Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=O)[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[O:22])[CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C([O-])(=O)C.[NH4+].C([BH3-])#[N:35].[Na+].O1CCCC1>CO.C(#N)C>[Cl:1][C:2]1[CH:11]=[C:10]([CH:12]([NH2:35])[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[O:22])[CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCN(C(=O)c2ccccn2)CC1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC#N
Product: CC(N)c1cc(Cl)c2cccnc2c1N1CCN(C(=O)c2ccccn2)CC1
Temperature: 65 °C

Procedure:
A mixture of 1-{5-chloro-8-[4-(pyridin-2-ylcarbonyl)piperazin-1-yl}quinolin-7-yl}ethanone (0.015 g, 0.038 mmol) and ammonium acetate (0.0293 g, 0.380 mmol) in methanol (0.2 mL) and acetonitrile (0.2 mL) was heated at 65° C. in a sealed tube for 1 hour. After cooling to room temperature, to the resulting mixture was added 1.0 M sodium cyanoborohydride in tetrahydrofuran (0.095 mL, 0.095 mmol). The reaction was heated at 65° C. overnight. The mixture was cooled to room temperature, quenched with sat. NaHCO3 solution, extracted with dichloromethane, dried over MgSO4 and concentrated to give the desired product. LCMS calculated for C21H23ClN5O (M+H)+: m/z=396.2; Found: 396.2.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[CH:15]1([NH2:18])[CH2:17][CH2:16]1>>[CH:15]1([NH:18][CH:11]2[CH2:12][CH2:13][N:8]([C:5]3[CH:4]=[N:3][C:2]([CH3:1])=[CH:7][N:6]=3)[CH2:9][CH2:10]2)[CH2:17][CH2:16]1
Reactant: Cc1cnc(N2CCC(=O)CC2)cn1
Reactant: NC1CC1
Product: Cc1cnc(N2CCC(NC3CC3)CC2)cn1

Procedure:
The title compound is prepared from 1-(5-methyl-pyrazin-2-yl)-piperidin-4-one and cyclopropylamine following a procedure analogous to that described in Intermediate 4. LC (method 7): tR=0.68 min; Mass spectrum (ESI+): m/z=233 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Sn](CCCC)(CCCC)[C:13]1[O:17][N:16]=[C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:14]=1)CCC.F[P-](F)(F)(F)(F)F.C([N+]1C=CN(C)C=1)CCC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:13]1[O:17][N:16]=[C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:14]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(C(=O)OCC)no1
Reactant: Brc1ccccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[n+]1ccn(C)c1
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1COCCO1
Product: CCOC(=O)c1cc(-c2ccccn2)on1
Reaction time: 1 h
Yield: 42.6 %

Procedure:
A 20 mL BIOTAGE® microwave vial and stir bar were oven dried and cooled under a stream of dry nitrogen. The vial was flushed with argon and charged with dichlorobis(triphenylphosphine)-palladium(II) (96 mg, 0.137 mmol) and dioxane (12 mL) followed by sparging with argon for several minutes. 2-Bromopyridine (0.217 mL, 2.28 mmol), ethyl 5-(tributylstannyl)isoxazole-3-carboxylate (980 mg, 2.28 mmol), and 1-butyl-3-methylimidazolium hexafluorophosphate (0.047 mL, 0.228 mmol) were added and sparging was continued for several minutes. The vial was sealed and processed in a BIOTAGE® microwave at 150° C. for 60 minutes. The solution was cooled, evaporated, and the residue was loaded onto a 120 g Isco silica gel cartridge, which was pre-equilibrated with hexanes, and then eluted with 0-50% EtOAc/Hexanes. The product fractions were evaporated to give a pale yellow oil, which solidified after being placed under high vacuum to afford ethyl 5-(pyridin-2-yl)isoxazole-3-carboxylate (212 mg, 0.972 mmol, 43% yield). The product had an HPLC retention. time=2.48 min.—Column: YMC S5 COMBISCREEN® 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. LC/MS M+1=219.1. 1H NMR (400 MHz, chloroform-d) δ ppm 1.42-1.48 (m, 3H), 4.49 (q, J=7.28 Hz, 2H), 7.31 (s, 1H), 7.39 (ddd, J=7.53, 4.89, 1.13 Hz, 1H), 7.87 (td, J=7.78, 1.76 Hz, 1H), 7.96 (d, J=7.78 Hz, 1H), and 8.73 (d, 1H).
Reaction SMILES: [CH2:1]([C:8]1[CH2:12][CH2:11][CH:10](O)[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCCCCC.[H-].[Na+].[Cl:22][C:23]([Cl:27])([Cl:26])[C:24]#[N:25].CC[O:30]CC>C1(C)C(C)=CC=CC=1>[CH2:1]([C:8]1([NH:25][C:24](=[O:30])[C:23]([Cl:27])([Cl:26])[Cl:22])[CH2:12][CH2:11][CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC1C=C(Cc2ccccc2)CC1
Reactant: N#CC(Cl)(Cl)Cl
Reactant: CCOCC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: CCCCCC
Product: O=C(NC1(Cc2ccccc2)C=CCC1)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 33 %

Procedure:
A solution of compound 3-benzyl-2-cyclopentenol (3.0 g, 17.2 mmol) in ether (50 mL) was added to a suspension of hexane washed 60% NaH (468 mg, 11.7 mmol) in ether (50 mL) at 0° C. under N2 and stirred for 1 h. Trichloroacetonitrile (3.0 g, 20.8 mmol) was slowly added and the resulting mixture was allowed to warm to ambient temperature and stirred overnight. The solvent was removed in vacuo, hexane (25 mL) was added and the mixture was cooled to 0° C. Methanol (1 mL) was added and the resulting solid was filtered through Celite. The organic solvent was removed in vacuo to give a crude intermediate (3.2 g). This intermediate was dissolved in xylene (0.1 L) and heated to reflux for 3 h under N2. The solvent was removed in vacuo, and the residue was purified by column on silica gel (100 g, EtOAc/hexane (1:9), to give the title compound (1.8 g, 33%) as a white crystal: mp 127-128° C.;
Reaction SMILES: COCCOC.[CH2:7]([O:14][CH2:15][CH:16]=[CH2:17])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Cl:18][C:19]([Cl:24])(Cl)[C:20](Cl)=[O:21]>O.C(OCC)C.[Zn].S([O-])([O-])(=O)=O.[Cu+2]>[CH2:7]([O:14][CH2:15][CH:16]1[CH2:17][C:20](=[O:21])[C:19]1([Cl:24])[Cl:18])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C=CCOCc1ccccc1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [Zn]
Solvent: COCCOC
Solvent: CCOCC
Solvent: O
Product: O=C1CC(COCc2ccccc2)C1(Cl)Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Zinc dust (6.54 g, 0.1 mol) was suspended in water (30 ml) and argon bubbled through the suspension for 15 minutes before the addition of copper (II) sulphate (780 mg, 3.1 mmol). The reaction mixture was stirred at room temperature, under argon for 30 minutes. The mixture was filtered under a stream of argon and the solid washed with water (100 ml), acetone (100 ml) and dried in vacuo for 4 hours. The resultant zinc/copper couple was suspended in diethyl ether:1,2-dimethoxyethane (70 ml:10 ml) under argon and allyl benzyl ether (4.6 ml, 30 mmol) added. A solution of trichloroacetyl chloride (9 ml, 81 mmol) in diethyl ether:1,2-dimethoxyethane (58 ml:7 ml) was added dropwise over 45 minutes and the reaction mixture heated to reflux for 48 hours. The reaction mixture was filtered through Celite® and the salts washed with diethyl ether (3×70 ml). The filtrate was evaporated in vacuo and the residue redissolved in hexane (150 ml). The remaining solids were removed by filtration and the filtrate washed with a saturated aqueous solution of sodium hydrogen carbonate (2×100 ml), brine (80 ml), dried over magnesium sulphate, filtered and evaporated in vacuo. The crude material was purified by column chromatography over silica gel eluting with 10-25% hexane:diethyl ether. The title compound was obtained as a yellow oil (7.03 g, 27.3 mmol, 91%).
Reaction SMILES: [CH:1]([Mg]Br)([CH3:3])[CH3:2].[C:6]1([P:12](Cl)Cl)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:15]1([Mg]Br)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CCOCC>[CH:1]([P:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:3])[CH3:2]
Reactant: CC(C)[Mg]Br
Reactant: ClP(Cl)c1ccccc1
Reactant: Br[Mg]c1ccccc1
Solvent: CCOCC
Product: CC(C)P(c1ccccc1)c1ccccc1
Temperature: -25 °C
Reaction time: 0.25 h
Yield: 49 %

Procedure:
193 ml of a 2.6 Molar solution of 503 mmoles of isopropylmagnesium bromide in ether was added dropwise to a stirred solution of 89.96 g (502.6 mmoles) of phenyldichlorophosphine in 750 ml of anhydrous ether, maintained at -25° C. under an inert atmosphere. After the addition was complete, the mixture was stirred for 15 minutes at a temperature of -25° C. and then was allowed to gradually warm to +8° C. 325 ml of a 2.01 Molar solution of 653 mmoles of phenylmagnesium bromide in ether was then added dropwise at a temperature of between +8° C. to +32° C. The mixture was refluxed for one-half hour, and hydrolyzed. Distillation gave isopropyldiphenylphosphine. 31P-NMR(delta)=0.49 ppm (relative intensity 999.96), Yield=about 49%, BP=122°-124° C. at 0.3 torr.
Reaction SMILES: [CH3:1][CH:2]([C:13](=O)[CH:14]([CH3:25])[CH2:15]C1C(C)(C)C2CC1CC2)[CH2:3][CH:4]1[C:9]([CH3:11])([CH3:10])[CH:8]2[CH2:12][CH:5]1[CH2:6][CH2:7]2.[NH2:27][CH2:28][CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.[H][H]>O=[Pt]=O.C(O)C>[CH3:25][CH:14]([CH:13]([NH:27][CH:28]([CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)[CH:4]1[C:9]([CH3:11])([CH3:10])[CH:8]2[CH2:12][CH:5]1[CH2:6][CH2:7]2)[CH:2]([CH3:1])[CH2:3][CH:4]1[C:9]([CH3:11])([CH3:10])[CH:8]2[CH2:12][CH:5]1[CH2:6][CH2:7]2)[CH3:15]
Reactant: [H][H]
Reactant: NCC1CCNCC1
Reactant: CC(CC1C2CCC(C2)C1(C)C)C(=O)C(C)CC1C2CCC(C2)C1(C)C
Agent: O=[Pt]=O
Solvent: CCO
Product: CC(C)C(NC(C1CCNCC1)C1C2CCC(C2)C1(C)C)C(C)CC1C2CCC(C2)C1(C)C

Procedure:
A mixture of 2,4-dimethyl-1,5-di-(3,3-dimethylnorborn-2-yl)-3-pentanone (g., 0.1 mole) and 4-aminomethylpiperidine (34.2 g., 0.3 mole) ml. ethanol is hydrogenated with PtO2 at room temperature and 40 psi hydrogen pressure. The 2.5 g. platinum catalyst is filtered off and the ethanol removed under reduced pressure. The residual oil is dissolved in ether and the ether solution washed several times with water to remove the excess 4-aminomethylpiperidine. The ether extracts are dried over anhydrous sodium sulfate and concentrated under vacuum to leave 4-[2,4-dimethyl-1,5-di-(3,3-dimethylnorborn-2-yl)-3-pentylaminomethyl]piperidine.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][S:9]([N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:5]=[N:6][CH:7]=1.[CH3:19][N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[C:21]1B(O)O>>[CH3:19][N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[C:21]1[C:2]1[CH:3]=[C:4]([O:8][S:9]([N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:5]=[N:6][CH:7]=1
Reactant: CN1CCN(S(=O)(=O)Oc2cncc(Br)c2)CC1
Reactant: Cn1c(B(O)O)cc2ccccc21
Product: CN1CCN(S(=O)(=O)Oc2cncc(-c3cc4ccccc4n3C)c2)CC1

Procedure:
4-Methyl-piperazine-1-sulfonic acid 5-bromo-pyridin-3-yl ester and N-methyl-indoleboronic acid are processed according to the method described in Example 100 to give 4-Methyl-piperazine-1-sulfonic acid 5-(1-methyl-1H-indol-2-yl)-pyridin-3-yl ester. MS (ESI) m/z 387.1 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([CH:8]([CH3:10])[CH3:9])[S:6][CH:7]=1.[P:11]([O:18]CC)([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14].C(OCC)(=O)C>C(OCC)(=O)C.C(O)C>[CH:8]([C:5]1[S:6][CH:7]=[C:3]([CH2:2][P:11](=[O:18])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])[N:4]=1)([CH3:10])[CH3:9]
Reactant: CC(C)c1nc(CCl)cs1
Reactant: CCOP(OCC)OCC
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOP(=O)(Cc1csc(C(C)C)n1)OCC
Temperature: 160 °C
Reaction time: 16 h
Yield: 82.7 %

Procedure:
A mixture of 4-chloromethyl-2-isopropyl-1,3-thiazole (1.90 g) and triethyl phosphite (3.49 g) was stirred at 160° C. for 16 hrs. Excess triethyl phosphite was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:1, v/v), ethyl acetate, then ethyl acetate-ethanol (10:1, v/v) to give diethyl [(2-isopropyl-1,3-thiazol-4-yl)methyl]phosphonate as a pale-yellow oil (2.48 g, yield 83%).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[Cl:13][C:14]1[CH:33]=[CH:32][C:17]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([OH:31])=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[C:16]([F:34])[CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:55][CH2:56][N:57]1[C:62](=[O:63])[CH2:61][O:60][CH2:59][C:58]1=[O:64]>C(Cl)Cl>[ClH:13].[Cl:13][C:14]1[CH:33]=[CH:32][C:17]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:31][CH2:55][CH2:56][N:57]4[C:62](=[O:63])[CH2:61][O:60][CH2:59][C:58]4=[O:64])=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[C:16]([F:34])[CH:15]=1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Reactant: O=C1COCC(=O)N1CCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCN1C(=O)COCC1=O
Product: Cl
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 39 %

Procedure:
Diethyl azodicarboxylate (472 μl, 3 mmol) was added dropwise to a mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (319.5 mg, 1 mmol), (prepared as described for the staring material in Example 2), triphenylphosphine (786 mg, 3 mmol) and 4-(2-hydroxyethyl)-3,5-dioxomorpholine (223 mg, 1.4 mmol) in methylene chloride (10 ml) under nitrogen. The mixture was stirred at ambient temperature for 4.5 hours and the insolubles were removed by filtration. The solvent was removed from the filtrate by evaporation and the residue was purified by column chromatography eluting with methylene chloride/acetonitrile/methanol (85/12.5/2.5). The purified product was dissolved in methylene chloride, 2M ethereal hydrogen chloride (1 ml) was added and the mixture was diluted with ether. The resulting precipitate was collected by filtration, washed with ether and dried under vacuum to give 4-(4-chloro-2-fluoroanilino)-7-(2-(3,5-dioxomorpholino)ethoxy)-6-methoxyquinazoline hydrochloride (97 mg, 20%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:12]=[N:13][C:14]4[C:19]([CH3:21])([CH3:20])[C:18](=[O:22])[N:17]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:15]=4[N:16]=3)=[N:9][N:8](CC3C=CC(OC)=CC=3)[C:5]2=[N:6][CH:7]=1.[N+]([O-])([O-])=O.[Ce+4].[NH4+].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O>C(#N)C.O>[F:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:12]=[N:13][C:14]4[C:19]([CH3:20])([CH3:21])[C:18](=[O:22])[N:17]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:29])([CH3:28])[CH3:30])[C:15]=4[N:16]=3)=[N:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COc1ccc(Cn2nc(-c3nnc4c(n3)N(COCC[Si](C)(C)C)C(=O)C4(C)C)c3cc(F)cnc32)cc1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: CC1(C)C(=O)N(COCC[Si](C)(C)C)c2nc(-c3n[nH]c4ncc(F)cc34)nnc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
4.148 g (7.546 mmol) of the compound from Example 35A were taken up in acetonitrile (110 ml) and water (55 ml), 12.411 g (22.638 mmol) of ammonium cerium(IV) nitrate were added and the mixture was stirred at room temperature for 20 min. Plenty of water was then added, and a precipitate was filtered off. This solid was washed with water and then with a little diethyl ether. This gave, after drying under high vacuum, 1.53 g (47% of theory) of the title compound.
Reaction SMILES: C([O:3][CH:4](OCC)[CH:5]([CH3:13])[CH:6](OCC)OCC)C.[NH2:17][NH2:18]>>[OH2:3].[NH2:17][NH2:18].[CH3:13][C:5]1[CH:6]=[N:17][NH:18][CH:4]=1
Reactant: CCOC(OCC)C(C)C(OCC)OCC
Agent: NN
Product: Cc1cn[nH]c1
Product: O

Procedure:
In the first step of the present synthesis of 4-MP, propionaldehyde is reacted with triethyl orthoformate in the presence of ethanol and ammonium nitrate to produce 1,1-diethoxypropane. In the second step, the 1,1-diethoxypropane produced in the first step is reacted neat (without a solvent) with a catalyst, which comprises an acid and an amine, to produce 1-ethoxy-1-propene (ethyl-1-propenyl ether). In the third step, this material is purified by washing and drying, without distillation. In the fourth step, the 1-ethoxy-1-propene from the third step is reacted with triethyl orthoformate in the presence of boron trifluoride-diethyl etherate to produce 1,1,3,3-tetraethoxy-2-methyl propane (“TEMP”). In the fifth step, the TEMP from the third step is reacted with hydrazine or a hydrazonium salt or hydrazine hydrate at elevated temperatures to produce 4-methylpyrazole.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[OH:20].C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CS(C)=O.O>[Br:1][C:2]1[C:3]([O:20][C:14]2[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:13]=2[F:12])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1cnc(Cl)c(Br)c1
Reactant: Oc1ccc(F)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)c1cnc(Oc2ccc(F)cc2F)c(Br)c1
Temperature: 100 °C
Yield: 67.7 %

Procedure:
5-Bromo-6-chloronicotinic acid (3.00 g, 12.7 mmol), 2,4-difluorophenol (3.30 g, 25.4 mmol) and cesium carbonate (16.5 g, 50.8 mmol) were combined in DMSO (25.4 mL), heated at 100° C. for 6 hours, cooled, diluted with 150 mL of iced water and the pH was adjusted to pH 3 with 12M HCl. The resulting solid was collected by filtration, washed with cold water and dried to constant mass to afford the title compound (2.84 g, 64%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.CCCCCC.C([Li])CCC.[CH2:20]([N:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]([CH2:37][C:38](OCC)=[O:39])([OH:36])[C:28]1=[O:43])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O1CCCC1.O>[CH2:20]([N:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]([OH:36])([CH2:37][C:38]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=2)=[O:39])[C:28]1=[O:43])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: Cc1ccc(N)cc1
Reactant: CCOC(=O)CC1(O)C(=O)N(Cc2ccccc2)c2ccccc21
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1ccc(NC(=O)CC2(O)C(=O)N(Cc3ccccc3)c3ccccc32)cc1
Reaction time: 0.17 h
Yield: 45.3 %

Procedure:
To a solution of 0.254 g of p-toluidine in 10 ml of dry tetrahydrofuran was added dropwise 1.3 ml of a 1.59M hexane solution of n-butyl lithium at -78° C. under a nitrogen atmosphere, followed by stirring at that temperature for 10 minutes. To the mixture was added a solution of 0.299 g of 1-benzyl-3-(ethoxycarbonylmethyl)-3-hydroxyindolin-2-one in 5 ml of dry tetrahydrofuran at -78° C., followed by stirring at that temperature for 30 minutes. Water was added to the reaction mixture, and the product was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=5/1) to give 0.161 g (44%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]2[CH2:8][CH:4]([CH2:5][CH2:6]2)[C:3]=1[CH:9]=O.C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[CH:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]2[CH2:8][CH:4]([CH2:5][CH2:6]2)[C:3]=1/[CH:9]=[CH:18]/[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: O=CC1=C(Cl)C2CCC1C2
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CCOC(=O)/C=C/C1=C(Cl)C2CCC1C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.9 %

Procedure:
To a solution of 334a (9.0 g, 57.7 mmol) in methylene chloride (250 mL) was added ethyl 2-(triphenyl-λ5-phosphanylidene)acetate (20 g, 57.7 mmol). The mixture was stirred at room temperature for overnight. After reaction the reaction solution was evaporated in vacuo. The residue was purified by column chromatography eluting with 1:100 ethyl acetate/petroleum ether to give 334b as a yellow oil (6.0 g, 46%). MS: [M+H]+ 227.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Br[C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][N:8]=1.C([O-])([O-])=O.[K+].[K+].O>CN1C(=O)CCC1>[Br:13][C:10]1[CH:11]=[CH:12][C:7]([N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)=[N:8][CH:9]=1
Reactant: Brc1ccc(Br)nc1
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Brc1ccc(-n2cncn2)nc1
Temperature: 100 °C
Reaction time: 5 h
Yield: 13.2 %

Procedure:
A mixture of 1,2,4-triazole (1.17 g, 16.9 mmol), 2,5-dibromopyridine (2 g, 8.4 mmol) and K2CO3 (1.2 g, 8.7 mmol) in NMP (20 mL) was heated at 100° C. with stirring for 5 hours. After cooling, the reaction mixture was poured into water (100 mL) and solid was collected by filtration and further purified by column chromatography on silica gel. Elution with EtOAc/Hexanes (0-50%) provided the title compound (250 mg, 13%).
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:12]2[NH:11][C:10]3[CH:9]=C(I)C4C(=O)NC(=O)C=4[C:5]=3[C:4]=2[CH:3]=1.[Br-].[Br:22][C:23]1[CH:48]=[CH:47][CH:46]=[CH:45][C:24]=1[CH2:25][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Li+].[CH3:50]C([N-]C(C)C)C>>[Br:22][C:23]1[CH:48]=[CH:47][CH:46]=[CH:45][C:24]=1/[CH:25]=[CH:9]/[C:10]1[NH:11][C:12]2[C:4]([CH:5]=1)=[CH:3][C:2]([O:1][CH3:50])=[CH:14][CH:13]=2
Reactant: O=C1NC(=O)c2c1c(I)cc1[nH]c3ccc(O)cc3c21
Reactant: CC(C)[N-]C(C)C
Reactant: Brc1ccccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li+]
Product: COc1ccc2[nH]c(/C=C/c3ccccc3Br)cc2c1
Reaction time: 5 h

Procedure:
The 5-methoxy-1H-indole-2-carbaldehyde (1) was reacted with (2-bromobenzyl)(triphenyl)phosphonium bromide using the procedure described in example 37, except that the aldehyde was added at 0° C., the ratio of LDA:aldehyde was 1.46:1 and the reaction time was 5 h, to give (after crystallisation from CH2Cl2/hexane) the diene (531) as a yellow solid (the pure E isomer) (88%), mp 120–123° C. 1H NMR (CDCl3) δ 8.21 (br s, 1H), 7.66 (dd, J=7.9, 1.5 Hz, 1H), 7.59 (dd, J=8.1, 1.0 Hz, 1H), 7.32 (br t, J=7.1 Hz, 1H), 7.27 (d, J=8.3 Hz, 1H), 7.22 (d, J=16.4 Hz, 1H), 7.12 (td, J=7.6, 1.5 Hz, 1H), 7.05 (d, J=16.4 Hz, 1H), 7.04 (d, J=2.4 Hz, 1H), 6.88 (dd, J=8.8, 2.4 Hz, 1H), 6.59 (d, J=1.7 Hz, 1H), 3.86 (s, 3H). Found: C, 61.97; H, 4.30; N, 4.17. C17H14BrNO requires C, 62.21; H, 4.30; N, 4.27.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.P(Cl)(Cl)(Cl)=O.[C:15]([O-])(=[O:17])C.[Na+]>CN(C)C=O.O>[CH:8]1[CH:9]=[C:4]2[CH:3]=[C:2]([CH:15]=[O:17])[O:1][C:5]2=[CH:6][CH:7]=1
Reactant: CC(=O)[O-]
Reactant: c1ccc2occc2c1
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cc2ccccc2o1
Reaction time: 8 h

Procedure:
A solution of benzofuran (163 g, 1.39 mole) in dimethylformamide (264 g, dried over magnesium sulfate overnight) in a 2-1, 3-necked flask was stirred and treated dropwise with phosphorus oxychloride (233 g, 136 ml). The solution was heated and stirred on a steam bath for 8 hrs. Another 88 g of dry dimethylformamide, followed by 70 g (42 ml) of phosphorus oxychloride, was added and the heating and stirring were continued overnight. After cooling, the solution was slowly poured into a stirred solution of 260 g of sodium acetate in 1500 ml of water. The solution was extracted four times with 500 ml of ether. The ether extracts were washed with dilute aqueous sodium hydroxide solution and then with water. The solution was then dried over magnesium sulfate and filtered.