Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Ti:1](Cl)(Cl)([Cl:3])[Cl:2].[CH:6]1[CH:11]=[C:10]([C:12]#[N:13])[C:9]([C:14]#[N:15])=[CH:8][CH:7]=1>ClC1C2C(=CC=CC=2)C=CC=1>[Cl:2][Ti:1][Cl:3].[CH:6]1[CH:7]=[CH:8][C:9]2[C:10](=[C:12]3[N:13]=[C:12]4[N:15]=[C:14]([C:9]5[CH:8]=[CH:7][CH:6]=[CH:11][C:10]=54)[N:15]=[C:14]4[NH:13][C:12]([C:10]5[CH:11]=[CH:6][CH:7]=[CH:8][C:9]=54)=[N:15][C:14]4=[N:13][C:12]([C:10]5[CH:11]=[CH:6][CH:7]=[CH:8][C:9]=54)=[N:15][C:14]=2[NH:13]3)[CH:11]=1
Reactant: Cl[Ti](Cl)(Cl)Cl
Reactant: N#Cc1ccccc1C#N
Solvent: Clc1cccc2ccccc12
Product: Cl[Ti]Cl
Product: c1ccc2c(c1)-c1nc-2nc2[nH]c(nc3nc(nc4[nH]c(n1)c1ccccc41)-c1ccccc1-3)c1ccccc21
Temperature: 250 °C
Reaction time: 3 h

Procedure:
Titanium tetrachloride (18 g) was added dropwise to a mixture of phthalodinitrile (40 g) and α-chloronaphthalene (500 ml) in a nitrogen stream. Thereafter, the reaction mixture was slowly heated to 250° C., at which it was stirred for 3 h to complete the reaction. Subsequently, the reaction mixture was left to cool to room temperature and filtered to obtain dichlorotitanium phthalocyanine as the reaction product. The dichlorotitanium phthalocyanine thus obtained was hydrolyzed with 300 ml of concentrated aqueous ammonia and thereafter washed with acetone to obtain TiOPc.
Reaction SMILES: [Br:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5](Br)=[N:4][CH:3]=1.[CH:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=2)[CH2:17][CH2:16]1)([CH3:14])[CH3:13].C(N(C(C)C)CC)(C)C>>[Br:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:27][C:24]2[CH:23]=[CH:22][C:21]([N:18]3[CH2:17][CH2:16][N:15]([CH:12]([CH3:14])[CH3:13])[CH2:20][CH2:19]3)=[CH:26][CH:25]=2)=[N:4][CH:3]=1
Reactant: Brc1ncc(Br)n2ccnc12
Reactant: CC(C)N1CCN(c2ccc(N)cc2)CC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N1CCN(c2ccc(Nc3ncc(Br)n4ccnc34)cc2)CC1
Yield: 43.1 %

Procedure:
A solution of 5,8-dibromo-imidazo[1,2-a]pyrazine (0.134 g, 0.48 mmol), 4-(4-isopropyl-piperazin-1-yl)-phenylamine (0.118 g, 0.54 mmol) and diisopropylethylamine (0.093 mL, 0.54 mmol) is stirred at 90° C. for 18 hours. The reaction mixture is concentrated in vacuo and partitioned between DCM and sat. NaHCO3. The organic layer is washed with brine, dried over MgSO4, filtered and concentrated. The residue is purified by silica gel column chromatography eluting with 98:2 DCM:MeOH to afford the title compound (0.086 g,. 43%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:20](OCC)(OCC)(OCC)[CH3:21]>C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[CH3:20][C:21]1[N:12]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1
Reactant: CCOC(C)(OCC)OCC
Reactant: CCOC(=O)CCNc1c(N)cnc2ccccc12
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Product: CCOC(=O)CCn1c(C)nc2cnc3ccccc3c21
Yield: 61.5 %

Procedure:
Ethyl N-(3-aminoquinolin-4-yl)-β-alaninate (9.0 g, 35 mmol) was treated with triethyl orthoacetate (8.91 mL, 48.6 mmol) and pyridinium p-toluenesulfonate (0.200 g) according to the method described in Part A of Example 10 to provide 6.10 g of ethyl 3-(2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)propanoate. The reaction was complete in two hours, and a precipitate was removed by filtration from the organic layer during the work-up procedure.
Reaction SMILES: [CH:1]([NH:4][S:5]([C:8]1[N:9]([S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])[C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:7])=[O:6])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:45](O)([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.O>[C:46]1([CH:45]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[N:4]([CH:1]([CH3:3])[CH3:2])[S:5]([C:8]2[N:9]([S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)(=[O:18])=[O:19])[C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)(=[O:7])=[O:6])[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: CC(C)NS(=O)(=O)c1cc2ccccc2n1S(=O)(=O)c1ccccc1
Reactant: OC(c1ccccc1)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)N(C(c1ccccc1)c1ccccc1)S(=O)(=O)c1cc2ccccc2n1S(=O)(=O)c1ccccc1
Yield: 79.2 %

Procedure:
To a solution of N-isopropyl-1-benzenesulfonylindole-2-sulfonamide (10.0 g, 26.42 mmol), triphenylphosphine (10.4 g, 39.63 mmol), and benzhydrol (7.30 g, 39.63 mmol) in 100 ml of tetrahydrofuran was dropwise added a solution of diethyl azodicarboxylate (6.24 ml, 39.63 mmol) in 100 ml of tetrahydrofuran with stirring, followed by stirring at room temperature for 2 hours. Water was added to the reaction mixture followed by extraction with ethyl acetate. The resulting organic layer was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to give 34.5 g of a crude product. The obtained crude product was purified with silica gel column chromatography (ethyl acetate/hexane=1/9) followed by crystallization from ethanol to give 11.4 g (yield: 79%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7](Br)[C:8]2[C:13]([C:14]=1[O:15][CH3:16])=[CH:12][CH:11]=[CH:10][C:9]=2[O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:4].[Cu][C:26]#[N:27]>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([C:26]#[N:27])[C:8]2[C:13]([C:14]=1[O:15][CH3:16])=[CH:12][CH:11]=[CH:10][C:9]=2[O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:4]
Reactant: N#C[Cu]
Reactant: COC(=O)c1nc(Br)c2c(Oc3ccccc3)cccc2c1OC
Solvent: CN(C)C=O
Product: COC(=O)c1nc(C#N)c2c(Oc3ccccc3)cccc2c1OC
Temperature: 25 °C
Yield: 82.7 %

Procedure:
A mixture of 1-bromo-4-methoxy-8-phenoxy-isoquinoline-3-carboxylic acid methyl ester (1.02 g, 2.63 mmol), copper (I) cyanide (470 mg, 5.25 mmol) and anhydrous dimethylformamide (8.8 mL) was refluxed for ten minutes before it was cooled to room temperature quenched with water and ethyl acetate. The slurry was filtered. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate, concentrated in vacuo and the residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and hexanes to give the title compound as a yellow solid (727 mg): MS: (+) m/z 334.83 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1Cl.[CH:10]1([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:14]=2[OH:20])[CH2:12][CH2:11]1.C(N(CCCC)CCCC)CCC.[OH-].[K+].Cl>CO>[Cl:8][C:6]1[N:5]=[N:4][C:3]([O:20][C:14]2[C:15]([CH3:19])=[CH:16][CH:17]=[CH:18][C:13]=2[CH:10]2[CH2:11][CH2:12]2)=[C:2]([OH:1])[CH:7]=1
Reactant: Oc1cc(Cl)nnc1Cl
Reactant: Cc1cccc(C2CC2)c1O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCCCN(CCCC)CCCC
Solvent: CO
Product: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1O
Temperature: 25 °C
Yield: 56.9 %

Procedure:
To a mixture of 314 mg (purity: 96.0%; 1.83 mmol) of 4-hydroxy-3,6-dichloropyridazine and 828 mg (5.50 mmol) of 2-cyclopropyl-6-methylphenol were added tributylamine (2.76 g) and 334 mg (5.56 mmol) of 95% potassium hydroxide at room temperature. The resultant mixture was heated to 180° C. while stirring, and stirred at that temperature for 4 hours. Then, the resultant reaction mixture was cooled to room temperature, and a 1 N aqueous hydrochloric acid solution and methanol were added to the reaction mixture to obtain a uniform solution. The obtained solution was quantitatively determined by an HPLC internal standard analysis method, which showed that 288 mg of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 57%) and 2.5 mg of 3-chloro-6-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 0.5%) were obtained.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=2/[CH:14]=[CH:15]/[C:16]2[N:17]=[C:18]3[S:26][CH:25]=[CH:24][N:19]3[C:20](=[O:23])[C:21]=2I)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:33](O)[CH3:34].O>C1(C)C=CC=CC=1>[CH3:16][N:17]([CH3:18])[C:34]1[CH:33]=[CH:3][C:2]([C:21]2[C:20](=[O:23])[N:19]3[CH:24]=[CH:25][S:26][C:18]3=[N:17][C:16]=2/[CH:15]=[CH:14]/[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([O:12][CH3:13])[C:6]=2[O:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)=[CH:1][CH:4]=1
Reactant: CCO
Reactant: COc1cccc(/C=C/c2nc3sccn3c(=O)c2I)c1OCC1CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cccc(/C=C/c2nc3sccn3c(=O)c2-c2ccc(N(C)C)cc2)c1OCC1CC1

Procedure:
The title compound was prepared from Intermediate 2 (150 mg, 31 mmol), 4-N,N-dimethylaminophenylboronic acid (61 mg, 37 mmol), Pd[(C6H5)3P]4 (61 mg, 37 mmol) and sodium carbonate (206 mg, 1.91 mmol) in a mixture of toluene, ethanol and water according to the procedure outlined in Example 1 to afford a crude product which was purified by silica gel column chromatography using 10% ethyl acetate in chloroform to give 110 mg of the product; 1H NMR (300 MHz, DMSO-d6) δ 0.26-0.28 (m, 1H), 0.50 (d, J=7.8 Hz, 2H), 1.06-1.08 (m, 1H), 6.77 (d, J=8.4 Hz, 2H), 6.88-6.90 (m, 1H), 6.97-7.04 (m, 3H), 7.14 (d, J=5.1 Hz, 2H), 7.95 (d, J=5.1 Hz, 1H), 8.10 (d, J=15.6 Hz, 1H); ESI-MS (m/z) 474.19 (M+H)+.
Reaction SMILES: [CH3:1][O-:2].[Na+].[CH3:4][OH:5].[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:8]=1[NH:14][S:15]([C:18]1[N:28]=[C:21]2[N:22]=[C:23](Cl)[CH:24]=[C:25](Cl)[N:20]2[N:19]=1)(=[O:17])=[O:16].Cl>>[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:8]=1[NH:14][S:15]([C:18]1[N:28]=[C:21]2[N:22]=[C:23]([O:5][CH3:4])[CH:24]=[C:25]([O:2][CH3:1])[N:20]2[N:19]=1)(=[O:17])=[O:16]
Reactant: C[O-]
Reactant: O=S(=O)(Nc1c(Cl)cccc1Cl)c1nc2nc(Cl)cc(Cl)n2n1
Reactant: CO
Agent: Cl
Agent: [Na+]
Product: COc1cc(OC)n2nc(S(=O)(=O)Nc3c(Cl)cccc3Cl)nc2n1
Reaction time: 0.25 h
Yield: 41.2 %

Procedure:
A solution of 20 ml (9.6 mmol) of sodium methoxide-methanol was treated with 1.0 g (2.4 mmol) of N-(2,6-dichlorophenyl)-5,7-dichloro-1,2,4-triazolo-[1,5-a]pyrimidine-2-sulfonamide and was stirred for 15 minutes at 25°-30° C. The solution was acidified with 6N aqueous HCl and then concentrated by rotary evaporation in vacuo. The residue was washed with water and then triturated with warm isopropanol (2X) to afford 0.4 g (41 percent) of a white powder; mp 232°-234° C. decomposition.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[O:20][CH3:21])=[CH:11][S:10][C:9]=2/[CH:22]=[CH:23]/[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:4][CH:3]=1.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:30]([CH3:29])(=[O:32])=[O:31])=[CH:7][CH:6]=3)=[C:9](/[CH:22]=[CH:23]/[C:24]([O:26][CH2:27][CH3:28])=[O:25])[S:10][CH:11]=2)=[C:14]([O:20][CH3:21])[CH:15]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)/C=C/c1scc(-c2ccc(Cl)cc2OC)c1-c1ccc(N)cc1
Solvent: ClCCl
Product: CCOC(=O)/C=C/c1scc(-c2ccc(Cl)cc2OC)c1-c1ccc(NS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of (E)-ethyl 3-(3-(4-aminophenyl)-4-(4-chloro-2-methoxyphenyl)thiophen-2-yl)acrylate (300 mg, 0.73 mmol) and TEA (75 mg, 0.73 mmol) in DCM (10 mL) was added MsCl (108 mg, 0.95 mmol), and the mixture was stirred at room temperature overnight. The reaction solution was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to give (E)-ethyl 3-(4-(4-chloro-2-methoxyphenyl)-3-(4-(methylsulfonamido) phenyl)thiophen-2-yl)acrylate, which was used in the next step without further purification.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:10][CH2:9][S:8](=[O:12])(=[O:11])[N:7]1[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][N:21]([CH2:32][C:33]2[C:38]([Cl:39])=[CH:37][CH:36]=[C:35]([O:40][CH3:41])[C:34]=2[F:42])[C@H:22]([CH2:28][N:29]([CH3:31])[CH3:30])[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH:15]=1)=[O:5])C.O.[OH-].[Li+].CO>O1CCCC1>[Cl:39][C:38]1[C:33]([CH2:32][N:21]([CH2:20][C:16]2[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=2)[CH2:13][N:7]2[CH:6]([C:4]([OH:5])=[O:3])[CH2:10][CH2:9][S:8]2(=[O:12])=[O:11])[C@H:22]([CH2:28][N:29]([CH3:30])[CH3:31])[CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[C:34]([F:42])[C:35]([O:40][CH3:41])=[CH:36][CH:37]=1
Reactant: CCOC(=O)C1CCS(=O)(=O)N1Cc1cccc(CN(Cc2c(Cl)ccc(OC)c2F)[C@H](CN(C)C)CC(C)(C)C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1ccc(Cl)c(CN(Cc2cccc(CN3C(C(=O)O)CCS3(=O)=O)c2)[C@H](CN(C)C)CC(C)(C)C)c1F
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
2-(3-{[(6-Chloro-2-fluoro-3-methoxy-benzyl)-((S)-1-dimethylaminomethyl-3,3-dimethyl-butyl)-amino]-methyl}-benzyl)-1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid ethyl ester (0.865 g, 1.4 mmol) was dissolved in tetrahydrofuran (5.6 mL). Water (5.6 mL) and lithium hydroxide (0.050 g, 2.07 mmol) and methanol (1.2 mL) were added. The reaction was stirred at room temperature for 2.5 hours after which the reaction was concentrated under reduced pressure. To the residue was added dichloromethane and aqueous hydrochloric acid (pH˜7) resulting in an emulsion. The reaction was then concentrated to dryness under reduced pressure. The crude material was purified by supercritical fluid chromatography into the corresponding Epimer 1 and Epimer 2 of 2-(3-{[(6-Chloro-2-fluoro-3-methoxy-benzyl)-((S)-1-dimethylaminomethyl-3,3-dimethyl-butyl)-amino]-methyl}-benzyl)-1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid (0.084 g (Epimer 1) and 0.089 g (Epimer 2), respectively, 99% (combined yield)).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([OH:14])=[C:10]([Br:13])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH2:15]1[CH:23]2[N:18]([CH2:19][CH2:20][C:21]([CH2:24]O)=[CH:22]2)[CH2:17][CH2:16]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(O)C=CC=CC=1>C1COCC1.C(OCC)(=O)C>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:14][CH2:24][C:21]3[CH2:20][CH2:19][N:18]4[CH:23]([CH:22]=3)[CH2:15][CH2:16][CH2:17]4)=[C:10]([Br:13])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2cc(O)c(Br)cc21
Reactant: OCC1=CC2CCCN2CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: Oc1ccccc1
Product: CC(=O)N1CCc2cc(OCC3=CC4CCCN4CC3)c(Br)cc21
Reaction time: 1 h
Yield: 13.3 %

Procedure:
1-Acetyl-6-bromo-5-hydroxyindoline (Tetrahedron, 1973, 29(8), 1115) (1.24 g, 4.8 mmol), 1,2,3,5,6,8a-hexahydroindolizine-7-methanol (D2, 0.74 g, 4.8 mmol) and triphenylphosphine (1.27 g, 4.8 mmol) were stirred under Ar in dry THF (50 ml) as diethyl azodicarboxylate (0.76 ml, 4.8 mmol) was added dropwise. The mixture was stirred for 1 h, diluted with ethyl acetate, and extracted with dil. HCl. The extract was basified with potassium carbonate, and extracted with chloroform. This extract was dried (Na2SO4) and evaporated to give a dark oil. Further treatment of this oil as above with the phenol, triphenylphosphine and diethyl azodicarboxylate caused reaction to proceed further. Chromatography on silica, eluting with 0-20% methanol/dichloromethane, gave the title compound (0.25 g, 13%) as a brown gum.
Reaction SMILES: [CH2:1]1[CH:13]2[CH:5]([C:6]3[C:11]([C:12]2=[O:14])=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:4][CH2:3][CH2:2]1.[C:15]1([CH3:25])C=CC(S(O)(=O)=O)=CC=1.[OH2:26]>C(OC(=O)C)(=O)C>[C:15]([C:11]12[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]1[C:5]1[C:13](=[CH:1][CH:2]=[CH:3][CH:4]=1)[C:12]2=[O:14])(=[O:26])[CH3:25]
Reactant: O
Reactant: O=C1c2ccccc2C2CCCCC12
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)C12CCCCC1c1ccccc1C2=O
Reaction time: 0.33 h

Procedure:
1,2,3,4,4a,9a-Hexahydrofluoren-9-one (9.6 g) was dissolved in acetic anhydride (40 ml). p-Toluenesulfonic acid (1 g) was added and the mixture was refluxed for 1 hour. The mixture was cooled in an ice bath and water (20 ml) was added. After stirring for 20 minutes solvent was removed with an evaporator. The residue was dissolved in ethyl acetate (60 ml) and extracted with 5% NaHCO3 solution (2×30 ml) and water (30 ml). The organic phase was dried over Na2SO4 and evaporated. Yield was 10.9 g.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([N+:12]([O-])=O)[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[NH4+].[Cl-]>CCO.O.[Zn]>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([NH2:12])[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2
Reactant: O=[N+]([O-])c1cc(F)cc2cccnc12
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CCO
Product: Nc1cc(F)cc2cccnc12
Temperature: 60 °C
Reaction time: 8 h
Yield: 74.3 %

Procedure:
To a mixture of 6-fluoro-8-nitroquinoline (1.6 g, 8.3 mmol), and NH4Cl (2 g, 41.5 mmol) in EtOH/H2O (10 mL/10 mL) in a round bottom flask equipped with a refluxing condenser was added Zn (5.4 g, 16.6 mmol) dust in portions at room temperature, and the resulting mixture was stirred at 60° C. overnight. The reaction mixture was filtered, and the filtrate was extracted with EtOAc. The combined organic layers were dried over Na2SO4, and concentrated to give 1.0 g of crude product, which was used directly for the next step without further purification. LC-MS: m/z 163.2 (M+H)+
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:12][C@H:11]([CH2:13][OH:14])[O:10][N:9]=2)=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[F:21][C:22]1[CH:23]=[C:24]([N:37]2[CH2:41][C@H:40]([CH2:42][NH:43][C:44](=[O:46])[CH3:45])[O:39][C:38]2=[O:47])[CH:25]=[CH:26][C:27]=1B1OC(C)(C)C(C)(C)O1>CN(C=O)C.O.C1(P([Pd-4](P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:21][C:22]1[CH:23]=[C:24]([N:37]2[CH2:41][C@H:40]([CH2:42][NH:43][C:44](=[O:46])[CH3:45])[O:39][C:38]2=[O:47])[CH:25]=[CH:26][C:27]=1[C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH2:12][C@H:11]([CH2:13][OH:14])[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: OC[C@H]1CC(c2ccc(Br)cn2)=NO1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(B3OC(C)(C)C(C)(C)O3)c(F)c2)C(=O)O1
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)NC[C@H]1CN(c2ccc(-c3ccc(C4=NO[C@@H](CO)C4)nc3)c(F)c2)C(=O)O1
Temperature: 75 °C

Procedure:
[(5R)-3-(5-Bromopyridin-2-yl)-4,5-dihydroisoxazol-5-yl]methanol (Intermediate 12, 0.5 g, 1.95 mmol), (0.35 g, 0.9 mmol), potassium carbonate (0.622 g, 4.5 mmol), N-({(5S)-3-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide (Intermediate 13, 0.736 g, 1.95 mmol) and tetrakis(triphenylphosphino)palladium(0) (0.225 g, 0.195 mmol) were combined and suspended in DMF (7 ml) and water (1 ml). The mixture was heated at 75° C. for 2 hours, then was poured into cold water (30 ml). The solids formed were collected, rinsed with water and washed with dichloromethane, dried under vaccum and collected as the title compound (0.42 g)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([F:17])([F:16])[F:15])[N:5]=[C:4]([NH2:18])[C:3]=1[N+:19]([O-:21])=[O:20].[H-].[Na+].[C:24]([C:28]1[CH:32]=[C:31]([C:33](O)=[O:34])[O:30][N:29]=1)([CH3:27])([CH3:26])[CH3:25].C(Cl)(=O)C(Cl)=O>C1COCC1.C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([F:15])([F:17])[F:16])[N:5]=[C:4]([NH:18][C:33]([C:31]2[O:30][N:29]=[C:28]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:32]=2)=[O:34])[C:3]=1[N+:19]([O-:21])=[O:20]
Reactant: CC(C)(C)c1cc(C(=O)O)on1
Reactant: Nc1nc(-c2ccccc2C(F)(F)F)cc(Cl)c1[N+](=O)[O-]
Agent: O=C(Cl)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(C(=O)Nc2nc(-c3ccccc3C(F)(F)F)cc(Cl)c2[N+](=O)[O-])on1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-chloro-3-nitro-6-(2-trifluoromethyl-phenyl)-pyridin-2-ylamine (100 mg, 0.315 mmol, prepared as described in Example 1, Step B above) in THF (10 mL) was treated with NaH (37.8 mg, 0.944 mmol, 60% dispersion in oil), and the mixture was allowed to stir at room temperature for 1 h. Simultaneously, a solution of 3-tert-butyl-isoxazole-5-carboxylic acid (69.2 mg, 0.409 mmol, prepared as described in Example I above) in DCM (10 mL) was treated with oxalyl chloride (35.7 μL, 0.409 mmol) and DMF (2 drops), and the resulting mixture was stirred at room temperature for 1 h. Volatile components were removed in vacuo, and the residue was taken up in anhydrous THF (6 mL). The above-prepared acid chloride solution was added to the sodium anilide solution above, and the resulting mixture was stirred at room temperature for 15 min. The resulting mixture was then quenched with saturated aqueous NH4Cl (20 mL) and extracted twice with EtOAc (30 mL). The combined organic extracts were dried over MgSO4 and concentrated in vacuo. The residue was purified on a 25-g SEPRA Si 50 SPE column (Flow rate=20 mL/min; Eluent=EtOAc-hexanes, 1:99 for 10 min, then 1:99 to 1:3 over 40 min) to yield 3-tert-butyl-isoxazole-5-carboxylic acid [4-chloro-3-nitro-6-(2-trifluoromethyl-phenyl)-pyridin-2-yl]-amide as a yellow solid. Mass Spectrum (LCMS, ESI pos.): Calculated for C21H16N4O4ClF3: 469.1 (M+H); Measured: 469.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:29])[CH2:9][NH:10][CH:11]([CH3:28])[CH2:12][C:13]2[CH:27]=[CH:26][C:16]3[O:17][C:18]([C:23]([OH:25])=[O:24])([C:20]([OH:22])=[O:21])[O:19][C:15]=3[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:30][C:31]([CH3:38])([CH2:34][CH:35]([CH3:37])[CH3:36])[CH2:32]O.[K+].[Br-].Cl>>[CH3:30][C:31]([CH3:38])([CH2:34][CH:35]([CH3:37])[CH3:36])[CH2:32][O:24][C:23]([C:18]1([C:20]([O:22][CH2:30][C:31]([CH3:38])([CH3:32])[CH2:34][CH:35]([CH3:37])[CH3:36])=[O:21])[O:17][C:16]2[CH:26]=[CH:27][C:13]([CH2:12][C@H:11]([NH:10][CH2:9][C@@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[OH:29])[CH3:28])=[CH:14][C:15]=2[O:19]1)=[O:25]
Reactant: CC(Cc1ccc2c(c1)OC(C(=O)O)(C(=O)O)O2)NCC(O)c1cccc(Cl)c1
Reactant: CC(C)CC(C)(C)CO
Agent: Cl
Agent: [Br-]
Agent: [K+]
Product: CC(C)CC(C)(C)COC(=O)C1(C(=O)OCC(C)(C)CC(C)C)Oc2ccc(C[C@@H](C)NC[C@H](O)c3cccc(Cl)c3)cc2O1

Procedure:
The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid and 2,2,4-trimethylpentanol according to the procedure of Example 1 as an off-white solid; 1H NMR (DMSO-d6,400 MHz) δ 0.65-0.9 (m, 24H, 8×CH3), 1.09 (d, J=6.4 Hz, 3H, CH3), 1.1-1.4 (m, 4H, CH2, CH2), 2.62 (m, 1H, CH), 3-3.3 (m, 3H, CH, CH2), 3.4 (brs, 1H, CH), 4.04 (s, 4H, OCH2, OCH2), 5.05 (m, 1H, CH), 6.34 (d, J=3.95 Hz, 1H, OH), 6.85 (dd, J=7.9, 1.32 Hz, 1H, Ar--H), 7.07 (m, 2H, Ar--H), 7.38-7.42 (m, 3H, Ar--H), 7.5 (s, 1H, Ar--H), 8.7 (brs, 1H, NH), 9.1 (brs, 1H, NH); IR (KBr, cm-1) 3300 (OH), 2900 (NH), 1760 (CO); MS m/e 646 (M+H)+ ; Analysis for: C36H52ClNO7 ×HCl: Calc'd: C, 63.33; H, 7.83; N, 2.05; Found: C, 62.96; H, 7.71; N, 2.44.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:14])([CH3:13])[CH2:7][N:8]([CH3:12])[CH2:9]2)=[CH:4][CH:3]=1.[Br:15]N1C(=O)CCC1=O>C(#N)C.O>[NH2:1][C:2]1[C:11]([Br:15])=[C:10]2[C:5]([C:6]([CH3:14])([CH3:13])[CH2:7][N:8]([CH3:12])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: CN1Cc2cc(N)ccc2C(C)(C)C1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CC#N
Product: CN1Cc2c(ccc(N)c2Br)C(C)(C)C1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 7-amino-2,4,4-trimethyl-1,2,3,4-tetrahydroisoquinoline from D3 (7 g) in acetonitrile (200 ml), was added N-bromo succinimide (7.21 g) portionwise over 10 min. The reaction mixture was cooled in an ice/methanol bath to prevent any large exotherm. and then stirred under argon for 45 min. The reaction was allowed to warm to 25° C., diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4) and evaporated to dryness in vacuo. The resultant brown solid was purified using dry flash column chromatography with ethyl acetate. Combination of appropriate fractions gave the title compound as an orange gum (3.95 g).