])=[C:31]3[C:27]=2[CH:28]=[N:29][NH:30]3)[C:12]([NH:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:13])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1c(Cl)cc(CC(NS(=O)(=O)c2ccccc2)C(=O)NCCCCc2ccccc2)c2cn[nH]c12
Agent: Cl
Agent: c1cc[nH+]cc1
Product: O=C(NCCCCc1ccccc1)C(Cc1cc(Cl)c(O)c2[nH]ncc12)NS(=O)(=O)c1ccccc1

Procedure:
2-Benzenesulfonylamino-3-(6-chloro-7-methoxy-1H-indazol-4-yl)-N-(4-phenyl-butyl)-propionamide (0.10 g, 0.19 mmol) and pyridinium hydrochloride (ca. 0.7 g) are combined in a 2 mL pressure vial. The reaction is heated to obtain a melt (ca. 170° C. bath). After 50 min. the reaction is cooled and partitioned between EtOAc and NH4Cl. The organic layer is washed with water, brine and dried over MgSO4. The solution is concentrated and purified by column chromatography (silica, 4% MeOH/CH2Cl2) to provide 2-benzenesulfonylamino-3-(6-chloro-7-hydroxy-1H-indazol-4-yl)-N-(4-phenyl-butyl)-propionamide.