Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[C:4]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[CH2:17][OH:18])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[N:6][C:5]2[NH:8][CH:9]=[C:10]3[C:4]=2[C:3]=1[O:18][CH2:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=1
Reactant: OCc1ccccc1-c1c[nH]c2ncc(Br)c(Cl)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1cnc2[nH]cc3c2c1OCc1ccccc1-3
Temperature: 80 °C
Reaction time: 14 h
Yield: 2 %

Procedure:
[2-(5-Bromo-4-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-phenyl]-methanol (66 mg, 0.2 mmol) was dissolved in 5 mL DMF and NaH was added until the gas evolution stops. The mixture was stirred at 80° C. for 14 h. The reaction was concentrated and quenched with saturated ammonium chloride solution (2 mL) and water (2 mL). The mixture was applied to a Varian chemelut cartridge and eluted with ethyl acetate. The crude product was purified by flash silica gel chromatography using a gradient of ethyl acetate in hexanes followed by mass triggered reverse phase HPLC to afford the title compound (1.3 mg, 0.004 mmol, 2.2% yield over 2 steps). 1H NMR (500 MHz, MeCN-d3) δ 8.23 (s, 1H), 7.75 (m, 2H), 7.43 (m, 2H), 7.25 (t, J=7 Hz, 1H), 5.30 (s, 2H). MS: m/z 301.0/303.0 (M+H+).
Reaction SMILES: [N:1]1[C:6]2[NH:7][C:8]3[CH:18]=[N:17][CH:16]=[CH:15][C:9]=3/[C:10](=[N:13]/[OH:14])/[C:11](=O)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:19]([OH:22])(=[O:21])C>C(OCC)(=O)C.O>[OH:14][N:13]1[C:10]2[C:9]3[CH:15]=[CH:16][N:17]=[CH:18][C:8]=3[NH:7][C:6]3[N:1]=[CH:2][CH:3]=[CH:4][C:5]=3[C:11]=2[N:13]=[C:10]1[C:9]1[CH:15]=[CH:16][N:17]=[CH:18][C:8]=1[NH:7][C:19](=[O:21])[O:22][C:5]([CH3:11])([CH3:6])[CH3:4]
Reactant: O=c1/c(=N\O)c2ccncc2[nH]c2ncccc12
Reactant: CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)Nc1cnccc1-c1nc2c(n1O)-c1ccncc1Nc1ncccc1-2
Temperature: 80 °C
Reaction time: 3 h
Yield: 69 %

Procedure:
A mixture of (6Z)-5H-dipyrido[2,3-b:4′,3′-f]azepine-5,6(11H)-dione 6-oxime (80.0 mg, 0.333 mmol), tert-butyl-(4fprmylpyridin-3yl)carbamate lammonium acetate (0.513 g, 6.66 mmol), water (0.12 mL) and acetic acid (0.76 mL) was stirred at 80° C. for 3 h. The solution was diluted with ethyl acetate and water, the organic solution was washed with brine, dried over MgSO4 and concentrated. The crude residue was purified by preparative LCMS to yield the desired product (102 mg, 69%). LCMS for C23H22N7O3(M+H)+: m/z=444.2.
Reaction SMILES: CN(C)C=O.[C:6]([NH:10][C:11]1[C:16]([F:17])=[C:15]([F:18])[N:14]=[C:13]([NH:19][CH:20]=[C:21]([C:27](=[O:38])[C:28]2[CH:33]=[C:32]([F:34])[C:31]([F:35])=[C:30]([Cl:36])[C:29]=2F)[C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:12]=1[F:39])([CH3:9])([CH3:8])[CH3:7].C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[C:6]([NH:10][C:11]1[C:16]([F:17])=[C:15]([F:18])[N:14]=[C:13]([N:19]2[C:29]3[C:28](=[CH:33][C:32]([F:34])=[C:31]([F:35])[C:30]=3[Cl:36])[C:27](=[O:38])[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20]2)[C:12]=1[F:39])([CH3:9])([CH3:7])[CH3:8]
Reactant: CCOC(=O)C(=CNc1nc(F)c(F)c(NC(C)(C)C)c1F)C(=O)c1cc(F)c(F)c(Cl)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(-c2nc(F)c(F)c(NC(C)(C)C)c2F)c2c(Cl)c(F)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 114.1 %

Procedure:
To 6 ml of N,N-dimethyl-formamide solution of 1.14 g of ethyl 3-[(4-t-butylamino-3,5,6-trifluoropyridin-2-yl)amino]-2-(3-chloro-2,4,5-trifluorobenzoyl)acrylate was added 700 mg of potassium carbonate, and the mixture was stirred at room temperature for 3.5 hours. The reaction solution was poured into ice water, and ethyl acetate was added for extraction. The organic layer was separated and dried over magnesium sulfate, and solvent was distilled off. The solid content was collected by filtration to obtain 1.25 g of the title compound as a colorless powder.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[NH:2][NH2:3].C(#N)C.[C:10]1([CH2:16][C:17](Cl)=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>O>[C:10]1([CH2:16][C:17]([NH:3][NH:2][C:1]([O:5][CH3:6])=[O:4])=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: COC(=O)NN
Solvent: CC#N
Solvent: O
Product: COC(=O)NNC(=O)Cc1ccccc1
Reaction time: 15 h
Yield: 76.1 %

Procedure:
To a solution of 90.1 g. (1.0 mole) of methyl carbazate and 500 ml. of acetonitrile 154.6 g. (1.0 mole) of phenyl acetyl chloride are added. The reaction mixture is heated to boiling for 15 hours and clarified. The residual oil is poured into 500 ml. of water, whereby the oil soon solidifies. Thus 158.4 g. of the white desired compound are obtained, yield 76.1%, m.p.: 94°-95° C.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:10]=[C:11]([CH:25]=[CH:26][CH:27]=2)[C:12]([NH:14][C@@H:15]([CH2:20][N+:21]([CH3:24])([CH3:23])[CH3:22])[CH2:16][C:17]([O-:19])=[O:18])=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[Pd]>[CH2:8]([C:9]1[CH:10]=[C:11]([CH:25]=[CH:26][CH:27]=1)[C:12]([NH:14][C@@H:15]([CH2:20][N+:21]([CH3:24])([CH3:23])[CH3:22])[CH2:16][C:17]([O-:19])=[O:18])=[O:13])[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[N+](C)(C)C[C@@H](CC(=O)[O-])NC(=O)c1cccc(C#Cc2ccccc2)c1
Agent: [Pd]
Product: C[N+](C)(C)C[C@@H](CC(=O)[O-])NC(=O)c1cccc(CCc2ccccc2)c1
Yield: 89 %

Procedure:
According to the method described in example S64, (R)-3-(3-(phenylethynyl)-benzamido)-4-(trimethylammonio)butanoate was treated with 10% Pd/C under hydrogen and the product purified to give the title compound as a white powder (7.2 mg, 89%). 1H NMR (400 MHz, D2O) δ 7.41 (d, 1H, J=8 Hz), 7.34 (s, 1H), 7.07 (t, 1H, J=8 Hz), 7.02-6.90 (m, 4H), 6.86 (d, 2H, J=8 Hz), 4.76 (m, 1H), 3.60-3.54 (m, 1H), 3.41 (d, 1H, J=13.2 Hz), 3.00 (s, 9H), 2.61 (br, 4H), 2.41-2.28 (m, 2H); MS ESI 369.2 [M+H]+, calcd for [C22H28N2O3+H]+ 369.22.
Reaction SMILES: [CH2:1]([N:4]1[C:11]([NH2:12])=[CH:10][C:8](=[O:9])[N:7]([CH2:13][CH2:14][CH3:15])[C:5]1=[O:6])[CH2:2][CH3:3].C(O)(=O)C.[N:20]([O-])=[O:21].[Na+].Cl>O>[CH2:1]([N:4]1[C:11]([NH2:12])=[C:10]([N:20]=[O:21])[C:8](=[O:9])[N:7]([CH2:13][CH2:14][CH3:15])[C:5]1=[O:6])[CH2:2][CH3:3]
Reactant: CCCn1c(N)cc(=O)n(CCC)c1=O
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCCn1c(N)c(N=O)c(=O)n(CCC)c1=O
Reaction time: 0.17 h
Yield: 146.3 %

Procedure:
1,3-Di-n-propyl-6-aminouracil (30 g) was suspended in 1 L of water with 41 ml of 20% acetic acid and overhead stirring. Sodium nitrite (9.03 g) in 41 ml of water was added in portions, keeping the solution acidic with 12 ml of concentrated hydrochloric acid. A purple precipitate formed. Addition was complete in 10 minutes and the suspension was allowed to stir for 2 hours. The solution was then filtered, and the filtrate was rinsed with water and dried under vacuum to yield 46 g of 1,3-di-n-propyl-5-nitroso-6-aminouracil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:24]1([CH2:30][S:31](Cl)(=[O:33])=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[OH:23][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][CH2:15][NH:14][C:10]2[N:9]=[C:8]([C:4]3[CH:3]=[C:2]([NH:1][S:31]([CH2:30][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)(=[O:33])=[O:32])[CH:7]=[CH:6][CH:5]=3)[CH:13]=[CH:12][N:11]=2)=[CH:22][CH:21]=1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: Nc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1
Product: O=S(=O)(Cc1ccccc1)Nc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1

Procedure:
Intermediate 24 was coupled with phenyl-methylsulfonyl chloride following procedure D. LC-MS showed the product had the expected M+H+ of 461. 1H NMR (Varian 300 MHz, DMSO-d6, shifts relative to the solvent peak at 2.49 ppm) δ 8.4 (d, 1H), 8.0 (d, 1H) 7.8 (d, 1H) 7.5 (t, 2H), 7.3 (m, 4H), 7.1 (d, 2H), 7.0 (d, 2H), 6.9 (d, 2H), 4.5 (s, 2H), 3.5 (t, 2H), δ 2.8 (t, 2H).
Reaction SMILES: [CH3:1][C:2]([O:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=1)([CH2:5][CH3:6])[C:3]#[CH:4]>C1(C)C(C)=CC=CC=1>[CH2:3]([C:2]1([CH3:1])[CH:5]=[CH:6][C:9]2[C:8](=[CH:15][CH:14]=[C:11]([CH:12]=[O:13])[CH:10]=2)[O:7]1)[CH3:4]
Reactant: C#CC(C)(CC)Oc1ccc(C=O)cc1
Solvent: Cc1ccccc1C
Product: CCC1(C)C=Cc2cc(C=O)ccc2O1
Yield: 100 %

Procedure:
A solution of 7 (170 mg) in xylene (3 mL) was subjected to microwave irradiation for 100 min at 220 W, 200 torr, 120° C. The solvent was removed in vacuum to give a quantitative yield of the product (170 mg). 1H NMR (CDCl3): δ 9.81 (s, 1H), 7.63 (dd, J=8.0 Hz, 2.0 Hz, 1H), 7.50 (d, J=2.0 Hz, 1H), 6.85 (d, J=8.4 Hz, 1H), 6.42 (d, J=10.0 Hz, 1H), 5.62 (d, J=10.0 Hz, 1H), 1.81-1.66 (m, 3H), 1.43 (s, 3H), 0.97 ppm (t, J=7.6 Hz, 3H).
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:15]([O:16]CC2C=CC=CC=2)[C@:14]2([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([CH2:32][C:33]4[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH3:41])=[CH:35][CH:34]=4)[CH:26]=3)[O:24][C@@:11]([CH:42]([OH:44])[CH3:43])([CH2:12][O:13]2)[C@@H:10]1[OH:45])C1C=CC=CC=1.Cl>[Pd].CO.O1CCCC1>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([C@@:14]23[O:24][C@@:11]([CH:42]([OH:44])[CH3:43])([CH2:12][O:13]2)[C@H:10]([OH:45])[C@H:9]([OH:8])[C@H:15]3[OH:16])=[CH:26][C:27]=1[CH2:32][C:33]1[CH:34]=[CH:35][C:36]([O:39][CH2:40][CH3:41])=[CH:37][CH:38]=1
Reactant: CCOc1ccc(Cc2cc([C@]34OC[C@](C(C)O)(O3)[C@H](O)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1
Agent: [Pd]
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: CCOc1ccc(Cc2cc([C@]34OC[C@](C(C)O)(O3)[C@H](O)[C@H](O)[C@H]4O)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 14.1 %

Procedure:
To a solution of (1R,2R,3S,4R,5S)-3,4-dibenzyloxy-5-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-1-(1-hydroxyethyl)-6,8-dioxabicyclo[3.2.1]octan-2-ol 281 (140 mg, 0.22 mmol) in a methanol/tetrahydrofuran mixture (v/v=4/1, 20 mL) were added hydrochloric acid (0.03 mL, 1.1 lmmol) and Pd/C (23 mg, 0.02 mmol, 10%) at room temperature. The mixture was stirred at room temperature under H2 for 1 hour and filtered. The filtrate was adjusted with saturated aqueous sodium bicarbonate till pH becomes 7 and extracted with ethyl acetate (10 mL×3). The combined organic layers were washed with water (10 mL×3) and saturated aqueous sodium chloride (10 mL×2), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography eluted with EtOAc to give the title compound 28 as a white solid (14 mg, 14.1%, HPLC: 86.0%). The compound was characterized by the following spectroscopic data: 1H NMR (600 MHz, DMSO-d6) δ(ppm): 7.45 (s, 1H), 7.40 (m, 1H), 7.34 (m, 1H), 7.10 (d, 2H), 6.83 (d, 2H), 5.35-5.30 (m, 1H), 4.78 (d, 1H), 4.68 (s, 2H), 4.60 (d, 1H), 4.21-4.16 (m, 1H), 4.02-3.95 (m, 4H), 3.82-3.75 (m, 1H), 3.71 (d, 1H), 3.66-3.55 (m, 2H), 1.30 (t, 3H), 1.02 (d, 3H); and MS (ESI, pos. ion) m/z: 451.1[M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:25][C:26]([OH:28])=O)[C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[N:21]=[CH:20][CH:19]=[CH:18]3)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:29]([NH:31][CH2:32][C:33]1[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=1)[CH3:30]>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]([C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[N:21]=[CH:20][CH:19]=[CH:18]3)[CH2:25][C:26]([N:31]([CH2:29][CH3:30])[CH2:32][C:33]2[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=2)=[O:28])(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CCNCc1cccnc1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N(CC(=O)O)c2ccc3ncccc3c2)cc1
Product: CCN(Cc1cccnc1)C(=O)CN(c1ccc2ncccc2c1)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-quinolin-6-yl-amino]-acetic acid with ethyl-pyridin-3-ylmethyl-amine
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2)([O-:3])=[O:2].S(OC)(O[CH3:18])(=O)=O.[I-:21].[K+]>O>[I-:21].[CH3:18][N+:9]1[C:10]2[C:5](=[C:4]([N+:1]([O-:3])=[O:2])[CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=[N+]([O-])c1cccc2ncccc12
Reactant: COS(=O)(=O)OC
Agent: [I-]
Agent: [K+]
Solvent: O
Product: C[n+]1cccc2c([N+](=O)[O-])cccc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
5-Nitroquinoline (4 g, 30 mmol) was melted at 85° C., prior to addition of dimethyl sulfate (2.2 ml, 30 mmol), and the resulting mixture was stirred at this temperature for 1.5 hours. The yellow gel was dissolved in water (35 ml) and cooled to room temperature. A saturated aqueous solution of potassium iodide (7.63 g, 45.9 mmol) was added, and the resulting orange precipitate was filtered, washing the residue with chilled water. After drying under vacuum at 60° C., for 2 hours, the brick-red solid was used in the next step without purification.
Reaction SMILES: [O:1]=[C:2]1[CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][N:3]1[CH2:14][C:15]([OH:17])=O.[F:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:21][CH:20]=1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[F:38][C:35]1[CH:34]=[CH:33][C:32]([CH:25]([C:22]2[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=2)[N:26]2[CH2:27][CH2:28][N:29]([C:15](=[O:17])[CH2:14][N:3]3[CH2:4][CH2:5][CH2:6][CH:7]([C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=4)[C:2]3=[O:1])[CH2:30][CH2:31]2)=[CH:37][CH:36]=1
Reactant: O=C(O)CN1CCCC(c2ccccc2)C1=O
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCCC(c2ccccc2)C1=O)N1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Temperature: 25 °C

Procedure:
A solution of 2-(2-oxo-3-phenylpiperidin-1-yl)acetic acid (Example 91D, 0.050 g, 0.214 mmol), 1-(bis(4-fluorophenyl)methyl)piperazine (0.068 g, 0.236 mmol) and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.062 g, 0.322 mmol) in dichloromethane (0.5 mL) was allowed to stir at room temperature. After stirring overnight, the reaction was loaded directly onto a SF15-12 silica gel column (Analogix®, Burlington, Wis.), and the title compound was eluted using a gradient of 5% to 100% ethyl acetate/hexanes over 15 minutes, maintaining 100% ethyl acetate for an additional 10 minutes (flow=30 mL/minute). 1H NMR (300 MHz, CDCl3) δ ppm 7.16-7.38 (m, 9H), 6.93-7.04 (m, 4H), 4.42 (d, J=15.5 Hz, 1H), 4.23 (s, 1H), 4.00 (d, J=15.5 Hz, 1H), 3.70 (dd, J=5.8, 4.6 Hz, 1H), 3.59-3.66 (m, 2H), 3.52-3.60 (m, 1H), 3.44-3.50 (m, 2H), 3.37-3.46 (m, 1H), 2.33-2.41 (m, 4H), 2.15-2.27 (m, 1H), 1.92-2.05 (m, 2H), 1.78-1.91 (m, 1H); MS (ESI−) m/z 502 (M−H)−.
Reaction SMILES: [F:1][C:2]1[C:3]([F:15])=[C:4]([F:14])[C:5]([F:13])=[C:6]2[C:11](=[O:12])[O:10][C:8](=O)[C:7]=12.[CH3:16][C@H:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)(Cl)Cl>[CH:18]1([C@@H:17]([N:24]2[C:11](=[O:12])[C:6]3[C:7](=[C:2]([F:1])[C:3]([F:15])=[C:4]([F:14])[C:5]=3[F:13])[C:8]2=[O:10])[CH3:16])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: C[C@H](N)c1ccccc1
Reactant: O=C1OC(=O)c2c(F)c(F)c(F)c(F)c21
Solvent: ClC(Cl)Cl
Product: C[C@@H](C1CCCCC1)N1C(=O)c2c(F)c(F)c(F)c(F)c2C1=O
Temperature: 180 °C
Yield: 65.3 %

Procedure:
220 mg of tetrafluorophthalic anhydride and 127 mg of (S)-α-methylbenzylamine were charged in an egg-plant type flask of 50 ml, followed by stirring under heating at a temperature of 180° C. for 1.5 hours. After cooled, the reaction product was dissolved in chloroform, purified by silica gel column chromatography (eluent; methylene chloride:methanol=30:1 v/v), recrystallized from a mixed solvent of n-hexane-ethyl acetate, to obtain 215 mg of the desired product as a colorless powder. Yield: 65%. m.p. 147-148° C.; [α]20D=5.26° (C=0.618 AcOEt); MS(EI+) 329(M)+
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[Br:9][C:10]1[CH:11]=[CH:12][C:13]2[O:22][CH2:21][CH2:20][C:19]3[CH:18]=[C:17]([C:23](Cl)=[O:24])[S:16][C:15]=3[C:14]=2[CH:26]=1.C(Cl)(=O)C(Cl)=O>CN(C)C=O>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:23]([C:17]1[S:16][C:15]2[C:14]3[CH:26]=[C:10]([Br:9])[CH:11]=[CH:12][C:13]=3[O:22][CH2:21][CH2:20][C:19]=2[CH:18]=1)=[O:24]
Reactant: Nc1ccccc1Cl
Reactant: O=C(Cl)c1cc2c(s1)-c1cc(Br)ccc1OCC2
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: O=C(Nc1ccccc1Cl)c1cc2c(s1)-c1cc(Br)ccc1OCC2

Procedure:
Reaction of 2-chloroaniline with 9-bromo-4,5-dihydro-6-oxa-1-thia-benzo[e]azulene-2-carbonyl chloride (prepared from the corresponding carboxylic acid using oxalyl chloride with catalytic N,N-dimethylformamide) yielded 9-bromo-4,5-dihydro-6-oxa-1-thia-benzo[e]azulene-2-carboxylic acid (2-chloro-phenyl)-amide.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]2([C:30]([F:33])([F:32])[F:31])[O:17][N:16]=[C:15]([C:18]3[N:23]4[CH:24]=[CH:25][N:26]=[C:22]4[C:21]([C:27](O)=[O:28])=[CH:20][CH:19]=3)[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:36][S:37][CH2:38][CH2:39][NH2:40]>>[CH3:36][S:37][CH2:38][CH2:39][NH:40][C:27]([C:21]1[C:22]2[N:23]([CH:24]=[CH:25][N:26]=2)[C:18]([C:15]2[CH2:14][C:13]([C:5]3[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=[C:3]([C:2]([F:35])([F:1])[F:34])[CH:4]=3)([C:30]([F:32])([F:33])[F:31])[O:17][N:16]=2)=[CH:19][CH:20]=1)=[O:28]
Reactant: CSCCN
Reactant: O=C(O)c1ccc(C2=NOC(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)(C(F)(F)F)C2)n2ccnc12
Product: CSCCNC(=O)c1ccc(C2=NOC(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)(C(F)(F)F)C2)n2ccnc12

Procedure:
Using a procedure similar to that described in Example 1, except using 5-[5-(3,5-bistrifluoromethylphenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-imidazo[1,2-a]pyridine-8-carboxylic acid (45 mg) and 2-methylthioethylamine (0.016 mL), the title compound was isolated as an orange-reddish solid (11.9 mg, 23%). MS (ES): M/Z [M+H]=585. 1H NMR (400 MHz, CHLOROFORM-d): 2.22 (s, 3H), 2.85 (t, J=6.8 Hz, 2H), 3.82 (q, J=6.6 Hz, 2H), 4.01 (d, J=17.0 Hz, 1H), 4.44 (d, J=16.8 Hz, 1H), 7.21 (d, J=7.6 Hz, 1H), 7.85 (s, 1H), 8.02 (s, 1H), 8.12 (s, 2H), 8.28 (d, J=7.6 Hz, 1H), 8.90 (d, J=1.0 Hz, 1H), 10.67 (br. s., 1H). 19F NMR (376 MHz, CHLOROFORM-d): −80.0 (s, 3F), −63.3 (s, 6F).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]([CH2:16][OH:17])[C:9]=2[F:18])[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.Cl[C:26]([O:28][CH3:29])=[O:27]>O1CCCC1>[CH3:29][O:28][C:26](=[O:27])[O:17][CH2:16][C:10]1[C:9]([F:18])=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C:13]([O:14][CH3:15])=[CH:12][CH:11]=1
Reactant: COc1ccc(CO)c(F)c1-c1cccc(Cl)c1
Reactant: COC(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COC(=O)OCc1ccc(OC)c(-c2cccc(Cl)c2)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (3′-Chloro-2-fluoro-6-methoxy-biphenyl-3-yl)-methanol (I-32, 3.00 g, 11.3 mmol) in pyridine (2.31 g, 29.3 mmol) and tetrahydrofuran (40 mL) was cooled to 0° C. in an ice water bath. The reaction vessel was purged with nitrogen and methyl chloroformate (2.34 g, 24.8 mmol) was added. The ice bath was removed and the reaction was stirred at room temperature overnight. The white suspension was adjusted to pH 2 by addition of 1 N aqueous hydrochloric acid (˜25 mL) and the yellow biphasic solution was diluted with dichloromethane (200 mL) and water (150 mL). The layers were separated, and the aqueous layer was extracted with dichloromethane (2×100 mL). The dichloromethane extracts were combined, washed with water (2×200 mL) and brine (200 mL), dried over sodium sulfate, filtered, and the solvent removed under vacuum to give I-145 (3.84 g, quantitative yield).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Br[CH:6]1[CH2:12][CH2:11][CH2:10][CH:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[NH:8][C:7]1=[O:19]>CN(C)C=O>[N:1]([C@@H:6]1[CH2:12][CH2:11][CH2:10][C@H:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[NH:8][C:7]1=[O:19])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1NC(c2ccccc2)CCCC1Br
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=N[C@@H]1CCC[C@H](c2ccccc2)NC1=O
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Sodium azide (8.73 g, 134 mmol) was added to a solution of 3-bromo-7-phenylazepan-2-one in N,N-dimethylformamide (40 mL) and the mixture heated to 60° C. After 2 h the reaction was allowed to cool to ambient temperature, concentrated, and diluted with water. The mixture was extracted with ethyl acetate, and the organic layer was washed with water (3×) and saturated brine, dried over magnesium sulfate, filtered, and concentrated. Purification by silica gel chromatography (30% ethyl acetate/hexanes→50% ethyl acetate/hexanes) gave the racemic cis and trans compounds. The cis enantiomers were separated on a Chiralpak AD column eluting with 100% methanol to give the title compound (1.09 g). MS 231 (M+1).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:11]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:9])[CH2:3][CH2:2]1.Br[CH2:27][CH2:28][CH2:29][C:30]([CH3:42])([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:31][C:32]([O:34][CH3:35])=[O:33].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:42][C:30]([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)([CH2:29][CH2:28][CH2:27][N:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:11]([C:16]3[CH:17]=[CH:18][C:19]([C:22]([F:23])([F:24])[F:25])=[CH:20][CH:21]=3)=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:9])[CH2:3][CH2:2]1)[CH2:31][C:32]([O:34][CH3:35])=[O:33]
Reactant: O=C(NC1CCNCC1)c1ccccc1-c1ccc(C(F)(F)F)cc1
Reactant: COC(=O)CC(C)(CCCBr)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CC(C)(CCCN1CCC(NC(=O)c2ccccc2-c2ccc(C(F)(F)F)cc2)CC1)c1ccccc1
Temperature: 90 °C
Reaction time: 72 h

Procedure:
0.611 g (1.75 mmol) of 4′-trifluoromethyl-biphenyl-2-carboxylic acid-piperidin-4-yl-amide, 0.5 g (1.75 mmol) of methyl 5-bromo-2-methyl-2-phenyl-pentanecarboxylate and 0.8 g (5.7 mmol) of potassium carbonate are dissolved in 50 ml dimethylformamide and mixed with water. The mixture is stirred for 72 hours at 90° C. Then the reaction mixture is poured onto water, the precipitate is filtered off and dried. After column chromatography on silica gel (eluant: ethyl acetate) colourless crystals are left.
Reaction SMILES: [CH2:1]([NH2:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[I:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24].Cl.C(N)CCCCCCCCCCCCCCCCC>CCOCC.C(O)C>[CH2:1]([NH:19][C:23](=[O:24])[C:22]1[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=1[I:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: O=C(Cl)c1ccccc1I
Reactant: CCCCCCCCCCCCCCCCCCN
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCCCCNC(=O)c1ccccc1I
Yield: 8 %

Procedure:
A solution of 17.9 g of octadecylamine in a mixture of 300 ml of ether and 10 ml of ethanol was reacted with a solution of 8.0 g of o-iodobenzoyl chloride in 25 ml of ether for 10 minutes. The precipitate which formed contained octadecylamine hydrochloride. This precipitate was recovered and discarded. The volume was thereafter reduced to approximately half at 65° on a water bath. The resulting precipitate was recovered in accordance with the procedure of Example 3. The crude product was recrystallized from benzene to yield 1.2 g of N-octadecyl-o-iodobenzamide as a white microcrystalline solid, m.p. 94°-96°, Rf 0.77.