Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.Cl[C:48]1[C:57]([Cl:58])=[N:56][C:55]2[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=2)[N:49]=1.[C:59]1([NH2:69])[C:68]2[C:63](=[CH:64][CH:65]=[CH:66][CH:67]=2)[CH:62]=[CH:61][CH:60]=1.CC(C)([O-])C.[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:58][C:57]1[C:48]([NH:69][C:59]2[C:68]3[C:63](=[CH:64][CH:65]=[CH:66][CH:67]=3)[CH:62]=[CH:61][CH:60]=2)=[N:49][C:50]2[C:55]([N:56]=1)=[CH:54][CH:53]=[CH:52][CH:51]=2
Reactant: Nc1cccc2ccccc12
Reactant: Clc1nc2ccccc2nc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Product: Clc1nc2ccccc2nc1Nc1cccc2ccccc12
Reaction time: 0.17 h
Yield: 33 %

Procedure:
BINAP (93.3 mg, 0.15 mmol) and palladium acetate (22.6 mg, 0.1 mmol) were dissolved in dry xylenes (50 mL) and stirred for 10 min in an inert atmosphere of nitrogen. 2,3-Dichloroquinoxaline (1.99 g, 10 mmol), 1-naphthylamine (1.50 g, 10.5 mmol) and potassium tert-butoxide (1.34 g, 12 mmol) were the added to the reaction mixture which was heated for 22 h under reflux. After cooling to room-temperature, the reaction mixture was filtered and inorganic precipitate washed with dichloromethane (3×50 mL). Removal of the solvent in vacuo results in a residue which was purified using silica gel chromatography (hexanes/EtOAc 9:1). Compound 2c was isolated as yellow-orange crystals, mp=157-159° C. Yield 33%. TLC Rf=0.45 (hexanes/EtOAc 3:1). HPLC/MS: [M+H]+ m/z 306. 1H NMR (CDCl3, 600 MHz): δ 7.50 (td, J=7.2 Hz, 1.2 Hz, 1H), 7.56-7.63 (m, 4H), 7.74 (d, J=8.4 Hz, 1H), 7.78 (dd, J=8.4 Hz, 1.2 Hz, 1H), 7.89 (dd, J=8.4 Hz, 1.2 Hz, 1H), 7.90 (d, J=8.4 Hz, 1H), 7.99-8.04 (m, 2H), 8.54 (d, J=7.2 Hz, 1H). 13C NMR (CDCl3, 150 MHz): δ 118.62, 120.31, 125.01, 125.85, 126.10, 126.26, 126.45, 126.74, 126.79, 127.89, 129.01, 130.42, 133.25, 134.26, 137.25, 138.12, 140.59, 145.71. HRMS: Calcd. for C18H13ClN3 [M+H]+ m/z 306.0793, Observed 306.0786.
Reaction SMILES: C(N(CC)CC)C.[N+]([O-])(O)=O.[N+:12]([O:15][CH2:16][CH2:17][NH2:18])([O-:14])=[O:13].[C:19]1([CH:29]2[S:33][C:32](=[O:34])[NH:31][CH:30]2[C:35](O)=[O:36])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1>O1CCCC1>[N+:12]([O:15][CH2:16][CH2:17][NH:18][C:35]([CH:30]1[CH:29]([C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)[S:33][C:32](=[O:34])[NH:31]1)=[O:36])([O-:14])=[O:13]
Reactant: NCCO[N+](=O)[O-]
Reactant: O=C1NC(C(=O)O)C(c2cccc3ccccc23)S1
Solvent: O=[N+]([O-])O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1NC(C(=O)NCCO[N+](=O)[O-])C(c2cccc3ccccc23)S1
Temperature: 25 °C
Reaction time: 4 h
Yield: 55.5 %

Procedure:
1.23 ml of triethylamine and 0.36 ml of diethyl cyanosphonate were added, whilst ice-cooling and stirring, to a suspension of 370 mg of N-(2-nitrooxyethyl)amine nitrate and 500 mg of 5-(1-naphthyl)-2-oxothiazolidine-4-carboxylic acid in 50 ml of dry tetrahydrofuran, and the resulting mixture was stirred at room temperature for 4 hours. At the end of this time, the solvent was removed by distillation under reduced pressure, and the residue was mixed with ethyl acetate. The resulting mixture was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, and the crystalline residue was recrystallized from ethanol, to give 367 mg of the title compound as colorless crystals, melting at 151°-153° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:43])[CH2:9][CH2:10][CH:11]([C:29](N2C(C3C=CC=CC=3)COC2=O)=[O:30])[CH:12]([C:21]2[CH:28]=[CH:27][C:24](C#N)=[CH:23][CH:22]=2)[NH:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.O.O.O.[F-].[CH2:48]([N+:52](CCCC)(CCCC)CCCC)CCC.C[Si](C([Si](C)(C)C)C(N)=O)(C)C.C(O)(=O)C>COC(C)(C)C>[F:20][C:17]1[CH:18]=[CH:19][C:14]([N:13]2[C:29](=[O:30])[CH:11]([CH2:10][CH2:9][CH:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[OH:43])[CH:12]2[C:21]2[CH:28]=[CH:27][CH:24]=[CH:23][C:22]=2[C:48]#[N:52])=[CH:15][CH:16]=1
Reactant: N#Cc1ccc(C(Nc2ccc(F)cc2)C(CCC(O)c2ccc(F)cc2)C(=O)N2C(=O)OCC2c2ccccc2)cc1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Agent: [F-]
Solvent: CC(=O)O
Solvent: COC(C)(C)C
Solvent: O
Product: N#Cc1ccccc1C1C(CCC(O)c2ccc(F)cc2)C(=O)N1c1ccc(F)cc1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
2 g of 4-[5-(4-Fluorophenyl)-1-(4-fluorophenylamino)-5-hydroxy-2-(2-oxo-4-phenyl-oxazolidine-3-carbonyl)-pentyl]-benzonitrile were dissolved in 20 ml of methyl-tert-butyl ether and, together with 100 mg of tetrabutylammonium fluoride trihydrate and 1.3 ml of bistrimethylsilyl acetamide, heated at 40° C. for about 1 h. The reaction was monitored by thin-layer chromatography. After the reaction ended, 0.2 ml of glacial acetic acid were initially added and the mixture was stirred for 30 min and then concentrated. 20 ml of a mixture of isopropanol/2N sulfuric acid=10:1 were added to the residue, and the mixture was stirred for 1 hour. Following addition of a spatula tip of solid sodium bicarbonate, the mixture was again concentrated under reduced pressure. The residue was taken up in ethyl acetate and the organic phase was washed with water and dried. The residue was, after removal of the solvent, purified by column chromatography (SiO2, CH2Cl2/methanol=100:1). This gave the product of molecular weight 418.45 (C25H20F2N2O2); MS (DCI+) 419 (M+H+).
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)[O:4][C:2]2=O.Cl.[CH3:14][O:15][C:16](=[O:22])[CH:17]([NH2:21])[CH2:18][CH2:19][CH3:20].C(N(CC)CC)C>CN(C=O)C.CCOC(C)=O>[CH3:14][O:15][C:16](=[O:22])[CH:17]([NH:21][C:2](=[O:4])[C:1]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH2:6])[CH2:18][CH2:19][CH3:20]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: CCCC(N)C(=O)OC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCC(NC(=O)c1ccccc1N)C(=O)OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.9 %

Procedure:
To a mixture of isatoic anhydride (750 mg, 4.60 mmol) and 2-amino-pentanoic acid methyl ester hydrochloride (1.4 g, 8.35 mmol) (prepared according to example C), in DMF (10 mL) is added triethylamine (2.0 mL, 14.30 mmol). The mixture is stirred at room temperature for 16 hours. The reaction mixture is diluted with EtOAc (100 mL) and is washed with H2O (50 mL×3). The organic layer is dried over sodium sulfate, concentrated and the resulting residue is purified by flash chromatography with 35% EtOAc in Hexane as the eluent to afford the desired 2-(2-amino-benzoylamino)-pentanoic acid methyl ester (575 mg, 50%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[N:9][C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[C:7]2[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1.[C:25]1([CH:35]=O)[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[N:9][C:8]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[C:7]2[C:18]1[CH:19]=[C:20]([NH:24][CH2:35][C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=[CH:27][CH:26]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: O=Cc1cccc2ccccc12
Reactant: Nc1cccc(-c2c(-c3ccccc3)nnc3c(Cl)cccc23)c1
Product: Clc1cccc2c(-c3cccc(NCc4cccc5ccccc45)c3)c(-c3ccccc3)nnc12

Procedure:
The title compound was prepared from 3-(8-chloro-3-phenyl-cinnolin-4-yl)-phenylamine and naphthalene-1-carbaldehyde according to the procedure of Step 5 Example 6. MS (ES) m/z 473.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]2[NH:17][C:16](=[O:18])[O:15][C:14]([CH3:20])([CH3:19])[C:13]=2[CH:21]=1.[Cl:22][C:23]1[CH:24]=[C:25]([SH:30])[CH:26]=[CH:27][C:28]=1[Cl:29]>>[Cl:22][C:23]1[CH:24]=[C:25]([S:30][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]3[NH:17][C:16](=[O:18])[O:15][C:14]([CH3:20])([CH3:19])[C:13]=3[CH:21]=2)[CH:26]=[CH:27][C:28]=1[Cl:29]
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCCCCBr)cc21
Reactant: Sc1ccc(Cl)c(Cl)c1
Product: CC1(C)OC(=O)Nc2ccc(OCCCCCCSc3ccc(Cl)c(Cl)c3)cc21

Procedure:
Prepared analogously to Example 1 from 6-(6-bromohexyloxy)-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 3,4-dichlorothiophenol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5][NH2:6].[CH3:13][O:14][C:15]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:16]=1[CH:17]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>C(O)C>[CH3:13][O:14][C:15]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:16]=1[CH2:17][NH:6][CH2:5][C:4]1[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(CN)c(OC)c1
Reactant: COc1ccc(C=O)c(OC)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc(CNCc2ccc(OC)cc2OC)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2,4-dimethoxybenzylamine (8.98 mL) and 2,4-dimethoxybenzaldehyde (9.94 g) in ethanol (200 mL) was stirred at room temperature for 2 hr. To the reaction mixture was added sodium triacetoxyborohydride (20.3 g), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added water, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (8 g).
Reaction SMILES: [N:1]([CH:4]([CH3:19])[CH2:5][N:6]1[CH:10]=[CH:9][C:8]2[CH2:11][C:12]3[C:17]([C:7]1=2)=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)=[N+:2]=[N-:3].[CH:20](Br)([CH3:22])[CH3:21].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[N:1]([CH:4]([CH3:19])[CH2:5][N:6]1[CH:10]=[CH:9][C:8]2[CH2:11][C:12]3[C:17]([C:7]1=2)=[CH:16][C:15]([O:18][CH:20]([CH3:22])[CH3:21])=[CH:14][CH:13]=3)=[N+:2]=[N-:3]
Reactant: CC(C)Br
Reactant: CC(Cn1ccc2c1-c1cc(O)ccc1C2)N=[N+]=[N-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(Cn1ccc2c1-c1cc(OC(C)C)ccc1C2)N=[N+]=[N-]
Yield: 28 %

Procedure:
A solution of 1.05 g of (RS)-1-(2-azido-propyl)-7-hydroxy-1,4-dihydro-indeno[1,2-b]pyrrole, 0.77 ml of isopropyl bromide and 1.14 g of potassium carbonate in 30 ml of N,N-dimethyl-formamide was heated to 50° for 48 hours. After cooling, the solution was poured into 150 ml of water and extracted twice with 150 ml of ethyl acetate each time. The combined organic phases were washed once with 70 ml of semi-saturated sodium chloride solution, dried over magnesium sulfate and the solution was concentrated in a vacuum. The crude product was purified by column chromatography on silica gel (toluene). 0.35 g (28%) of (RS)-1-(2-azido-propyl)-7-iso-propoxy-1,4-dihydro-indeno[1,2-b]pyrrole was obtained as an orange oil which was used directly in the next reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([NH:11][C@H:12]([C:14]([OH:16])=[O:15])[CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1.[S:17]1[CH:21]=[CH:20][C:19]([CH2:22]O)=[CH:18]1>>[S:17]1[CH:21]=[CH:20][C:19]([CH2:22][O:15][C:14](=[O:16])[C@H:12]([CH3:13])[NH:11][C:9](=[O:10])[CH2:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)=[CH:18]1
Reactant: OCc1ccsc1
Reactant: C[C@H](NC(=O)Cc1cccc(Cl)c1)C(=O)O
Product: C[C@H](NC(=O)Cc1cccc(Cl)c1)C(=O)OCc1ccsc1

Procedure:
Following General Procedure C above, and using N-(3-chlorophenylacetyl alanine (from Example D above) and 3-thiophenemethanol (Aldrich) the title compound can be prepared. The reaction was monitored by tlc on silica gel and purification was by liquid chromatography using 3:7 EtOAc:hexane as the eluant.
Reaction SMILES: [CH2:1]([NH:4][C:5](=[O:13])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8](Br)[CH:7]=1)[CH2:2][CH3:3].[C:14]1(B(O)O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:1]([NH:4][C:5](=[O:13])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:7]=1)[CH2:2][CH3:3]
Reactant: OB(O)c1ccccc1
Reactant: CCCNC(=O)c1cccc(Br)c1
Product: CCCNC(=O)c1cccc(-c2ccccc2)c1
Yield: 96 %

Procedure:
Using Preparation Method 2, N-n-propyl-3-bromobenzamide from Example 1A was reacted with phenyl boronic acid. The resulting reaction mixture was purified using SiO2 with CH2Cl2 (100%) to CH2Cl2/MeOH 90:10 to give N-n-propyl-3-phenylbenzamide as a white solid (96%). NMR 1H (ppm, CDCl3): 7.97 (t, J4=1.53 Hz, 1H), 7.69 (dd, J3=7.91 Hz, J4=1.84 Hz, 2H), 7.61-7.58 (m, 2H), 7.51-7.24 (m, 4H), 6.17 (br. s., 1H), 3.47-3.40 (m, 2H), 1.65 (sext., J3=7.32 Hz, 2H), 0.98 (t, J3=7.38 Hz, 3H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][S:5]([CH2:8][CH:9]([O:30][CH3:31])[CH2:10][O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)(=[O:7])=[O:6].C(N(CC)CC)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>ClCCl>[CH3:31][O:30][CH:9]([CH2:10][O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH:24]1[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1)[CH2:8][S:5]([CH2:4][CH2:3][CH2:2][O:1][S:40]([CH3:39])(=[O:42])=[O:41])(=[O:7])=[O:6]
Reactant: CS(=O)(=O)Cl
Reactant: COC(COCCCCCCCCCCCCC1CCCCC1)CS(=O)(=O)CCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(COCCCCCCCCCCCCC1CCCCC1)CS(=O)(=O)CCCOS(C)(=O)=O
Yield: 100 %

Procedure:
In 100 ml of dichloromethane are dissolved 8.9 g of 2-methoxy-3-(12-cyclohexyldodecyloxy)propyl 3-hydroxypropyl sulfone and 3.7 ml of triethylamine, to which 3.0 g of methanesulfonyl chloride is added dropwise with stirring under ice cooling. After 2 hours stirring at room temperature, the reaction solution is washed with water, an aqueous sodium bicarbonate solution and water, and dried. The solvent is then distilled off under reduced pressure to leave 10.4 g of the captioned compound.
Reaction SMILES: [CH2:1]([CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][CH2:13][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22]CC2C=CC=CC=2)=[O:15])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].Cl.[OH-].[Na+].C(Cl)Cl.CO>CCO.[Pd]>[CH2:1]([CH:5]1[CH2:6][CH2:7][N:8]([CH2:11][CH2:12][CH2:13][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[OH:22])=[O:15])[CH2:9][CH2:10]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1CCN(CCCC(=O)c2ccccc2OCc2ccccc2)CC1
Agent: [Pd]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Solvent: CO
Product: CCCCC1CCN(CCCC(=O)c2ccccc2O)CC1
Temperature: 25 °C
Yield: 57.7 %

Procedure:
4-n-Butyl-1-[4-(2-hydroxyphenyl)-4-oxol-butyl]piperidine (27)-3 To a 25 mL reaction flask was added a solution of 4-n-Butyl-1-[4-(2-benzyloxyphenyl)-4-oxo-1-butyl]piperidine (26) (49 mg, 1.2 mmol) dissolved in dry EtOH (10 mL) and conc. HCl (0.1 mL) followed by addition of palladium on charcoal (40 mg). The reaction flask was then charged with H2 by the use of balloon technique and left stirring at rt over-night under H2 atmosphere. The reaction mixture was basified by addition of NaOH (2 mL, 2.0 M) and filtered through celite. The aqueous phase was extracted with ethyl acetate (3×50 mL) and the combined organic phases were washed with brine (10 mL) and NaOH (10 mL, 2 M), dried (MgSO4) and evaporated to dryness to produce 0.42 g of crude 27. The crude product was subjected to CC [eluent: : CH2Cl2: MeOH (99:1)] to give pure 27 (0.21 g, 58%); LC-MS [M+H]+ 303 (cald. 303.2).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]2=[N:8][C:9]([C:11]3[CH:12]=[CH:13][C:14]([C:24]([F:27])([F:26])[F:25])=[C:15]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[CH:16]=3)=[CH:10][N:4]2[N:3]=1.[CH3:28][NH2:29]>C1COCC1>[CH3:20][C:19]([CH3:22])([CH3:21])[C:18]([NH:17][C:15]1[CH:16]=[C:11]([C:9]2[N:8]=[C:5]3[N:4]([CH:10]=2)[N:3]=[C:2]([NH:29][CH3:28])[CH:7]=[CH:6]3)[CH:12]=[CH:13][C:14]=1[C:24]([F:27])([F:26])[F:25])=[O:23]
Reactant: CC(C)(C)C(=O)Nc1cc(-c2cn3nc(Cl)ccc3n2)ccc1C(F)(F)F
Reactant: CN
Solvent: C1CCOC1
Product: CNc1ccc2nc(-c3ccc(C(F)(F)F)c(NC(=O)C(C)(C)C)c3)cn2n1
Temperature: 80 °C
Yield: 35.1 %

Procedure:
A 8 mL vial is charged with N-[5-(6-chloroimidazo[2,1-f]pyridazin-2-yl)-2-(trifluoromethyl)phenyl]-2,2-dimethyl-propanamide (0.032 g, 0.08 mmol), THF (0.649 mL), and methylamine (0.08 mL, 2 M in THF, 0.16 mol). The mixture is stirred and heated to 80° C. for 16 hr. The mixture is concentrated onto celite and purified by silica gel chromatography (0-100% EtOAc in CH2Cl2) to give the title compound (11 mg, 35% yield). LCMS m/z=392.5 [M+H]+, tR=2.36 min. (compound same as Example 137)
Reaction SMILES: O.[NH2:2][NH2:3].[N:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][NH:13][C:14]([C:16]2[S:20][C:19]([C:21]([O:23]C)=O)=[CH:18][CH:17]=2)=[O:15])=[CH:6][CH:5]=1>CO>[N:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][NH:13][C:14]([C:16]2[S:20][C:19]([C:21]([NH:2][NH2:3])=[O:23])=[CH:18][CH:17]=2)=[O:15])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(C(=O)NCCCc2ccncc2)s1
Reactant: NN
Solvent: O
Solvent: CO
Product: NNC(=O)c1ccc(C(=O)NCCCc2ccncc2)s1
Reaction time: 95 h
Yield: 61 %

Procedure:
80% Hydrazine monohydrate (0.17 mL, 2.8 mmol) was added to methyl 5-[3-(pyridin-4-yl)propylcarbamoyl]thiophene-2-carboxylate (0.28 g, 0.92 mmol) in methanol (10 mL), and the reaction solution was left at 50° C. for 95 hours. After addition of 80% hydrazine monohydrate (0.17 mL, 2.8 mmol), it was left at 55° C. for another 14 hours and concentrated to dryness by evaporating the solvent under reduced pressure. Methanol (2 mL) was added to the residue, and the resulting solution was put on a sonicator. The precipitated solid was recovered by filtration and dried to give the desired product, 5-hydrazinocarbonylthiophene-2-carboxylic acid 3-(pyridin-4-yl)propylamide (yield 61%).
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([O:9][C:10]([F:13])([F:12])[F:11])[CH:6]=[CH:5][C:3]=1[NH2:4].SC1SC2C=C(OC(F)(F)F)C=CC=2N=1.[Cl:29][C:30]1[S:31]C2C=CC(Cl)=CC=2N=1>>[Cl:29][C:30]1[S:31][C:2]2[CH:8]=[C:7]([O:9][C:10]([F:13])([F:12])[F:11])[CH:6]=[CH:5][C:3]=2[N:4]=1
Reactant: Nc1ccc(OC(F)(F)F)cc1Br
Reactant: Clc1ccc2sc(Cl)nc2c1
Agent: FC(F)(F)Oc1ccc2nc(S)sc2c1
Product: FC(F)(F)Oc1ccc2nc(Cl)sc2c1
Temperature: 150 °C

Procedure:
The title compound was prepared from 2-bromo-4-trifluoromethoxyaniline via 2-mercapto-6-trifluoromethoxy-1,3-benzothiazole as described for 2,5-dichloro-1,3-benzothiazole except that in the first step the reaction mixture was heated to 150° C. for 16 h.
Reaction SMILES: [OH:1][CH:2]([C:15]1[CH:20]=[C:19]([C:21]23[CH2:30][CH:25]4[CH2:26][CH:27]([CH2:29][CH:23]([CH2:24]4)[CH2:22]2)[CH2:28]3)[C:18]([O:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH3:37])=[CH:17][C:16]=1[O:38][CH2:39][O:40][CH2:41][CH2:42][O:43][CH3:44])[C:3]#[C:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11]C)=[O:10])=[CH:7][CH:6]=1.[OH-].[Li+]>C1COCC1>[OH:1][CH:2]([C:15]1[CH:20]=[C:19]([C:21]23[CH2:30][CH:25]4[CH2:26][CH:27]([CH2:29][CH:23]([CH2:24]4)[CH2:22]2)[CH2:28]3)[C:18]([O:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH3:37])=[CH:17][C:16]=1[O:38][CH2:39][O:40][CH2:41][CH2:42][O:43][CH3:44])[C:3]#[C:4][C:5]1[CH:6]=[CH:7][C:8]([C:9]([OH:11])=[O:10])=[CH:13][CH:14]=1
Reactant: COCCOCOc1cc(OCOCCOC)c(C23CC4CC(CC(C4)C2)C3)cc1C(O)C#Cc1ccc(C(=O)OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COCCOCOc1cc(OCOCCOC)c(C23CC4CC(CC(C4)C2)C3)cc1C(O)C#Cc1ccc(C(=O)O)cc1

Procedure:
800 mg (1.3 mmol) of the above methyl ester (e), 340 mg (7.8 mmol) of lithium hydroxide and 50 ml of THF were introduced into a round-bottomed flask and the mixture was heated at reflux for twelve hours. It was evaporated to dryness, the residue was taken up in water, acidified to pH 1 and extracted with ethyl ether. The organic phase was separated out after settling had taken place, dried over magnesium sulfate and evaporated. The residue obtained was purified by chromatography on a column of silica, eluted with ethyl ether. 420 mg (54%) of 4-[3-hydroxy-3-[3-1-adamantyl)-2,4-di(methoxyethoxymethoxy)phenyl]-1-propynyl]benzoic acid, having a melting point of 79°-81° C., were recovered.
Reaction SMILES: [CH3:1][CH:2]([OH:16])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:5]([Cl:15])[CH:4]=1>CC(C)=O.S(=O)(=O)(O)O.[O-2].[O-2].[O-2].[Cr+6]>[Cl:15][C:5]1[CH:4]=[C:3]([C:2](=[O:16])[CH3:1])[CH:8]=[CH:7][C:6]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(O)c1ccc(-c2ccccc2)c(Cl)c1
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [O-2]
Solvent: CC(C)=O
Product: CC(=O)c1ccc(-c2ccccc2)c(Cl)c1

Procedure:
α-methyl-3-chloro-4-phenylbenzyl alcohol, 28.6 g, was dissolved in 36 ml of acetone. To the resulting solution was added dropwise, with cooling and vigorous agitation, a solution of 12 g of chromium trioxide in 42 ml of 35 percent aqueous sulfuric acid. A large volume of acetone then was added; the aqueous layer was separated and washed with acetone. The acetone layer and acetone extracts were combined and dried over anhydrous sodium sulfate. The acetone was evaporated and the residue was distilled in vacuo to give 26.3 g of 3'-chloro-4'-phenylacetophenone, bp 132°-141°C/0.09 mm. The following elemental analysis was obtained:
Reaction SMILES: [C:1]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[C:8]([C:17]#[N:18])=[N:9][C:10]([O:15]C)=[C:11]([O:13]C)[CH:12]=2)[CH:2]=1.B(Br)(Br)Br>C(Cl)Cl>[C:1]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:12]=[C:11]([OH:13])[C:10](=[O:15])[NH:9][C:8]=2[C:17]#[N:18])[CH:2]=1
Reactant: COc1cc(-c2cccc(-c3ccccc3)c2)c(C#N)nc1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Product: N#Cc1[nH]c(=O)c(O)cc1-c1cccc(-c2ccccc2)c1
Temperature: 50 °C
Reaction time: 21 h
Yield: 55.1 %

Procedure:
To a solution of 3-(biphenyl-3-yl)-5,6-dimethoxypyridine-2-carbonitrile (34 mg, 0.107 mmol) in CH2Cl2 (1 mL) was added BBr3 solution (1 M in CH2Cl2, 2.149 mL) and stirred at 50° C. for 21 h. The reaction mixture was concentrated and the residue was stirred in 3 N aqueous HCl. After 1 h, this mixture was concentrated and purified by preparative HPLC (5-60% CH3CN/H2O over 20 min, 0.05% added TFA) to give 17 mg (55%) of 3-(biphenyl-3-yl)-5-hydroxy-6-oxo-1,6-dihydropyridine-2-carbonitrile as a light pink solid. 1H NMR (400 MHz, CDCl3): δ 7.75-7.65 (m, 2H), 7.65-7.53 (m, 3H), 7.47 (t, J=8.0 Hz, 3H), 7.39 (t, J=7.6 Hz, 1H), 7.12 (s, 1H). LC/MS (M+H)+ 289.2.
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].Br[C:14]1[C:18](Br)=[CH:17][S:16][CH:15]=1.O>C(OCC)C.Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([C:14]1[C:18]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[CH:17][S:16][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCC[Mg]Br
Reactant: Brc1cscc1Br
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CCOCC
Product: CCCCCCCCCCc1cscc1CCCCCCCCCC
Yield: 76 %

Procedure:
Decylmagnesium bromide (140 mmol) was added dropwise at 0° C. to a mixture solution of 3,4-dibromothiophene (50 mmol) and [1,3-bis(diphenylphosphino)propane]dichloronickel(II) (0.3 mmol) in 100 mL of dry diethyl ether. The resulting mixture was heated and refluxed for 6 hours. The reaction mixture was combined with water, and extracted with diethyl ether. The extract solution was dried over magnesium sulfate, and the solvent was evaporated therefrom to obtain a crude product. The crude product was purified by silica gel column chromatography and by distillation to obtain the intended product (38 mmol) in a 76% yield.