Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][CH2:21][NH:22][C:23](=[O:29])[C@@H:24]([NH2:28])[CH:25]([CH3:27])[CH3:26])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]#[C:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1.C(N(CC)CC)C.[CH2:37]([S:40](Cl)(=[O:42])=[O:41])[CH2:38][CH3:39].[Cl-].[Na+]>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][CH2:21][NH:22][C:23](=[O:29])[C@@H:24]([NH:28][S:40]([CH2:37][CH2:38][CH3:39])(=[O:42])=[O:41])[CH:25]([CH3:27])[CH3:26])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]#[C:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1
Reactant: CCCS(=O)(=O)Cl
Reactant: COc1cc(CCNC(=O)[C@@H](N)C(C)C)ccc1OCC#Cc1ccc(Cl)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCCS(=O)(=O)N[C@H](C(=O)NCCc1ccc(OCC#Cc2ccc(Cl)cc2)c(OC)c1)C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.5 g of (S)-2-amino-3-methyl-butyric acid N-[2-{3-methoxy-4-(3-(4-chlorophenyl)-2-propyn-1-yloxy)-phenyl}-ethyl]-amide and 0.5 ml of triethylamine are dissolved in 50 ml of dioxane. 0.4 ml of 1-propanesulfonyl chloride is added, and the reaction mixture is stirred overnight at room temperature. It is introduced into 200 ml of saturated sodium chloride solution. Extraction is carried out twice using 150 ml of ethyl acetate each time. The organic phases are washed once with 100 ml of saturated sodium chloride solution, dried over magnesium sulfate and concentrated, yielding (S)-2-(propylsulfonyl-amino)-3-methyl-butyric acid N-[2-{3-methoxy-4-(3-(4-chlorophenyl)-2-propyn-1-yloxy)-phenyl}-ethyl]-amide, which is chromatographed on silica gel with ethyl acetate/n-hexane (1:1) and recrystallised from ethyl acetate/n-hexane, m.p. 131-133° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH:19]=O)=[N:4][CH:5]=[C:6]([N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])[CH:7]=1.[CH3:21][C:22]([S@@:25]([NH2:27])=[O:26])([CH3:24])[CH3:23]>C(Cl)Cl.S([O-])([O-])(=O)=O.[Cu+2]>[Br:1][C:2]1[C:3](/[CH:19]=[N:27]\[S@:25]([C:22]([CH3:24])([CH3:23])[CH3:21])=[O:26])=[N:4][CH:5]=[C:6]([N:8]2[C:9](=[O:18])[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:16]2=[O:17])[CH:7]=1
Reactant: O=Cc1ncc(N2C(=O)c3ccccc3C2=O)cc1Br
Reactant: CC(C)(C)[S@@](N)=O
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: CC(C)(C)[S@](=O)/N=C\c1ncc(N2C(=O)c3ccccc3C2=O)cc1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Copper(II) sulfate (anhydrous, 5.8 g, 36.2 mmol) was added to a solution of 3-bromo-5-(1,3-dioxoisoindolin-2-yl)picolinaldehyde (30B, 6 g, 18 mmol) and (S)-2-methylpropane-2-sulfinamide (2.2 g, 18 mmol) in CH2Cl2 (60 mL). The reaction mixture was stirred at ambient temperature for 2 hours and then filtered and washed with CH2Cl2. The filtrate was concentrated and the residue was purified by silica gel chromatography eluting with EtOAc and methylene chloride to yield the title compound. MS (m/z) 433.87 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][CH:3]=1.C([Li])CCC.[F:20][C:21]([F:28])([F:27])[C:22](OCC)=[O:23]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:11])([CH3:13])[CH3:12])=[C:6]([C:22](=[O:23])[C:21]([F:28])([F:27])[F:20])[CH:7]=1
Reactant: CCOC(=O)C(F)(F)F
Reactant: CC(C)(C)C(=O)Nc1ccc(Cl)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Nc1ccc(Cl)cc1C(=O)C(F)(F)F
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
To a −40° C. mixture of N-(4-chlorophenyl)-2,2-dimethylpropanamide (4.0 g, 18.9 mmol) and anhydrous tetrahydrofuran (38 ml), n-butyllithium (1.6M, 45.2 mmol) was added under nitrogen atmosphere. The reaction was stirred for 30 minutes at −40° C. and allowed to warm to 0° C. where upon the yellow homogenous mixture turned gradually darker to a deep yellow color. After 30 minutes of stirring at 0° C., the reaction was cooled to 40° C. Ethyl trifluoroacetate (6.1 g, 43.5 mmol) was added to the mixture and allowed to warm to room temperature overnight. The reaction was quenched with water (100 ml) and saturated aqueous ammonium chloride solution (80 ml). The aqueous layer was extracted with ethyl acetate (3×75 ml). Combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo to afford a dark yellow oil. Flash chromatography on silica gel (0-50% ethyl acetate/hexanes) afforded N-[4-chloro-2-(trifluoroacetyl)phenyl]-2,2-dimethyl-propanamide. 1H NMR (CDCl3, 400 MHz) δ 11.15 (s), 8.89 (d, J=9.2 Hz, 1H), 7.92 (m, 1H), 7.65 (dd, J=2.4 and 9.2 Hz, 1H), 1.36 (s, 9H). MS (Electrospray): m/z 308.0 (M+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]3[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:15][CH:16]=3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[F:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1>>[F:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([C:11]4[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][C:19]5[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=5)[CH2:15][CH:16]=4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:31])=[CH:28][CH:27]=1
Reactant: Nc1ccc2[nH]cc(C3=CCN(CCc4ccccc4)CC3)c2n1
Reactant: O=C(Cl)c1ccc(F)cc1
Product: O=C(Nc1ccc2[nH]cc(C3=CCN(CCc4ccccc4)CC3)c2n1)c1ccc(F)cc1

Procedure:
Beginning with 0.015 gm (0.047 mMol) 5-amino-3-(1-(2-phenyleth-1-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo[3,2-b]pyridine and 0.007 mL (0.061 mMol) 4-fluorobenzoyl chloride, the title compound was prepared essentially by the procedure described in Example 7. MS(m/e): 441(M+1)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5]([CH2:11][CH2:12][C:13]#[N:14])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[H-].[Na+].Cl[C:19]1[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][C:22]([CH3:28])=[CH:21][N:20]=1>O1CCCC1>[CH3:28][C:22]1[CH:23]=[C:24]([N+:25]([O-:27])=[O:26])[C:19]([C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:15])([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:11][CH2:12][C:13]#[N:14])=[N:20][CH:21]=1
Reactant: CCOC(=O)C(CCC#N)C(=O)OCC
Reactant: Cc1cnc(Cl)c([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(CCC#N)(C(=O)OCC)c1ncc(C)cc1[N+](=O)[O-]
Yield: 37.4 %

Procedure:
2-(2-Cyanoethyl)malonic acid diethylester (40 g) was reacted with sodium hydride (4.4 gm) in tetrahydrofuran at 20° C. 2-Chloro-5-methyl-3-nitro-pyridine (35 g) was added and the internal temperature was raised to 100° C. (some tetrahydrofuran distilled off) over 4.25 hrs. The reaction mixture was partitioned between chloroform and water and treated with charcoal. Vacuum distillation of the chloroform extract and then chromatography (CHCl3, silica column) of the distillation residues gave 4-(5-methyl-3-nitropyrid-2-yl)-4,4-bis(carbethoxy)butyronitrile (24.5 g) as a yellow solid m.p. 48°-49° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[C:11](OC(=O)C)(=[O:13])[CH3:12].Cl>O>[CH3:12][C:11]([NH:8][C:6]1[CH:5]=[CH:4][C:3]([O:9][CH3:10])=[C:2]([NH2:1])[CH:7]=1)=[O:13]
Reactant: COc1ccc(N)cc1N
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: O
Product: COc1ccc(NC(C)=O)cc1N
Yield: 75 %

Procedure:
Other aqueous processes of acylation have been taught to yield the single desired isomer compound I where R is --CH3 and --XR1 is --COCH3, but at lower yield. German 1,543,625, Example 1, teaches the acylation of freshly-distilled 2,4-diaminoanisole with acetic anhydride in water solution, without the addition of hydrochloric acid, to give 3-amino-4-methoxyacetanilide in 75% yield before recrystallization. Publication, Board of Federal Intelligence Agency, P.B. 74 051, p. 33 teaches a similar conversion of 2,4-diaminoanisole to 2-amino-4-acetamidoanisole, in aqueous solution, with acetic anhydride, in the presence of magnesia at 65% yield.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[C:6]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1>[Cl:4][CH:14]([C:6](=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: O=S(=O)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)C(Cl)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.3 %

Procedure:
A solution of sulfuryl chloride (12.4 mmol) in toluene (5 mL) was added dropwise via an additional funnel to a solution of ethyl benzoylacetate (12.4 mmol) in toluene (20 mL) over 5 minutes at room temperature. The resulting mixture was stirred at room temperature overnight. Water was added slowly and resulting two-phase mixture was basified with saturated NaHCO3 and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, and evaporated to afford 2.2 g (84%) of product as a pale yellow oil; MH+=227.0, retention time (LC-MS)=2.77 min.
Reaction SMILES: [CH2:1]([N:8]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C@H:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2B2OC(C)(C)C(C)(C)O2)[O:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:36]1[CH:37]=[N:38][C:39]([CH:42]2[CH2:44][CH2:43]2)=[N:40][CH:41]=1>>[CH2:28]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@H:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2[C:36]2[CH:37]=[N:38][C:39]([CH:42]3[CH2:44][CH2:43]3)=[N:40][CH:41]=2)[O:11][CH2:10]1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: Brc1cnc(C2CC2)nc1
Reactant: CC1(C)OB(c2cccc3c2C[C@H](N(Cc2ccccc2)Cc2ccccc2)CO3)OC1(C)C
Product: c1ccc(CN(Cc2ccccc2)[C@@H]2COc3cccc(-c4cnc(C5CC5)nc4)c3C2)cc1
Yield: 53 %

Procedure:
The title compound was synthesized as described for Intermediate example I-28 in 53% yield, starting from (3S)-N,N-dibenzyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)chroman-3-amine and 5-bromo-2-cyclopropylpyrimidine (1.1 equiv); 1H NMR (400 MHz, CDCl3) δ ppm 8.55 (s, 2 H), 7.27-7.36 (m, 8 H), 7.13-7.26 (m, 3 H), 6.86 (dd, 1 H), 6.75 (dd, 1 H), 4.32-4.41 (m, 1 H), 4.02 (t, 1 H), 3.70 (s, 4 H), 3.14-3.25 (m, 1 H), 2.76-2.89 (m, 1 H), 2.59-2.69 (m, 1 H), 2.30-2.40 (m, 1 H), 1.22-1.28 (m, 2 H), 1.13-1.21 (m, 2 H); MS (ESI) m/z 448[M+H+].
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][C@@H:19]([C:21]([O:23][CH3:24])=[O:22])[CH3:20])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.Cl.Cl[CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[N:29]1([CH2:28][CH2:27][N:18]([S:15]([C:12]2[CH:13]=[CH:14][C:9]([S:8][C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=3)=[CH:10][CH:11]=2)(=[O:17])=[O:16])[C@@H:19]([C:21]([O:23][CH3:24])=[O:22])[CH3:20])[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1
Reactant: ClCCN1CCOCC1
Reactant: COC(=O)[C@@H](C)NS(=O)(=O)c1ccc(Sc2ccc(C)cc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](C)N(CCN1CCOCC1)S(=O)(=O)c1ccc(Sc2ccc(C)cc2)cc1
Temperature: 70 °C
Yield: 81.9 %

Procedure:
A mixture of N-[[4-[(4-methylphenyl)thio]phenyl]sulfonyl]-D-alanine, methyl ester from Example 4b (6.4 g, 17.5 mmol), 4-(2-chloroethyl)morpholine hydrochloride (9.77 g, 52.5 mmol), and potassium carbonate (10 g, 72.4 mmol) in dry DMF (60 mL) was heated to 70° C. for 16 hours. After cooling to room temperature, mixture was poured into water and extracted with ethyl acetate. The combined ethyl acetate layers were washed with water and brine, dried over MgSO4, and concentrated to afford an oil which was purified by chromatography (40/100 acetone/hexane) to give N-[2-(4-morpholinyl)ethyl]-N-[[4-[(4-methylphenyl)thio]phenyl]sulfonyl]-D-alanine, methyl ester, (6.86 g, 81.86%) as an oil. The proton NMR was consistent with N-[2-(4-morpholinyl)ethyl]-N-[[4-[(4-methylphenyl)thio]phenyl]sulfonyl]-D-alanine, methyl ester. HR mass calculated for C23H30N2O5S2 : 478.1597.Found: 478.1596.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH3:22])[C:6]=1[N:7]1[CH2:13][CH2:12][CH:11]([F:14])[CH:10]([NH:15]C(=O)C(F)(F)F)[CH2:9][CH2:8]1.C(OC([NH:30][C:31]1[S:35][C:34]([C:36]2[C:41]([F:42])=[CH:40][CH:39]=[CH:38][N:37]=2)=[N:33][C:32]=1[C:43](O)=[O:44])=O)(C)(C)C>>[NH2:30][C:31]1[S:35][C:34]([C:36]2[C:41]([F:42])=[CH:40][CH:39]=[CH:38][N:37]=2)=[N:33][C:32]=1[C:43]([NH:1][C:2]1[CH:3]=[N:4][N:5]([CH3:22])[C:6]=1[N:7]1[CH2:13][CH2:12][C@H:11]([F:14])[C@@H:10]([NH2:15])[CH2:9][CH2:8]1)=[O:44]
Reactant: Cn1ncc(N)c1N1CCC(F)C(NC(=O)C(F)(F)F)CC1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2ncccc2F)nc1C(=O)O
Product: Cn1ncc(NC(=O)c2nc(-c3ncccc3F)sc2N)c1N1CC[C@H](N)[C@@H](F)CC1
Yield: 72 %

Procedure:
Following the procedure for Example 107 starting from N-(1-(4-amino-1-methyl-1H-pyrazol-5-yl)-5-fluoroazepan-4-yl)-2,2,2-trifluoroacetamide and 5-(tert-butoxycarbonylamino)-2-(3-fluoropyridin-2-yl)thiazole-4-carboxylic acid gave 297 as a pale brown solid (424 mg, 72% over 2 steps). 1H NMR (400 MHz, CDCl3) δ 8.70 (s, 1H), 8.39 (dt, J=4.6, 1.4 Hz, 1H), 7.86 (s, 1H), 7.52 (ddd, J=10.8, 8.3, 1.4 Hz, 1H), 7.32-7.26 (m, 1H), 6.32 (s, 2H), 4.51 (dtd, J=47.9, 8.5, 3.6 Hz, 1H), 3.73 (s, 3H), 3.40-3.17 (m, 5H), 2.34-2.19 (m, 1H), 2.16-1.96 (m, 2H), 1.79-1.66 (m, 1H). Alkyl NH2 not seen. LCMS (ES+) m/z 449 (M+1)
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[Cl:11][C:12]1[CH:13]=[C:14]([CH2:19][CH2:20][NH:21][C:22]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:26][N:25]=2)=O)[CH:15]=[CH:16][C:17]=1[Cl:18].O>C1COCC1>[C:30]([C:27]1[CH:28]=[CH:29][C:24]([CH2:22][NH:21][CH2:20][CH2:19][C:14]2[CH:15]=[CH:16][C:17]([Cl:18])=[C:12]([Cl:11])[CH:13]=2)=[N:25][CH:26]=1)([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)c1ccc(C(=O)NCCc2ccc(Cl)c(Cl)c2)nc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1ccc(CNCCc2ccc(Cl)c(Cl)c2)nc1
Reaction time: 0.25 h
Yield: 68.4 %

Procedure:
Diisobutylaluminum hydride (1 M solution in THF, 0.40 mL, 0.40 mmol) was added dropwise to a solution of 5-tert-butyl-pyridine-2-carboxylic acid [2-(3,4-dichloro-phenyl)-ethyl]-amide (195 mg, 0.555 mmol) in THF (2 mL) at 0° C., then after 15 min, the reaction was stopped by careful addition of water. The reaction mixture was partitioned between ethyl acetate and 1 M aq. potassium sodium tartrate solution, the organic layer was washed with brine, dried (MgSO4), and concentrated. Chromatography (SiO2, heptane/ethyl acetate 1:1, then dichloromethane/methanol 9:1) afforded (5-tert-butyl-pyridin-2-ylmethyl)-[2-(3,4-dichloro-phenyl)-ethyl]-amine (128 mg, 68%). Yellow oil, MS (ISP): 337.3 (M+H)+.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1.[C:14]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1)(=[O:16])[CH3:15].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:14]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:3][C:4]2[CH:13]=[CH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)=[CH:20][CH:19]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)Nc1ccc(O)cc1
Reactant: ClCc1ccc2ccccc2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(OCc2ccc3ccccc3n2)cc1
Temperature: 0 °C

Procedure:
A mixture containing 2-(chloromethyl)quinoline hydrochloride (100.0 g), 4-acetamidophenol (70.69 g) and milled anhydrous potassium carbonate (194 g) was stirred in DMF (1.2 L) using a mechanical stirrer for 48 hours. The mixture was carefully poured onto ice/water (3 L) with vigourous stirring. After the ice had melted, the solid was filtered and rinsed thoroughly with water. It was recrystallized from 95% ethanol and filtered to give the title compound in three crops.
Reaction SMILES: CC1C=CC=C(C)N=1.[N+](C1C=CC(C=O)=CC=1)([O-])=[O:10].[N+:20]([C:23]1[CH:47]=[CH:46][C:26]([CH:27]=[CH:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([CH:35]=[CH:36][C:37]3[CH:42]=[CH:41][C:40]([N+:43]([O-:45])=[O:44])=[CH:39][CH:38]=3)[N:30]=2)=[CH:25][CH:24]=1)([O-:22])=[O:21].ClC1C=CC=C(C(OO)=O)C=1>ClCCl>[N+:20]([C:23]1[CH:47]=[CH:46][C:26]([CH:27]=[CH:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([CH:35]=[CH:36][C:37]3[CH:42]=[CH:41][C:40]([N+:43]([O-:45])=[O:44])=[CH:39][CH:38]=3)[N+:30]=2[O-:10])=[CH:25][CH:24]=1)([O-:22])=[O:21]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: O=[N+]([O-])c1ccc(C=Cc2cccc(C=Cc3ccc([N+](=O)[O-])cc3)n2)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: O=[N+]([O-])c1ccc(C=Cc2cccc(C=Cc3ccc([N+](=O)[O-])cc3)[n+]2[O-])cc1

Procedure:
More specifically, the synthesizing procedure is as follows. 2,6-dimethylpyridine or a substituted product thereof, is reacted with p-nitrobenzenealdehyde or a substituted product according to a method described, for example, in Journal of Organic Chemistry, vol. 15, P. 1184 (1950) to synthesize 2,6-di(p-nitrostyryl)pyridine (K). 30 g of this nitro compound is reacted wtih 27 g of m-chloroperbenzoic acid in three liter of dichloromethane to obtain 24 g of 2,6-di(p-nitrostyryl)pyridine-N-oxide. 24 g of this pyridine-N-oxide is reacted with 90 g of sodium sulfide in a solution mixed four liter of water with four liter of ethanol to reduce nitro group selectively and form 18 g of 2,6-di(p-aminostyryl)pyridine-N-oxide (M). The N-oxide amino compound is converted into a diazo compound according to a conventional method, and thereby tetrazonium salt is isolated as 15 g of hydroborofluoric salt (N). 5.0 g of the tetrazonium salt (N) and 5.0 g of 2-hydroxy-3-phenylcarbamoylnaphthalene (O) were dissolved in one liter of DMF, to which aqueous sodium acetate solution (7 g/100 ml) was added to perform coupling reaction. After two hours of stirring, the resultant crystals were separated by filtration, and the crystals were rinsed three times respectively with five liter water, three times respectively with five liter THF, then dried, to obtain 4.0 g of the final product, azo compound (P - 1).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:9]([Cl:10])=[C:8]([O:11][CH3:12])[CH:7]=[CH:6][C:5]=1[OH:13].F[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1>CN(C=O)C>[Cl:10][C:9]1[C:4]([Cl:3])=[C:5]([O:13][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)[CH:6]=[CH:7][C:8]=1[O:11][CH3:12]
Reactant: COc1ccc(O)c(Cl)c1Cl
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(Oc2ccc([N+](=O)[O-])cc2)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a suspension of NaH (2.5 g., 0.052 mole of a 50% mineral oil suspension) in 60 ml. of DMF was added portionwise 2,3-dichloro-4-methoxyphenol (9.0 g., 0.047 mole) prepared as described by F. Dallacker and J. Van Wersch, Chem. Ber., 105, 3301 (1972). The mixture was stirred at room temperature under nitrogen for 15 minutes and then p-fluoronitrobenzene was rapidly added. The resulting mixture was heated at 100° for 2.5 hr., cooled to room temperature, and poured into ice water. The precipitate was filtered, washed with methanol and dried to give 13 g. of product, m.p. 165°-166°.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][C:5]=1[C:11]([F:14])([F:13])[F:12].[C:17]([Si:21]([CH3:31])([CH3:30])[O:22][CH:23]1[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]1)([CH3:20])([CH3:19])[CH3:18].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[C:17]([Si:21]([CH3:31])([CH3:30])[O:22][CH:23]1[CH2:28][CH2:27][CH:26]([NH:10][C:7]2[CH:8]=[CH:9][C:4]([O:3][C:2]([F:15])([F:16])[F:1])=[C:5]([C:11]([F:12])([F:13])[F:14])[CH:6]=2)[CH2:25][CH2:24]1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(=O)CC1
Reactant: Nc1ccc(OC(F)(F)F)c(C(F)(F)F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC1CCC(Nc2ccc(OC(F)(F)F)c(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 144 h
Yield: 66 %

Procedure:
(4-Trifluoromethoxy-3-trifluoromethyl-phenyl)-amine (735 mg, 3 mmol) and 4-(tert-butyl-dimethyl-silyloxy)-cyclohexanone (685 mg, 3 mmol) were dissolved in dichloromethane (25 mL). Next, sodium triacetoxyborohydride (1.27 g, 6 mmol) was added. The resulting mixture was stirred at room temperature for 6 days. Afterward, the mixture was diluted with dichloromethane (25 mL), washed with water (20 mL), washed with HCl 1N (20 mL), washed with water (20 mL), and washed with brine (20 mL). The organic layer was collected, dried over magnesium sulfate, filtered, and concentrated under vacuum to afford an oily residue. The residue was purified by column chromatography on silica gel (pentane/ether gradient). The desired product was isolated as a colorless oil (900 mg of 1:1 mixtures of cis and trans isomers, 66% yield).
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][C:6]=1[Cl:15])(=O)C.[CH3:16][NH:17][CH3:18].Cl.CO>>[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:17]([CH3:18])[CH3:16])(=[O:13])=[O:12])=[CH:7][C:6]=1[Cl:15]
Reactant: CNC
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1Cl
Agent: Cl
Solvent: CO
Product: CN(C)S(=O)(=O)c1ccc(N)c(Cl)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 15.8 %

Procedure:
A suspension of 4-acetamido-3-chlorobenzene-1-sulfonyl chloride (0.96 g, 3.58 mmol) in a dimethylamine solution (2M in MeOH, 5.37 mL, 10.7 mmol) was stirred at room temperature for 2.5 hours. The reaction mixture was concentrated under reduced pressure and the residue was then redissolved in MeOH (17.9 mL). A 1M HCl solution in MeOH (5.37 mL, 5.37 mmol) was added and the reaction mixture was refluxed for 6 hours before being concentrated under reduced pressure. The residue was purified via Biotage silica gel column chromatography eluting with (cyclohexane/EtOAc 80/20 to 60/40) to afford the title product as a white solid (133 mg, 16%). 1H NMR (500 MHz, CDCl3) d 2.70 (s, 6H), 4.54 (br s, 2H), 6.83 (d, J=8.5 Hz, 1H), 7.48 (dd, J=8.5, 2.1 Hz, 1H), 7.70 (d, J=2.1 Hz, 1H).
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][CH2:3][C:4]#[CH:5].[F:9][C:10]1[C:11](I)=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])/[C:13]/2=[CH:20]\[C:21]1[NH:22][CH:23]=[CH:24][C:25]=1[O:26][CH3:27]>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.CN(C=O)C.CCN(CC)CC>[CH3:8][O:7][C:1](=[O:6])[CH2:2][CH2:3][C:4]#[C:5][C:11]1[C:10]([F:9])=[CH:18][CH:17]=[C:16]2[C:12]=1/[C:13](=[CH:20]/[C:21]1[NH:22][CH:23]=[CH:24][C:25]=1[O:26][CH3:27])/[C:14](=[O:19])[NH:15]2
Reactant: C#CCCC(=O)OC
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)CCC#Cc1c(F)ccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2

Procedure:
Using Method C above, 4-pentynoic acid methyl ester (75.7 mg, 0.68 5 mmol) (see Example 8, supra) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (100 mg, 0.26 mmol) (Starting Material 6, supra) using (Ph3P)4Pd (31.2 mg) and Cul (5.0 mg) as catalyst in DMF (4 mL) and Et3N (4 mL) as solvent at 80° C. for 7 h to yield (Z)-5-[2,3-Dihydro-5-fluoro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2-oxo-1H-indol-4-yl]-4-pentynoic acid methyl ester. (Yield 86 mg, 90%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19]([NH:22][CH3:23])(=[O:21])=[O:20]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[S:19]([NH:22][CH3:23])(=[O:21])=[O:20])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: CNS(=O)(=O)c1ccccc1N
Solvent: ClC(Cl)Cl
Product: CNS(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1[N+](=O)[O-]
Temperature: 61 °C

Procedure:
2,4-Dichloro-5-nitro-pyrimidine (1.94 g, 10 mmol) and 2-amino-N-methyl-benzenesulfonamide (1.86 g, 10 mmol) are dissolved in CHCl3 (30 mL). The reaction mixture is heated at 61° C. for 2 h. The solvent is evaporated and the residue is washed with ether to give the title product.