Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16]([C:18]2[C:23]([O:24][CH2:25][CH2:26][CH3:27])=[CH:22][CH:21]=[CH:20][N:19]=2)=[O:17])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.O1CCOCC1.CO>O>[CH2:25]([O:24][C:23]1[C:18]([C:16]([NH:15][C:6]2([C:4]([OH:5])=[O:3])[CH2:7][C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:14]2)=[O:17])=[N:19][CH:20]=[CH:21][CH:22]=1)[CH2:26][CH3:27]
Reactant: CCCOc1cccnc1C(=O)NC1(C(=O)OCC)Cc2ccccc2C1
Solvent: C1COCCO1
Solvent: O
Solvent: CO
Product: CCCOc1cccnc1C(=O)NC1(C(=O)O)Cc2ccccc2C1
Reaction time: 22 h
Yield: 101.4 %

Procedure:
A 100 mL round bottom flask which contains 2-[(3-propoxy-pyridine-2-carbonyl)-amino]-indan-2-carboxylic acid ethyl ester (332, 620 mg, 1.68 mmol) is charged with 1,4-dioxane (6 mL) and MeOH (6 mL). A stirring bar is added and stirring is initiated. After dissolution, water (3 mL) is added followed by the LiOH monohydrate (178 mg, 4.25 mmol). After 22 h, tlc analysis (silica, 50% EtOAc/heptanes) indicates that the starting material is completely consumed. Amberlyst highly acidic exchange resin (0.5 g) is added to the reaction flask. The reaction is capped and allowed to stir at ambient temperature. After 125 h, the contents of the flask are filtered through a pad of Celite. The solvent is removed from the filtrate. The residue is reconstituted with iPrOH/toluene (20+10 mL) and the solvent is removed. This process is repeated 1 time. Pumping to constant weight provides 0.58 g of white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]=[O:11])[C:5]=1[NH:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14].Cl.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32]Cl)[CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]=[O:11])[C:5]=1[N:12]([S:13]([C:16]1[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=1)(=[O:14])=[O:15])[CH2:32][C:28]1[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=1
Reactant: COC(=O)c1cccc(C=O)c1NS(=O)(=O)c1ccc(OC)cc1
Reactant: ClCc1cccnc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc(C=O)c1N(Cc1cccnc1)S(=O)(=O)c1ccc(OC)cc1
Reaction time: 18 h
Yield: 62.6 %

Procedure:
To a solution of 0.20 g (0.573 mmol) of the product of Example 321 in 2.5 mL of DMF was added 0.099 g (0.602 mmol) of 3-picolyl chloride hydrochloride and 0.249 g (1.805 mmol) of potassium carbonate. The reaction was stined for 18 h at room temperature and then the reaction was then diluted with water and extracted with ether. The combined organics were washed with water, dried over Na2SO4, filtered and concentrated in vacuo. The residue was triturated with ether to give 0.158 g (63%) of the product as tan crystals. Electrospray Mass Spec: 440.9 (M+H)+.
Reaction SMILES: [Cl-].[Cl-].[CH-:3]1[CH:7]=[CH:6][CH:5]=[CH:4]1.[CH-:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1.[Zr+2:13].C[Li]>C(OCC)C>[CH3-:3].[CH3-:8].[CH-:3]1[CH:7]=[CH:6][CH:5]=[CH:4]1.[CH-:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1.[Zr+4:13]
Reactant: [Zr+2]
Agent: [Cl-]
Agent: [Li]C
Agent: c1cc[cH-]c1
Solvent: CCOCC
Product: [CH3-]
Product: [Zr+4]
Temperature: -20 °C

Procedure:
60 ml dried diethylether and 5.34g of zirconocene dichloride were mixed and stirred at -20° C. in an argon atmosphere. 1.5 M methyl lithium was added little by little to this mixture and stirred for 70 minutes. The mixture was further stirred at 0° C. for 30 minutes, and the diethylether was removed whereby a white solid was obtained. The white solid thus formed was sublimated to give zirconocene dimethyl.
Reaction SMILES: [C:1]([OH:13])(=O)[CH2:2][C:3]1[C:4](=[CH:8][CH:9]=[CH:10][CH:11]=1)[C:5]([OH:7])=O.[CH2:14]([NH2:17])[CH:15]=[CH2:16]>>[CH2:14]([N:17]1[C:1](=[O:13])[CH2:2][C:3]2[C:4](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:5]1=[O:7])[CH:15]=[CH2:16]
Reactant: O=C(O)Cc1ccccc1C(=O)O
Reactant: C=CCN
Product: C=CCN1C(=O)Cc2ccccc2C1=O
Yield: 46 %

Procedure:
A mixture of homophthalic acid (9.0 g., 0.05 mole) and allylamine (2.8 g., 0.05 mole) was heated by an oil bath to 185°-190° C. for 40 minutes. The mixture solidified upon cooling, and was recrystallized twice from isopropanol, giving 2-allylisoquinoline-1,3 (2H, 4H)-dione, 4.6 g. (46% yield), m.p. 75°-77° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1[F:12])[NH:8][CH:7]=[C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:5]2=[O:19].C(=O)([O-])[O-].[K+].[K+].[CH2:26](I)[CH3:27]>CN(C)C=O>[CH2:26]([N:8]1[C:9]2[C:4](=[CH:3][C:2]([F:1])=[C:11]([F:12])[C:10]=2[F:13])[C:5](=[O:19])[C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:7]1)[CH3:27]
Reactant: CCOC(=O)c1c[nH]c2c(F)c(F)c(F)cc2c1=O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CC)c2c(F)c(F)c(F)cc2c1=O

Procedure:
A 49.1 g portion of 6,7,8-trifluoro-1,4-dihydro-oxo-3-quinolinecarboxylic acid, ethyl ester was reacted with 85 g of potassium carbonate, 266 g of ethyl iodide and 600 ml of dimethylformamide, giving 1-ethyl-1,4-dihydro-6,7,8-trifluoro-4-oxo-3-quinolinecarboxylic acid, ethyl ester.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[C@@H:5]([OH:31])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:20][CH:19]=2)=[CH:9][CH:8]=1)[CH3:2].[CH2:33](I)[CH3:34]>ClCCl>[CH2:1]([O:3][C:4](=[O:32])[CH:5]([O:31][CH2:33][CH3:34])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:19]=[CH:20][C:21]([O:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[CH:22][CH:23]=2)=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCI
Reactant: CCOC(=O)[C@@H](O)Cc1ccc(OCCCOc2ccc(Oc3ccccc3)cc2)cc1
Solvent: ClCCl
Product: CCOC(=O)C(Cc1ccc(OCCCOc2ccc(Oc3ccccc3)cc2)cc1)OCC

Procedure:
A solution of (2S)-2-hydroxy-3-{4-[3-(4-phenoxy-phenoxy)-propoxy]-phenyl}-propionic acid ethyl ester, AgO2 (1.5 eq) and ethyl iodide (excess) in dichloromethane was stirred over 10 days. The crude mixture was filtered through celite and concentrated to dryness. The compound was purified by chromatography to give the title product. 1H-NMR (CDCl3, 200.15 MHz): δ 7.34–7.26 (m, 2H), 7.18–6.82 (m, 11H), 4.18–4.17 (m, 6H), 4.01–3.94 (m, 1H), 3.68–3.53 (m, 1H), 3.43–3.28 (m, 1H), 2.96 (d, 2H, J=6.5), 2.25 (qn, 2H, J=6.2), 1.20 (dt, 6H, J=12.6, 7.3).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=3)=[N:8][C:7]=12)#[CH:2].C(OC([N:33]1[CH2:38][CH2:37][N:36]([S:39]([C:42]2[S:43][C:44](Br)=[CH:45][CH:46]=2)(=[O:41])=[O:40])[CH2:35][CH2:34]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[N:36]1([S:39]([C:42]2[S:43][C:44]([C:2]#[C:1][C:3]3[CH:4]=[N:5][N:6]4[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]5[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=5)=[N:8][C:7]=34)=[CH:45][CH:46]=2)(=[O:41])=[O:40])[CH2:35][CH2:34][NH:33][CH2:38][CH2:37]1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3cccc(C(F)(F)F)c3)nc12
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(Br)s2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(c1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4cccc(C(F)(F)F)c4)nc23)s1)N1CCNCC1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(3-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.10) (178 mg, 0.5 mmol) and 4-(5-bromo-thiophene-2-sulfonyl)-piperazine-1-carboxylic acid tert-butyl ester (example B.52) (206 mg, 0.5 mmol) according to general procedure II and subsequent cleavage of the protecting group with TFA in dichloromethane at 0° C. Obtained as an orange solid (96 mg, 33%). MS (ISP) 586.1 [(M+H)+]; mp 160° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][NH2:10])[CH:2]=1.[CH3:11][N:12]([CH3:26])[C:13]1[CH:14]=[C:15]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:16]2=[C:17]([CH:25]=1)[C:18](S)=[N:19]3>C(O)C>[CH3:11][N:12]([CH3:26])[C:13]1[CH:14]=[C:15]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:16]2=[C:17]([CH:25]=1)[C:18]([NH:10][CH2:9][CH2:8][CH2:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)=[N:19]3
Reactant: CN(C)c1cc2c3c(cccc3c1)N=C2S
Reactant: NCCCc1cccnc1
Solvent: CCO
Product: CN(C)c1cc2c3c(cccc3c1)N=C2NCCCc1cccnc1

Procedure:
The reaction of equivalent molar quantities of 3-(3-pyridinyl)propanamine, 4-dimethylaminobenz(cd)indol-2thiol, and mercuric acetate in refluxing ethanol, under the conditions of Example 55 leads to the formation of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:14]=[N:15][C:16]([C:19]([C:22]3([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=4[F:32])[CH2:24][O:23]3)([F:21])[F:20])=[CH:17][CH:18]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[NH:33]1[CH:37]=[N:36][N:35]=[N:34]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C(Cl)Cl>[Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:20])[C:22]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=3[F:32])([OH:23])[CH2:24][N:33]3[CH:37]=[N:36][N:35]=[N:34]3)=[N:15][CH:14]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: c1nnn[nH]1
Reactant: Fc1ccc(C2(C(F)(F)c3ccc(Oc4ncc(C(F)(F)F)cc4Cl)cn3)CO2)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: OC(Cn1cnnn1)(c1ccc(F)cc1F)C(F)(F)c1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cn1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a magnetically stirred mixture of 3-chloro-2-((6-((2-(2,4-difluorophenyl)oxiran-2-yl)difluoromethyl)pyridin-3-yl)oxy)-5-(trifluoromethyl)pyridine (U) (356 mg, 0.744 mmol) and 1H-tetrazole (62.5 mg, 0.892 mmol) in dry DMSO (3.718 mL) was added potassium carbonate (206 mg, 1.487 mmol) in a dry 25 mL vial under N2 atmosphere. The reaction mixture was stirred at 60° C. overnight, cooled to RT and diluted with ice-cold water/2N HCl and DCM and the layers were separated on a Phase Separator. The aq. layer was extracted again with DCM and the combined organic extracts were evaporated. The crude residue was purified on silica (ISCO, 40 gram column, gradient to 40% EtOAc/Hexanes over 20 minutes) to afford the title compound. Yield=119 mg (27.7%) of a brown glass. 1H NMR (400 MHz, CDCl3) δ 8.76 (s, 1H), 8.50 (d, J=2.3 Hz, 1H), 8.27 (dd, J=2.1, 0.9 Hz, 1H), 8.05 (d, J=2.0 Hz, 1H), 7.74-7.63 (m, 2H), 7.34 (td, J=8.9, 6.4 Hz, 1H), 7.21 (s, 1H), 6.83-6.72 (m, 1H), 6.72-6.64 (m, 1H), 5.64 (d, J=14.3 Hz, 1H), 5.13 (d, J=14.1 Hz, 1H). 1H-decoupled 19F NMR (376 MHz, CDCl3) δ−61.74 (s), −103.20 (d, J=15.0 Hz), −103.72-−104.09 (m), −107.86 (d, J=10.9 Hz), −110.78 (d, J=45.0 Hz), −111.48 (d, J=45.0 Hz). MS (ESI): m/z 549.1 (M+H)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:12]([CH2:13]O)=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:3][CH2:2]1.S(Cl)([Cl:17])=O>ClCCl>[Cl-:17].[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:12]([CH2:13][Cl:17])=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:3][CH2:2]1
Reactant: OCc1cccnc1N1CCOCC1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: ClCc1cccnc1N1CCOCC1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of (2-morpholino-3-pyridinyl)methanol (1 g, 5.01 mmol) in dichloromethane (20 ml) was added thionyl chloride (3 ml) dropwise at 0° C. and allowed to warm to room temperature. After stirring at room temperature for 6 h, solvents were removed under reduced pressure and the residue was dissolved and concentrated repeatedly in dichloromethane to remove excess of thionyl chloride. The obtained crude chloride intermediate, (2-morpholino-3-pyridinyl)methylchloride, was immediately dissolved in acetone (25 ml) and added sodium azide (1.63 g, 25.05 mmol) at room temperature. The reaction was refluxed for overnight, solvents were removed under reduced pressure, dissolved in dichloromethane (25 ml) and washed with 1M NaHCO3 (25 ml). The aqueous layer was extracted with dichloromethane (2×20 ml). The combined organic extracts were dried (Na2SO4), filtered and concentrated to yield 0.62 g (57%) of product as a thick yellowish liquid. MS (ESI+) m/z 220 (M+H)+;
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5]1([CH3:15])[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1>O.C(O)C>[C:5]1([CH3:15])[CH:10]=[CH:9][C:8]([S:11]([N:1]=[N+:2]=[N-:3])(=[O:13])=[O:12])=[CH:7][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reaction time: 2.5 h

Procedure:
Sodium azide (22.5 g, 0.35 mol) was dissolved in H2O(65 ml) and diluted with 90% aqueous ethanol (130 ml). To this mixture, a solution of p-toluenesulfonyl chloride (60 g, 0.32 mol) in ethanol (300 ml) was added dropwise at 10°-25° C. and stirring was continued for 2.5 hours at room temperature. The reaction mixture was evaporated under reduced pressure, the resultant residue was washed with H2O for several times, dried over anhydrous MgSO4 and filtered with suction to give the title compound as a colorless oil; yield: 50.7 g.
Reaction SMILES: O1CCCC1.[CH2:6]([Sn:10]([CH2:17][CH2:18][CH2:19][CH3:20])([CH2:13][CH2:14][CH2:15][CH3:16])[C:11]#[CH:12])[CH2:7][CH2:8][CH3:9].[N+:21]([CH2:24][CH2:25][C:26]1[CH:39]=[CH:38][C:29]([CH2:30][O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)=[CH:28][CH:27]=1)([O-:23])=O.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>CN(C)C1C=CN=CC=1.O.C(OCC)(=O)C>[CH2:17]([Sn:10]([CH2:13][CH2:14][CH2:15][CH3:16])([CH2:6][CH2:7][CH2:8][CH3:9])[C:11]1[O:23][N:21]=[C:24]([CH2:25][C:26]2[CH:39]=[CH:38][C:29]([CH2:30][O:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=3)=[CH:28][CH:27]=2)[CH:12]=1)[CH2:18][CH2:19][CH3:20]
Reactant: O=[N+]([O-])CCc1ccc(COc2ccccn2)cc1
Reactant: C#C[Sn](CCCC)(CCCC)CCCC
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cc(Cc2ccc(COc3ccccn3)cc2)no1
Temperature: 25 °C
Reaction time: 15 h
Yield: 100.2 %

Procedure:
To a tetrahydrofuran solution (90 mL) of tri-n-butylethynyl tin (3 g), the 2-(4-(2-nitro-ethyl)-benzyloxy)-pyridine (4.9 g) described in Manufacturing Example 1-1-4 and 4-dimethylaminopyridine (116 mg) was added a tetrahydrofuran solution (30 mL) of di-tert-butyl dicarbonate (7.3 g), which was stirred at room temperature for 15 hours. Ethyl acetate and water were added to the mixture. The organic layer was isolated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and then filtered. The filtrate was adsorbed on silica gel, and purified by silica gel column chromatography (heptane:ethyl acetate=4:1) to obtain the title compound (5.3 g).
Reaction SMILES: C(OC1C=CN(CC(C2C=CC(CO)=CC=2)=O)C(=O)C=1)C1C=CC=CC=1.[CH2:27]([O:34][C:35]1[CH:40]=[N:39][NH:38][C:37](=[O:41])[CH:36]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.Cl[CH2:43][C:44]([C:46]1[CH:47]=[C:48]2[C:52](=[CH:53][CH:54]=1)[CH2:51][N:50]([C:55](=[O:60])[C:56]([F:59])([F:58])[F:57])[CH2:49]2)=[O:45]>CS(C)=O>[CH2:27]([O:34][C:35]1[CH:40]=[N:39][N:38]([CH2:43][C:44](=[O:45])[C:46]2[CH:47]=[C:48]3[C:52](=[CH:53][CH:54]=2)[CH2:51][N:50]([C:55](=[O:60])[C:56]([F:59])([F:57])[F:58])[CH2:49]3)[C:37](=[O:41])[CH:36]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=c1cc(OCc2ccccc2)cn[nH]1
Reactant: O=C(CCl)c1ccc2c(c1)CN(C(=O)C(F)(F)F)C2
Agent: O=C(Cn1ccc(OCc2ccccc2)cc1=O)c1ccc(CO)cc1
Solvent: CS(C)=O
Product: O=C(Cn1ncc(OCc2ccccc2)cc1=O)c1ccc2c(c1)CN(C(=O)C(F)(F)F)C2

Procedure:
5-Benzyloxy-2-{2-oxo-2-[2-(2,2,2-trifluoro-acetyl)-2,3-dihydro-1H-iso indol-5-yl]-ethyl}-2H-pyridazin-3-one is prepared following preparation 15b from 1.38 g (6.80 mmol) 5-benzyloxy-2H-pyridazin-3-one (preparation 5c) and 2.08 g (7.14 mmol) 1-[5-(2-chloro-acetyl)-1,3-dihydroisoindol-2-yl]-2,2,2-trifluoro-ethanone (see preparation 23) in DMSO as solvent (purification via reversed HPLC chromatography).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[NH2:6].C(N(CC)C(C)C)(C)C.Cl[C:26]([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:27]>ClCCl>[C:29]1([O:28][C:26](=[O:27])[NH:6][C:5]2[CH:4]=[C:3]([C:2]([F:14])([F:15])[F:1])[CH:9]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:7]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 42.8 %

Procedure:
3,5-Bis-(trifluoromethyl)aniline (2.0 g, 8.7 mmol) was dissolved in dichloromethane (80 mL) and N,N-diisopropylethylamine (1.6 mL, 9.6 mmol) was added followed by slow addition of phenyl chloroformate (1.1 mL, 8.7 mmol). The resulting mixture was stirred at room temperature for 16 hours. The mixture was successively washed with 1N hydrochloric acid (3×100 mL), water (3×100 mL), a mixture of water and saturated aqueous sodium hydrogen carbonate (1:1, 2×100 mL) and a mixture of water and saturated aqueous sodium chloride (1:1, 3×100 mL), dried (MgSO4) and concentrated in vacuo. The residue was crystallised from heptane containing a little diethyl ether to afford 1.3 g (43%) of (3,5-bis-trifluoromethylphenyl)carbamic acid phenyl ester as a solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:16][C:17]1[C:18]([CH3:23])=[N:19][O:20][C:21]=1[CH3:22]>CN(C=O)C.O>[CH3:23][C:18]1[C:17]([CH2:16][N:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:8]=[N:7]2)=[C:21]([CH3:22])[O:20][N:19]=1
Reactant: O=[N+]([O-])c1cn[nH]c1
Reactant: Cc1noc(C)c1CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1noc(C)c1Cn1cc([N+](=O)[O-])cn1
Yield: 67.5 %

Procedure:
1H-pyrazole (10 g, 147 mmol) was added in small portions to concentrated H2SO4 (100 mL), cooled to 0° C. via an ice/water bath, maintaining the internal reaction temperature below 40° C. Concentrated HNO3 (10 mL) was carefully added, dropwise, to the reaction mixture maintaining the internal reaction temperature below 55° C. The reaction was then heated to 55° C. and stirred for 5 hours. The mixture was cooled to 0° C. and carefully made basic (pH˜8) with aqueous NaOH solution (110 g NaOH in 150 mL H2O) until a white precipitate formed, carefully ensuring the internal temperature of the solution remain below 40° C. The white solid was collected by filtration and washed with ethyl acetate/hexanes (1/3) then dried en vacuo to afford 4-nitro-1H-pyrazole (7 g, 42%, isolated yield). 13C NMR (DMSO-d6, 137.0, 126.4. To 4-nitro-1H-pyrazole (9 g, 80 mmol) in DMF (100 mL) 100 MHz) δ was added cesium carbonate (26 g, 80 mmol) followed by the addition of 4-(chloromethyl)-3,5-dimethylisoxazole (12.3 g, 85 mmol). The reaction mixture was stirred in DMF (100 mL) at 80° C. for 30 minutes, then cooled, diluted with H2O (150 mL) and extracted with ethyl acetate (3×, 75 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was taken up in ethyl acetate (200 mL) and washed with H2O (2×, 100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The solid product was triturated with ethyl acetate/hexanes (1/9) and collected by filtration. The product was dried under high vacuum to afford 3,5-dimethyl-4-((4-nitro-1H-pyrazol-1-yl)methyl)isoxazole (12 g, 67%) as a light yellow solid. 1H NMR (CDCl3, 400 MHz): δ 2.23 (s, 3H), 2.46 (s, 3H), 5.08 (s, 2H), 8.02 (s, 1H), 8.08 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[NH2:8].[C:20](O)(=O)[CH:21]=[O:22].C(O)C>C(O)(=O)C>[Cl:15][C:14]1[C:9]([C:4]2[CH:3]=[C:2]3[C:7]([N:8]=[CH:20][C:21](=[O:22])[NH:1]3)=[CH:6][CH:5]=2)=[N:10][CH:11]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:13]=1
Reactant: Nc1ccc(-c2ncc(C(F)(F)F)cc2Cl)cc1N
Reactant: O=CC(=O)O
Solvent: CCO
Solvent: CC(=O)O
Product: O=c1cnc2ccc(-c3ncc(C(F)(F)F)cc3Cl)cc2[nH]1
Temperature: 23 °C
Reaction time: 2.5 h
Yield: 87 %

Procedure:
A mixture of 10.0 g of 2-(3,4-diaminophenyl)-3-chloro-5-trifluoromethylpyridine, 5.7 g of a 50% strength by weight aqueous glyoxalic acid solution, 100 ml of ethanol and 50 ml of glacial acetic acid was stirred at 23° C. for 2.5 hours. The solid portion formed was separated off, washed with ethanol and dried. After concentrating, the filtrate gave a further amount of the products. Total yield: 87% (9.9 g of colorless crystals); isomeric ratio according to 1H-NMR=about 1:1).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[CH:9]=[C:10]([CH:15]([OH:24])[CH:16]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[OH:17])[CH:11]=[CH:12][C:13]=1[Cl:14].C(N(CC)CC)C>ClCCl.CS(C)=O>[Cl:7][C:8]1[CH:9]=[C:10]([C:15](=[O:24])[C:16]([C:18]2[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=2)=[O:17])[CH:11]=[CH:12][C:13]=1[Cl:14]
Reactant: OC(c1ccncc1)C(O)c1ccc(Cl)c(Cl)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(C(=O)c1ccc(Cl)c(Cl)c1)c1ccncc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 85.1 %

Procedure:
Dimethylsulfoxide (37ml, 0.53 mol) was dissolved in dichloromethane (250 ml) and cooled to −78° C. Oxalyl chloride (34.5 ml, 0.40 mol) was added dropwise and the solution stirred for 20 min. A solution of the product of Step 1 (34 g, 0.12 mol) in dimethylsulfoxide (40 ml) and dichloromethane (200 ml) was added dropwise at −78° C., and the solution stirred for 30 min. Triethylamine (104 ml, 0.74 mol) was added dropwise and the solution became floculent such that overhead stirring became necessary. The solution was allowed to stir at room temperature over 2 hours then was poured on to ice/saturated sodium bicarbonate solution. The aqueous layer was separated, and re-extracted with dichloromethane. The combined organic phases were concentrated under reduced pressure to a green-yellow solid. The solid was redissolved in dichloromethane and washed with water and brine, dried (MgSO4) and evaporated to a solid. The crude solid was purified by silica gel chromatography eluting with dichloromethane, to afford the title compound (28.6 g, 85%) as a yellow solid; MS(-ve ion) m/e 279/281/283 [M−H]−.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Br:11][C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([Cl:19])[CH:13]=1.Cl[C:21]1[C:26]([C:27]([OH:29])=[O:28])=[CH:25][N:24]=[C:23]([Cl:30])[C:22]=1[Cl:31]>C1COCC1.Cl.C(OCC)(=O)C>[Br:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:21]2[C:26]([C:27]([OH:29])=[O:28])=[CH:25][N:24]=[C:23]([Cl:30])[C:22]=2[Cl:31])=[C:14]([Cl:19])[CH:13]=1
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1Cl
Reactant: Nc1ccc(Br)cc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(O)c1cnc(Cl)c(Cl)c1Nc1ccc(Br)cc1Cl
Temperature: -78 °C
Reaction time: 1 h
Yield: 74.1 %

Procedure:
LiHMDS (1.0 M solution in hexanes, 53.0 mL, 53.0 mmol) was added dropwise to a stirred solution of 4-bromo-2-chlorophenylamine (7.10 g, 35.0 mmol) in THF (15 mL) cooled to −78° C. After one hour, 4,5,6-trichloronicotinic acid (3.73 g, 16.5 mmol) was added dropwise as a solution in THF (12 mL). The reaction was allowed to warm to room temperature slowly while stirring overnight. The suspension was diluted with 1 M HCl and ethyl acetate, and the aqueous phase was extracted with ethyl acetate (3×). The combined organic phases were dried over Na2SO4 and concentrated to a tan solid. The solid was triturated with diethyl ether overnight and the solids were isolated by filtration to provide the desired product (25) as a tan-colored solid (4.85 g, 75%). MS APCI (−) m/z 395, 397 (M−, Cl, Br pattern) detected.