Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[C:6]([Br:9])[C:5]([F:10])=[C:4]([Br:11])[N:3]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:14]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([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)=CC=1.O1CCCC1>[Br:11][C:4]1[C:5]([F:10])=[C:6]([Br:9])[C:7]([F:8])=[C:2]([C:14]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:13]=2[F:12])[N:3]=1
Reactant: CC1(C)OB(c2cc([N+](=O)[O-])ccc2F)OC1(C)C
Reactant: Fc1c(Br)nc(Br)c(F)c1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(F)c(-c2nc(Br)c(F)c(Br)c2F)c1
Temperature: 55 °C
Reaction time: 48 h
Yield: 28.2 %

Procedure:
To a degassed mixture of 2,4,6-tribromo-3,5-difluoropyridine (4.26 g, 12.1 mmol), 2-(2-fluoro-5-nitrophenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (2.80 g, 10.4 mmol), aqueous sodium carbonate (10 ml of a 2 M solution), and tetrahydrofuran (40 ml) was added tetrakis(triphenylphosphine)palladium(0) (0.67 g). The mixture was then stirred at 55° C. for 48 h under an atmosphere of nitrogen. The reaction mixture was then partitioned between water and ethyl acetate. The organic layer was separated and evaporated, and the residue chromatographed (silica gel, 20-40% CH2Cl2/isohexane) to afford 1.209 g of 2,4-dibromo-3,5-difluoro-6-(2-fluoro-5-nitrophenyl)pyridine as a solid: 1H NMR (400 MHz, CDCl3) δ 7.37 (1H, t, J 8.8 Hz), 8.38 (1H, m), 8.55 (1H, dd, J 2.9, 6.1 Hz).
Reaction SMILES: [Na].[CH:2]1([OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[OH:8].Cl[CH:11]([CH3:15])[C:12](O)=[O:13].S(=O)(=O)(O)O>C(O)C.O>[CH3:15][CH:11]1[O:9][CH:2]2[CH:3]([CH2:4][CH2:5][CH2:6][CH2:7]2)[O:8][C:12]1=[O:13]
Reactant: OC1CCCCC1O
Reactant: CC(Cl)C(=O)O
Agent: O=S(=O)(O)O
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CC1OC2CCCCC2OC1=O
Reaction time: 5 h

Procedure:
25.3 gm (1.1 mol) of sodium were dissolved in 500 ml of ethanol under dry nitrogen. 116 gm (1 mol) of 1,2-cyclohexane-diol were added to the solution at room temperature. Then, the ethanol was completely removed under vacuum. 163 gm (1.2 mol) of the ethyl ester of 2-chloropropionic acid were added to the mono-sodium salt of 1,2-cyclohexane-diol so obtained, at 50° C., and the mixture was allowed to stand for 5 hours at 80° C. to react further. Then, the reaction mixture was decomposed with water and acidified with sulfuric acid. The organic phase was separated and the aqueous phase was extracted twice with ether. After combining the organic phases, these were washed neutral with water and sodium bicarbonate solution, dried over sodium sulfate and reduced under vacuum. The crude product obtained was distilled under high vacuum. 76 gm of 4-methyl-2,5-dioxabicyclo-[4,4,0]-decan-3-one were obtained with the following analytical data:
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:7][O:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([NH2:15])[CH:14]=1.[C:16]([Cl:19])(=[O:18])[CH3:17]>C1COCC1>[ClH:19].[ClH:19].[CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:7][O:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([NH:15][C:16](=[O:18])[CH3:17])[CH:14]=1
Reactant: CN1CCC[C@H]1COc1cncc(N)c1
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Product: CC(=O)Nc1cncc(OC[C@@H]2CCCN2C)c1
Product: Cl

Procedure:
The 3-((1-methyl-2-(S)-pyrrolidinyl)methoxy)-5-amino-pyridine from Example 94 is dissolved in THF and reacted with acetyl chloride according to standard procedures. The product is purified by chromatography on silica gel and converted into the title compound by treatment with HCl in ether according to Example 14c.
Reaction SMILES: C([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][CH2:28][OH:29])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])C.Br[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[Cl:38]>>[Cl:38][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[CH2:31][O:29][CH2:28][CH2:27][C:22]1[C:23]([CH3:26])=[N:24][O:25][C:21]=1[C:18]1[CH:19]=[CH:20][C:15]([C:12]2[CH:13]=[CH:14][C:9]([C:6]3([C:4]([OH:3])=[O:5])[CH2:8][CH2:7]3)=[CH:10][CH:11]=2)=[CH:16][CH:17]=1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CCO)cc3)cc2)CC1
Reactant: Clc1ccccc1CBr
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1CCOCc1ccccc1Cl

Procedure:
Prepared according to the procedure described in Example 14, Step 4, using 1-{4′-[4-(2-hydroxy-ethyl)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 1-bromomethyl-2-chloro-benzene.
Reaction SMILES: [OH-:1].[Ca+2:2].[OH-:3].[S:4](=[O:6])=[O:5]>O>[S:4]([O-:1])([O-:6])=[O:5].[Ca+2:2].[S:4]([O-:3])([O-:1])(=[O:6])=[O:5].[Ca+2:2]
Reactant: O=S=O
Reactant: [OH-]
Agent: [Ca+2]
Solvent: O
Product: O=S(=O)([O-])[O-]
Product: O=S([O-])[O-]

Procedure:
In one aspect disclosed herein there is provided a method for reducing lime consumption in DFGD systems that includes introducing lime and water into a slaker to produce a slaked lime slurry. The slaked lime slurry is subsequently introduced into a spray dryer where prior to the introduction of the slurry into the spray dryer, water is added to the slurry. Once introduced into the spray dryer, the slurry is atomized. A flue gas stream is also introduced into the spray dryer and reacts with the atomized slaked lime slurry. This reaction causes sulfur dioxide in the flue gas to be absorbed into droplets that form part of the atomized slurry. The sulfur dioxide reacts with the slaked lime in the slurry to form calcium sulfite and calcium sulfate particulate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:17][CH:18]1[CH2:23][CH:22]([NH2:24])[CH2:21][CH2:20][O:19]1>>[CH3:17][CH:18]1[CH2:23][CH:22]([NH:24][C:14]([C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[N:13]=2)=[O:16])[CH2:21][CH2:20][O:19]1
Reactant: CC1CC(N)CCO1
Reactant: O=C(O)c1cccc(-c2cccc(Cl)c2)n1
Product: CC1CC(NC(=O)c2cccc(-c3cccc(Cl)c3)n2)CCO1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(3-chlorophenyl)-2-pyridinecarboxylic acid (CAN 863704-38-5) and tetrahydro-2-methyl-2H-pyran-4-amine (CAN 89584-06-5) as starting materials, MS (EI): m/e=331.1 [M+H]+.
Reaction SMILES: CC1C=[C:12]2[O:14]C=1C[C@H:5]([C:21](C)=C)[CH2:6][CH2:7][C:8]1C(=O)O[C@@H:10]([C@H:11]2C(C)=C)[CH:9]=1.[C:24]([O:28][C:29](=[O:42])[N:30]([C@H]1CC[C@H](C=C(Br)Br)CC1)[CH3:31])([CH3:27])([CH3:26])[CH3:25].[Li]CCCC.C=O>C1COCC1>[C:24]([O:28][C:29](=[O:42])[N:30]([C@H:6]1[CH2:5][CH2:21][C@H:9]([C:10]#[C:11][CH2:12][OH:14])[CH2:8][CH2:7]1)[CH3:31])([CH3:27])([CH3:26])[CH3:25]
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](C=C(Br)Br)CC1
Reactant: C=C(C)[C@@H]1CCC2=C[C@@H](OC2=O)[C@@H](C(=C)C)c2cc(C)c(o2)C1
Agent: C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](C#CCO)CC1
Temperature: 25 °C

Procedure:
The following reaction was performed in analogy to the reaction described in: Marshall, James A.; Bartley, Gary S.; Wallace, Eli M. Total Synthesis of the Pseudopterane (−)-Kallolide B, the Enantiomer of Natural (+)-Kallolide B. J. Org. Chem. (1996), 61(17), 5729–5735 and Baker, Raymond; Boyes, Alastair L.; Swain, Christopher J. Synthesis of talaromycins A, B, C, and E. J. Chem. Soc., Perkin Trans. 1 (1990), (5), 1415–21.). A solution of 993 mg (2.5 mmol) of trans-[4-(2,2-Dibromo-vinyl)-cyclohexyl]-methyl-carbamic acid tert-butyl ester in 20 ml THF was treated at −78° C. with 3.28 ml (5.25 mmol) of BuLi (ca 1.6 M in hexane). After 2 h at this temperature 790 mg (25 mmol) of paraformaldehyde were added. The reaction mixture was warmed up to RT for 3 h and after 1 h at this temperature extracted with water/Et2O (3×). The organic phases were washed with aqueous 10% NaCl, dried over Na2SO4 and evaporated. Purification by flash-chromatography on silica gel (hexane/EtOAc 4:1) yielded 530 mg (79%) of trans-[4-(3-Hydroxy-prop-1-ynyl)-cyclohexyl]-methyl-carbamic acid tert-butyl ester, MS: 268 (MH+).
Reaction SMILES: C([C:5]1[CH:6]=[CH:7][C:8]2[C:9]3[C:10](=[N:26][N:27]([CH2:30][CH3:31])[C:28]=3[CH3:29])[C:11]([N:19](C([O-])=O)C([O-])=O)=[N:12][C:13]=2[C:14]=1C(C)(C)C)(C)(C)C.C(C1C=CC2C3C(=NN(CCC)C=3C)C(N(C([O-])=O)C([O-])=O)=NC=2C=1C(C)(C)C)(C)(C)C.[O:64]=[C:65]1[CH2:70][CH2:69][S:68][CH2:67][CH2:66]1.C1(=O)CCC1>>[NH2:19][C:11]1[C:10]2=[N:26][N:27]([CH2:30][CH3:31])[C:28]([CH2:29][C:65]3([OH:64])[CH2:70][CH2:69][S:68][CH2:67][CH2:66]3)=[C:9]2[C:8]2[CH:7]=[CH:6][CH:5]=[CH:14][C:13]=2[N:12]=1
Reactant: O=C1CCSCC1
Reactant: CCn1nc2c(N(C(=O)[O-])C(=O)[O-])nc3c(C(C)(C)C)c(C(C)(C)C)ccc3c2c1C
Agent: CCCn1nc2c(N(C(=O)[O-])C(=O)[O-])nc3c(C(C)(C)C)c(C(C)(C)C)ccc3c2c1C
Agent: O=C1CCC1
Product: CCn1nc2c(N)nc3ccccc3c2c1CC1(O)CCSCC1

Procedure:
4-[(4-Amino-2-ethyl-2H-pyrazolo[3,4-c]quinolin-1-yl)methyl]tetrahydro-2H-thiopyran-4-ol was prepared according to the method of Example 1 Part F using di(tert-butyl)2-ethyl-1-methyl-2H-pyrazolo[3,4-c]quinolin-4-ylimidodicarbonate in lieu of di(tert-butyl)1-methyl-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-ylimidodicarbonate and 4-oxothiane in lieu of cyclobutanone. The crude product was recrystallized from acetonitrile to provide 0.475 g of 4-[(4-amino-2-ethyl-2H-pyrazolo[3,4-c]quinolin-1-yl)methyl]tetrahydro-2H-thiopyran-4-ol as a white powder, mp 251.5-255° C.
Reaction SMILES: S(=O)(=O)(O)O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:18]1([CH2:24][C:25](=[O:33])[C:26]([O:28][CH2:29]CCC)=[O:27])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC1C=CC=CC=1C>[C:18]1([CH2:24][C:25](=[O:33])[C:26]([O:28][CH3:29])=[O:27])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCCCOC(=O)C(=O)Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: Cc1ccccc1C
Product: COC(=O)C(=O)Cc1ccccc1

Procedure:
Following the procedure of step (iii) of Example 1 but charging 1 g of sulfuric acid into the three-necked flask in lieu of p-toluenesulfonic acid monohydrate, and the whole o-xylene solution containing 95 g (0.43 mole) of butyl phenylpyruvate and sulfuric acid as obtained in step (ii) of Example 8 into the dropping funnel in place of methyl phenylpyruvate, the reaction was carried out in the same manner as in step (iii) of Example 1. The total reaction time was prolonged to 6 hours. The conversion of butyl phenylpyruvate was 97 percent and the selectivity toward butyl α-acetamidocinnamate 85 mole percent (yield of butyl α-acetamidocinnamate: 93 g). The reaction mixture was washed with water in the same manner as in step (iii) of Example 1 to give about 650 ml of an o-xylene solution containing butyl α-acetamidocinnamate in a concentration of about 0.55 mole per liter.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=[CH:7]2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[F:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1>C(Cl)Cl>[F:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([N:1]2[CH2:6][CH2:5][C:4]3([C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[CH:8]=[CH:7]3)[CH2:3][CH2:2]2)(=[O:31])=[O:30])=[CH:25][CH:24]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: C1=CC2(CCNCC2)c2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(c1ccc(F)cc1)N1CCC2(C=Cc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Spiro(1H-indene-1,4'-piperidine) (40 mg, 0.18 mmol) was suspended in CH2Cl2 (2 ml) and treated with triethylamine (52.6 μl, 0.378 mmol) followed by 4-fluorobenzenesulfonyl chloride (38.6 mg, 0.198 mmol). The reaction was stirred 1 hr at ambient temperature and chromatographed on a silica gel column eluted with 20% hexane in CH2Cl2. The product fractions were evaporated to dryness in vacuo and the residue crystallized from ether to provide the title compound: (mp 169°-174°).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=O)[CH2:6][CH2:5]2.[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][C:13]1=[O:21].[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.O>CN(C)C=O>[N:22]1([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[C:7](=[C:14]2[C:15]4[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=4)[NH:12][C:13]2=[O:21])[CH2:6][CH2:5]3)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=C1CCc2cc(F)ccc21
Reactant: C1CCNCC1
Reactant: O=C1Cc2ccccc2N1
Solvent: CN(C)C=O
Solvent: O
Product: O=C1Nc2ccccc2C1=C1CCc2cc(N3CCCCC3)ccc21
Temperature: 125 °C

Procedure:
A mixture of 0.5 g 5-fluoro-1-indanone, 13 g oxindole and 1 ml piperidine in 4 ml dimethylforamide was heated in a sealed tube at 125° C. for 2.5 hours. The reaction mixture was poured into water and the aqueous layer was decanted. Ethyl acetate was then added slowly until a solid formed. The solid was filtered and washed with ethyl acetate/hexanes to yield a curry colored solid. The solid was then further purified by washing with dimethylforamide/acetone to give 122 mg of 3-(5-piperidin-1-yl-indan-1-ylidene)-1,3-dihydroindol-2-one as an orange solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]([OH:9])=[O:8])[CH2:2]1.[OH-].[Na+].Br[C:13]1([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=2)[C:21]2[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=2)[NH:15][C:14]1=[O:23].Cl>O.O1CCOCC1>[Cl:22][C:18]1[CH:17]=[C:16]2[C:21]([C:13]([N:1]3[CH2:6][CH2:5][CH2:4][CH:3]([C:7]([OH:9])=[O:8])[CH2:2]3)([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=3)[C:14](=[O:23])[NH:15]2)=[CH:20][CH:19]=1
Reactant: O=C1Nc2cc(Cl)ccc2C1(Br)Cc1cccc(Cl)c1
Reactant: O=C(O)C1CCCNC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)C1CCCN(C2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the mixture of piperidine-3-carboxylic acid (600 mg, 4.5 mmol) and NaOH (360 mg, 9 mmol) in water (5 mL) and dioxane (5 mL) was added rac-3-bromo-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one (1.1 g, 3 mmol). The mixture was stirred at room temperature for 1 h and then diluted by water (30 mL). The resulting solution was neutralized to pH=7 with hydrochloride acid and extracted by dichloromethane. The organic phase was dried over Na2SO4, filtered and concentrated to give rac-1-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-3-carboxylic acid yield: (0.9 g, 71%). MS: [M−H]−=417.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=O)=[CH:4][CH:3]=1.[CH3:10][O:11][C:12](=[O:33])[CH:13]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C1(C)C=CC=CC=1.CCOC(C)=O>[CH3:10][O:11][C:12](=[O:33])[CH:13]=[CH:8][C:5]1[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: O=Cc1ccc(Cl)nc1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)C=Cc1ccc(Cl)nc1
Yield: 90.7 %

Procedure:
To 6-chloro-pyridine-3-carboxaldehyde (300 mg, 2.12 mmol) in toluene was added methyl(triphenylphosphoranylidene)acetate (708 mg, 2.12 mmol) and the solution was refluxed for 6 hrs. The reaction mixture was diluted with EtOAc and then washed three times with H2O, brine, dried. Na2SO4, filtered and concentrated under reduced pressure. The obtained residue was column-chromatographed to yield 3-(6-chloro-pyridin-3-yl)-acrylic acid methyl ester (380 mg, 90%).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH:13]1([NH2:20])[CH2:19][CH2:18][CH2:17][CH2:16]CC1.[CH3:21][C:22]1[CH:26]=[C:25]([CH3:27])[NH:24][N:23]=1>>[ClH:1].[CH:13]1([NH:20][C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=[C:2]([N:23]3[C:22]([CH3:21])=[CH:26][C:25]([CH3:27])=[N:24]3)[N:11]=2)[CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: NC1CCCCCC1
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: Cc1cc(C)[nH]n1
Product: Cc1cc(C)n(-c2nc(NC3CCCC3)c3ccccc3n2)n1
Product: Cl

Procedure:
Was prepared according to Method A from 2,4-dichloroquinazoline, cycloheptylamine and 3,5-dimethylpyrazole. Mp. 207° C.
Reaction SMILES: [Cl:1][C:2]([Cl:11])([Cl:10])[C:3]([C:5]1[NH:6][CH:7]=[CH:8][CH:9]=1)=[O:4].[N+:12]([O-:15])(O)=[O:13].[CH:16](O)(C)C>C(OC(=O)C)(=O)C>[N+:12]([C:8]1[CH:9]=[C:5]([C:3](=[O:4])[C:2]([Cl:1])([Cl:10])[Cl:11])[N:6]([CH3:16])[CH:7]=1)([O-:15])=[O:13]
Reactant: O=C(c1ccc[nH]1)C(Cl)(Cl)Cl
Reactant: CC(C)O
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Product: Cn1cc([N+](=O)[O-])cc1C(=O)C(Cl)(Cl)Cl
Temperature: -40 °C
Reaction time: 4 h

Procedure:
To a well stirred solution of trichloroacetyl chloride (1 kg, 5.5 mole) in 1.5 liter ethyl ether in a 12 liter flask was added dropwise over a period of 3 h a solution of N-methylpyrrole (0.45 kg, 5.5 mole) in 1.5 liter anhydrous ethyl ether. The reaction was stirred for an additional 3 hours and quenched by the dropwise addition of a solution of 400 g potassium carbonate in 1.5 liters water. The layers were separated and the ether layer concentrated in vacuo to provide 2-(trichloroacetyl)pyrrole (1.2 kg, 5.1 mol) as a yellow crystalline solid sufficiently pure to be used without further purification. To a cooled (−40° C.) solution of 2-(trichloroacetyl) pyrrole (1.2 kg, 5.1 mol) in acetic anhydride (6 L) in a 12 L flask equipped with a mechanical stirrer was added 440 mL fuming nitric acid over a period of 1 hour while maintaining a temperature of (−40° C.). The reaction was carefully allowed to warm to room temperature and stir an additional 4 h. The mixture was cooled to −30° C., and isopropyl alcohol (6 L) added. The solution was stirred at −20° C. for 30 min during which time a white precipitate forms. The solution was allowed to stand for 15 min and the resulting precipitate collected by vacuum filtration.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11](O)[CH3:12].P(Br)(Br)[Br:15]>C1(C)C=CC=CC=1>[Br:15][CH:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)[CH3:12]
Reactant: CC(O)c1ccc2ccccc2c1
Reactant: BrP(Br)Br
Solvent: Cc1ccccc1
Product: CC(Br)c1ccc2ccccc2c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1-(Naphthalen-2-yl)ethanol (2.0 g, 11.6 mmol) was dissolved in toluene (30 mL). The solution was cooled to 0° C. PBr3 (1.09 mL, 11.6 mmol) was added dropwise over 15 min. The reaction mixture was then brought up to room temperature and stirred for 1 h. The mixture was washed with K2CO3 solution and extracted with EtOAc (3×30 mL). The EtOAc layer was washed with brine and dried (MgSO4). The solvent was evaporated off in-vacuo to give crude 2-(1-bromoethyl)naphthalene. This intermediate was used in the following step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[C:15](Br)[CH:14]=[C:13]3[Br:21])=[O:9])=[CH:4][CH:3]=1.[OH2:22]>C1(C)C=CC=CC=1.CCOC(C)=O>[Br:21][C:13]1[C:12]2[C:17](=[CH:18][CH:19]=[C:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[O:9])[CH:11]=2)[N:16]=[C:15]([O:22][C:5]([CH3:8])([CH3:6])[CH3:4])[CH:14]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc2nc(Br)cc(Br)c2c1
Reactant: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)Oc1cc(Br)c2cc(C(=O)c3ccc(Cl)cc3)ccc2n1
Temperature: 70 °C

Procedure:
A mixture of (4-chlorophenyl)(2,4-dibromoquinolin-6-yl)methanone (5 g) and KOBut (1.1 eq. 12.93 mmol) in dry toluene (60 mL) was heated at 70° C. for 2 hr. and then cooled to room temperature. The reaction was diluted with EtOAc and water. The aqueous layer was extracted with ethyl acetate. The organics were combined and then washed with water, concentrated and subjected to chromatography (5-15% EtOAc/hexanes silica column) to yield (4-bromo-2-(tert-butoxy)quinolin-6-yl)(4-chlorophenyl)methanone.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:12]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[N:11]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[C:10]=1[C:35]([O:37]CC)=[O:36])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[CH2:42]([N:44]([CH2:47][CH3:48])[CH2:45][CH3:46])[CH3:43]>C1COCC1.CCO.O>[CH2:1]([O:8][C:9]1[C:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:12]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[N:11]([C:27]2[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=2)[C:10]=1[C:35]([O-:37])=[O:36])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[CH2:42]([NH+:44]([CH2:47][CH3:48])[CH2:45][CH3:46])[CH3:43]
Reactant: CCN(CC)CC
Reactant: CCOC(=O)c1c(OCc2ccccc2)c(OCc2ccccc2)c(C(=O)OCC)n1-c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)c1c(OCc2ccccc2)c(OCc2ccccc2)c(C(=O)[O-])n1-c1ccc(OC)cc1
Product: CC[NH+](CC)CC
Temperature: 50 °C
Reaction time: 16 h
Yield: 83 %

Procedure:
To a solution of diethyl 3,4-bis(benzyloxy)-1-(4-methoxyphenyl)-1H-pyrrole-2,5-dicarboxylate (1) (39.6 g, 74.8 mmol) in THF/EtOH (300/50 mL) was added NaOH (3.07 g, 77 mmol) as a solution in water (20 mL). The reaction was stirred at 50° C. for 16 h. Triethylamine was added (30 mL, 215 mmol) and the volatiles were removed in vacuo. The residue was purified by silica gel chromatography (50% isohexane:DCM (+2% Et3N), then 20% MeOH/EtOAc (+2% Et3N)) to afford triethylammonium 3,4-bis(benzyloxy)-5-(ethoxycarbonyl)-1-(4-methoxyphenyl)-1H-pyrrole-2-carboxylate (5) (39.3 g, 83%) as a yellow oil: m/z 502 (M+H)+ (ES+); 500 (M−H)− (ES−). 1H NMR (400 MHz, DMSO-d6) δ: 7.51-7.26 (m, 10H), 7.11-7.05 (m, 2H), 6.92-6.83 (m, 2H), 5.09 (s, 2H), 5.06 (s, 2H), 3.95 (q, J=7.1 Hz, 2H), 3.79 (s, 3H), 2.85-2.62 (m, 6H), 1.08-0.92 (m, 12H).
Reaction SMILES: C[O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH3:12])[C:7]([Cl:13])=[C:6]([NH2:14])[CH:5]=1.[CH:16]([S:18]([CH:21]=[CH2:22])(=[O:20])=[O:19])=[CH2:17].O>P(=O)(O)(O)O>[Cl:13][C:7]1[C:8]([O:10][CH2:11][CH3:12])=[CH:9][C:4]([C:3]([OH:2])=[O:15])=[CH:5][C:6]=1[N:14]1[CH2:22][CH2:21][S:18](=[O:20])(=[O:19])[CH2:16][CH2:17]1
Reactant: CCOc1cc(C(=O)OC)cc(N)c1Cl
Reactant: C=CS(=O)(=O)C=C
Agent: O=P(O)(O)O
Solvent: O
Product: CCOc1cc(C(=O)O)cc(N2CCS(=O)(=O)CC2)c1Cl
Temperature: 140 °C
Yield: 12.4 %

Procedure:
A mixture of 3-amino-4-chloro-5-ethoxy-benzoic acid methyl ester (1.0 g, 4.35 mmol, 1.0 equiv) and divinylsulfone (0.44 mL, 0.51 g, 4.35 mmol, 1.0 equiv) in phosphoric acid 85% (25 mL) was heated to 140° C. overnight. The reaction mixture was poured into water (50 mL) and extracted with dichloromethane (3×50 mL). The combined organic phases were dried over MgSO4, the solvent removed by evaporation under reduced pressure and the crude material purified with column chromatography on silica eluting with heptane/ethyl acetate (1:1+1% acetic acid) yielding 0.18 g (12%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 1.51 (t, J=7.0 Hz, 3H), 3.25-3.29 (m, 4H), 3.57-3.60 (m, 4H), 4.19 (q, J=7.0 Hz, 2H), 7.44 (d, J=1.7 Hz, 1H), 7.47 (d, J=1.7 Hz, 1H). MS (ISN): 332.1 [M−H]−.