Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][CH2:2][CH2:3][OH:4].[H-].[Na+].Cl[C:8]1[N:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:24])[CH:14]=2)[N:9]=1.O>CN(C=O)C>[Cl:24][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([S:1][CH2:2][CH2:3][OH:4])[N:17]=[C:16]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Clc1ccc2nc(Cl)nc(-c3ccccc3)c2c1
Reactant: OCCS
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: OCCSc1nc(-c2ccccc2)c2cc(Cl)ccc2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
To a solution of 86 mg of 2-mercaptoethanol in DMF (7.5 ml) was added 44 mg of sodium hydride (60%), followed by stirring at room temperature for 30 minutes. To the reaction mixture was added 275 mg of 2,6-dichloro-4-phenylquinazoline (compound No. Ia1-3), followed by stirring at room temperature for 2 hours. The reaction solution was poured into 100 ml of water and extracted with ethyl acetate. The resultant extract was concentrated. The resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:5) to obtain 266 mg of the titled compound. Mp.124.4° C. 1H NMR (CDCl3): 3.50 (2H, t, J=5.5 Hz), 3.64 (1H, br. t), 4.07 (2H, q-like, J=5.5 Hz), 7.57-7.61 (3H, m), 7.71-7.74 (2H, m), 7.77 (1H, dd, J=8.9, 2.3 Hz), 7.85 (1H, d, J=8.9 Hz), 7.97 (1H, d, J=2.3 Hz).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]#[CH:19])=[CH:14][CH:13]=1>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=[O:5])=[CH:14][CH:13]=1
Reactant: C#Cc1ccc(OC)cc1
Reactant: O=Cc1ccccc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: COc1ccc(C#Cc2ccccc2C=O)cc1
Temperature: 50 °C
Yield: 88.9 %

Procedure:
To a solution of 2-bromobenzaldehyde (1.85 g, 10 mmol) and 4-methoxyphenyl acetylene (1.58 g, 12 mmol) in 40 mL of triethylamine were added dichlorobis(triphenylphosphine)palladium(II) (140 mg, 2 mol %) and copper (I) iodide (20 mg, 1 mol %). The reaction mixture was heated at 50° C. under nitrogen for 3 h. The reaction mixture was cooled to room temperature and the ammonium salt was removed by filtration. The filtrate was concentrated under reduced pressure. Purification of the crude compound by column chromatography (silica gel 230-400 mesh; 10% ethyl acetate in hexanes as eluent) afforded 2-(4-methoxyphenylethynyl)benzaldehyde (2.1 g, 89%). The above compound (2.06 g, 8.73 mmol) and t-butylamine (3.83 g, 52.4 mmol) were stirred under nitrogen for 24 h at room temperature. The resulting mixture was extracted with ether and the organic layer was dried over anhydrous Na2SO4, and concentrated to give the imine (2.4 g, 94%), which was used in the next step without further purification. To a solution of the above imine (2.39 g, 8.2 mmol) in 100 mL anhydrous DMF was added (0.156 g, 0.82 mmol) copper (I) iodide, and the solution was flushed with nitrogen. The reaction mixture was heated at 100° C. for 4 h. The mixture was cooled to room temperature, and diluted with ether (200 mL). The organic layer was washed with saturated aqueous ammonium chloride (3×100 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated to give the crude compound as a dark colored solid. Purification by column chromatography (silica gel 230-400 mesh; 10% ethylacetate in hexanes as eluent) afforded 3-(4-methoxyphenyl)isoquinoline (1.064 g, 55%), as a white solid. The 3-(4-methoxyphenyl)isoquinoline (1.05 g, 4.47 mmol) was suspended in 30 mL hydroiodic acid and 12 mL of acetic acid was added. The reaction mixture was stirred at 110° C. for 2 h, then cooled to room temperature. The precipitate formed was filtered off, washed with acetic acid (2×5 mL) and dried under vacuum, to give a yellow solid. The crude compound was purified by triturating with 5% methanol in ether to give 4-isoquinolin-3-yl-phenol (0.83 g, 84%) as a white powder. Selected data: MS (ES) m/z: 222.89, 221.86; MP 218-219° C.
Reaction SMILES: [NH3:1].[Br:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11].BrCC1C=CC(S(Cl)(=O)=O)=CC=1>O1CCCC1>[Br:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH2:1])(=[O:12])=[O:11]
Reactant: N
Reactant: O=S(=O)(Cl)c1ccccc1CBr
Agent: O=S(=O)(Cl)c1ccc(CBr)cc1
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccccc1CBr

Procedure:
A solution of ammonia (1.0 ml) in tetrahydrofuran (50 ml) at -78° was contacted dropwise with a solution of a 60/40 mixture of 2-(bromomethyl)benzenesulfonyl chloride/4-(bromomethyl)benzenesulfonyl chloride (4.52 g) in tetrahydrofuran (20 ml). The stirred mixture was allowed to warm to 0° and volatiles were removed in vacuo. The residue was contacted with water (50 ml) and extracted three times with ethyl acetate. Combined organic portions were washed with brine, dried, and evaporated to give 4.00 g of white solid.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][C@@H:4]1[N:8]1[C:12](=[O:13])[C:11]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:10]2[C:9]1=[O:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:38]([C:47]1[CH:52]=[CH:51][C:50](O)=[CH:49][CH:48]=1)([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)([CH3:40])[CH3:39].N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:40][C:38]([C:41]1[CH:46]=[CH:45][C:44]([O:1][CH2:2][C@@H:3]2[CH2:7][CH2:6][CH2:5][C@@H:4]2[N:8]2[C:9](=[O:18])[C:10]3=[CH:17][CH:16]=[CH:15][CH:14]=[C:11]3[C:12]2=[O:13])=[CH:43][CH:42]=1)([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[CH3:39]
Reactant: O=C1c2ccccc2C(=O)N1[C@H]1CCC[C@H]1CO
Reactant: CC(C)(c1ccccc1)c1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(c1ccccc1)c1ccc(OC[C@@H]2CCC[C@@H]2N2C(=O)c3ccccc3C2=O)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 26.8 %

Procedure:
To an ice cold solution of (±) cis-1-hydroxymethyl-2-phthalimidocyclopentane (1.0 g, 4.08 mmol), triphenylphosphine (1.28 g, 4.9 mmol) and 4-cumylphenol (1.04 g, 4.9 mmol) in dry tetrahydrofuran (40 ml) was added diethyl azodicarboxylate (0.77 ml, 4.9 mmol). The mixture was allowed to warm to room temperature and stirred for 48 h. The reaction was poured into ice water (200 ml) and extracted into diethyl ether (3×100 ml). The combined extracts were washed with brine, dried over sodium sulfate and concentrated in vacuo. The resulting crude product was purified by chromatography on a silica gel column eluting with 10-40% diethyl ether in petroleum ether 40-60. Pooling of pure fractions afforded the title compound as a colourless oil (0.48 g). Additional fractions afforded a further 0.76 g of product which was slightly contaminated with 4-cumylphenol.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-])=O)=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([CH3:14])[CH2:10][CH2:9]2)[CH:7]=1.[Cl-].[NH4+].CCO>[Fe].O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:15])=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([CH3:14])[CH2:10][CH2:9]2)[CH:7]=1
Reactant: CC1CCN(c2cc(Br)ccc2[N+](=O)[O-])CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CC1CCN(c2cc(Br)ccc2N)CC1
Temperature: 80 °C
Yield: 90.1 %

Procedure:
A flask charged with 1-(5-bromo-2-nitro-phenyl)-4-methyl-piperidine (1.0 g, 3.3 mmol) (as prepared in the previous step), ammonium chloride (1.8 g, 33 mmol), iron powder (0.93 g, 16 mmol), EtOH (12 mL) and water (6 mL) was heated at 80° C. for 1 h. The reaction was filtered though Celite, concentrated and eluted from a 20-g SPE cartridge (silica) with 100% DCM to give 0.80 g (91%) of the title compound as a yellow oil. Mass spectrum (ESI, m/z): Calcd. for C12H17BrN2, 269.1/271.1 (M+H), found 269.1/271.1.
Reaction SMILES: [C:1]([O:9][CH:10]1[CH:17]2[CH:13]([C:14](=[O:18])[NH:15][CH2:16]2)[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1C2C(NC(=O)C2)CC1)(=O)C1C=CC=CC=1.[H-].[Na+].Br[CH2:40][C:41]1[CH:48]=[CH:47][C:44]([C:45]#[N:46])=[C:43]([Cl:49])[C:42]=1[CH3:50]>C1COCC1.CN(C=O)C>[C:1]([O:9][CH:10]1[CH:17]2[CH:16]([N:15]([CH2:40][C:41]3[CH:48]=[CH:47][C:44]([C:45]#[N:46])=[C:43]([Cl:49])[C:42]=3[CH3:50])[C:14](=[O:18])[CH2:13]2)[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OC1CCC2C(=O)NCC12)c1ccccc1
Reactant: Cc1c(CBr)ccc(C#N)c1Cl
Agent: O=C1CC2C(CCC2OC(=O)c2ccccc2)N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1c(CN2C(=O)CC3C(OC(=O)c4ccccc4)CCC32)ccc(C#N)c1Cl
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a solution containing mixtures of compound 1I and 1J (170 mg, 0.69 mmol, different batch than previous lot in example 1) in anhydrous THF (4 mL) and anhydrous DMF (4 mL) was added sodium hydride (27.7 mg, 0.69 mmol) at 0° C., and stirred at 0° C. for 45 min. Compound 7C (169 mg, 0.69 mmol) was added at 0° C., the ice-water bath was removed, and the stirring was continued between 0° C. to RT for 2 hr before it was quenched with saturated NH4Cl solution. The mixture was diluted with EtOAc, organic layer was separated, washed with water, dried over MgSO4, and concentrated. Purification by silica gel chromatography (30-100% EtOAc in hexanes) provide the title compound 7D (90 mg) and 7E (151 mg). Compound 7D: (ES) m/z 409 [M+H]+. Compound 7E: (ES) m/z 409 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:16][CH2:15][NH:14][C:13](=O)[CH2:12]1)=[O:10].F[B-](F)(F)F.C[O+](C)C.[CH3:27][C:28]1[S:32][CH:31]=[N:30][C:29]=1[C:33]([NH:35][NH2:36])=O>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:16][CH2:15][N:14]2[C:33]([C:29]3[N:30]=[CH:31][S:32][C:28]=3[CH3:27])=[N:35][N:36]=[C:13]2[CH2:12]1)=[O:10]
Reactant: Cc1scnc1C(=O)NN
Reactant: O=C1CN(C(=O)c2ccc(Cl)cc2Cl)CCN1
Agent: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: Cc1scnc1-c1nnc2n1CCN(C(=O)c1ccc(Cl)cc1Cl)C2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-[(2,4-Dichlorophenyl)carbonyl]-2-piperazinone (I6) (0.250 g, 0.915 mmol) was suspended in dry Dichloromethane (DCM) (3 mL) before treating with trimethyloxonium tetrafluoroborate (0.171 g, 1.098 mmol) and stirring for 16 hours at RT, under argon before adding 5-methyl-1,3-thiazole-4-carbohydrazide (I123)(0.216 g, 1.373 mmol) and stirring for a further 3 hours. DCM was removed by evaporation and the residue was dissolved in 1-butanol (3.00 mL) before heating at 110° C. for 19 hours. 3 Å molecular sieves were added and the reaction mixture was left heating for a further 6 hours before being cooled to RT over the weekend. The reaction was worked up by diluting with DCM (50 ml) and washing with saturated sodium bicarbonate solution (50 ml). The aqueous layer was extracted with DCM (2×30 ml), combined extracts were washed with brine (30 ml), dried (MgSO4), filtered and evaporated to afford a brown gum. The product was purified by MDAP (formic acid method), the desired fraction isolated and the solvent evaporated to afford a colourless gum. Placed in a registration vial and dried overnight to afford an off white foam of desired product in 122 mg.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].[CH3:14][NH:15][S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21](Br)[CH:20]=1)(=[O:18])=[O:17]>CN(C=O)C.[Cu]I>[CH3:14][NH:15][S:16]([C:19]1[CH:20]=[C:21]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:22]=[CH:23][CH:24]=1)(=[O:18])=[O:17]
Reactant: Oc1ccccc1
Reactant: CNS(=O)(=O)c1cccc(Br)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CNS(=O)(=O)c1cccc(Oc2ccccc2)c1
Yield: 11.4 %

Procedure:
To a slurry of phenol (1.9 g, 20 mmol), K2CO3 (6.0 g, 40 mmol), and CuI (4 g, 20 mmol) in DMF (25 mL) was added N-methyl-3-bromobenzenesulfonamide (2.5 g, 10 mmol), and the resulting mixture was stirred at the reflux temp. overnight, cooled to room temp., and separated between EtOAc (50 mL) and a 1 N HCl solution (50 mL). The aqueous layer was back-extracted with EtOAc (2×50 mL). The combined organic phases were sequentially washed with water (2×50 mL) and a saturated NaCl solution (50 mL), dried (MgSO4), and concentrated under reduced pressure. The residual oil was purified by column chromatography (30% EtOAc/70% hexane) to give 4-(3-(N-methylsulfamoyl)phenyloxy)benzene (0.30 g). Step 3. Synthesis of 4-(3-(N-methylsulfamoyl)phenyloxy)-1-nitrobenzene
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([OH:14])=[O:13])=[CH:6]2.Br[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH-].[K+]>CN(C)C=O.[Cu]=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:7]([C:12]([OH:14])=[O:13])=[CH:6]2
Reactant: COc1ccc2[nH]c(C(=O)O)cc2c1
Reactant: Brc1ccccc1
Agent: O=[Cu]
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)cc(C(=O)O)n2-c1ccccc1
Temperature: 0 °C
Yield: 97 %

Procedure:
A mixture of 60.0 g (0.32 mole) of 5-methoxy-1H-indole-2-carboxylic acid, 35.0 ml (52.2 g; 0.32 mole) of bromobenzene, 36.0 g (0.64 mole) of potassium hydroxide, and 10.0 g (0.13 mole) of copper (II) oxide in 750 ml of N,N-dimethylformamide was stirred and heated at reflux under a nitrogen atmosphere for six hours. The cooled reaction mixture was added to 1.5 kg of ice/water and filtered through a bed of Celite filter-aid. Acidification of the filtrate with dilute hydrochloric acid precipitated the product. The solid was filtered and washed with water to yield 83.0 g (95% yield) of crude acid product. A sample recrystallized from ether/hexane was analytically pure, mp 197°-204° C.
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(O)=O.[Na+].[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([C:37]2[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=2)[N:17]2[CH2:22][CH2:21][N:20]([S:23]([C:26]3[CH:31]=[CH:30][C:29](/[CH:32]=[CH:33]/[C:34](Cl)=[O:35])=[CH:28][CH:27]=3)(=[O:25])=[O:24])[CH2:19][CH2:18]2)=[CH:12][CH:11]=1>O1CCCC1.O>[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([C:37]2[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=2)[N:17]2[CH2:22][CH2:21][N:20]([S:23]([C:26]3[CH:31]=[CH:30][C:29](/[CH:32]=[CH:33]/[C:34]([NH:2][OH:3])=[O:35])=[CH:28][CH:27]=3)(=[O:25])=[O:24])[CH2:19][CH2:18]2)=[CH:12][CH:11]=1
Reactant: NO
Reactant: O=C(Cl)/C=C/c1ccc(S(=O)(=O)N2CCN(C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(/C=C/c1ccc(S(=O)(=O)N2CCN(C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)cc1)NO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33.7 %

Procedure:
To a suspension of hydroxylamine hydrochloride (0.18 g, 2.5 mmol) in tetrahydrofuran (5.0 mL) a solution of NaHCO3 (0.30 g, 3.5 mmol) in water (5 mL) was added and the resultant mixture was stirred at ambient temperature for 5 minutes. The reaction mixture was added to a solution of (E)-3-[4-({4-[bis(4-fluorophenyl)methyl]-1-piperazinyl}sulfonyl)phenyl]-2-propenoyl chloride (10b) (0.26 g) in tetrahydrofuran (5 mL) and the obtained mixture was stirred at ambient temperature for 0.5 hours. The mixture was poured into water (25 mL), extracted with ethyl acetate, the extract was washed with water, brine, and dried (Na2SO4). The solvent was removed and the residue was chromatographed on silica gel with chloroform—isopropanol (9:1) as eluent to give the title compound (0.087 g, 34%). M.p. 125-126° C. 1H NMR (DMSO-de, HMDSO), δ: 2.26-2.42 (4H, m); 2.81-3.00 (4H, m); 4.39 (1H, s); 6.64 (1H, d, J=15.8 Hz); 7.07 (4H, t, J=8.6 Hz); 7.37 (4H, dd, J8.4 and 5.6 Hz); 7.57 (1H, d, J=15.8 Hz); 7.74 (2H, d, J=8.0 Hz); 7.83 (2H, d, J=8.0 Hz); 9.19 (1H, s); 10.93 (1H, s). HPLC analysis on Alltima C18 column: impurities 2% (column size 4.6×150 mm; mobile phase acetonitrile−0.1M phosphate buffer (pH 2.5), 70:30; sample concentration 1.0 mg/ml; flow rate 1.0 ml/min; detector: UV 215 nm). Anal. Calcd for C26H25F2N3O4S*0.3 Et20*0.2 iso-PrOH*0.1 CHCl3 (an exhaustively dried material contains all the indicated traces of solvents (PMR)), %: C, 59.87; H, 5.35; N, 7.51; S, 5.73. Found, %: C, 59.85; H, 5.36; N, 7.29; S, 5.60.
Reaction SMILES: [CH2:1]([C:3]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][NH:5][N:4]=1)[CH3:2].[CH3:12][O:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1.N1C=CC=CC=1>CN(C)C(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:1]([C:3]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][N:5]([C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([O:13][CH3:12])[CH:19]=2)[N:4]=1)[CH3:2]
Reactant: CCc1n[nH]cc1C(=O)OC
Reactant: COc1cccc(B(O)O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CC(=O)N(C)C
Solvent: c1ccncc1
Product: CCc1nn(-c2cccc(OC)c2)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.5 %

Procedure:
Methyl 3-ethyl-1H-pyrazole-4-carboxylate (2.5 g) synthesized in Example 39(1) was dissolved in N,N-dimethylacetamide (50 mL), 3-methoxyphenylboronic acid (5.0 g), copper acetate (6.0 g) and pyridine (5.3 mL) were added, and the mixture was stirred at room temperature overnight. The reaction mixture was filtered through celite, 1N hydrochloric acid (50 mL) was added to the filtrate, and the mixture was extracted with diethyl ether. The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2, volume ratio) to give the title object compound (2.3 g, 54%) as a pale-yellow oil.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([F:25])([F:24])[C:14]([F:23])([F:22])[C:15]([F:21])([F:20])[C:16]([F:19])([F:18])[F:17].[P:26]([O:33]CC)([O:30][CH2:31][CH3:32])[O:27][CH2:28][CH3:29]>>[CH2:28]([O:27][P:26]([CH:12]([C:13]([F:25])([F:24])[C:14]([F:23])([F:22])[C:15]([F:21])([F:20])[C:16]([F:19])([F:18])[F:17])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH3:2])([O:30][CH2:31][CH3:32])=[O:33])[CH3:29]
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)CCCCCCCCCCCBr
Reactant: CCOP(OCC)OCC
Product: CCCCCCCCCCC(C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)P(=O)(OCC)OCC
Temperature: 150 °C
Reaction time: 18 h
Yield: 94.9 %

Procedure:
A mixture of 15.03 g of 1-bromo-11-(nonafluorobutyl)undecane and 15.00 g of triethyl phosphite was heated at 150° C. After 18 hr, an additional 9.00 g of triethyl phosphite was added, and heating was continued for 24 hr. Diethyl ethylphosphonate and other volatiles were removed by distillation, b.p. 30-50° C. at 0.05 torr (7 Pa). Bulb-to-bulb distillation of the concentrate provided 16.07 g of 1-(diethylphosphono)-1-(nonafluorobutyl)undecane as a clear, colorless liquid, b.p. 170-200° C. at 0.05 torr (7 Pa).
Reaction SMILES: Cl[C:2]1[C:3](=[O:17])[N:4]([CH2:15][CH3:16])[S:5](=[O:14])(=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH:18]1[CH:22]=[C:21]([CH2:23][CH2:24][NH2:25])[N:20]=[CH:19]1>>[CH2:15]([N:4]1[C:3](=[O:17])[C:2]([NH:25][CH2:24][CH2:23][C:21]2[N:20]=[CH:19][NH:18][CH:22]=2)=[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[S:5]1(=[O:14])=[O:13])[CH3:16]
Reactant: CCN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: NCCc1c[nH]cn1
Product: CCN1C(=O)C(NCCc2c[nH]cn2)=C(c2ccccc2)S1(=O)=O

Procedure:
The title compound was prepared from 4-chloro-2-ethyl-5-phenylisothiazol-3(2H)-one 1,1-dioxide and 2-(1H-imidazol-4-yl)ethanamine in a similar manner as described for Example 1. 1H NMR (500 MHz, CD3OD): δ 7.54-7.42 (m, 6H), 6.51-6.48 (m, 1H), 3.71 (q, 2H), 3.14 (t, 2H), 2.55 (t, 2H), 1.36 (t, 3H); 13C NMR (125 MHz, CD3OD): δ 159.9, 137.3, 136.1, 132.9, 132.3, 130.6, 129.7, 126.9, 117.2, 107.2, 44.6, 36.0, 27.8, 14.0; Mass Spectrum: M+H+ 347.
Reaction SMILES: F[C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[CH:6][C:7]=1[I:8].O.[NH2:12][NH2:13]>C(O)CCC>[I:8][C:7]1[CH:6]=[CH:5][N:4]=[C:3]2[C:9]([NH2:10])=[N:12][NH:13][C:2]=12
Reactant: N#Cc1nccc(I)c1F
Reactant: NN
Solvent: O
Solvent: CCCCO
Product: Nc1n[nH]c2c(I)ccnc12
Temperature: 105 °C

Procedure:
3-Fluoro-4-iodopicolinonitrile (25.6 g) was dissolved in n-butan-1-ol (250 mL) then hydrazine hydrate (100%, 23.3 mL) was added. The reaction was heated at 105° C. for 2 hours. The reaction mixture was cooled to room temperature, filtered, rinsed with water, and dried for 30 minutes under vacuum to give 7-iodo-1H-pyrazolo[4,3-b]pyridine-3-amine (25 g) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 5.35-5.55 (2H, m) 7.73-7.74 (1H, m) 7.939-7.94 (1H, m). MS [M+H] found 261.0.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:19])[N:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[N:5]=[CH:6][C:7]=1Cl.[CH3:20][NH:21][NH2:22].O>CO>[Cl:1][C:2]1[C:3](=[O:19])[N:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[N:5]=[CH:6][C:7]=1[N:21]([CH3:20])[NH2:22]
Reactant: O=c1c(Cl)c(Cl)cnn1-c1cccc(C(F)(F)F)c1
Reactant: CNN
Solvent: O
Solvent: CO
Product: CN(N)c1cnn(-c2cccc(C(F)(F)F)c2)c(=O)c1Cl
Temperature: 45 °C

Procedure:
To a solution consisting of 15.5 grams of 4,5-dichloro-2-(3-trifluoromethylphenyl)-pyridazine-3(2H)-one in 120 grams of methanol is added 9.2 grams methylhydrazine. The reaction mixture is heated to 45° C for three hours, cooled and poured onto 250 grams of water. The resulting precipitate is separated by filtration, washed with water and dried. The solid is crystallized from benzene to yield 4-chloro-2-(3-trifluoromethylphenyl)-5-(1-methylhydrazino)-pyridazin-3(2H)-one (m.p. 140° to 141° C, with decomposition).
Reaction SMILES: [CH:1]([C@H:3]1[CH2:7][O:6][C:5]([CH3:9])([CH3:8])[N:4]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:2].[CH3:17][Mg]Br>C1COCC1>[OH:2][CH:1]([C@H:3]1[CH2:7][O:6][C:5]([CH3:9])([CH3:8])[N:4]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH3:17]
Reactant: C[Mg]Br
Reactant: CC(C)(C)OC(=O)N1[C@@H](C=O)COC1(C)C
Solvent: C1CCOC1
Product: CC(O)[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.3 %

Procedure:
To a solution of (R)-tert-butyl 4-formyl-2,2-dimethyloxazolidine-3-carboxylate (Intermediate 182, 10.18 g, 44.40 mmol) in THF (188 mL) at −78° C. was added methyl magnesium bromide (16.28 mL, 48.84 mmol) dropwise. The reaction mixture was allowed to warm to room temperature and stir overnight under nitrogen atmosphere. Re-cooled reaction mixture to −78° C. and added dropwise additional 13 mL (0.9 eq, to bring total to 2 eq) of methyl magnesium bromide. Allowed reaction mixture to stir at −78° C. for 3 hours and warm to room temperature. The reaction mixture was quenched with water and diluted with ethyl acetate saturated sodium chloride (brine). The resulting emulsion was filtered thru celite and the layers separated. The organic layers were dried over magnesium sulfate, filtered, concentrated. Silica gel chromatography (0%-20% ethyl acetate/hexanes) afforded the title compound as a colorless oily solid (8.42 g, 77%).
Reaction SMILES: C1(S(O[CH:11]2[CH2:24][N:23]3[C:14](=[N:15][C:16]4[C:21]([C:22]3=[O:25])=[CH:20][CH:19]=[C:18]([Br:26])[CH:17]=4)[CH2:13][CH2:12]2)(=O)=O)C=CC=CC=1.[CH3:27][NH:28][CH3:29]>C(#N)C.O>[Br:26][C:18]1[CH:17]=[C:16]2[C:21]([C:22](=[O:25])[N:23]3[CH2:24][CH:11]([N:28]([CH3:29])[CH3:27])[CH2:12][CH2:13][C:14]3=[N:15]2)=[CH:20][CH:19]=1
Reactant: O=c1c2ccc(Br)cc2nc2n1CC(OS(=O)(=O)c1ccccc1)CC2
Reactant: CNC
Solvent: CC#N
Solvent: O
Product: CN(C)C1CCc2nc3cc(Br)ccc3c(=O)n2C1
Temperature: 25 °C

Procedure:
A solution of 3-bromo-11-oxo-7,8,9,11-tetrahydro-6H-pyrido[2,1-b]quinazolin-8-yl benzenesulfonate (0.15 g, 0.34 mmol, 1 equiv) and excess aq. dimethylamine in acetonitrile (6 mL) was stirred at 70° C. for 3 hours. After it was cooled to rt, the reaction mixture was diluted with water and extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over Na2SO4. After filtration and concentration, the residue was purified by silica gel chromatography to give the desired product.