Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]2=[N:12][N:13]=[C:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[N:4]2[N:3]=1.[H-].[Na+].Br[CH:26]1[CH2:30][CH2:29][NH:28][C:27]1=[O:31].O>CN(C)C=O>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]2[N:4]3[N:3]=[C:2]([O:1][CH:26]4[CH2:30][CH2:29][NH:28][C:27]4=[O:31])[C:11]4[C:6]([C:5]3=[N:12][N:13]=2)=[CH:7][CH:8]=[CH:9][CH:10]=4)=[CH:16][CH:17]=1
Reactant: COc1ccc(-c2nnc3c4ccccc4c(O)nn23)cc1
Reactant: O=C1NCCC1Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2nnc3c4ccccc4c(OC4CCNC4=O)nn23)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
6-Hydroxy-3-(4-methoxyphenyl)-1,2,4-triazolo[3,4-a]phthalazine, (9.8 g), is suspended in N,N-dimethylformamide (100 ml) and added of 50% sodium hydride in mineral oil (1.7 g). The mixture is heated to 50°-60° C. and stirred for about 2 hours. After cooling to room temperature the mixture is added portionwise with 3-bromo-2-pyrrolidone (5.5 g). [This product is prepared according to F. Korte, H. Wanholf, Ber. 97, 1976 (1964)]. Then stirring is continued for about 5 hours at a temperature of about 70° C. The mixture is then cooled to room temperature and poured into water (800 ml). The residue, which is collected by filtration, is then crystallized from ethanol/chloroform. (Yield=82%). M.p. 290°-293° C.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[Na+].[Cl:6][C:7]([Cl:23])([Cl:22])[CH:8](Cl)[CH:9]([N:16]1[CH:20]=[N:19][CH:18]=[N:17]1)[C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12].O>C(O)(=O)C>[Cl:23][C:7]([Cl:6])([Cl:22])[CH:8]([O:3][C:1](=[O:4])[CH3:2])[CH:9]([N:16]1[CH:20]=[N:19][CH:18]=[N:17]1)[C:10](=[O:15])[C:11]([CH3:13])([CH3:12])[CH3:14]
Reactant: CC(C)(C)C(=O)C(C(Cl)C(Cl)(Cl)Cl)n1cncn1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)OC(C(C(=O)C(C)(C)C)n1cncn1)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
16.4 g (0.2 mol) of anhydrous sodium acetate were added to 31.5 g (0.1 mol) of 1,1,1,2-tetrachloro-3-(1,2,4-triazol-1-yl)-5,5-dimethyl-hexan-4-one in 150 ml of glacial acetic acid. The mixture was stirred at room temperature overnight and then heated to 40° C. for about 4 hours. The reaction mixture was then added to 1,000 ml of water and extracted twice with 250 ml of chloroform each time. The combined organic phases were dried over sodium sulphate and concentrated by distilling off the solvent in vacuo. The solid residue was recrystallized from ethanol and rinsed with a little hexane. 27.8 g (77.8% of theory) of 1,1,1-trichloro-2-acetoxy-3-(1,2,4-triazol-1-yl)-5,5-dimethylhexan-4-one were obtained as a diastereomer mixture of melting point 115°-119° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH2:10][OH:11].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>ClCCl.CCOCC>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]=[O:11]
Reactant: OCc1c(Cl)ccc(F)c1Cl
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: O=Cc1c(Cl)ccc(F)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.8 %

Procedure:
To a solution of (2,6-dichloro-3-fluorophenyl)methanol (9.0 g, 46 mmol) in dichloromethane (200 mL) was added molecular sieves (4A, powder, 40g) and pyridinium dichromate (PDC: 45g, 120 mmol). The mixture was stirred at room temperature for 2 h and diluted with Et2O (200 mL). The mixture was filtered through Celite and the solvent was removed in vacuum. The residue was washed with a small amount of dichloromethane to give a white solid (4.6 g, yield 52%).
Reaction SMILES: C(O[C:9]1[CH:10]=[C:11]([C@@H:15]([NH:21][C:22]([C@@H:24]2[CH2:29][CH2:28][CH2:27][N:26]([C:30](=[O:46])[CH2:31][CH2:32][CH:33]3[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]3)[CH2:25]2)=[O:23])[CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH:12]=[N:13][CH:14]=1)C1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(C)C=CC(S([O:62][CH2:63][CH2:64][O:65][S:66]([C:69]2[CH:74]=[CH:73][C:72]([CH3:75])=[CH:71][CH:70]=2)(=[O:68])=[O:67])(=O)=O)=CC=1>CN(C)C=O>[CH3:20][O:19][C:17](=[O:18])[CH2:16][C@H:15]([NH:21][C:22]([C@@H:24]1[CH2:29][CH2:28][CH2:27][N:26]([C:30](=[O:46])[CH2:31][CH2:32][CH:33]2[CH2:34][CH2:35][N:36]([C:39]([O:41][C:42]([CH3:43])([CH3:45])[CH3:44])=[O:40])[CH2:37][CH2:38]2)[CH2:25]1)=[O:23])[C:11]1[CH:12]=[N:13][CH:14]=[C:9]([O:62][CH2:63][CH2:64][O:65][S:66]([C:69]2[CH:70]=[CH:71][C:72]([CH3:75])=[CH:73][CH:74]=2)(=[O:67])=[O:68])[CH:10]=1
Reactant: COC(=O)C[C@H](NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(OCc2ccccc2)c1
Reactant: Cc1ccc(S(=O)(=O)OCCOS(=O)(=O)c2ccc(C)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)C[C@H](NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(OCCOS(=O)(=O)c2ccc(C)cc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.5 %

Procedure:
Tert-butyl 4-{3-[(3R)-3-({(1S)-1-[5-(benzyloxy)pyridin-3-yl]-3-methoxy-3-oxopropyl}carbamoyl)piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate (example 5e, 200 mg, 0.37 mmol) was dissolved in N,N-dimethylformamide (25.3 mL). Cesium carbonate (298 mg, 0.92 mmol) and ethylene glycol bis-p-toluenesulfonate (203 mg, 0.55 mmol) were added. The mixture was stirred at room temperature for 2 hours and stored at 5° C. for 17 hours. The mixture was quenched by addition of saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The combined extracts were washed with brine and dried over sodium sulfate. The solution was concentrated under reduced pressure and the residue was purified by preparative thin layer chromatography on silica gel (ethyl acetate 100%) to yield 109 mg of tert-butyl 4-{3-[(3R)-3-({(1S)-3-methoxy-1-[5-(2-{[(4-methylphenyl)sulfonyl]oxy}ethoxy)pyridin-3-yl]-3-oxopropyl}carbamoyl)piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylat.
Reaction SMILES: Cl.[NH:2]1[C:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]2([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[O:4][C:3]1=[O:17].[Cl:18][C:19]1[C:24]2[NH:25][C:26]([CH:28]3[CH2:32][CH2:31][O:30][CH2:29]3)=[N:27][C:23]=2[CH:22]=[C:21]([O:33][C:34]2[CH:39]=[C:38](Cl)[N:37]=[CH:36][N:35]=2)[CH:20]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:18][C:19]1[C:24]2[NH:25][C:26]([CH:28]3[CH2:32][CH2:31][O:30][CH2:29]3)=[N:27][C:23]=2[CH:22]=[C:21]([O:33][C:34]2[N:35]=[CH:36][N:37]=[C:38]([N:14]3[CH2:13][CH2:12][C:5]4([O:4][C:3](=[O:17])[NH:2][C:7]5[N:8]=[CH:9][CH:10]=[CH:11][C:6]4=5)[CH2:16][CH2:15]3)[CH:39]=2)[CH:20]=1
Reactant: O=C1Nc2ncccc2C2(CCNCC2)O1
Reactant: Clc1cc(Oc2cc(Cl)c3[nH]c(C4CCOC4)nc3c2)ncn1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1Nc2ncccc2C2(CCN(c3cc(Oc4cc(Cl)c5[nH]c(C6CCOC6)nc5c4)ncn3)CC2)O1

Procedure:
36 mg (0.14 mmol) spiro[piperidin-4,4′-pyrido[2,3-d][1,3]oxazin]-2′(1′H)-one hydrochloride, 50 mg (0.14 mmol) 7-chloro-5-(6-chloropyrimidin-4-yloxy)-2-(tetrahydrofuran-3-yl)-1H-benzo[d]imidazole and 50 μL (0.30 mmol) DIPEA in 2.0 mL DMF were stirred overnight at RT. The reaction mixture was purified by chromatography. The fractions containing product were combined and lyophilised.
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[Na+].[F:6][C:7]1[CH:12]=[C:11]([I:13])[CH:10]=[C:9](I)[C:8]=1[OH:15]>C(O)(=O)C>[F:6][C:7]1[CH:12]=[C:11]([I:13])[CH:10]=[C:9]([N+:1]([O-:4])=[O:2])[C:8]=1[OH:15]
Reactant: O=[N+]([O-])[O-]
Reactant: Oc1c(F)cc(I)cc1I
Agent: [Na+]
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(I)cc(F)c1O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Sodium nitrate (4.3 g) was added in portions over 1 hour to a solution of 2-fluoro-4,6-diiodophenol (16.3 g) in acetic acid (100 ml). The mixture was stirred for a further 15 minutes and was then poured into ice water (250 ml). The aqueous solution was concentrated under reduced pressure, extracted with chloroform and the organic solvent removed under reduced pressure. The residue was steam distilled to give 2-fluoro-4-iodo-6-nitrophenol which crystallised from aqueous ethanol (1.8 g) m.p. 96°.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O-:8])=[O:7])=[CH:4][CH:3]=1.[Na+].Cl[CH2:13][CH2:14][CH2:15][C:16](Cl)=[O:17].C([O-])([O-])=O.[Na+].[Na+]>C1C=CC=CC=1>[O:17]=[C:16]1[CH2:15][CH2:14][CH2:13][N:1]1[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1
Reactant: Nc1ccc(C(=O)[O-])cc1
Reactant: O=C(Cl)CCCCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Product: O=C(O)c1ccc(N2CCCC2=O)cc1
Temperature: 60 °C
Reaction time: 20 h

Procedure:
Sodium 4-aminobenzoate (42.5 g,0.267 mol) was suspended in 250 ml benzene. To this solution, upon vigorous stirring, 4-chlorobutyryl chloride (29 ml, 0.248 mol) was added slowly. The temperature of the reaction mixture was heated to 60° C. It is at 60° C. that the reaction was continued for another 20 hours. Na2CO3 solution (20%, 600 ml) was then added and the benzene layer was separated. The aqueous layer was acidified and the white precipitate was filtrated and recrystallized from methanol to form colorless crystal of 4-(2-oxo-pyrrolidin-1-yl)-benzoic acid. Mass Spectra: m/e (relative intensity) 205(M+, 44.23).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[SH:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>CC(C)=O>[N+:9]([C:6]1[CH:7]=[CH:8][C:3]([CH2:2][S:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:4][CH:5]=1)([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CCOC(=O)CCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CCSCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.1 %

Procedure:
A mixture of 1-(bromomethyl)-4-nitrobenzene (Aldrich, 3.8 g; 17.6 mmol) in acetone (100 ml) was treated with potassium carbonate (2.22 g; 15.9 mmol) and ethyl 3-mercaptopropanoate (Aldrich, 2.14 g; 15.9 mmol). After stirring at RT for 18 hours the mixture filtered and the solid washed with acetone. The organic fractions were combined and the solvent removed in vacuo. The residue was purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of Et2O to give the title compound as an off-white solid (3.6 g, 84%).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[Br:9][C:10](=[CH2:13])[CH2:11]Br>>[Br:9][C:10](=[CH2:11])[CH2:13][S:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8]
Reactant: C=C(Br)CBr
Reactant: Oc1ccccc1S
Product: C=C(Br)CSc1ccccc1O
Yield: 58 %

Procedure:
This compound was prepared from 2-mercaptophenol and 2-bromoallyl bromide in 58% yield according to the general procedure given for 16p in Example VII. Yellow oil; 1H NMR (CDCl3): δ 3.57 (s, 2H), 5.33 (d, J=14.55 Hz, 2H), 6.69 (d, J=2.50 Hz, 1H), 6.87, (t, J=7.40 Hz, 1H), 6.99 (d, J=8.25 Hz, 1H), 7.28 (t, J=7.70 Hz, 1H), 7.45 (d, J=7.70 Hz, 1H); 13C NMR (CDCl3): δ 47.63, 115.12, 120.39, 120.93, 124.92, 128.39, 131.89, 136.60, 157.56; HRMS (FAB): 243.9557 calcd for C9H9BrOS [M]+. found 243.9557.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](=[O:26])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[C:14]([F:25])[CH:13]=3)[O:11][C:6]=2[C:5]([F:27])=[C:4]([CH3:28])[C:3]=1[F:29].CN(C)C=O.[H-].[Na+].I[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]>O>[F:29][C:3]1[C:4]([CH3:28])=[C:5]([F:27])[C:6]2[O:11][C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[C:14]([F:25])[CH:13]=3)=[CH:9][C:8](=[O:26])[C:7]=2[C:2]=1[NH:1][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]
Reactant: Cc1c(F)c(N)c2c(=O)cc(-c3ccc(NC(=O)C(C)(C)C)c(F)c3)oc2c1F
Reactant: CCCCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCNc1c(F)c(C)c(F)c2oc(-c3ccc(NC(=O)C(C)(C)C)c(F)c3)cc(=O)c12
Temperature: 25 °C
Reaction time: 20 h
Yield: 53.3 %

Procedure:
653 mg (1.62 mmol) of the above 5-amino-6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-7-methyl-4H-1-benzopyran-4-one was dissolved ion 20 mL of dimethylformamide under argon atmosphere, 200 mg (5.00 mmol) of sodium hydride (60% oil dispersion) and 0.48 mL (3.2 mmol) of 1-iodohexane were added under ice-cooling and the mixture was stirred at room temperature for 20 hours. Water was added to the reaction solution and the mixture was extracted twice with ethyl acetate. The organic layer was washed once with water and once with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by medium pressure liquid chromatography to give 422 mg of 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-5-(1-hexylamino)-7-methyl-4H-1-benzopyran-4-one (yield: 54%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](B2OC(C)(C)C(C)(C)O2)=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.Br[C:36]1[C:47]([CH3:48])=[CH:46][C:39]([O:40][CH2:41][C:42]([CH3:45])([OH:44])[CH3:43])=[CH:38][C:37]=1[CH3:49]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:36]2[C:47]([CH3:48])=[CH:46][C:39]([O:40][CH2:41][C:42]([OH:44])([CH3:43])[CH3:45])=[CH:38][C:37]=2[CH3:49])=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2
Reactant: Cc1cc(OCC(C)(C)O)cc(C)c1Br
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(OCC(C)(C)O)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate and 1-(4-bromo-3,5-dimethylphenoxy)-2-methylpropan-2-ol following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 8): tR=0.77 min; Mass spectrum (ESI+): m/z=535 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[CH2:14][S:13][CH2:12][C:11](=[O:15])[N:10]2[CH2:16][C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH:5]=[C:6]([F:8])[CH:7]=1.C[OH:28]>OO.Cl>[F:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[CH2:14][S:13](=[O:28])[CH2:12][C:11](=[O:15])[N:10]2[CH2:16][C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CO
Reactant: O=C(CN1C(=O)CSC[C@H]1c1cc(F)cc(F)c1)OCc1ccccc1
Agent: Cl
Agent: OO
Product: O=C(CN1C(=O)CS(=O)C[C@H]1c1cc(F)cc(F)c1)OCc1ccccc1
Temperature: 40 °C

Procedure:
To a solution of benzyl [(3R)-3-(3,5-difluorophenyl)-5-oxothiomorpholin-4-yl]acetate (151 mg, 0.399 mmol, from Step A.) in MeOH (10 mL) was added aqueous hydrogen peroxide (30 drops, ˜0.8 mL, 30% by weight), and aqueous HCl (5 drops, 3 M HCl). This mixture was then heated to 40° C. for 2.5 hours. After cooling to ambient temperature, the bulk of the MeOH was removed in vacuo, and the residue was partitioned between 50 mL of water and 100 mL of diethyl ether. The organics were washed with saturated brine, then dried over sodium sulfate, filtered, and concentrated in vacuo to give a residue that was purified by silica gel chromatography eluting with a gradient of Hexanes:EtOAc—1:1 to 100% EtOAc, to yield 24.5 mg of the minor sulfoxide isomer and 93.6 mg of the major sulfoxide isomer. MS: m/z=394 (M+1).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]3[C:16]([F:30])=[C:17]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=4)[C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)=[CH:10][N:9]2[CH:31]=1)=O)C.[NH3:32].CO>>[Cl:29][C:25]1[CH:24]=[C:23]([C:17]2[C:18]([O:21][CH3:22])=[CH:19][CH:20]=[C:15]([CH2:14][C:11]3[CH:12]=[CH:13][C:8]4[N:9]([CH:31]=[C:6]([C:4]([NH2:32])=[O:3])[N:7]=4)[CH:10]=3)[C:16]=2[F:30])[CH:28]=[CH:27][CH:26]=1
Reactant: N
Reactant: CCOC(=O)c1cn2cc(Cc3ccc(OC)c(-c4cccc(Cl)c4)c3F)ccc2n1
Solvent: CO
Product: COc1ccc(Cc2ccc3nc(C(N)=O)cn3c2)c(F)c1-c1cccc(Cl)c1
Temperature: 60 °C
Reaction time: 20 h
Yield: 71 %

Procedure:
Into an 8 mL vial was added 6-(3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester (I-37) synthesized above (37 mg, 0.084 mmol) and 2 mL of 7N NH3/MeOH. After stirring for 20 hours at 60° C., the reaction was concentrated. Trituration with ether provided 6-(3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-imidazo[1,2-a]pyridine-2-carboxylic acid amide (P-429) (24.5 mg, 71%) as a white solid. 1H-NMR (400 MHz, DMSO-d6): 8.42 (s, 1H), 8.30 (s, 1H), 7.64 (br s, 1H), 7.53 (d, J=4.6 Hz, 1H), 7.42 (m, 5H), 7.30 (m, 1H), 7.23 (dd, 1H, J=9.6, 1.6 Hz), 6.97 (d, 1H), 8.4 Hz), 3.95 (s, 2H), 3.74 (s, 3H) ppm. LC/MS=83.4%, 410.0 (APCI+).
Reaction SMILES: COC[O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([CH2:28]C=C)[C:10]([C:18]3[CH:23]=[CH:22][C:21]([O:24]COC)=[CH:20][CH:19]=3)([CH2:15][CH2:16][CH3:17])[CH2:11][O:12]2)=[CH:7][CH:6]=1.[F:31][C:32]([F:55])([C:51]([F:54])([F:53])[F:52])[CH2:33][CH2:34][CH2:35][CH2:36][CH:37]([CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH:49]=[CH2:50])[C:38]([O:40]CC)=[O:39]>>[OH:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([CH2:28][CH2:50][CH2:49][CH2:48][CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][CH:37]([CH2:36][CH2:35][CH2:34][CH2:33][C:32]([F:31])([F:55])[C:51]([F:52])([F:53])[F:54])[C:38]([OH:40])=[O:39])[C:10]([C:18]3[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=3)([CH2:15][CH2:16][CH3:17])[CH2:11][O:12]2)=[CH:7][CH:6]=1
Reactant: C=CCC1c2ccc(OCOC)cc2OCC1(CCC)c1ccc(OCOC)cc1
Reactant: C=CCCCCCCC(CCCCC(F)(F)C(F)(F)F)C(=O)OCC
Product: CCCC1(c2ccc(O)cc2)COc2cc(O)ccc2C1CCCCCCCCCC(CCCCC(F)(F)C(F)(F)F)C(=O)O

Procedure:
Starting with (3RS,4RS)-7-methoxymethoxy-3-(4-methoxymethoxyphenyl)-4-(2-propenyl)-3-propylchroman prepared as in Example 21 and ethyl 2-(5,5,6,6,6-pentafluorohexyl)-9-decenoate prepared separately, the same procedure as shown in Example 21 was repeated to give 11-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-propylchroman-4-yl]-2-(5,5,6,6,6-pentafluorohexyl)undecanoic acid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:22][NH2:23])=[C:6]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.[CH:24](O)=O>O>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][C:11]([Cl:14])=[CH:12][CH:13]=2)=[C:6]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C:5]2[N:4]([CH:24]=[N:23][N:22]=2)[N:3]=1
Reactant: NNc1nnc(Cl)c(-c2ccc(Cl)cc2)c1-c1ccc(Cl)cc1
Reactant: O=CO
Solvent: O
Product: Clc1ccc(-c2c(Cl)nn3cnnc3c2-c2ccc(Cl)cc2)cc1
Temperature: 120 °C
Yield: 91 %

Procedure:
To a round bottom flask was added 3-chloro-4,5-bis(4-chlorophenyl)-6-hydrazinylpyridazine (3.0 gm, 8.2 mmol) and formic acid (15 ml). The reaction was heated at 120° C. for 2 hrs. The reaction mixture was cooled to rt, poured into water (100 ml) and solid precipitated. The solid was collected by filtration to give product 6-chloro-7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazine as a grey solid (2.8 gm, 91% yield). LCMS (M+H)=376.9; 1HNMR (CDCl3, 400 Hz): 9.16 (1H, s), 7.38-7.40 (4H, m), 7.37 (2H, d), 7.15 (2H, d).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[NH2:10])[CH2:5][NH2:6].[N+]([O-])(O)=O.CC1C=C(C)[N:18]([C:22](N)=[NH:23])N=1>C(O)C>[I:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[NH2:10])[CH2:5][NH:6][C:22]([NH2:23])=[NH:18]
Reactant: NCc1ccc(N)c(I)c1
Reactant: Cc1cc(C)n(C(=N)N)n1
Solvent: O=[N+]([O-])O
Solvent: CCO
Product: N=C(N)NCc1ccc(N)c(I)c1

Procedure:
An ethanol (5 ml) solution of 3-iodo-4-aminobenzylamine (0.220 g, 0.887 mmol) and 3,5-dimethylpyrazole-1-carboxamidine nitrate (0.179 g, 0.087 mmol) was heated at reflux temperature for 3 hr. under argon. The solvent was evaporated in vacuo and the residue washed with ether and dichloromethane to remove 3,5-dimethylpyrazole and unreacted amine. The crude product was recrystallized from methanol/ether to give fine, pale-yellow needles (0.163 g, 72.5%), mp 135°-137° C.; PMR (DMSO-d6) γ6.62-7.66 (m, 9H), 4.1 (s, 2H); IR (Nujol) 1660, 1620 cm-1 (C=N); Anal. Calcd. for C18H11IN4. HNO3.0.5H2O): C, 27.20; H, 3.42, N, 19.08. Found C, 26.70; H, 3.33; N, 19.08.
Reaction SMILES: [O:1]=[C:2]1[C:8]2=[CH:9][N:10]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)(=[O:17])=[O:16])[C:11]3[CH:12]=[CH:13][CH:14]=[C:6]([C:7]=32)[CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.[C:31]([OH:37])([C:33]([F:36])([F:35])[F:34])=[O:32]>C(Cl)Cl>[F:34][C:33]([F:36])([F:35])[C:31]([OH:37])=[O:32].[C:18]1([S:15]([N:10]2[C:11]3[CH:12]=[CH:13][CH:14]=[C:6]4[CH2:5][NH:4][CH2:3][C:2](=[O:1])[C:8]([C:7]=34)=[CH:9]2)(=[O:17])=[O:16])[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CC(=O)c2cn(S(=O)(=O)c3ccccc3)c3cccc(c23)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CNCc2cccc3c2c1cn3S(=O)(=O)c1ccccc1

Procedure:
tert-Butyl 3-oxo-1-(phenylsulfonyl)-1,3,4,6-tetrahydro-5H-azepino[5,4,3-cd]indole-5-carboxylate, Intermediate 18 (5.0 mg, 0.012 mmol) was dissolved in DCM (1 ml). TFA (0.5 ml) was added and the solution was heated to boiling. The solvent was evaporated. Obtained 5.2 mg of the TFA salt. MS (ESI+) m/z 327 [M+H]+.
Reaction SMILES: Cl[CH2:2][O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9](=[O:12])[N:8]([CH2:13][CH2:14][O:15][C:16](=[O:32])[C@H:17]([CH:29]([CH3:31])[CH3:30])[NH:18][C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH:7]=1)=[O:5].[I-:33].[Na+]>C(#N)C>[I:33][CH2:2][O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9](=[O:12])[N:8]([CH2:13][CH2:14][O:15][C:16](=[O:32])[C@H:17]([CH:29]([CH3:31])[CH3:30])[NH:18][C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH:7]=1)=[O:5]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCCn1cc(C(=O)OCCl)ccc1=O
Reactant: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCCn1cc(C(=O)OCI)ccc1=O
Temperature: 60 °C
Reaction time: 4 h
Yield: 94.7 %

Procedure:
To a solution of 1-(2-N-CBz-L-valyloxyethyl)-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid chloromethyl ester (1.80 g, 3.87 mmol) in acetonitrile (30 mL), was added sodium iodide (2.32 g, 15.5mmol). The solution was stirred for 4 h at 60° C. The resulting suspension was filtered and the filtrate was evaporated. The residue was dissolved in CH2Cl2 and washed with aqueous sodium thiosulfate (0.1 M). The organic phase was dried (Na2SO4) and concentrated under reduced pressure. The crude product was column chromatographed (silica gel, 1% MeOH in CH2Cl2), to give 2.04 g 1-(2-N-CBz-L-valyloxyethyl)-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid iodomethyl ester.
Reaction SMILES: [F:1][C:2]1[C:3]([N:9]=[CH:10][N:11]([CH3:13])[CH3:12])=[N:4][C:5]([OH:8])=[N:6][CH:7]=1.[CH2:14]([N:17]=[C:18]=[O:19])[CH2:15][CH3:16]>ClCCl>[CH2:14]([NH:17][C:18]([N:6]1[CH:7]=[C:2]([F:1])[C:3]([N:9]=[CH:10][N:11]([CH3:13])[CH3:12])=[N:4][C:5]1=[O:8])=[O:19])[CH2:15][CH3:16]
Reactant: CN(C)C=Nc1nc(O)ncc1F
Reactant: CCCN=C=O
Solvent: ClCCl
Product: CCCNC(=O)n1cc(F)c(N=CN(C)C)nc1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a 7 milliliter (mL) screw-cap vial were added dichloromethane (CH2Cl2; 5 milliliters (mL)), N′-(5-fluoro-2-hydroxy-pyrimidin-4-yl)-N,N-dimethylformamidine (200 milligrams (mg), 1.09 millimoles (mmol)), and propyl isocyanate (94 mg, 1.10 mmol). The mixture was shaken at room temperature for 16 hours (h). After evaporation and recrystallization of the crude product from CH2Cl2 and heptane, the title compound was isolated as a white solid (274 mg, 94%): mp 266-268° C.; 1H NMR (300 MHz, CDCl3) δ10.42 (br s, 1H), 8.84 (s, 1H), 8.46 (d, J=6.6 Hz, 1H), 3.39-3.30 (m, 2H), 3.25 (s, 6H), 1.70-1.57 (m, 2H), 0.97 (t, J=7.4 Hz, 3H); ESIMS m/z 270 ([M+H]+).