Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([CH2:17][C@@H:18]([OH:29])[CH2:19][C@@H:20]2[OH:28])=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].[OH2:30].[BH4-].[Na+]>O1CCCC1>[OH:28][C@@H:20]1[C@@:21]2([CH3:22])[C:16](=[CH:15][CH2:14][C@@H:13]3[C@@H:23]2[CH2:24][CH2:25][C@@:26]2([CH3:27])[C@H:12]3[CH2:11][CH2:10][C@@H:9]2[C@H:7]([CH3:8])[CH2:6][CH2:5][CH2:4][C:2]([OH:30])([CH3:3])[CH3:1])[CH2:17][C@@H:18]([OH:29])[CH2:19]1
Reactant: O
Reactant: CC(C)=CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@H](CCCC(C)(C)O)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 2 h
Yield: 85 %

Procedure:
To a cooled, stirred solution of 4.05 g (10.1 mmol) of cholesta-5,24-diene-1α,3β-diol in 53 ml of tetrahydrofuran in an ice bath was added 33 ml of water followed by 4.0 g (12.5 mmol) of mercuric acetate. The bath was removed. After 2 hr., the reaction was still incomplete (tlc) so 0.4 g (1.3 mmol) of mercuric acetate was added. After 4 hr., 800 mg (21.1 mol) of sodium borohydride was added, followed after 30 min. by 190 ml of saturated brine and extraction of the resulting suspension with 5×50 ml of methylene chloride. The organic phases were backwashed with 20 ml of brine, dried (Na2SO4), filtered and evaporated. The residue was chromatographed on 400 g of silica gel. Elution with 5% methanol--chloroform and combination of fractions according to tlc (10% methanol--chloroform) afforded 3.60 g (85%) of 1α,25-dihydroxycholesterol, mp 165°- 167° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[CH2:11][CH2:10][C:9]2[N:8]=[CH:7][N:6]=[C:5]([N:12]3[CH2:18][C:17]4[CH:19]=[C:20]([C:23]5[CH:24]=[C:25]([NH2:30])[C:26]([NH2:29])=[N:27][CH:28]=5)[CH:21]=[CH:22][C:16]=4[O:15][CH2:14][CH2:13]3)[C:4]=2[CH2:3]1.C(N(CC)CC)C.[C:39](Cl)(=[O:43])[CH2:40][CH2:41][CH3:42]>O1CCCC1>[NH2:29][C:26]1[C:25]([NH:30][C:39](=[O:43])[CH2:40][CH2:41][CH3:42])=[CH:24][C:23]([C:20]2[CH:21]=[CH:22][C:16]3[O:15][CH2:14][CH2:13][N:12]([C:5]4[C:4]5[CH2:3][C:2]([CH3:31])([CH3:1])[CH2:11][CH2:10][C:9]=5[N:8]=[CH:7][N:6]=4)[CH2:18][C:17]=3[CH:19]=2)=[CH:28][N:27]=1
Reactant: CC1(C)CCc2ncnc(N3CCOc4ccc(-c5cnc(N)c(N)c5)cc4C3)c2C1
Reactant: CCCC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCC(=O)Nc1cc(-c2ccc3c(c2)CN(c2ncnc4c2CC(C)(C)CC4)CCO3)cnc1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-[4-(6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-4-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]pyridine-2,3-diamine (32 mg, 0.077 mmol) and triethylamine (11 uL, 0.077 mmol) in tetrahydrofuran (1 mL) was add butyryl chloride (7.0 uL, 0.077 mmol), and the resulting mixture was stirred at room temperature for one hour. The reaction mixture was concentrated to give N-{2-amino-5-[4-(6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-4-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]pyridin-3-yl}butanamide crude product (50 mg). MS (EI) for C28H34N6O2: 487 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:30][CH3:31])=[CH:5][C:6]2[C:15]3[C:10](=[C:11]4[C:19]([N+:20]([O-])=O)=[CH:18][CH:17]=[CH:16][C:12]4=[N:13][CH:14]=3)[N:9]([CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[C:8](=[O:28])[C:7]=2[CH:29]=1>C(O)C.[Ni].O.NN>[NH2:20][C:19]1[C:11]2[C:12](=[N:13][CH:14]=[C:15]3[C:10]=2[N:9]([CH2:23][CH2:24][N:25]([CH3:26])[CH3:27])[C:8](=[O:28])[C:7]2[CH:29]=[C:3]([O:2][CH3:1])[C:4]([O:30][CH3:31])=[CH:5][C:6]3=2)[CH:16]=[CH:17][CH:18]=1
Reactant: COc1cc2c(=O)n(CCN(C)C)c3c(cnc4cccc([N+](=O)[O-])c43)c2cc1OC
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: O
Product: COc1cc2c(=O)n(CCN(C)C)c3c(cnc4cccc(N)c43)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of compound 3d (37 mg, 0.088 mmol) in ethanol (8 mL) was added 1 pinch of Raney Nickel and 5 drops of hydrazine hydrate, and the mixture was stirred at ambient temperature for 2 h. The mixture was filtered through Celite and the filtrate was evaporated. The residue was dissolved in chloroform (25 mL) and washed with brine (25 mL), dried (MgSO4), and evaporated, giving 28 mg (81%) as a yellow solid; mp 239-241° C.; 1H NMR (CDCl3) δ 1.80 (s, 6H), 2.10 (m, 2H), 4.05 (s, 3H), 4.13 (s, 3H), 4.48 (m, 3H), 5.07 (m, 1H), 6.79 (dd, 1H, J=6.3, J=2.5), 7.52 (m, 2H), 7.64 (s, 1H), 7.87 (s, 1H), 9.38 (s, 1H); 13C NMR (CDCl3) δ 45.1, 50.5, 56.3, 56.4, 57.4, 102.0, 109.1, 109.6, 111.3, 112.6, 118.7, 119.5, 127.7, 130.0, 141.0, 142.6, 144.8, 149.8, 150.0, 154.3, 164.5; HRMS calcd for C22H24O3N4H: 393.1927; found: 393.1925.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:9]=[C:8]([CH2:10]I)[N:7]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:6]=1)=[O:4].[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>CO>[CH3:1][O:2][C:3]([C:5]1[N:9]=[C:8]([CH2:10][N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[N:7]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:6]=1)=[O:4]
Reactant: COC(=O)c1nc(CI)n(-c2ccc(Cl)cc2C(=O)c2ccccc2)n1
Reactant: C1COCCN1
Solvent: CO
Product: COC(=O)c1nc(CN2CCOCC2)n(-c2ccc(Cl)cc2C(=O)c2ccccc2)n1

Procedure:
A mixture of 8.8 g (0.018 mole) of 1-(2-benzoyl-4-chlorophenyl)-5-(iodomethyl)-1H-1,2,4-triazole-3-carboxylic acid methyl ester and 3.5 ml (0.040 mole) of morpholine are stirred in 175 ml of methanol at 40° for 6 hours. The reaction mixture is thereupon concentrated in vacuo, water is added to the residue, and extraction is performed twice with methylene chloride. The organic phase is washed three times with water and once with saturated sodium chloride solution; it is dried over sodium sulphate and concentrated in vacuo. The residue is triturated with ether, whereupon the reaction product is obtained in crystalline form. After filtration with suction and drying in vacuo, there is obtained 1-(2-benzoyl-4-chlorophenyl)-5-(morpholinomethyl)-1H-1,2,4-triazole-3-carboxylic acid methyl ester, m.p. 165°-170°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12](O)[CH3:13])[CH2:11][O:10]1.[CH3:15][C:16]1[N:17]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]([F:35])([F:34])[CH:31]([F:33])[F:32])=[CH:24][CH:23]=2)[C:18](=[O:21])[NH:19][N:20]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([O:10][CH2:11]1)[C@H:12]([N:19]1[C:18](=[O:21])[N:17]([C:22]2[CH:23]=[CH:24][C:25]([O:28][CH2:29][C:30]([F:34])([F:35])[CH:31]([F:32])[F:33])=[CH:26][CH:27]=2)[C:16]([CH3:15])=[N:20]1)[CH3:13]
Reactant: Cc1n[nH]c(=O)n1-c1ccc(OCC(F)(F)C(F)F)cc1
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Product: Cc1nn([C@H](C)[C@@]2(c3ccc(F)cc3F)CO2)c(=O)n1-c1ccc(OCC(F)(F)C(F)F)cc1
Yield: 46.2 %

Procedure:
In the same manner as in Reference Example 5, starting from 0.50 g of (1S)-1-[(2R)-(2,4-difluorophenyl)-2-oxiranyl]ethanol and 0.61 g of 5-methyl-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-3(2H,4H)-1,2,4-triazolone, 0.45 g of 2-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-5-methyl-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-3(2H,4H)-1,2,4-triazolone was obtained as a colorless oil.
Reaction SMILES: [H-].[Na+].CN(C)P(N(C)C)(N(C)C)=O.[C:14]([O:22][CH2:23][CH3:24])(=[O:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].[Br:25][C:26]1[CH:31]=[CH:30][C:29](I)=[CH:28][CH:27]=1>O1CCOCC1.[Cu]Br>[Br:25][C:26]1[CH:31]=[CH:30][C:29]([CH:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:14]([O:22][CH2:23][CH3:24])=[O:21])=[CH:28][CH:27]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Brc1ccc(I)cc1
Agent: [Cu]Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1COCCO1
Product: CCOC(=O)C(C(=O)OCC)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.4 %

Procedure:
To a solution of 60 wt %-sodium hydride (2.47 g, 61.7 mmol) in 1,4-dioxane (103 ml) and hexamethylphosphoramide (7.70 ml) was added diethyl malonate (9.88 g, 61.7 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for one hour and copper(I) bromide (10.6 g, 74.0 mmol) and 1-bromo-4-iodobenzene (19.2 g, 67.9 mmol) was added. The mixture was refluxed for 5 hours and cooled to room temperature. The solid materials were filtered off through a pad of Celite. After concentration, the residue was partitioned between water and ethyl acetate. The organic layer was dried over sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluant: hexane/ethyl acetate=24/1) to afford diethyl 2-(4-bromophenyl)malonate as colorless oil (8.82 g, 41%).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[C:26]([O:28][CH2:29][C:30]([F:33])([F:32])[F:31])[CH:25]=[CH:24][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][CH:15]([C:19]([O:21]CC)=[O:20])[O:16]2)=[CH:11][CH:10]=1.[OH-].[Na+]>C(O)(C)C>[Cl:1][C:2]1[CH:27]=[C:26]([O:28][CH2:29][C:30]([F:31])([F:33])[F:32])[CH:25]=[CH:24][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][CH:15]([C:19]([OH:21])=[O:20])[O:16]2)=[CH:11][CH:10]=1
Reactant: CCOC(=O)C1CCc2ccc(OCCCOc3ccc(OCC(F)(F)F)cc3Cl)cc2O1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: O=C(O)C1CCc2ccc(OCCCOc3ccc(OCC(F)(F)F)cc3Cl)cc2O1
Temperature: 70 °C
Yield: 99.2 %

Procedure:
To a 2 ml isopropanol solution of ethyl 7-(3-(2-chloro-4-(2,2,2-trifluoroethoxy)phenoxy)propoxy)-chromane-2-carboxylate (17 mg, 0.035 mmol) was added 2N aq. sodium hydroxide. This mixture was heated to 70° C. overnight. The solvent was removed under reduced pressure. The residue was diluted with AcOEt and 2N hydrochloric acid. The organic layer was separated, and the aqueous layer was extracted twice with AcOEt. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to give the title compound 16 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23].O.ON1C2C=CC=CC=2N=N1.[Cl:38][C:39]1[CH:44]=[C:43]([Cl:45])[CH:42]=[C:41]([O:46][CH3:47])[C:40]=1[CH2:48][CH2:49][NH2:50].Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](=[O:18])[NH:50][CH2:49][CH2:48][C:40]3[C:41]([O:46][CH3:47])=[CH:42][C:43]([Cl:45])=[CH:44][C:39]=3[Cl:38])=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Reactant: COc1cc(Cl)cc(Cl)c1CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4c(Cl)cc(Cl)cc4OC)cc3)c(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.4 %

Procedure:
To a stirred solution of 4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (Preparation 1; 0.75 g; 2.0 mmol), 1-hydroxybenzotriazole hydrate, and 2-(2,4-dichloro-6-methoxyphenyl)ethanamine (Preparation 7; 0.48 g, 2.19 mmol) in 6 mL DMF at ambient temperature was added solid 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.46 g; 2.4 mmol). The resulting solution was stirred at ambient temperature overnight for convenience. The solution was diluted with 60 mL water and after stirring for 10 minutes, the mixture was transferred to a separatory funnel and extracted with 30 mL EtOAc. 1M HCl (30 mL) was added to enable layer separation. The organic layer was dried over sodium sulfate and evaporated. The residue was purified by silica gel chromatography on a Biotage 40M column, eluting with 70/30 hexane/EtOAc, to give 0.56 g of ethyl 6-chloro-7-(4-(2,4-dichloro-6-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylate as a white glass. MS (apci, pos) m/z=578.
Reaction SMILES: [CH2:1]([C:3]1[N:11]=[C:10]([O:12][CH3:13])[C:9]([NH:14][C:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[C:25]([O:31][CH3:32])[CH:24]=3)[CH2:19][CH2:18]2)=[O:16])=[CH:8][C:4]=1[C:5](O)=[O:6])[CH3:2].[CH:33]1[C:46]2[C:37](=[N:38][C:39]3[C:44]([C:45]=2[NH:47][C:48]2[CH:49]=[C:50]([NH:56][C:57](=[O:61])[CH:58]([NH2:60])[CH3:59])[CH:51]=[C:52]([CH2:54][OH:55])[CH:53]=2)=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH:36]=[CH:35][CH:34]=1>>[CH:43]1[C:44]2[C:39](=[N:38][C:37]3[C:46]([C:45]=2[NH:47][C:48]2[CH:49]=[C:50]([NH:56][C:57]([CH:58]([NH:60][C:5]([C:4]4[CH:8]=[C:9]([NH:14][C:15]([N:17]5[CH2:18][CH2:19][N:20]([C:23]6[CH:24]=[C:25]([O:31][CH3:32])[CH:26]=[C:27]([O:29][CH3:30])[CH:28]=6)[CH2:21][CH2:22]5)=[O:16])[C:10]([O:12][CH3:13])=[N:11][C:3]=4[CH2:1][CH3:2])=[O:6])[CH3:59])=[O:61])[CH:51]=[C:52]([CH2:54][OH:55])[CH:53]=2)=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:40]=[CH:41][CH:42]=1
Reactant: CCc1nc(OC)c(NC(=O)N2CCN(c3cc(OC)cc(OC)c3)CC2)cc1C(=O)O
Reactant: CC(N)C(=O)Nc1cc(CO)cc(Nc2c3ccccc3nc3ccccc23)c1
Product: CCc1nc(OC)c(NC(=O)N2CCN(c3cc(OC)cc(OC)c3)CC2)cc1C(=O)NC(C)C(=O)Nc1cc(CO)cc(Nc2c3ccccc3nc3ccccc23)c1
Yield: 49.1 %

Procedure:
The same reaction procedure to the example 1 were carried out using 2-ethyl-5-{[4-(3,5-dimethoxyphenyl)-piperazine-1-carbonyl]-amino}-6-meth oxy-nicotinic acid and N-[3-(acridine-9-yl-amino)-5-hydroxymethyl-phenyl]-2-aminopropaneamide to give the titled compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH:3]=1.[OH:18][C:19]1[CH:28]=[C:27]2[C:22]([CH:23]=[CH:24][CH:25]=[N:26]2)=[CH:21][CH:20]=1.CC(C)([O-])C.[K+]>CN1CCCC1=O>[F:15][C:14]([F:17])([F:16])[C:11]1[CH:12]=[CH:13][C:8]([C:4]2[CH:3]=[C:2]([O:18][C:19]3[CH:28]=[C:27]4[C:22]([CH:23]=[CH:24][CH:25]=[N:26]4)=[CH:21][CH:20]=3)[CH:7]=[CH:6][N:5]=2)=[CH:9][CH:10]=1
Reactant: Oc1ccc2cccnc2c1
Reactant: FC(F)(F)c1ccc(-c2cc(Cl)ccn2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: FC(F)(F)c1ccc(-c2cc(Oc3ccc4cccnc4c3)ccn2)cc1

Procedure:
This material was prepared following the methods described in Example 8 (b) using 4-chloro-2-(4-trifluoromethyl-phenyl)-pyridine (Example 8 (a), 43 mg, 0.16 mmol), 7-hydroxyquinoline (46 mg, 0.32 mmol) and potassium t-butoxide (38 mg, 0.34 mmol) in N-methylpyrrolidone (0.6 mL). The compound was purified by flash chromatography using 1:4 of EtOAc/hexanes, to provide the title compound as a white solid. MS (ESI, pos. ion) m/z: 367 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]C(=O)C(C)(C)C)=[C:4]([CH3:15])[C:3]=1[C:16]([F:19])([F:18])[F:17].Cl>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([CH3:15])[C:3]=1[C:16]([F:17])([F:18])[F:19]
Reactant: Cc1c(NC(=O)C(C)(C)C)ccc(Cl)c1C(F)(F)F
Agent: Cl
Solvent: CCO
Product: Cc1c(N)ccc(Cl)c1C(F)(F)F
Yield: 75.8 %

Procedure:
N-(4-Chloro-2-methyl-3-trifluoromethylphenyl)-2,2-dimethyl-propionamide 1.0 g, 3.4 mmol) was added to a 1:1 mixture (15 mL) of concentrated HCl and ethanol and heated at reflux for overnight. The reaction was cooled and concentrated in vacuo to give a tan solid which was then partitioned between EtOAc and saturated NaHCO3. The organic layer was separated, washed with water, brine, dried (Na2SO4), filtered and concentrated to give compound 760C (0.54 g, 76%) as a brown oily solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([N+:20]([O-])=O)=[CH:14][C:13]=2[F:23])=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:10])([F:9])[F:8]>C(O)(=O)C.[Fe]>[Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([NH2:20])=[CH:14][C:13]=2[F:23])=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:10])([F:8])[F:9]
Reactant: COc1cc(-c2nn(C)c(C(F)(F)F)c2Cl)c(F)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: COc1cc(-c2nn(C)c(C(F)(F)F)c2Cl)c(F)cc1N
Yield: 95.5 %

Procedure:
To a solution of 4.05 g of 4-chloro-3-(2-fluoro-5-methoxy-4-nitrophenyl)-1-methyl-5-(trifluoro-methyl)-1H-pyrazole in 50 ml of acetic acid was added 1.39 g (0.0249 mol) of iron powder. The reaction mixture was heated near reflux for 2 hours, treated with 1.39 g of iron powder, and heated at near reflux for another hour. After cooling, concentrating and chromatography, 3.54 g of 4-chloro-3-(4-amino-2-fluoro-5-methoxyphenyl)-1-methyl-5-(trifluoromethyl)-1H-pyrazole was isolated.
Reaction SMILES: C([O:5][C:6](=[O:36])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][N:14]2[C:19](=[O:20])[C:18]3[CH:21]=[C:22]([C:25]#[C:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:23]=[CH:24][C:17]=3[N:16]([CH3:34])[S:15]2=[O:35])=[CH:9][CH:8]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:34][N:16]1[S:15](=[O:35])[N:14]([CH2:13][C:10]2[CH:9]=[CH:8][C:7]([C:6]([OH:36])=[O:5])=[CH:12][CH:11]=2)[C:19](=[O:20])[C:18]2[CH:21]=[C:22]([C:25]#[C:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:23]=[CH:24][C:17]1=2
Reactant: CN1c2ccc(C#CCc3ccccc3)cc2C(=O)N(Cc2ccc(C(=O)OC(C)(C)C)cc2)S1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1c2ccc(C#CCc3ccccc3)cc2C(=O)N(Cc2ccc(C(=O)O)cc2)S1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 10.2 %

Procedure:
A solution of 4-[1-methyl-2,4-dioxo-6-(3-phenyl-prop-1-ynyl)-1,4-dihydro-2H-2λ4-benzo[1,2,6]thiadiazin-3-yl methyl]benzoic acid tert-butyl ester (0.33 g, 0.66 mmol) in methylene chloride (10 mL) was treated with trifluoroacetic acid (3 mL), and stirred at room temperature for 1 hour. The reaction mixture was evaporated to dryness, treated with hot ethyl acetate, allowed to cool, and the solid collected by filtration. The solid was triturated with ethyl ether, the solid collected by filtration, and allowed to air dry under house vacuum. The process afforded 0.03 g of 4-[1-methyl-2,4-dioxo-6-(3-phenyl-prop-1-ynyl)-1,4-dihydro-2H-2λ4-benzo[1,2,6]thiadiazin-3-yl methyl]benzoic acid as a blue/green solid (9.5% yield. 1H-NMR (CDCl3); d 8.30 (d, 1H), 8.08-8.06 (d, 2H), 7.69-7.67 (dd, 1H), 7.48-7.46 (d, 2H), 7.40-7.32 (m, 4H), 7.27-7.23 (m, 1H), 6.97-6.95 (d, 1H), 5.44-5.40 (d, 1H), 4.81-4.77 (d, 1H), 3.83 (s, 2H), 3.41 (s, 3H). MS: M++1=445.1 Da
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[CH:5]=[C:4]([Cl:13])[C:3]=1[OH:14].Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]1[O:25][N:24]=[C:23]([CH3:26])[CH:22]=1>>[Cl:13][C:4]1[CH:5]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[C:2]([Cl:1])[C:3]=1[O:14][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]1[O:25][N:24]=[C:23]([CH3:26])[CH:22]=1
Reactant: Oc1c(Cl)cc(-c2ccco2)cc1Cl
Reactant: Cc1cc(CCCCCBr)on1
Product: Cc1cc(CCCCCOc2c(Cl)cc(-c3ccco3)cc2Cl)on1
Yield: 40 %

Procedure:
5-{5-[2,6-Dichloro-4-(2-furanyl)phenoxy]pentyl}-3-methylisoxazole [II; R1 and R2 =Cl, Het=2-furanyl] was prepared from 2,6-dichloro-4-(2-furanyl)phenol and 5-(5-bromopentyl)-3-methylisoxazole according to the procedure of Example 1(c), and was obtained in about 40% yield as a pale-yellow oil which could be caused to crystallize from isopropyl acetate-hexane as a pale-yellow solid, m.p. 29-30° C.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]=[C:6]([CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:7][NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])C.C(=O)=O.CC(C)=O.[H-]>O1CCCC1>[C:12]([O:11][C:9](=[O:10])[NH:8][CH2:7][C:6]([CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:5][CH2:4][OH:3])([CH3:14])([CH3:15])[CH3:13]
Reactant: CCOC(=O)C=C(CNC(=O)OC(C)(C)C)CNC(=O)OC(C)(C)C
Agent: O=C=O
Agent: [H-]
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)NCC(=CCO)CNC(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 2 h
Yield: 95.6 %

Procedure:
To a solution of 4-tert-butoxycarbonylamino-3-(tert-butoxycarbonylamino-methyl)-but-2-enoic acid ethyl ester (7.0 g, 19.5 mmol) in tetrahydrofuran (195 ml), at a reaction temperature of −78° C. (dry ice/acetone) was added a solution of diissobutylaluminum hydride (1 M in CH2Cl2, 59 ml, 59 mmol) and the reaction mixture stirred at −78° C. for 2 hours under a N2 atmosphere. The reaction was quenched with a saturated solution of sodium tartrate tetrahydrate (300 ml), stirred vigorously until the layers clarified then extracted with methylene chloride (2×100 ml). The combined organic extracts were dried (Na2SO4), filtered, and concentrated in vacuo to afford a yellow oil. Purification via column chromatography on silica gel (ethyl acetate:hexane, 1:1, v/v) afforded the product as a yellow oil (5.90 g, 96%). 1HNMR (CDCl3) δ 1.43 (s, 18H), 3.72 (s, 4H), 4.18 (t, 2H), 4.76 (s, 1H), 5.54 (s, 1H), 5.96 (t, 1H).
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C=CN=C1.[O:14]=[C:15]1[NH:19][N:18]=[C:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:16]1>C(#N)C.O>[Si:1]([O:14][C:15]1[NH:19][N:18]=[C:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:16]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C1=NNC(=O)C1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CC#N
Product: CCOC(=O)c1cc(O[Si](C)(C)C(C)(C)C)[nH]n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.2 %

Procedure:
Tert-butyldimethylsilyl chloride (6.05 g, 40.15 mmol) and imidazole (2.92 g, 42.82 mmol) were added to a stirred solution of ethyl 5-oxo-4,5-dihydro-1H-pyrazole-3-carboxylate (4.18 g, 26.76 mmol) in ACN (90 mL). The mixture was stirred at room temperature for 30 minutes, then diluted with water and extracted with AcOEt. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo to yield ethyl 5-{[tert-butyl(dimethyl)silyl]oxy}-1H-pyrazole-3-carboxylate (3.2 g, 44% yield) as a yellow solid, that was used in the next step without further purification.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:4][NH:3]1.[H-].[Na+].[Br:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][C:22]=1[Cl:29].O>CN(C)C=O>[Cl:29][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:21]=1[Br:20])[CH2:25][N:3]1[N:4]=[C:5]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]1=[O:1]
Reactant: Clc1cc(CBr)ccc1Br
Reactant: CCOC(=O)Cc1n[nH]c(=O)c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cc1nn(Cc2ccc(Br)c(Cl)c2)c(=O)c2ccccc12
Temperature: 60 °C
Reaction time: 1 h
Yield: 33.8 %

Procedure:
A mixture of ethyl 1,2-dihydro-1-oxophthalazin-4-ylacetate (11.5 g.) and sodium hydride (2.7 g.; 50% w/w dispersion in mineral oil) in dimethylformamide (125 ml.) was stirred at 60° C. for 1 hour under nitrogen. The solution obtained was cooled to room temperature and then 4-bromo-3-chlorobenzyl bromide (15.0 g.) was added, and the mixture stirred at 60° C. for 2 hours. After cooling to 25° C. the reaction mixture was poured into water (500 ml.). The aqueous mixture obtained was extracted with ethyl acetate (400 ml.). The extracts were washed with water, dried (MgSO4), and evaporated to give a solid, which was crystallised from propan-2-ol to yield ethyl 2-(3-chloro-4-bromobenzyl)-1,2-dihydro-1-oxophthalazin-4-ylacetate (7.3 g.), m.p. 142°-145° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[S:13][N:12]=[C:11]([OH:14])[C:10]=1[C:15]#[N:16].C(N(CC)CC)C.[O:24](S(C(F)(F)F)(=O)=O)[S:25]([C:28]([F:31])([F:30])[F:29])(=O)=[O:26]>ClCCl>[F:29][C:28]([F:31])([F:30])[S:25]([O:14][C:11]1[C:10]([C:15]#[N:16])=[C:9]([C:3]2[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=2[F:1])[S:13][N:12]=1)(=[O:26])=[O:24]
Reactant: Cc1ccc(-c2snc(O)c2C#N)c(F)c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(-c2snc(OS(=O)(=O)C(F)(F)F)c2C#N)c(F)c1
Temperature: 20 °C
Reaction time: 8 h

Procedure:
Into a 100-mL round-bottom flask, was placed 5-(2-fluoro-4-methylphenyl)-3-hydroxy-1,2-thiazole-4-carbonitrile (700 mg, 2.99 mmol, 1.00 equiv), dichloromethane (20 mL), triethylamine (302 mg, 2.98 mmol, 1.00 equiv). This was followed by the addition of Tf2O (1.69 g, 5.99 mmol, 2.00 equiv) at 0-5° C. The resulting solution was stirred overnight at 20° C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5). This resulted in 800 mg (73%) of 4-cyano-5-(2-fluoro-4-methylphenyl)-1,2-thiazol-3-yl trifluoromethanesulfonate as colorless oil.