Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([O:14][CH2:15][C@H:16]2[CH2:18][O:17]2)[C@H:11]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH:27]=[CH2:28])=[CH:21][CH:20]=2)[C@@H:10]([O:29][CH2:30][C:31]2[CH:40]=[C:39]([O:41][CH3:42])[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH:32]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:43][O-:44].[Na+]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][C@H:10]([O:29][CH2:30][C:31]2[CH:40]=[C:39]([O:41][CH3:42])[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH:32]=2)[C@@H:11]([C:19]2[CH:20]=[CH:21][C:22]([O:25][CH2:26][CH:27]=[CH2:28])=[CH:23][CH:24]=2)[C@H:12]([O:14][CH2:15][C@H:16]([OH:17])[CH2:18][O:44][CH3:43])[CH2:13]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: C[O-]
Reactant: C=CCOc1ccc([C@@H]2[C@@H](OCc3cc(OC)c4ccccc4c3)CN(C(=O)OC(C)(C)C)C[C@H]2OC[C@H]2CO2)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOc1ccc([C@@H]2[C@@H](OCc3cc(OC)c4ccccc4c3)CN(C(=O)OC(C)(C)C)C[C@H]2OC[C@H](O)COC)cc1

Procedure:
In analogy to the procedure described in example 1 (k) the (3R,4R,5S)-4-(4-allyloxy-phenyl)-3-(4-methoxy-naphthalen-2-ylmethoxy)-5-[(2R)-oxiranylmethoxy]-piperidine-1-carboxylic acid tert-butyl ester was treated with sodium methylate in N,N-dimethylformamide to yield the (3S,4R,5R)-4-(4-allyloxy-phenyl)-3-[(2R)-2-hydroxy-3-methoxy-propoxy]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid tert-butyl ester as colorless oil; MS: 608 (M+H)+.
Reaction SMILES: C1(C(C2C=CC=CC=2)([PH:15]([O-])([O-:17])[O-:16])C(CC)CCCC)C=CC=CC=1.[OH:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([C:35]2[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=2)([CH3:34])[CH3:33])=[CH:28][CH:27]=1.[Na]>>[C:32]([C:29]1[CH:28]=[CH:27][C:26]([OH:25])=[CH:31][CH:30]=1)([C:35]1[CH:36]=[CH:37][C:38]([OH:41])=[CH:39][CH:40]=1)([CH3:34])[CH3:33].[CH2:26]([O:25][P:15]([O-:17])[O-:16])[CH2:27][CH2:28][CH2:29][CH2:32][CH2:35][CH2:36][CH3:37]
Reactant: CCCCC(CC)C(c1ccccc1)(c1ccccc1)[PH]([O-])([O-])[O-]
Agent: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Agent: [Na]
Product: CCCCCCCCOP([O-])[O-]

Procedure:
In a round bottom flask, 34.6 g (0.1 mol) of diphenyl-(2-ethylhexyl)phosphite, 22.8 g (0.1 mol) of bisphenol-A, and a catalytic quantity of metallic sodium (or alcoholate of an alkali metal) was heated at 180° C. under an atmosphere of nitrogen for one hour. The temperature was reduced to 90-100° C. The phenol was then removed under vacuum (10 mm) over 2.5 hours. When the residual pressure dropped to 1 mm, the reaction mass was subjected to vacuum for two more hours. The yield was quantitative. The phosphorus-31 NMR showed a series of peaks from 126 to 131 ppm.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][S:7]([NH:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][C:12]=1[CH3:21])(=[O:9])=[O:8].[K].CC(C)([O-])C>CN(C=O)C>[O:8]=[S:7]1(=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:10]1[C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][C:12]=1[CH3:21]
Reactant: COC(=O)c1ccc(NS(=O)(=O)CCCCCCl)c(C)c1
Agent: CC(C)(C)[O-]
Agent: [K]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(N2CCCCCS2(=O)=O)c(C)c1

Procedure:
Prepared analogously to Example 83b from methyl 4-(5-chloropentyl-sulphonyl-amino)-3-methyl-benzoate and potassium-tert.-butoxide in DMF.
Reaction SMILES: [CH2:1]([C:3]([CH3:19])([CH2:17][CH3:18])[C:4](=[O:16])CC(N)(P(O)(=O)O)P(O)(=O)O)[CH3:2].N([O-])=[O:21].[Na+]>O>[CH2:17]([C:3]([CH3:19])([CH2:1][CH3:2])[C:4]([OH:16])=[O:21])[CH3:18]
Reactant: CCC(C)(CC)C(=O)CC(N)(P(=O)(O)O)P(=O)(O)O
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CCC(C)(CC)C(=O)O
Temperature: 50 °C
Reaction time: 7 h

Procedure:
0.20 mol (63.4 g) 4-ethyl-4-methyl-3-oxo-1-aminohexane-1,1-di-phosphonic acid (IV) R2 =R3 =CH2CH3, R4 =CH3) were suspended in 600 ml 2N hydrochloric acidd and a solution of 0.8 mol (55.2 g) sodium nitrite dissolved in 1104 ml water were added dropwise to the resulting suspension with stirring over a period of 7 hours at 50° C. 2-Ethyl-2-methyl-butyric acid was formed as the organic phase and was extracted with ether. Unused nitrous acid was removed with hydrazine before working up. The aqueous phase was concentrated to around 300 ml in a rotary evaporator and alkylized to pH 9 with sodium hydroxide. The tetrasodium salt of hydroxyacetonitrile diphosphonic acid (III, M=Na) crystallized out from the cold solution in the form of the octahydrate. The yield comprised 65% (58.4 g).
Reaction SMILES: C([NH:9][C:10]([NH:12][CH2:13][CH:14]1[CH2:19][CH2:18][CH:17]([NH:20][C:21](=[O:30])[O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:16][CH2:15]1)=[S:11])(=O)C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>CO.O>[CH2:23]([O:22][C:21](=[O:30])[NH:20][CH:17]1[CH2:16][CH2:15][CH:14]([CH2:13][NH:12][C:10]([NH2:9])=[S:11])[CH2:19][CH2:18]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(NC1CCC(CNC(=S)NC(=O)c2ccccc2)CC1)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: NC(=S)NCC1CCC(NC(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 94.7 %

Procedure:
To a solution of benzyl N-[4-({[(benzoyl-amino)carbothioyl]amino}methyl)-cyclohexyl]carbamate (5.023 g, 11.4 mmol) in MeOH (110 ml) was added a solution of K2CO3 (3.5 g, 25.3 mmol) in water (30 ml). The solution was stirred for 24 hours at room temperature and the solvent was removed in vacuo with repeated additions of MeOH to azeotropically remove water. The resulting solid was treated with acetone (60 ml) and filtered. The filtrate was evaporated to yield 95% (3.47 g) of a yellow solid.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])(=[O:6])[CH:4]=[CH2:5].[Cl:12][CH:13](Cl)[C:14]([O:16][CH3:17])=[O:15].Cl>CN(C)C=O.O>[C:8]([O:7][C:3]([CH:4]1[CH2:5][C:13]1([Cl:12])[C:14]([O:16][CH3:17])=[O:15])=[O:6])([CH3:11])([CH3:10])[CH3:9]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: COC(=O)C(Cl)Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C1(Cl)CC1C(=O)OC(C)(C)C
Temperature: 10 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
80 g of 60% sodium hydride was suspended in 1,000 ml of N,N-dimethylformamide. To this suspension was dropped 352 ml of tert-butyl acrylate within 30 minutes under ice-cooling. Then 207 ml of methyl dichloroacetate was dropped into this reaction mixture within 1.5 hours while maintaining the internal temperature at 10° C. After the completion of the addition, the mixture was stirred for 2 hours while maintaining the internal temperature at 10° to 20° C. Then the reaction mixture was neutralized by adding concentrated hydrochloric acid and water was-further added thereto. The reaction mixture was extracted with ethyl acetate and the organic layer was washed with a saturated aqueous solution of sodium chloride. The extract was dried over anhydrous sodium sulfate and then the solvent was evaporated under reduced pressure. The obtained residue was distilled under reduced pressure to thereby give 384 g (yield 84%) of methyl 2-tert-butoxycarbonyl-1-chloro-1-cyclopropanecarboxylate in the form of a colorless oily product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([CH3:21])[CH:3]=1.BrC1C=CC(C(O)=O)=C(C)C=1.N1(C2CCNCC2)CCCC1.BrC1C(C)=C(C(N2CCC(N3CCCC3)CC2)=O)C=CC=1.[F:65][C:66]([F:78])([F:77])[O:67][C:68]1[CH:69]=[C:70](B(O)O)[CH:71]=[CH:72][CH:73]=1>>[CH3:21][C:4]1[CH:3]=[C:2]([C:70]2[CH:71]=[CH:72][CH:73]=[C:68]([O:67][C:66]([F:65])([F:77])[F:78])[CH:69]=2)[CH:7]=[CH:6][C:5]=1[C:8]([N:10]1[CH2:15][CH2:14][CH:13]([N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:12][CH2:11]1)=[O:9]
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Reactant: Cc1cc(Br)ccc1C(=O)N1CCC(N2CCCC2)CC1
Agent: C1CCN(C2CCNCC2)C1
Agent: Cc1c(Br)cccc1C(=O)N1CCC(N2CCCC2)CC1
Agent: Cc1cc(Br)ccc1C(=O)O
Product: Cc1cc(-c2cccc(OC(F)(F)F)c2)ccc1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for example 1, (4-bromo-2-methyl-phenyl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (prepared from 4-bromo-2-methyl-benzoic acid and 4-pyrrolidin-1-yl-piperidine in analogy to the procedure described for the preparation of intermediate 2) was reacted with 3-trifluoromethoxy-phenyl boronic acid to give the title compound as light yellow solid. MS: 433.3 (MH+).
Reaction SMILES: Br[C:2]1[C:10]2[CH:9]=[N:8][C:7]([NH:11][CH2:12][CH2:13][CH2:14][CH3:15])=[N:6][C:5]=2[N:4]([CH2:16][C@H:17]2[CH2:22][CH2:21][C@H:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:19][CH2:18]2)[CH:3]=1.[F:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH2:12]([NH:11][C:7]1[N:8]=[CH:9][C:10]2[C:2]([C:35]3[CH:36]=[CH:37][C:32]([F:31])=[CH:33][CH:34]=3)=[CH:3][N:4]([CH2:16][C@H:17]3[CH2:22][CH2:21][C@H:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:19][CH2:18]3)[C:5]=2[N:6]=1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCNc1ncc2c(Br)cn(C[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)c2n1
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCCCNc1ncc2c(-c3ccc(F)cc3)cn(C[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)c2n1
Temperature: 120 °C

Procedure:
A 10 mL microwave tube was charged with tert-butyl trans-4-((5-bromo-2-(butylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)cyclohexylcarbamate (0.096 g, 0.20 mmol), 4-fluorophenylboronic acid (0.042 g, 0.30 mmol), potassium carbonate (0.055 g, 0.40 mmol), tetrakis(triphenylphosphine)palladium (0.024 g, 0.020 mmol), dioxane (2 mL) and water (0.50 mL). The reaction was heat at 120° C. for 10 min in microwave. The reaction was diluted with EtOAc and washed with water. The aqueous layer was extracted with EtOAc (3×). The combined organic layers were dried (Na2SO4), concentrated, and purified by Isco to provide tert-butyl trans-4-((2-(butylamino)-5-(4-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)cyclohexylcarbamate. This intermediate was dissolved in CH2Cl2 (2 mL). Trifluoroacetic acid (0.6 mL) was added at ambient temperature. After stirring for 2 h, the solvent was evaporated. The residue was purified by preparative HPLC to provide 7-((trans-4-aminocyclohexyl)methyl)-N-butyl-5-(4-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine (UNC1537A) as a yellow solid (TFA salt) (UNC1537A) (0.032 g, 41%). 1H NMR (400 MHz, CD3OD) δ 8.76 (s, 1H), 7.67 (s, 1H), 7.67-7.61 (m, 2H), 7.21 (t, J=8.5 Hz, 2H), 4.10 (d, J=7.0 Hz, 2H), 3.54 (t, J=7.1 Hz, 2H), 3.16-3.01 (m, 1H), 2.07 (d, J=10.3 Hz, 2H), 2.04-1.92 (m, 1H), 1.85 (d, J=12.2 Hz, 2H), 1.76-1.65 (m, 2H), 1.54-1.44 (m, 2H), 1.44-1.34 (m, 2H), 1.34-1.20 (m, 2H), 1.01 (t, J=7.4 Hz, 3H); MS m/z 396.3 [M+H]+.
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].I[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18](=[O:30])[N:19]([CH:21]([C:26]([NH:28][CH3:29])=[O:27])[C:22]([O:24][CH3:25])=[O:23])[CH3:20])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C(Cl)(Cl)Cl>[OH:4][CH2:1][C:2]#[C:3][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18](=[O:30])[N:19]([CH:21]([C:26]([NH:28][CH3:29])=[O:27])[C:22]([O:24][CH3:25])=[O:23])[CH3:20])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1
Reactant: C#CCO
Reactant: CNC(=O)C(C(=O)OC)N(C)C(=O)c1ccc(-c2ccc(I)cc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: ClC(Cl)Cl
Product: CNC(=O)C(C(=O)OC)N(C)C(=O)c1ccc(-c2ccc(C#CCO)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 63.7 %

Procedure:
Prop-2-yn-1-ol (0.19 g), PdCl2(PPh3)2 (39 mg), CuI (21 mg) and TEA (0.17 g) were added to a chloroform (10 mL) solution of 4-iodo-4′-{[1-methoxy-3-(methylamino)-1,3-dioxopropan-2-yl](methyl)carbamoyl}biphenyl (0.52 g) as obtained in Example 20-(1). The mixture was stirred for 3 hours at room temperature in a nitrogen atmosphere, and then the reaction mixture was concentrated. The resulting residue was purified by OH type silica gel chromatography (gradient elution with hexane/ethyl acetate=50/50→0/100) to obtain 4-(3-hydroxyprop-1-yn-1-yl)-4′-{[1-methoxy-3-(methylamino)-1,3-dioxopropan-2-yl](methyl)carbamoyl}biphenyl (white solid) (0.28 g, 63%).
Reaction SMILES: [NH2:1][C:2]1[N:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:3]=1[C:4](N(OC)C)=[O:5].[F:15][C:16]1[CH:21]=[CH:20][C:19](I)=[CH:18][CH:17]=1>>[NH2:1][C:2]1[C:3]([C:4]([C:19]2[CH:20]=[CH:21][C:16]([F:15])=[CH:17][CH:18]=2)=[O:5])=[CH:10][CH:11]=[C:12]([Cl:14])[N:13]=1
Reactant: Fc1ccc(I)cc1
Reactant: CON(C)C(=O)c1ccc(Cl)nc1N
Product: Nc1nc(Cl)ccc1C(=O)c1ccc(F)cc1

Procedure:
The title compound was prepared from 2-Amino-6-chloro-N-methoxy-N-methyl-nicotinamide (Example 3) and 1-fluoro-4-iodobenzene (Aldrich 99%) using the procedure described in Example 7. HRMS, observed: 250.0314, Calcd for M+: 250.0309.
Reaction SMILES: [OH:1][CH2:2][C:3]1([C:18]2[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:19]=2O)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:4]1=[O:17].C1(CCN2C3C(=CC=CC=3)C(C3C(O)=CC4OCOC=4C=3)(CO)C2=O)CC1>>[CH2:12]([N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:3]2([C:18]3[CH:23]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:21]=[CH:20][C:19]=3[O:1][CH2:2]2)[C:4]1=[O:17])[CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCN1C(=O)C(CO)(c2cc(C(F)(F)F)ccc2O)c2ccccc21
Agent: O=C1N(CCC2CC2)c2ccccc2C1(CO)c1cc2c(cc1O)OCO2
Product: CCCCCN1C(=O)C2(COc3ccc(C(F)(F)F)cc32)c2ccccc21
Yield: 27 %

Procedure:
Following the procedure as described in EXAMPLE 1, and making non-critical variations using 3-(hydroxymethyl)-3-[2-hydroxy-5-(trifluoromethyl)phenyl]-1-pentyl-1,3-dihydro-2H-indol-2-one to replace 1-(2-cyclopropylethyl)-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one, the title compound was obtained in 27% yield: 1H NMR (300 MHz, CDCl3) δ 7.48 (dd, 1H), 7.35 (td, 1H), 7.16-6.90 (m, 5H), 5.02 (d, 1H), 4.76 (d, 1H), 3.91-3.65 (m, 2H), 1.82-1.67 (m, 2H), 1.47-1.29 (m, 4H), 0.91 (t, 3H); 13C NMR (75 MHz, CDCl3) δ 176.5, 163.3, 142.6, 131.8, 129.8, 129.3, 127.7, 124.1, 124.0, 123.9, 123.6, 121.0, 110.6, 108.9, 80.5, 57.6, 40.5, 29.0, 27.1, 22.3, 13.9; MS (ES+) m/z 376 (M+1).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][NH:20][C:21](=[O:57])[C@@H:22]([NH2:56])[CH2:23][S:24][CH2:25][C@H:26]([O:42][C:43](=[O:55])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[CH2:27][O:28][C:29](=[O:41])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].N1C=CC=CC=1.[C:64](Cl)(=[O:80])[CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH3:79]>C(Cl)Cl>[C:43]([O:42][C@H:26]([CH2:27][O:28][C:29](=[O:41])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:25][S:24][CH2:23][C@H:22]([NH:56][C:64](=[O:80])[CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH3:79])[C:21](=[O:57])[NH:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][P:4]([O:5][CH2:6][CH3:7])([O:3][CH2:1][CH3:2])=[O:8])(=[O:55])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54]
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](N)C(=O)NCCOCCOCCOCCP(=O)(OCC)OCC)OC(=O)CCCCCCCCCCC
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCC)OC(=O)CCCCCCCCCCC)C(=O)NCCOCCOCCOCCP(=O)(OCC)OCC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of (14R,18R)-14-amino-18-(dodecanoyloxy)-13,21-dioxo-3,6,9,20-tetraoxa-16-thia-12-azadotriacontylphosphonic acid diethyl ester (1 eq, from example 18, step 6) in DCM (0.1 M) was cooled in an ice bath. Pyridine (1.2 eq) was added followed by palmitoyl chloride (1.1 eq). The reaction mixture was stirred for 10 minutes then warmed up to room temperature, and stirred for 2 hours. The reaction mixture was diluted with DCM, washed with saturated aqueous NH4Cl. The aqueous phase was back extracted with DCM. The combined organic phases were washed with brine, dried over anhydrous Na2SO4 and concentrated en vaccuo. The resulting crude was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-10% MeOH/DCM to give the title product as a white solid.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:17]=[CH:16][S:15][C:14]=1[C:18]([NH2:20])=[O:19]>>[I:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([NH:12][C:13]2[CH:17]=[CH:16][S:15][C:14]=2[C:18]([NH2:20])=[O:19])=[O:11])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(I)cc1
Reactant: NC(=O)c1sccc1N
Product: NC(=O)c1sccc1NC(=O)Cc1ccc(I)cc1

Procedure:
This compound was prepared from 2-(4-iodophenyl)acetic acid and 3-aminothiophene-2-carboxamide using protocol B. Method[1], MS(ESI) 387.0, Retention time=1.777 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:13][CH2:14][NH2:15])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[C:16](OC(=O)C)(=[O:18])C>C(O)=O>[CH:16]([CH:13]([C:5]1[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH2:14][NH2:15])=[O:18]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(CCN)cc(OC)c1OC
Solvent: O=CO
Product: COc1cc(C(C=O)CN)cc(OC)c1OC

Procedure:
1.422 kg of 3,4,5-trimethoxy-phenylethylamine is slowly added to a mixture of 2.185 kg of 98% formic acid and 1.728 kg of acetic anhydride, while maintaining the temperature at about 50°. The reaction bath is maintained at this temperature for about 3 hours and the formic acid and acetic acid mixture and the excess anhydride is distilled. The formylated derivative thus obtained (1.734 kg) is used unpurified.
Reaction SMILES: [C:1]1([C:11]2[CH:15]=[C:14]([NH2:16])[NH:13][N:12]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:17](OC)(=O)[CH2:18][C:19](OC)=O.C(O)C.C[O-].[Na+].CO>>[C:1]1([C:11]2[CH:15]=[C:14]3[N:16]=[CH:17][CH:18]=[CH:19][N:13]3[N:12]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)CC(=O)OC
Reactant: Nc1cc(-c2cccc3ccccc23)n[nH]1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: c1ccc2c(-c3cc4ncccn4n3)cccc2c1
Temperature: 120 °C

Procedure:
To a solution of 3-(1-naphthyl)-1H-pyrazol-5-amine (654 mg, 3.12 mmol) and dimethyl malonate (0.394 mL, 3.44 mmol) in anhydrous ethanol (9.44 mL, 162 mmol) is added 0.5 M sodium methoxide in methanol (12.5 mL, 6.25 mmol). The mixture is heated at 120° C. under a nitrogen atmosphere overnight. The reaction mixture is cooled to room temperature and the solvent is removed in vacuo. The residue is suspended in water and the precipitate is collected in a Buchner funnel to provide 2-(1-naphthyl)pyrazolo[1,5-a]pyrimidine, 7-diol (534 mg, yield 62%). LCMS: (AA) M+1 278; 1H NMR (400 MHz, DMSO) δ 10.17 (s, 1H), 8.73 (dd, J=8.2, 4.8 Hz, 1H), 7.99-7.88 (m, 2H), 7.72 (dd, J=7.1, 1.1 Hz, 1H), 7.58-7.49 (m, 4H), 5.83 (s, 1H), 4.14 (s, 1H).
Reaction SMILES: [O:1]=[C:2]1[NH:11][C:10]2[N:9]=[C:8]([O:12][CH2:13][CH2:14][CH2:15][CH:16]=O)[CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1.[Cl:18][C:19]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C>[Cl:18][C:19]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=1[N:26]1[CH2:31][CH2:30][N:29]([CH2:16][CH2:15][CH2:14][CH2:13][O:12][C:8]2[N:9]=[C:10]3[C:5]([CH2:4][CH2:3][C:2](=[O:1])[NH:11]3)=[CH:6][CH:7]=2)[CH2:28][CH2:27]1
Reactant: Clc1cccc(N2CCNCC2)c1Cl
Reactant: O=CCCCOc1ccc2c(n1)NC(=O)CC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: O=C1CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)nc2N1
Reaction time: 0.25 h
Yield: 60.7 %

Procedure:
In the final step of the synthesis reaction, the title compound, 7-{4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-butoxy}-3,4-dihydro-1H-[1,8]naphthyridin-2-one was produced as follows: To a solution of 4-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde (1.06 g, crude from previous reaction) was added a solution of 2,3-dichlorophenylpiperazine (1.02 g, 4.40 mmol) in dichloroethane (5 mL). The solution was stirred for 15 min and NaBH(OAc)3 (1.21 g, 5.72 mmol, 1.3 equiv) was added as a powder. The reaction was stirred at room temperature for 3 h and quenched with saturated NaHCO3 and H2O. The mixture was extracted with EtOAc. The organic layer was washed with saturated NaHCO3, H2O and brine, dried over Na2SO4 and concentrated to give a yellow foam/oil. Purification by liquid chromatography (4% MeOH/CH2Cl2) afforded the title compound as a white foam (1.20 g, 2.67 mmol, 61% over 2 steps). The HCl salt was formed by dissolving the title compound (800 mg, 1.78 mmol) in Et2O (20 mL) and CH2Cl2 (2 mL) followed by the addition of 1N HCl in Et2O (1.75 mL). The resulting white precipitate was collected by filtration, washed with Et2O and dried to give a white solid (801 mg). MS: APCI: M+1: 449.1 (Exact Mass: 448.14).
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2([C:24](=[O:26])[CH3:25])[CH2:13][C:14]1[CH:15]=[N:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=1.Cl[Si](C)(C)C.[Br-:32].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1>C1COCC1>[Br:32][CH2:25][C:24]([C:6]1([CH2:13][C:14]2[CH:15]=[N:16][C:17]([C:20]([F:22])([F:23])[F:21])=[CH:18][CH:19]=2)[C:7]2[C:3](=[C:2]([F:1])[C:10]([O:11][CH3:12])=[CH:9][CH:8]=2)[CH2:4][CH2:5]1)=[O:26]
Reactant: [Br-]
Reactant: COc1ccc2c(c1F)CCC2(Cc1ccc(C(F)(F)F)nc1)C(C)=O
Agent: C[N+](C)(C)c1ccccc1
Agent: C[Si](C)(C)Cl
Solvent: C1CCOC1
Product: COc1ccc2c(c1F)CCC2(Cc1ccc(C(F)(F)F)nc1)C(=O)CBr
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
1-(4-fluoro-5-methoxy-1-{[6-(trifluoromethyl)pyridin-3-yl]methyl}-2,3-dihydro-1H-inden-1-yl)ethanone (600 mg, 1.6 mmol) was diluted in THF (3 ml). This solution was cooled to −78° C. and Sodium bis(hexamethylsilyl) amide (1.8 ml, 1.8 mmol) was added. After stirring for 10 min, chloro trimethylsilane (230 μl, 1.8 mmol) was added drop wise at −78° C., after which the reaction was warmed to 0° C., and left stirring for 30 min. To this solution was added Phenyltrimethylammonium tribromide (680 mg, 1.8 mmol) portion wise, and THF (1 mL) was added for solubility purposes. The reaction mixture was allowed to warm to room temp. Aqueous work up, extracted with dichloromethane, dried over magnesium sulfate, filtered, concentrated under reduced pressure furnished 2-bromo-1-(4-fluoro-5-methoxy-1-{[6-(trifluoromethyl)pyridin-3-yl]methyl}-2,3-dihydro-1H-inden-1-yl)ethanone. Used without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:37])[CH2:7][CH2:6][C:5]([C:8]2[C:13]([NH:14][C:15]([C:17]3[N:18](COCC[Si](C)(C)C)[C:19]([C:22]#[N:23])=[CH:20][N:21]=3)=[O:16])=[CH:12][CH:11]=[C:10]([C:32]([O:34]CC)=[CH2:33])[N:9]=2)=[CH:4][CH2:3]1.CCO.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:32]([C:10]1[N:9]=[C:8]([C:5]2[CH2:6][CH2:7][C:2]([CH3:37])([CH3:1])[CH2:3][CH:4]=2)[C:13]([NH:14][C:15]([C:17]2[NH:18][C:19]([C:22]#[N:23])=[CH:20][N:21]=2)=[O:16])=[CH:12][CH:11]=1)(=[O:34])[CH3:33]
Reactant: C=C(OCC)c1ccc(NC(=O)c2ncc(C#N)n2COCC[Si](C)(C)C)c(C2=CCC(C)(C)CC2)n1
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)c1ccc(NC(=O)c2ncc(C#N)[nH]2)c(C2=CCC(C)(C)CC2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The title compound was prepared from 5-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid [2-(4,4-dimethyl-cyclohex-1-enyl)-6-(1-ethoxy-vinyl)-pyridin-3-yl]-amide (as prepared in the previous step, 12 mg, 0.023 mmol)) as a solution in 10 mL of DCM with 0.4 mL of EtOH and 10 mL of TFA; the mixture was stirred for 1 h at RT. The mixture was concentrated and triturated with Et2O to give (4.4 mg, 52%). Mass spectrum (ESI, m/z): Calcd. for C20H21N5O2, 364.1 (M+H), found 364.1.