Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:10][CH:9]=2)[N:3]=1.C([N-]C(C)C)(C)C.[Li+].[B:31](OC)([O:34]C)[O:32]C.Cl>C1COCC1.O>[F:1][C:2]1[C:7]([B:31]([OH:34])[OH:32])=[CH:6][CH:5]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:12][CH:13]=2)[N:3]=1
Reactant: COB(OC)OC
Reactant: CCCCCCCCCc1ccc(-c2cccc(F)n2)cc1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCCc1ccc(-c2ccc(B(O)O)c(F)n2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 28.8 %

Procedure:
A solution of 100 mol of 2-fluoro-6-(4-nonylphenyl)pyridine in 500 ml of dry THF is added dropwise to a solution of 110 mmol of lithium diisopropylamide in 100 ml of dry tetrahydrofuran at −70° C. under a protective gas atmosphere. The mixture is stirred for an additional 4 h at this temperature. A solution of 200 mmol of trimethyl borate in 40 ml of dry tetrahydrofuran is then added dropwise at a temperature of less than −60° C. The reaction mixture is then slowly warmed up to room temperature, admixed with a solution of 60 ml of water and 20 ml of concentrated hydrochloric acid while cooling with ice, and stirred for another hour at room temperature. The reaction mixture is extracted with tert-butyl methyl ether, the combined organic extracts are washed with water and saturated sodium chloride solution and dried with sodium sulfate, and the solvents are removed under reduced pressure. The raw product is crystallized from n-heptane/acetone 4:1, giving 19.8 g (58%) of 2-fluoro-6-(4-nonylphenyl)pyridine-3-boronic acid.
Reaction SMILES: [CH2:1]([N:15]([CH3:17])[CH3:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C(N(CC(O)=O)CCN(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=[O:23]>>[OH2:23].[OH2:23].[CH2:1]([N+:15]([O-:23])([CH3:17])[CH3:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCCCN(C)C
Reactant: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CCN(CC(=O)O)CC(=O)O
Product: CCCCCCCCCCCCCC[N+](C)(C)[O-]
Product: O
Temperature: 65 °C
Yield: 87 %

Procedure:
In a glass reaction flask was placed 100 g tetradecyl dimethylamine and 0.5 g diethylenetriamine pentaacetic acid. Carbon dioxide sparge into the liquid phase was started and the mixture was stirred and heated to 65° C. The CO2 sparge was stopped and a CO2 gas phase was maintained over the reaction mixture. Dropwise feed of 70 weight percent aqueous hydrogen peroxide was started. At the same time, addition of ethyl acetate was commenced. After 10 minutes all the hydrogen peroxide and 28 mL of ethyl acetate had been added. Cooling was required to maintain the temperature under 75° C. Heat was applied and the reaction continued for two more hours. Dropwise addition of ethyl acetate was continued for the first 19 minutes of the two-hour period. Total ethyl acetate feed was 43 mL. The reaction mixture was a clear gel-free solution. The reaction mixture was analyzed by NMR showing a 100 percent amine conversion. The reaction mixture was poured into a flask containing 300 mL of ethyl acetate and cooled to 15° C. Needle-like crystals of tetradecyl dimethylamine oxide dihydrate formed (106 g) indicating a 87 percent yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[C:5]([NH2:16])[CH:4]=1.[O:17]1[CH:21]=[CH:20][C:19](/[CH:22]=[CH:23]/[C:24](Cl)=O)=[CH:18]1.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1.[C:50]([OH:55])(=[O:54])[C:51]([OH:53])=[O:52]>C(OCC)(=O)C>[C:50]([OH:55])(=[O:54])[C:51]([OH:53])=[O:52].[O:17]1[CH:21]=[CH:20][C:19](/[CH:22]=[CH:23]/[C:24]2[N:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=3)[C:6]3[CH:14]=[CH:15][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[N:16]=2)=[CH:18]1
Reactant: COc1ccc(Nc2ccccn2)c(N)c1
Reactant: O=C(Cl)/C=C/c1ccoc1
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)nc(/C=C/c1ccoc1)n2-c1ccccn1

Procedure:
Free base of the titled compound was prepared from 4-methoxy-2-amino-N-(2-pyridyl)aniline and (E)-3-(3-furyl)acryloyl chloride according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method A). The free base and oxalic acid were dissolved into ethyl acetate. Concentration and recrystallization from ethyl acetate/n-hexane yielded the titled compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[Li]CCCC.CN(C)[CH:22]=[O:23]>O1CCCC1>[F:12][C:11]([F:14])([F:13])[C:4]1[CH:5]=[C:6]2[C:10](=[C:2]([CH:22]=[O:23])[CH:3]=1)[NH:9][CH:8]=[CH:7]2
Reactant: FC(F)(F)c1cc(Br)c2[nH]ccc2c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1cc(C(F)(F)F)cc2cc[nH]c12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 84 %

Procedure:
To a −78° C. solution of 7-bromo-5-(trifluoromethyl)-1H-indole (8.77 g, 33.2 mmol) in tetrahydrofuran (200 mL), n-BuLi (1.6 M in hexanes, 72.7 mL, 116 mmol) was added slowly. The reaction was warmed to 0° C. and stirred for 15 min. The reaction was recooled to −78° C., treated with dimethylformamide (12.9 mL, 166 mmol), warmed to ambient temperature, and stirred for 30 min. The reaction was quenched by slow addition of 1N hydrochloric acid (50 mL) and was then extracted with ethyl acetate (2×40 mL). The organic layers were dried (magnesium sulfate) and evaporated. The residue was purified by chromatography on silica gel with 15% ethyl acetate/hexanes. The product 5-(trifluoromethyl)-1H-indole-7-carbaldehyde (5.95 g, 27.9 mmol, 84% yield) was obtained as an orange solid. 1H-NMR (CDCl3, 400 MHz) δ 10.28 (bs, 1H), 10.16 (s, 1H), 8.20 (d, J=0.6 Hz, 1H), 7.90 (d, J=0.6 Hz), 7.45 (dd, J=3.2, 2.5 Hz, 1H), 6.72 (dd, J=3.2, 2.4 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:15]([O:17]CC)=[O:16])[C:11]([CH3:14])=[N:12][CH:13]=2)=[CH:4][CH:3]=1>[OH-].[Na+].C(O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11]([CH3:14])=[N:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc(-c2ccc(Cl)cc2)cnc1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1ncc(-c2ccc(Cl)cc2)cc1C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.2 %

Procedure:
5-(p-Chlorophenyl)-2-methyl-3-ethoxycarbonylpyridine (25 g) was suspended in sodium hydroxide (3.99 g) in ethanol (100 ml) and water (50 ml). Stirring at room temperature for 3 hours gave a solution which was concentrated to dryness. The residue was dissolved in water and the solution washed with ethyl acetate; its pH was then brought to 5. The product which precipitated was collected, washed well with water and then with acetone and then dried to give the title compound (20.94 g), m.p. 297°-300° (dec).
Reaction SMILES: [CH3:1][C:2]1[S:9][C:8]2[CH:7]=[C:6]([C:10]([OH:12])=O)[NH:5][C:4]=2[C:3]=1[N:13]([CH3:22])[S:14]([C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)(=[O:16])=[O:15].Cl.[CH3:24]OCN.[N:28]1([OH:37])[C:32]2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>O.CN(C)C=O.C(N(CC)CC)C>[CH3:24][O:37][N:28]([CH3:32])[C:10]([C:6]1[NH:5][C:4]2[C:3]([N:13]([CH3:22])[S:14]([C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)(=[O:16])=[O:15])=[C:2]([CH3:1])[S:9][C:8]=2[CH:7]=1)=[O:12]
Reactant: Cc1sc2cc(C(=O)O)[nH]c2c1N(C)S(=O)(=O)c1cccs1
Reactant: On1nnc2ccccc21
Reactant: COCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CON(C)C(=O)c1cc2sc(C)c(N(C)S(=O)(=O)c3cccs3)c2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.9 %

Procedure:
To a mixture of 2-methyl-3-[methyl(2-thienylsulfonyl)amino]-4H-thieno[3,2-b]pyrrole-5-carboxylic acid (0.30 g), N-methoxymethylamine hydrochloride (100 mg), 1H-1,2,3-benzotriazol-1-ol (150 mg), triethylamine (0.15 mL) and N,N-dimethylformamide (10 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (190 mg), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. Crystallization from diethyl ether gave N-methoxy-N,2-dimethyl-3-[methyl(2-thienylsulfonyl)amino]-4H-thieno[3,2-b]pyrrole-5-carboxamide (262 mg, yield 80%) as colorless crystals. melting point 187° C.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[C:6]([F:12])[CH:5]=1)([O-:3])=[O:2].[C:13]([CH2:18][CH:19]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:15][CH2:16][CH3:17])=[O:14].CCCCCCC>C1(C)C=CC=CC=1>[F:12][C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:11]=[CH:10][C:7]=1/[CH:8]=[C:18](\[CH3:19])/[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1F
Reactant: CCOC(=O)CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCCCCCC
Product: CCOC(=O)/C(C)=C/c1ccc([N+](=O)[O-])cc1F
Temperature: 120 °C
Yield: 79132.3 %

Procedure:
Compound 14b (14.6 mg) was dissolved in toluene (132 ml), and (carbetoxyethylidene)triphenylphosphorane (46.9 g) was added thereto. The obtained mixture was stirred under heating at 120° C. for 2 hours. After the reaction mixture was allowed to cool, n-heptane was added thereto and stirred. The precipitated solid was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in methanol (125 ml), and purified water was added thereto. The precipitated solid was filtered off and then dried under reduced pressure. Thus, Compound 14c (17.3 g, 79%) was obtained as an opalescent solid.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[F:13][C:14]1[C:19]([F:20])=[CH:18][C:17]([O:21][CH3:22])=[C:16]([NH2:23])[C:15]=1[NH:24][C:25]1[CH:30]=[CH:29][C:28]([I:31])=[CH:27][C:26]=1[F:32].C(OCC)(=O)C>C(Cl)Cl.CCCCCC>[F:20][C:19]1[CH:18]=[C:17]([O:21][CH3:22])[C:16]2[NH:23][C:1](=[O:2])[N:24]([C:25]3[CH:30]=[CH:29][C:28]([I:31])=[CH:27][C:26]=3[F:32])[C:15]=2[C:14]=1[F:13]
Reactant: COc1cc(F)c(F)c(Nc2ccc(I)cc2F)c1N
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1cc(F)c(F)c2c1[nH]c(=O)n2-c1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.9 %

Procedure:
1,1′-Carbonyldiimidazole (4.68 g, 288 mmol) was added portion wise to a solution of 3,4-difluoro-N2-(2-fluoro-4-iodo-phenyl)-6-methoxy-benzene-1,2-diamine (I-5a: 6.3 g, 144 mmol) in DCM (60 mL) and the resulting mixture was stirred at room temperature overnight. The reaction was monitored by TLC (50% ethyl acetate in hexane). The reaction mixture was filtered, the residue was washed with DCM and dried under reduced pressure to afford 6.0 g of the product (89.5% yield).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[S:10][C:9]([C:11]3[N:12]=[N:13][N:14]([CH2:16][Si](C)(C)C)[CH:15]=3)=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.O>[Cl:1][C:2]1[C:3]2[S:10][C:9]([C:11]3[N:12]=[N:13][N:14]([CH3:16])[CH:15]=3)=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: C[Si](C)(C)Cn1cc(-c2cc3ncnc(Cl)c3s2)nn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: Cn1cc(-c2cc3ncnc(Cl)c3s2)nn1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of compound 48.3 (0.5 mmol) in THF (10.0 mL) was added several drops of water and TBAF (0.55 mmol; 1.0 M in THF) at 0° C. The resulting mixture was stirred at 0° C. for 15 minutes, concentrated and washed with hexanes. The white solid that formed was suspended in ice water (10 mL), filtered, washed with ice water and dried in vacuo to provide 4-chloro-6-(1-methyl-1H-[1,2,3]triazol-4-yl)-thieno[3,2-d]pyrimidine (compound 48.4) in 95% yield. EIMS (m/z): calcd. for C9H6ClN5S (M+)+H 252.00. found 252.00.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[CH3:20]C([N-]C(C)C)C.IC>C1COCC1>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[CH:10]([CH3:20])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)[N-]C(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(=O)c2ccccc21
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CC1CN(C(=O)OC(C)(C)C)c2ccccc2C1=O
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 23 %

Procedure:
To a solution of 1-tert-butyloxycarbonyl-1,2,3,4-tetrahydro-4-quinolinone (structure 68A of Scheme LI, where R1-2═H) (EXAMPLE 325) (500 mg, 0.002 mol) in THF (5 mL) at −78° C. was added 2.0 M LDA in THF (1.01 mL, 0.002 mol). The reaction mixture was stirred at −78° C. for 15 min and iodomethane (126 mL, 0.002 mol) was added all at once. The temperature was raised to 0° C. and the resulting mixture stirred for 4 h. The reaction was then quenched with sat'd NH4Cl (5 mL), extracted with ethyl acetate (2×10 mL), dried (Na2SO4) and concentrated in vacuo to a solid residue that was subjected to flash column chromatography (silica gel, hexanes/ethyl acetate, 95:5) to give 117 mg (23%) of 1-tert-butyloxycarbonyl-1,2,3,4-tetrahydro-3-methyl-4-quinolinone (structure 69A of Scheme LI, where R1-2═H, R3═methyl), 128 mg (23%) of 1-tert-butyloxycarbonyl-1,2,3,4-tetrahydro-3,3-dimethyl-4-quinolinone (structure 70A of Scheme LII, where R1-2═H, R3-4═methyl) and 200 mg (40%) of recovered starting material. Data for 1-tert-butyloxycarbonyl-1,2,3,4-tetrahydro-3-methyl-4-quinolinone: 1H NMR (400 MHz, CDCl3) 7.99 (dd, J=7.9, 1.7, 1H), 7.77 (d, J=8.4, 1H), 7.48 (ddd, J=7.3, 7.3, 1.7, 1H), 7.13 (dd, J=7.4, 1.0, 1H), 4.32 (dd, J=13.4, 4.4, 1H), 3.69 (dd, J=13.3, 9.8, 1H), 2.76 (ddq, J=9.8, 7.0, 4.4, 1H), 1.56 (s, 9H), 1.24 (d, J=7.0, 3H).
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]([NH:13][C:14]([C:16]2[CH:21]=[CH:20][C:19]([NH:22]C(=O)OC(C)(C)C)=[CH:18][CH:17]=2)=[O:15])=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:22][C:19]1[CH:20]=[CH:21][C:16]([C:14]([NH:13][C:11]2[S:12][C:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[N:9][N:10]=2)=[O:15])=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(=O)Nc2nnc(Cc3ccccc3)s2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccc(C(=O)Nc2nnc(Cc3ccccc3)s2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 92.1 %

Procedure:
0.2 g of tert-butyl [4-(5-benzyl[1.3.4]thiadiazol-2-ylcarbamoyl)phenyl]carbamate (0.49 mmol, 1 eq.) is placed in 5 mL of dichloromethane. 1 mL of trifluoroacetic acid (13.54 mmol, 27.6 eq.) is added and the reaction medium is stirred for 3 days at room temperature. The solvents are evaporated off and the residue is taken up in diethyl ether and pentane to give 0.14 g of 4-amino-N-(5-benzyl[1.3.4]thiadiazol-2-yl)-benzamide acid.
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[C@@H:4]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:20]([O:23][CH:24]1[CH2:32][C:31]2[C:26](=[CH:27][C:28]([O:33][CH3:34])=[CH:29][CH:30]=2)[CH:25]1[NH2:35])[CH:21]=[CH2:22]>C(#N)C>[CH2:20]([O:23][C@H:24]1[CH2:32][C:31]2[C:26](=[CH:27][C:28]([O:33][CH3:34])=[CH:29][CH:30]=2)[C@H:25]1[NH:35][CH2:3][C@@H:2]([OH:1])[C@@H:4]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:21]=[CH2:22]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H]1CO1
Reactant: C=CCOC1Cc2ccc(OC)cc2C1N
Solvent: CC#N
Product: C=CCO[C@H]1Cc2ccc(OC)cc2[C@H]1NC[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 45 °C

Procedure:
Step AE (4): A solution of tert-butyl (S)-1-((S)-oxiran-2-yl)-2-phenylethylcarbamate (298 mg) and LiClO4 (mg) in acetonitrile (3.0 mL) was stirred at rt for 10 min. To the above solution was added 1R,2S)-2-(allyloxy)-6-methoxy-2,3-dihydro-1H-inden-1-amine from Step AE (3) (137 mg) in acetonitrile (0.50 mL), and the reaction mixture was heated at 45° C. for 36 h. Solvents were removed in vacuo, and the residue was purified by HPLC to give tert-butyl (2S,3R)-4-((1R,2S)-2-(allyloxy)-6-methoxy-2,3-dihydro-1H-inden-1-ylamino)-3-hydroxy-1-phenylbutan-2-ylcarbamate as an oil (77 mg). retention time: 1.85 min (method B). MS (ESI) (M+H)+ 483.30.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][C:11]([I:14])=[C:10]([CH:15]=[O:16])[C:9]2=[O:17])=[CH:4][CH:3]=1.[OH:18]P([O-])(O)=O.[Na+].CC(=CC)C.Cl([O-])=O.[Na+]>C1COCC1.O.C(O)(C)(C)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:13]=[CH:12][C:11]([I:14])=[C:10]([C:15]([OH:18])=[O:16])[C:9]2=[O:17])=[CH:6][CH:7]=1
Reactant: O=P([O-])(O)O
Reactant: O=Cc1c(I)ccn(-c2ccc(F)cc2)c1=O
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Solvent: O
Product: O=C(O)c1c(I)ccn(-c2ccc(F)cc2)c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-(4-Fluorophenyl)-4-iodo-2-oxo-1,2-dihydropyridine-3-carbaldehyde (10.0 g, 29.2 mmol) and sodium phosphate monobasic (10.1 g, 73 mmol, Aldrich) were stirred vigourously in 35 mL each of THF, tert-butanol, and water at 0° C. 2-Methyl-2-butene (45.2 mL, 2.0 M in THF, Aldrich) was added to the reaction mixture, followed by sodium chlorite (6.06 g, 67.1 mmol, Aldrich). The ice bath was removed and the reaction mixture was warmed to room temperature, stirring very rapidly. After a few minutes the desired product began precipitating out of solution. Stirring was continued for 1 h, then 20 mL of 1N aqueous HCl was added, and stirring was continued for another 5 minutes. The desired product was filtered off, then washed with water, ethyl acetate, and ether. The filtrate was taken and the layers were separated. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting solid was suspended in ethyl acetate, filtered, and washed with ethyl acetate and ether to yield additional desired product. The pale yellow solids were combined to yield 8.22 g (78%) of 1-(4-fluorophenyl)-4-iodo-2-oxo-1,2-dihydropyridine-3-carboxylic acid (92% pure, 8% starting material remaining). This material was dissolved in a minimal amount of 1N aqueous NaOH. Ethyl acetate was added and the mixture was stirred vigourously for 5 minutes. The layers were separated, and the aqueous layer was extracted with ethyl acetate. The aqueous layer was acidified, with stirring, using concentrated HCl to pH 1. The pale yellow solid that precipitated out of solution was collected, washed with water, ethyl acetate, diethyl ether and then dried under vacuum to afford 7.33 g (70%) of 1-(4-fluorophenyl)-4-iodo-2-oxo-1,2-dihydropyridine-3-carboxylic acid (95.4% pure by HPLC). 1H NMR (DMSO-d6) δ 13.53 (s, 1H), 7.52-7.49 (m, 3H), 7.38 (t, 2H, J=8.8 Hz), 6.81 (d, 1H, J=7.2 Hz); MS (ESI+) m/z 360.14 (M+H)+.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH2:5]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:19](Cl)(=[O:21])[CH3:20]>ClC(Cl)C>[CH2:5]([C:13]1[CH:14]=[CH:15][C:16]([C:19](=[O:21])[CH3:20])=[CH:17][CH:18]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCc1ccccc1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: CCCCCCCCc1ccc(C(C)=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Aluminum chloride (22.6 g) is suspended in dichloroethane (500 ml) and octylbenzene (16) (21.5 g) is added at room temperature. To the mixture is added acetyl chloride (8.87 g) under ice-cooling. The mixture is stirred at room temperature overnight. The reaction mixture is poured into ice water and extracted with ether. The organic layer is washed with brine and dried over sodium sulfate. The solvent is evaporated to give 4′-octylacetophenone (18′) as a colorless oil.
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][CH2:8][N:7]([C:10]3[N:15]=[N:14][C:13]([C:16]4[CH:17]=[C:18]([NH2:22])[CH:19]=[CH:20][CH:21]=4)=[CH:12][CH:11]=3)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:30](Cl)(=[O:32])[CH3:31]>C(Cl)Cl>[CH:1]1([N:4]2[CH2:5][CH2:6][N:7]([C:10]3[N:15]=[N:14][C:13]([C:16]4[CH:17]=[C:18]([NH:22][C:30](=[O:32])[CH3:31])[CH:19]=[CH:20][CH:21]=4)=[CH:12][CH:11]=3)[CH2:8][CH2:9]2)[CH2:3][CH2:2]1
Reactant: Nc1cccc(-c2ccc(N3CCN(C4CC4)CC3)nn2)c1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cccc(-c2ccc(N3CCN(C4CC4)CC3)nn2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-[6-(4-cyclopropyl-piperazin-1-yl)-pyridazin-3-yl]-phenylamine (400 mg, 1.36 mmol) in CH2Cl2 (25 mL) was added triethylamine (275 mg, 2.72 mmol). Then acetyl chloride (171 mg, 2.18 mmol) was added dropwise and the resulting mixture was stirred overnight at rt. The reaction was quenched with water (15 mL) and the phases were separated. The organic phase was washed with brine, dried (Na2SO4) and concentrated to give a crude product, which was recrystallized from MeOH. This afforded 201 mg (48%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([N:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([CH3:22])[CH:18]=3)[CH:13]2[CH3:23])[C:9]2[C:4](=[C:5]([O:24][CH3:25])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[F:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[C:29]([CH3:34])[CH:28]=1>CN(C)C=O>[ClH:1].[F:26][C:27]1[CH:33]=[CH:32][C:30]([NH:31][C:2]2[N:11]=[C:10]([N:12]3[CH2:21][CH2:20][C:15]4[C:14](=[CH:19][CH:18]=[C:17]([CH3:22])[CH:16]=4)[CH:13]3[CH3:23])[C:9]3[C:4](=[C:5]([O:24][CH3:25])[CH:6]=[CH:7][CH:8]=3)[N:3]=2)=[C:29]([CH3:34])[CH:28]=1
Reactant: Cc1cc(F)ccc1N
Reactant: COc1cccc2c(N3CCc4cc(C)ccc4C3C)nc(Cl)nc12
Solvent: CN(C)C=O
Product: COc1cccc2c(N3CCc4cc(C)ccc4C3C)nc(Nc3ccc(F)cc3C)nc12
Product: Cl
Yield: 33 %

Procedure:
In accordance with the same procedures as in Example 18, except that to a mixture of 2.50 g of the compound (7.06 mM) prepared in Example 15 and 10 ml of dimethyl-formamide, 1.21 ml of 4-fluoro-2-methylaniline(14.9 mM) was added, 1.10 g of the title compound was prepared.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH2:6][CH2:7][Cl:8])=[O:3].[Cl:9][C:10]1[CH:11]=[C:12]([CH:17]2[CH2:21][NH:20][CH2:19][CH:18]2[N:22]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[C:27]([F:35])[CH:26]=2)[CH3:23])[CH:13]=[CH:14][C:15]=1[Cl:16].C(N(CC)CC)C>C1COCC1>[Cl:8][CH2:7][CH2:6][CH2:5][O:4][C:2]([N:20]1[CH2:19][CH:18]([N:22]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:32])[F:33])=[C:27]([F:35])[CH:26]=2)[CH3:23])[CH:17]([C:12]2[CH:13]=[CH:14][C:15]([Cl:16])=[C:10]([Cl:9])[CH:11]=2)[CH2:21]1)=[O:3]
Reactant: CN(Cc1ccc(C(F)(F)F)c(F)c1)C1CNCC1c1ccc(Cl)c(Cl)c1
Reactant: O=C(Cl)OCCCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(Cc1ccc(C(F)(F)F)c(F)c1)C1CN(C(=O)OCCCCl)CC1c1ccc(Cl)c(Cl)c1
Yield: 104.9 %

Procedure:
To a stirred solution of 3-chloropropyl chloroformate (0.058 ml, 0.47 mmol) in THF (5 ml) at RT was added over 1 hour a solution of [(3RS,4SR)-4-(3,4-Dichloro-phenyl)-pyrrolidin-3-yl]-(3-fluoro-4-trifluoromethyl-benzyl)-methyl-amine (Intermediate VIII-1, 0.187 g, 0.44 mmol) and triethyl amine (0.068 ml, 0.48 mmol) in THF (2 mL). The reaction was stirred over night, quenched by addition of an aqueous solution of NaHCO3, and the product extracted with EtOAC. The organic phases were concentrated under vacuo to yielded 0.25 g (99%) of the title compound as a light yellow oil. The product was used in the next steps without further purification. ES-MS m/e: 542.7 (M+H+).