Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].[CH3:9][C:10]1[C:11]([N+:17]([O-:19])=[O:18])=[C:12]([OH:16])[CH:13]=[CH:14][CH:15]=1.[C:20]1([C:26]2[N:27]=[CH:28][N:29]([CH2:31][CH2:32][CH2:33]Cl)[CH:30]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O>[N+:17]([C:11]1[C:12]([O:16][CH2:33][CH2:32][CH2:31][N:29]2[CH:30]=[C:26]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:27]=[CH:28]2)=[CH:13][CH:14]=[CH:15][C:10]=1[CH3:9])([O-:19])=[O:18]
Reactant: ClCCCn1cnc(-c2ccccc2)c1
Reactant: Cc1cccc(O)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc(OCCCn2cnc(-c3ccccc3)c2)c1[N+](=O)[O-]
Temperature: 100 °C
Yield: 90 %

Procedure:
9.02 g of potassium carbonate and a catalytic amount of sodium iodide were added to a dimethylformamide solution of 5 g of 3-methyl-2-nitrophenol and 7.2 g of 4-phenyl-1-(3-chloropropyl)-1H-imidazole. The obtained mixture was heated at 100° C. for 2 hours to conduct a reaction. After the completion of the reaction, the reaction mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over magnesium sulfate and distilled to remove the solvent. The obtained oily substance .was purified by silica gel chromatography to give 9.91 g of 2-nitro-3-[3-(4-phenyl-1H-imidazol-1-yl)propoxy]toluene. This product was catalytically reduced and condensed with butyl isocyanate according to a conventional process to give 11.2 g of the title compound having a melting point of 102° to 110° C.
Reaction SMILES: COC([NH:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][NH:8][C:7]1=[O:16])=O.C[Si](I)(C)C>C(#N)C.C(OCC)(=O)C>[NH2:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][NH:8][C:7]1=[O:16]
Reactant: COC(=O)NC1C(=O)NCc2ccccc21
Agent: C[Si](C)(C)I
Solvent: CCOC(C)=O
Solvent: CC#N
Product: NC1C(=O)NCc2ccccc21
Temperature: 65 °C

Procedure:
Step D—Removal of the Methoxyoxycarbonyl Group (MOC): To the 4-methoxycarbonylamino-1,2,3,4-tetrahydroisoquinoline-3-one (3.4 mmoles) in 30 mL of acetonitrile was added 2 mole equivalents of trimethylsilyliodide (TMSI). The reaction mixture was heated to 50-80° C. for 3 hrs and then cooled and poured into a separatory funnel. The reaction mixture was diluted with ethyl acetate and washed with 1 molar K2CO3 and then with 5% NaHSO3. The organic layer was dried over Na2SO4 and filtered. The solvent was removed under reduced pressure to give the 4-amino-1,2,3,4-tetrahydroisoquinoline-3-one derivative. Typical yields range from 50-87%.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH2:5]([O:7][C:8]([CH:10]1[O:14][C:13]2[CH:15]=[CH:16][C:17]([CH3:19])=[CH:18][C:12]=2[O:11]1)=[O:9])[CH3:6].[CH2:20]([N:23]([CH2:36][CH2:37][CH3:38])[S:24]([C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1)(=[O:26])=[O:25])[CH2:21][CH3:22]>ClCCCl>[CH2:5]([O:7][C:8]([CH:10]1[O:11][C:12]2[CH:18]=[C:17]([CH3:19])[C:16]([C:31](=[O:32])[C:30]3[CH:34]=[CH:35][C:27]([S:24](=[O:25])(=[O:26])[N:23]([CH2:20][CH2:21][CH3:22])[CH2:36][CH2:37][CH3:38])=[CH:28][CH:29]=3)=[CH:15][C:13]=2[O:14]1)=[O:9])[CH3:6]
Reactant: CCOC(=O)C1Oc2ccc(C)cc2O1
Reactant: CCCN(CCC)S(=O)(=O)c1ccc(C(=O)Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CCCN(CCC)S(=O)(=O)c1ccc(C(=O)c2cc3c(cc2C)OC(C(=O)OCC)O3)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
46.6 g (0.35 mol) of aluminum chloride are added portionwise within 25 minutes at 5° to 10° C., with stirring, to a solution of 31.2 g (0.15 mol) of 5-methyl-1,3-benzodioxole-2-carboxylic acid ethyl ester and 54.7 g (0.18 mol) of 4-(dipropylsulfamoyl)-benzoyl chloride in 350 ml of 1,2-dichloroethane. The reaction mixture is then stirred for a further 90 minutes at 5°-10° C. and for 30 minutes at room temperature, after which time all the aluminum chloride has been dissolved. After standing for about 24 hours at room temperature, the reaction mixture is poured into about 2 kg of an ice/water mixture. The organic phase is separated; it is subsequently washed once with 2N hydrochloric acid, twice with water, once with 1N sodium bicarbonate solution and again twice with water; it is afterwards dried over sodium sulfate and concentrated by evaporation in vacuo. The 5-[4-(dipropylsulfamoyl)-benzoyl]-6-methyl- 1,3-benzodioxole-2-carboxylic acid ethyl ester obtained as residue melts at 97°-99° C. after recrystallisation.
Reaction SMILES: C[O:2][C:3]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].O>I>[OH:2][C:3]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: COc1c(C(=O)O)cccc1C(=O)O
Agent: I
Solvent: O
Product: O=C(O)c1cccc(C(=O)O)c1O
Yield: 96.9 %

Procedure:
A solution of 2-methoxyisophthalic acid (1.0 g) in 55% hydriodic acid (10 ml) was heated at 80° C. for 1 hour. The reaction mixture was poured into iced water and the precipitate was collected by filtration to give the desired compound (0.9 g, yield 95%) as a pale yellow solid.
Reaction SMILES: [C:1]1([CH2:7][CH:8]=[N+:9]([O-:11])[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12]1(=[O:18])[CH2:17][CH2:16][CH2:15][CH:14]=[CH:13]1>>[CH2:7]([C@@H:8]1[C@@H:13]2[C:12](=[O:18])[CH2:17][CH2:16][CH2:15][C@@H:14]2[O:11][N:9]1[CH3:10])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1C=CCCC1
Reactant: C[N+]([O-])=CCc1ccccc1
Product: CN1O[C@H]2CCCC(=O)[C@H]2[C@H]1Cc1ccccc1
Temperature: 100 °C
Reaction time: 15 h
Yield: 75 %

Procedure:
In a dry sealed tube under N2 were placed N-(2-phenylethylidene)methylamine N-oxide (2.0 g, 13.4 mmol) and 2-cyclohexenone (5 ml). The reagents were stirred at 100° C. for 15 hours. Unreacted 2-cyclohexenone was removed by Kugelrohr distillation to yield the crude product as a viscous brown oil (K100%). The crude product was purified by flash chromatography on silica gel (Sorbsil C60, 60A) using 60:40 v/v petroleum ether (fraction of bp 40°-60° C.):ethyl acetate as the solvent system to give the unsubstituted title compound as an orange oil (2.48 g. 75%), νmax (film) 2944, 2872, 1709, 1455, 1238 cm-1 ; δH (250 MHz, CDCl3 --Me4Si) 1.75-1.95 (4H, br m), 2.20-2.40 (2H, br m), 2.50 (3H, s), 3.70-3.80 (1H, t), 2.85-2.95 (2H, t), 3.45-3.55 (1H, br m), 4.30-4.40 (1H, br m), 7.15-7.30 (5H, br m), M/z 246 (MH+ 100%) (Found: MH+ 246.149; C15H19NO2 requires MH+ 246.1522).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]2[CH:14]=[N:15][C:16]([N:19]3[CH:23]=[CH:22][CH:21]=[N:20]3)=[CH:17][CH:18]=2)=[CH:4][C:3]=1[C:24]([NH:26][C@H:27]1[CH2:32][CH2:31][CH2:30][CH2:29][C@@H:28]1[OH:33])=[O:25].[C:34](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C.C(OCC)(=O)C>[OH:33][C@H:28]1[CH2:29][CH2:30][CH2:31][CH2:32][C@@H:27]1[NH:26][C:24]([C:3]1[CH:4]=[C:5]([CH2:12][C:13]2[CH:14]=[N:15][C:16]([N:19]3[CH:23]=[CH:22][CH:21]=[N:20]3)=[CH:17][CH:18]=2)[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]=1[O:1][CH3:34])=[O:25]
Reactant: O=C(N[C@H]1CCCC[C@@H]1O)c1cc(Cc2ccc(-n3cccn3)nc2)c2ccccc2c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CI
Product: COc1c(C(=O)N[C@H]2CCCC[C@@H]2O)cc(Cc2ccc(-n3cccn3)nc2)c2ccccc12
Reaction time: 24 h

Procedure:
To a solution of 1-hydroxy-N-[(1S,2S)-2-hydroxycyclohexyl]-4-{[6-(1H-pyrazol-1-yl)pyridine-3-yl]methyl}-2-naphthamide (Example 6, 0.120 g, 0.271 mmol) in 4 mL of DMF was added potassium carbonate (0.041 g, 0.30 mmol) and iodomethane (0.042 g, 0.30 mmol). After 24 hours, the reaction was diluted with ethyl acetate, washed with water, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 0-10% methanol in dichloromethane to provide the title compound that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 457.4 for [M+H]+: 1H NMR (400 MHz, CDCl3) δ 8.50 (br s, 1H), 8.30 (br s, 1H), 8.22-8.11 (m, 2H), 8.03 (s, 1H), 7.92 (d, J=6.9 Hz, 1H), 7.84 (br s, 1H), 7.70 (br s, 1H), 7.57 (br s, 2H), 6.44 (br s, 1H), 4.44 (s, 2H), 4.03 (s, 3H), 3.98 (br s, 1H), 3.53 (br s, 1H), 2.36-2.14 (m, 3H), 1.79 (br s, 2H), 1.47-1.26 (m, 3H).
Reaction SMILES: [NH2:1][C:2]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]2[C:17](=[O:18])[N:16]([CH3:19])[CH:15]=[C:14]([C:20]3[CH:30]=[CH:29][CH:28]=[C:27]([N:31]4[N:40]=[CH:39][C:38]5[C:33](=[C:34]([F:45])[CH:35]=[C:36]([C:41]([CH3:44])([CH3:43])[CH3:42])[CH:37]=5)[C:32]4=[O:46])[C:21]=3[CH2:22][O:23]C(=O)C)[CH:13]=2)=[N:9][CH:10]=1)([CH3:4])[CH3:3].O.[OH-].[Li+].CO>O1CCOCC1>[NH2:1][C:2]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]2[C:17](=[O:18])[N:16]([CH3:19])[CH:15]=[C:14]([C:20]3[C:21]([CH2:22][OH:23])=[C:27]([N:31]4[N:40]=[CH:39][C:38]5[C:33](=[C:34]([F:45])[CH:35]=[C:36]([C:41]([CH3:42])([CH3:43])[CH3:44])[CH:37]=5)[C:32]4=[O:46])[CH:28]=[CH:29][CH:30]=3)[CH:13]=2)=[N:9][CH:10]=1)([CH3:4])[CH3:3]
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccc(C(C)(C)N)cn3)c(=O)n(C)c2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Solvent: O
Product: Cn1cc(-c2cccc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2CO)cc(Nc2ccc(C(C)(C)N)cn2)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 679.8 %

Procedure:
Acetic acid 2-{5-[5-(1-amino-1-methyl-ethyl)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl}-6-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-benzyl ester (159 mg, 0.0255 mmol) was dissolved in dioxane (3 ml). 2 M lithium hydroxide monohydrate solution (0.76 ml, 1.53 mmol) was added and stirred for 3hr at r.t. MeOH was added and the mixture purified purified by chromatography. Isolated product was dried under high vacuum at 50° C. to give 2-(3-{5-[5-(1-Amino-1-methyl-ethyl)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl}-2-hydroxymethyl-phenyl)-6-tert butyl-8-fluoro-2H-phthalazin-1-one (101 mg, 68%) as a off-white crystalline product. MS (H+)=583.3.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:42])[CH2:7][C:8]1[C:17]([CH3:18])=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25](=[O:40])(=[O:39])[N:26]([CH:36]([CH3:38])[CH3:37])[CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=3)=[CH:21][CH:20]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:41])[CH:14]=2)[CH:9]=1.C1COCC1.O>CCCCCC>[Cl:41][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH2:7][C:6]([OH:42])=[O:5])[C:17]([CH3:18])=[C:16]2[C:19]1[CH:20]=[CH:21][C:22]([S:25](=[O:39])(=[O:40])[N:26]([CH:36]([CH3:38])[CH3:37])[CH2:27][C:28]2[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=2)=[CH:23][CH:24]=1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(S(=O)(=O)N(Cc3ccc(OC)cc3)C(C)C)cc2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: COc1ccc(CN(C(C)C)S(=O)(=O)c2ccc(-c3c(C)c(CC(=O)O)cc4ccc(Cl)cc34)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.9 %

Procedure:
Lithium hydroxide monohydrate (0.034 g, 0.80 mmol) was added to a solution of (6-chloro-4-{4-[isopropyl-(4-methoxy-benzyl)-sulfamoyl]-phenyl}-3-methyl-naphthalen-2-yl)-acetic acid methyl ester (0.115 g, 0.20 mmol) in a 3:1 mixture of THF—H2O mixture (15 mL). The reaction mixture was stirred for 16 hours at room temperature. The reaction mixture was concentrated to remove the THF, and the crude material was diluted with water, acidified [pH˜2] with a 6 N aqueous solution of hydrochloric acid. The mixture was extracted twice with ethyl acetate. The collected organic layers were washed with water and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product. Trituration with hexane gave (6-chloro-4-{4-[isopropyl-(4-methoxy-benzyl)-sulfamoyl]-phenyl}-3-methyl-naphthalen-2-yl)-acetic acid (0.096 g, 86%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.51 (br. s, 1 H), 8.01 (d, J=8.31 Hz, 2 H), 7.98 (d, J=8.80 Hz, 1 H), 7.92 (s, 1 H), 7.46-7.52 (m, 3 H), 7.34 (d, J=8.80 Hz, 2 H), 7.00 (s, 1 H), 6.91 (d, J=8.80 Hz, 2 H), 4.43 (s, 2 H), 4.13 (spt, J=6.60 Hz, 1 H), 3.87 (s, 2 H), 3.74 (s, 3 H), 2.08 (s, 3 H), 0.93 (d, J=6.85 Hz, 6 H). MS calcd. for C30H29ClNO2S [(M−H)−] 550, obsd. 550.2.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[CH:22]=[CH:21][C:12]([C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=O)=[CH:11][CH:10]=1.[ClH:23].[CH3:24][O:25][NH2:26].C([O-])(=O)C.[Na+]>C(O)C>[CH3:24][O:25][N:26]=[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:12]1[CH:21]=[CH:22][C:9]([NH:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH2:1])=[CH:10][CH:11]=1.[ClH:23]
Reactant: Nc1ccccc1Nc1ccc(C(=O)c2ccccc2)cc1
Reactant: CON
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CON=C(c1ccccc1)c1ccc(Nc2ccccc2N)cc1
Temperature: 25 °C

Procedure:
To a solution of 4-(2-aminophenylamino)benzophenone (Compound 101. 0.29 g, 1mmol) and O-methylhydroxylamine hydrochloride (0.30 g, 3.5 mmol) in ethanol (10 ml) was added sodium acetate (0.30 g, 4 mmol). The reaction mixture was refluxed for 25 hours, cooled to room temperature, filtered, and evaporated in vacuo. The residue was treated with diluted ammonium hydroxide (10 ml) and extracted with ethyl acetate (2×25 ml). The organic phase was dried (MgSO4), filtered and evaporated in vacuo. The residue was dissolved in diethyl ether and acidified with hydrochloric acid in diethyl ether. The hydrochloride of the title compound instantaneously precipitate. The precipitate was triturated with ethyl acetate and washed with diethyl ether to yield the title compound as a hydrochloride.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][C@H:5]([NH:9][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C:6]([OH:8])=O)[CH3:3].[NH:20]1[CH2:25][CH2:24][CH:23]([O:26][CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:22][CH2:21]1>>[CH2:13]([O:12][C:10]([NH:9][C@H:5]([C:6]([N:20]1[CH2:21][CH2:22][CH:23]([O:26][CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:25]1)=[O:8])[CH2:4][CH:2]([CH3:1])[CH3:3])=[O:11])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)(C)OC(=O)COC1CCNCC1
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC(OCC(=O)OC(C)(C)C)CC1
Yield: 95.4 %

Procedure:
By coupling 2.6 g of Z-L-leucine with 2 g of t-butyl 4-piperidinyloxyacetate as described in Example 1d) there are obtained 4.1 g of t-butyl [[1-[N-[(benzyloxy)carbonyl]-L-leucyl]-4-piperidinyl]oxy]acetate, MS (FAB): 463 (M+H)+.
Reaction SMILES: [CH2:1]([N:7]1[CH2:12][CH:11]2[CH:9]([C:10]2([C:14]2[CH:15]=[C:16]([NH2:20])[CH:17]=[CH:18][CH:19]=2)[CH3:13])[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].N1C=CC=CC=1.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([S:33](Cl)(=[O:35])=[O:34])[CH:28]=1>ClCCl>[CH2:1]([N:7]1[CH2:12][CH:11]2[CH:9]([C:10]2([C:14]2[CH:15]=[C:16]([NH:20][S:33]([C:29]3[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=3)(=[O:35])=[O:34])[CH:17]=[CH:18][CH:19]=2)[CH3:13])[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCN1CC2C(C1)C2(C)c1cccc(N)c1
Reactant: O=S(=O)(Cl)c1cccnc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCN1CC2C(C1)C2(C)c1cccc(NS(=O)(=O)c2cccnc2)c1
Reaction time: 48 h
Yield: 59.8 %

Procedure:
To a solution of 3-(3-hexyl-6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenylamine (Preparation 12, 220 mg, 0.809 mmol) in dichloromethane (5 ml) at room temperature was added pyridine (0.196 ml, 2.42 mmol) then dropwise over 5 minutes 3-pyridinesulfonylchloride (198 mg, 1.21 mmol). The mixture was stirred for 48 hours, concentrated in vacuo and the residue was purified by silica (10 g) column chromatography eluting with ethyl acetate then 90:10:1 ethyl acetate:methanol:ammonia solution (0.880). Product-containing fractions were combined and concentrated in vacuo to give the title compound as a pale orange oil (200 mg, 60%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:8])[CH2:5][CH2:6][NH2:7].[C:9](Cl)(=[O:11])[CH3:10]>>[CH3:2][O:3][C:4](=[O:8])[CH2:5][CH2:6][NH:7][C:9](=[O:11])[CH3:10]
Reactant: CC(=O)Cl
Reactant: COC(=O)CCN
Agent: Cl
Product: COC(=O)CCNC(C)=O

Procedure:
According to scheme II, β-alanine methyl ester hydrochloride 4 is reacted with acetyl chloride giving N-acetyl-β-alanine methyl ester 5 which is reacted with disulfide cystamine 6 upon heating neat at 80° C. giving the tetraamide disulfide product N, N - (Dithiodi-2, 1-ethanediyl bis [3-(acetylamino) propanamide 7. Reductive cleavage of the disulfide bond of 7 with sodium borohydride in methanol gives the unstable thiol 8 which is reacted in situ with an excess of oleoyl chloride 1, giving the thioester product S-[2-[[3-(acetylamino)-1-oxopropyl]amino]ethyl]-9(Z)-octadecenethioate 9. ##STR11##
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](Cl)=[N:9]2)=[N:4][CH:3]=1.[NH3:13].O>O1CCOCC1>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([NH2:13])=[N:9]2)=[N:4][CH:3]=1
Reactant: N
Reactant: Clc1ccc2ncc(Br)cc2n1
Solvent: O
Solvent: C1COCCO1
Product: Nc1ccc2ncc(Br)cc2n1
Temperature: 160 °C
Reaction time: 24 h
Yield: 79.8 %

Procedure:
In a sealed reactor, 500 mg (1.23 mmol, 1 eq) of 7-bromo-2-chloro-1,5-naphthyridine and 7 mL (41.6 mmol, 33 eq) of 20% aqueous ammonia solution were introduced in 7 mL of dioxane. The mixture was stirred at 160° C. for 24 h. The mixture was allowed to reach rt and water was added. Aqueous layer was extracted with ethyl acetate. Organic layers were dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by column chromatography using methylene chloride and then methylene chloride/ethanol: 98/2 as eluent. The solvent was evaporated to dryness to afford 220 mg of white powder with 80% yield.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[F:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([CH:18]=[CH:19][C:20]1[O:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=1)[NH:12][C:11]2=O>P(Cl)(Cl)(Cl)=O>[F:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([CH:18]=[CH:19][C:20]1[O:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=1)[N:12]=[C:11]2[Cl:2]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=c1[nH]c(C=Cc2ccc([N+](=O)[O-])o2)nc2ccc(F)cc12
Solvent: O=P(Cl)(Cl)Cl
Product: O=[N+]([O-])c1ccc(C=Cc2nc(Cl)c3cc(F)ccc3n2)o1
Yield: 63.3 %

Procedure:
A 500 ml 3 necked flask fitted with a stirrer, reflux condenser and protected by a calcium chloride trap was charged with 9.0 g of phosphorus pentachloride (0.043 mole) and 70 ml of phosphorus oxychloride and the mixture stirred. To this 11.3 g (0.04 mole) of 6-fluoro-2-[2-(5-nitro-2-furyl)vinyl]-4-(3H)quinazolinone was added and rinsed into the flask with 15 ml of phosphorus oxychloride. The mixture was heated under reflux for 4 hours, cooled in an ice bath and diluted with 150 ml of diethyl ether. The 6-fluoro-2-[2-(5-nitro-2-furyl)vinyl]-4-chloroquinazoline which precipitated was collected by filtration, washed with 100-150 ml of diethyl ether, slurried in 100 ml of diethyl ether and then refiltered to obtain 8.09 g of the desired product.
Reaction SMILES: CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.O1CCOCC1.Cl[C:50]1[N:55]=[C:54]([C:56]2[C:57]([O:62][C:63]3[CH:68]=[CH:67][C:66]([NH:69][C:70]4[C:79]5[C:74](=[CH:75][CH:76]=[CH:77][CH:78]=5)[C:73]([C:80]5[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=5)=[N:72][N:71]=4)=[CH:65][CH:64]=3)=[N:58][CH:59]=[CH:60][CH:61]=2)[C:53]([F:86])=[CH:52][N:51]=1.[C:87](=[O:94])([O:89][C:90]([CH3:93])([CH3:92])[CH3:91])[NH2:88].C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC([O-])=O.CC([O-])=O.[Pd+2].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CO>[F:86][C:53]1[C:54]([C:56]2[C:57]([O:62][C:63]3[CH:68]=[CH:67][C:66]([NH:69][C:70]4[C:79]5[C:74](=[CH:75][CH:76]=[CH:77][CH:78]=5)[C:73]([C:80]5[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=5)=[N:72][N:71]=4)=[CH:65][CH:64]=3)=[N:58][CH:59]=[CH:60][CH:61]=2)=[N:55][C:50]([NH:88][C:87](=[O:94])[O:89][C:90]([CH3:93])([CH3:92])[CH3:91])=[N:51][CH:52]=1
Reactant: CC(C)(C)OC(N)=O
Reactant: Fc1cnc(Cl)nc1-c1cccnc1Oc1ccc(Nc2nnc(-c3ccccc3)c3ccccc23)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1ncc(F)c(-c2cccnc2Oc2ccc(Nc3nnc(-c4ccccc4)c4ccccc34)cc2)n1
Temperature: 110 °C
Reaction time: 0.17 h

Procedure:
The title compound was prepared according to the procedure described in Garnier, E.; Andoux, J.; Pasquinet, E.; Suzenet, F.; Poullain, D.; Lebret, B.; Guillaumet, G. J Org. Chem. 2004, 69, 7809. Xantphos (281 mg, 486 μmol) and 1,4-dioxane (12151 μl, 2430 μmol) were added into a sealed tube. The tube was purged with argon, then palladium(II) acetate (55.0 mg, 243 μmol) was added. The mixture was stirred under argon for 10 min. In a separate sealed tube, N-(4-(3-(2-chloro-5-fluoropyrimidin-4-yl)pyridin-2-yloxy)phenyl)-4-phenylphthalazin-1-amine (1.27 mg, 2.43 mmol), tert-butyl carbamate (712 mg, 6.08 mmol), potassium carbonate (10.1 g, 72.9 mmol), and 1,4-dioxane (12.2 ml, 2.43 mmol) were added. Then Pd(OAc)2/Xantphos solution was added via a syringe. The resulting mixture was heated to 110° C. under argon with vigorous stirring. After 3.5 h, LCMS showed mainly product at 1.793 min as [M+H]+=602 and deBoc product at 1.602 min as [M+H]+=502. The reaction was cooled to RT, diluted with DCM, passed through a pad of celite and silica gel (1 cm thick each) with an aid of DCM and a bit of MeOH. The filtrate was concentrated to afford tert-Butyl 5-fluoro-4-(2-(4-(4-phenylphthalazin-1-ylamino)phenoxy)pyridin-3-yl)pyrimidin-2-ylcarbamate, which was carried on without further purification. MS Calcd for C34H28FN7O3: [M]+=601. Found: [M+1]+=602.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[C@@H:11]3[CH2:12][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][C@H:10]3[CH2:9][NH:8][C:7](=[O:22])[C:6]=2[CH:23]=1.I[CH3:25].[H-].[Na+].O>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[C@@H:11]3[CH2:12][N:13]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:14][C@H:10]3[CH2:9][N:8]([CH3:25])[C:7](=[O:22])[C:6]=2[CH:23]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CNC(=O)c3cc(F)ccc3[C@@H]2C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN1C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2c2ccc(F)cc2C1=O
Reaction time: 2 h

Procedure:
To a suspension of Example 224A (3.8 g, 11.9 mmol) and iodomethane (2.1 g, 15 mmol) in tetrahydrofuran (15 mL) was added NaH (0.6 g, 60%, 15 mmol) in portions at 0° C. The mixture was stirred for 2 hours and water was then added. The precipitates were collected to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.33 (m, 1H), 7.29 (m, 1H), 7.28 (m, 1H), 3.69 (m, 1H), 3.60 (m, 1H), 3.54 (m, 1H), 3.35 (m, 2H), 3.17 (m, 1H), 3.10 (s, 3H), 3.00 (m, 1H), 2.16 (m, 1H), and 1.43 (s, 9H).
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])[CH2:5][C@H:4]1[F:36].[C:37](Cl)(=[O:39])[CH3:38]>>[C:37]([NH: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[CH2:33][CH2:34]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][C@H:4]1[F:36])(=[O:39])[CH3:38]
Reactant: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@H](N)[C@H](F)C1
Reactant: CC(=O)Cl
Agent: Cl
Product: CC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C(F)F)ccc4OCC4CC4)ncnc23)C[C@H]1F

Procedure:
Starting from N-[(1S*,3R*,4S*)-4-amino-3-fluorocyclohexyl]-4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f72) and commercially available acetyl chloride the title compound is obtained as colorless solid.