Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(C(C)C)C([S:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[NH:14][C:15](=O)[C:16]1[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:23])=S)(C)C.[OH-].[Na+]>Cl>[Cl:23][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([Cl:22])[C:16]=1[C:15]1[S:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][C:13]=2[N:14]=1
Reactant: CC(C)N(C(=S)Sc1cnccc1NC(=O)c1c(Cl)cccc1Cl)C(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Clc1cccc(Cl)c1-c1nc2ccncc2s1
Yield: 77.6 %

Procedure:
A solution of 4-(2,6-dichlorobenzamido)pyridin-3-yl diisopropylcarbamodithioate (50 mg, 0.11 mmol) in 5 M HCl (10 mL) was stirred at 100° C. for 4 hours. The pH of the mixture was adjusted to 7 by the addition of 2N sodium hydroxide solution and the aqueous phase extracted with EtOAc (3×100 mL). The combined organic extract was washed with water (2×50 mL) and brine (100 ml), dried over Na2SO4 and evaporated. The crude product was re-crystallized from EtOAc/DCM/petroleum ether (1:10:10) to give the product as a white solid (24 mg, 76% yield). 1H NMR (500 MHz, MeOH-d4): δ 9.30 (s, 1H), 8.60 (d, J=5.5 Hz, 1H), 8.03 (d, J=5.5 Hz, 1H), 7.54-7.50 (m, 3H). LCMS (Method A): RT=4.84 min, m/z: 281.0 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[CH:4][C:3]=1[NH:10]N=C1CCCCC1=O.OS(O)(=O)=O.[C:24]([O-:27])(O)=O.[Na+]>CC#N>[Cl:9][C:5]1[C:6]([Cl:8])=[CH:7][C:2]([Cl:1])=[C:3]2[C:4]=1[C:2]1[CH2:3][CH2:4][CH2:5][C:24](=[O:27])[C:7]=1[NH:10]2
Reactant: O=C1CCCCC1=NNc1cc(Cl)c(Cl)cc1Cl
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC#N
Product: O=C1CCCc2c1[nH]c1c(Cl)cc(Cl)c(Cl)c21
Temperature: 80 °C
Yield: 35 %

Procedure:
2-(2-(2,4,5-Trichlorophenyl)hydrazono)cyclohexanone (0.3 g, 0.98 mmol) was dissolved in MeCN (6 mL) and H2SO4 (0.1 mL, 1.8 M solution) was added. The reaction mixture was heated to 80° C. for 4 h and slowly cooled to room temperature. Saturated NaHCO3 was added to the reaction mixture until pH 5-6 was obtained and then extracted with EtOAc (3×20 mL). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo to obtain the crude compound which was purified by silica gel chromatography [EtOAc-hexane (1:4) as eluant] to furnish the title compound as a brown solid (0.1 g, 35%). 1H NMR (200 MHz, DMSO-d6, δ in ppm) 12.55 (bs, 1H), 7.68 (s, 1H), 3.27 (t, J=5.6 Hz, 2H), 2.63 (t, J=6.0 Hz, 2H), 2.19 (m, 2H).
Reaction SMILES: [C:1]1([CH:9]=[C:7]([OH:8])[CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[CH:10]1([CH:15]([C:21]([CH3:23])=O)[C:16](OCC)=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11]1.Cl>C(O)C>[CH:10]1([C:15]2[C:16](=[O:17])[O:2][C:1]3[CH:9]=[C:7]([OH:8])[CH:6]=[C:4]([OH:5])[C:3]=3[C:21]=2[CH3:23])[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: Oc1cc(O)cc(O)c1
Reactant: CCOC(=O)C(C(C)=O)C1CCCC1
Agent: Cl
Solvent: CCO
Product: Cc1c(C2CCCC2)c(=O)oc2cc(O)cc(O)c12

Procedure:
A solution of phloroglucinol (2.00 g) and ethyl 2-cyclopentylaceto-acetate (3.14 g) in ethanol (40 ml) was treated with dry HCl at 0° C. for 2.5 hours and the solution kept at that temperature overnight. Solvent was evaporated and the precipitate purified with flash chromatography eluting with toluene-EtOAc-AcOH (8: 1:1). Yield 1.22 g (29%).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:13]=[C:12]([OH:14])[C:11]([OH:15])=[CH:10][C:4]=2[S:5][C:6]=1[C:7]([OH:9])=[O:8].[N+:16]([O-])([OH:18])=[O:17]>C(OCC)(=O)C.ClCCl>[Cl:1][C:2]1[C:3]2[CH:13]=[C:12]([OH:14])[C:11]([OH:15])=[C:10]([N+:16]([O-:18])=[O:17])[C:4]=2[S:5][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1sc2cc(O)c(O)cc2c1Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(O)c1sc2c([N+](=O)[O-])c(O)c(O)cc2c1Cl
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
3-Chloro-5,6-dihydroxy-benzo[b]thiophene-2-carboxylic acid was dissolved in ethyl acetate and a solution of nitric acid in dichloromethane (2M, 0.38 ml) was gradually added at 20° C. The solution was stirred 10 min at room temperature and then it was poured into ice-cold water and extracted with ethyl acetate. The organic extracts were combined, dried and evaporated to dryness. The residue was recrystallized from acetic acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:10][CH3:11])[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.[CH3:12][O:13]C(Cl)Cl>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:11][O:10][C:4]1[C:5]([O:8][CH3:9])=[CH:6][C:7]([CH:12]=[O:13])=[C:2]([F:1])[CH:3]=1
Reactant: COc1ccc(F)cc1OC
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1cc(F)c(C=O)cc1OC
Temperature: 0 °C

Procedure:
In a flame-dried, round-bottomed flask fitted with a magnetic stirrer and N2 inlet was placed 4-fluoroveratrole (0.78 g, 5.0 mmol, Aldrich Chemical Co.) in 20 ml of anhydrous CH2Cl2. After cooling to 0° C., titanium (IV) chloride (0.91 ml, 1.57 g, 8.3 mmol) was added, followed after 10 min. by a,a-dichloromethyl methyl ether (0.45 ml, 0.575 g, 5.0 mmol). The mixture was allowed to warm to room temperature and after 2 hr it was quenched with an excess of aqueous saturated NaHCO3. The suspension was filtered through a pad of d.e. (diatomaceous earth), the aqueous phase was extracted with additional amounts of CH2Cl2 and the organic phases were combined and washed with water followed by saturated aqueous NaCl. After drying with MgSO4, the organic solvent was removed in vacuo to give the title compound as a white solid, 910 mg.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([O:18][CH2:19][CH:20]=[CH2:21])=[O:17])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[OH:8].[CH3:22][O:23][CH:24]([O:41][CH3:42])[C:25]1[C:30]([O:31][CH2:32][O:33][CH3:34])=[C:29]([C:35]([F:38])([F:37])[F:36])[CH:28]=[CH:27][C:26]=1[CH2:39]O>>[CH3:42][O:41][CH:24]([O:23][CH3:22])[C:25]1[C:30]([O:31][CH2:32][O:33][CH3:34])=[C:29]([C:35]([F:38])([F:37])[F:36])[CH:28]=[CH:27][C:26]=1[CH2:39][O:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([O:18][CH2:19][CH:20]=[CH2:21])=[O:17])=[CH:11][CH:10]=2)=[CH:3][C:2]=1[F:1]
Reactant: COCOc1c(C(F)(F)F)ccc(CO)c1C(OC)OC
Reactant: C=CCOC(=O)Cc1ccc(-c2ccc(O)c(F)c2)cc1
Product: C=CCOC(=O)Cc1ccc(-c2ccc(OCc3ccc(C(F)(F)F)c(OCOC)c3C(OC)OC)c(F)c2)cc1
Yield: 93 %

Procedure:
According to a method similar to Example (6-7), from allyl (3′-fluoro-4′-hydroxy-1,1′-biphenyl-4-yl)acetate (300 mg, 1.05 mmol) obtained in Example (12-2) and [2-(dimethoxymethyl)-3-(methoxymethoxy)-4-(trifluoromethyl)phenyl]methanol (500 mg, 1.61 mmol) obtained in Example (6-6), allyl (4′-{[2-(dimethoxymethyl)-3-(methoxymethoxy)-4-(trifluoromethyl)benzyl]oxy}-3′-fluoro-1,1′-biphenyl-4-yl)acetate was obtained (618 mg, yield: 93%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][CH3:19])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][CH:15]=[C:16]([I:17])[C:9]=23)[CH:7]=1.[H-].[Na+].[CH3:22][Si:23]([CH3:30])([CH3:29])[CH2:24][CH2:25][O:26][CH2:27]Cl>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][CH3:19])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[N:14]([CH2:27][O:26][CH2:25][CH2:24][Si:23]([CH3:30])([CH3:29])[CH3:22])[CH:15]=[C:16]([I:17])[C:9]=23)[CH:7]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: COc1ccc(F)cc1-c1ccnc2[nH]cc(I)c12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(F)cc1-c1ccnc2c1c(I)cn2COCC[Si](C)(C)C
Temperature: -5 °C
Reaction time: 0.5 h

Procedure:
A solution of Example 14B (15.1 g, 41.0 mmol) in tetrahydrofuran under nitrogen was cooled to −8° C. and 60% sodium hydride in mineral oil (2.461 g, 61.5 mmol) was added in portions at a rate such that the temperature was maintained at or below −5° C. The solution was stirred 30 minutes at −5° C. and 2-(trimethylsilyl)ethoxymethyl chloride (8.73 mL, 49.2 mmol) was added dropwise over 15 minutes. The mixture was stirred for 30 minutes at −5° C. and allowed to warm to ambient temperature and stirred overnight. The reaction was quenched carefully with aqueous saturated ammonium chloride and diluted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified on an Analogix MPLC using a silica gel column eluting with 100% heptane followed by 7% ethyl acetate/heptanes to provide the title compound. MS (ESI+) m/z 498.8 (M+H)+.
Reaction SMILES: Cl.[Si]([O:9][C@H:10]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[C:11]1=[O:23])(C(C)(C)C)(C)C>C(Cl)Cl>[OH:9][C@H:10]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[C:11]1=[O:23]
Reactant: Cc1ccc(CN2CC[C@H](O[Si](C)(C)C(C)(C)C)C2=O)cc1
Agent: Cl
Solvent: ClCCl
Product: Cc1ccc(CN2CC[C@H](O)C2=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.1 %

Procedure:
HCl (4 M in 1,4-dioxane, 25.5 ml, 102 mmol) was added in one portion to a solution of (S)-3-((tert-butyldimethylsilyl)oxy)-1-(4-methylbenzyl)pyrrolidin-2-one (6.53 g, 20.4 mmol) in anyhdrous DCM (20.44 ml) at rt. A slight exotherm was noted. The reaction mixture was allowed to stir at rt for 2 h and then evaporated in vacuo. The residue was taken up in DCM (100 mL) and washed with a satd. sodium bicarbonate solution (100 mL) and brine (50 mL), and then the solution was dried over MgSO4 and concentrated to a residue. The crude product was purified by silica gel chromatography (120 g of silica) eluting with a gradient of 40% to 100% ethyl acetate in hexanes to provide 3.73 g (89%) of the desired product. LC/MS (Conditions B) RT=2.338 min, (M+H)+=206.2; 1H NMR (400 MHz, chloroform-d) δ 7.26-7.02 (m, 4H), 4.43 (d, J=3.5 Hz, 2H), 4.41-4.37 (m, 1H), 3.66 (d, J=2.6 Hz, 1H), 3.34-3.05 (m, 2H), 2.41 (dddd, J=12.8, 8.4, 6.6, 2.2 Hz, 1H), 2.34 (s, 3H), 1.93 (dq, J=12.8, 8.8 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[S:10][CH:11]=[C:12]([C:15]([CH3:17])=O)[C:13]=2[OH:14])[CH:5]=[CH:6][C:7]=1[Cl:8].[NH:18]([C:20]([C:22]1[S:26][C:25]([C:27]([NH:29][CH2:30][CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[O:28])=[CH:24][CH:23]=1)=[O:21])[NH2:19].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[S:10][CH:11]=[C:12]([C:15](=[N:19][NH:18][C:20]([C:22]3[S:26][C:25]([C:27]([NH:29][CH2:30][CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[O:28])=[CH:24][CH:23]=3)=[O:21])[CH3:17])[C:13]=2[OH:14])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(=O)c1csc(-c2ccc(Cl)c(Cl)c2)c1O
Reactant: CC(C)(C)OC(=O)CCNC(=O)c1ccc(C(=O)NN)s1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Solvent: O
Product: CC(=NNC(=O)c1ccc(C(=O)NCCC(=O)OC(C)(C)C)s1)c1csc(-c2ccc(Cl)c(Cl)c2)c1O
Temperature: 25 °C
Yield: 84.3 %

Procedure:
2-(3,4-Dichlorophenyl)-3-hydroxy-4-methylcarbonylthiophene (24 mg, 0.083 mmol) in isopropanol (2.0 mL) was heated with tert-butyl 3-{[5-(hydrazinocarbonyl)thiophene-2-carbonyl]amino}propionate (18 mg, 0.057 mmol) prepared in Reference Synthetic Example 7 and 6 mg of p-toluenesulfonic acid monohydrate at 100° C. for 8 hours and allowed to cool to room temperature. Water was added to the reaction mixture, and the precipitated solid was collected by filtration, washed with water, methanol and chloroform and dried to give 28 mg of the desired product (yield 85%).
Reaction SMILES: [CH2:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([OH:10])[C:4]=2[CH2:3][CH2:2]1.[C:11](OC(=O)C)(=[O:13])[CH3:12].S(=O)(=O)(O)O.O>O(CC)CC>[C:11]([O:10][C:5]1[C:4]2[CH2:3][CH2:2][CH2:1][C:9]=2[CH:8]=[CH:7][CH:6]=1)(=[O:13])[CH3:12]
Reactant: Oc1cccc2c1CCC2
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: O
Product: CC(=O)Oc1cccc2c1CCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 115 %

Procedure:
A mixture of 2,3-dihydro-1H-inden-4-ol (0.37 mol) and acetic anhydride (0.37 mol) in sulfuric acid (300 mol) was stirred for 1 hour at room temperature. The reaction mixture was poured out into a mixture of water and 1,1'-oxybisethane. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated, yielding 75 g (>100% crude residue) of 2,3-dihydro-1H-inden-4-ol acetate (ester) (interm. 1-a).
Reaction SMILES: [Br:1][C:2]1[CH:20]=[C:19]([F:21])[C:5]([CH2:6][NH:7][C:8]2[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=2[N+:16]([O-])=O)=[C:4]([F:22])[CH:3]=1.O.O.Cl[Sn]Cl.C([O-])(O)=O.[Na+]>CCO>[Br:1][C:2]1[CH:20]=[C:19]([F:21])[C:5]([CH2:6][NH:7][C:8]2[C:9]([NH2:16])=[CH:10][CH:11]=[C:12]([O:14][CH3:15])[CH:13]=2)=[C:4]([F:22])[CH:3]=1
Reactant: COc1ccc([N+](=O)[O-])c(NCc2c(F)cc(Br)cc2F)c1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc(N)c(NCc2c(F)cc(Br)cc2F)c1
Temperature: 100 °C

Procedure:
To a solution of N-(4-bromo-2,6-difluorobenzyl)-5-methoxy-2-nitroaniline (600 mg, 1.61 mmol) in EtOH (100 mL) was added SnCl2.2H2O (1.8 g, 8.1 mmol). The mixture was heated at 100° Celsius for 16 h. The mixture was cooled to RT and NaHCO3 (200 mL) was added. The mixture was filtered through celite and the filtrate extracted with EtOAc (3×200 mL). The combine organics were concentrated to dryness to provide the title compound which was used in the next step without further purification. MS (ESI): mass calcd. for C14H13BrF2N2O, 342.02; m/z found, 343.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][N:3]=1.[F:15][C:16]([F:20])([F:19])[CH2:17][NH2:18].C(N(CC)C(C)C)(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN1CCCC1=O>[N+:8]([C:7]1[C:2]([NH:18][CH2:17][C:16]([F:20])([F:19])[F:15])=[N:3][CH:4]=[C:5]([C:11]([F:14])([F:13])[F:12])[CH:6]=1)([O-:10])=[O:9]
Reactant: NCC(F)(F)F
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cnc1Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cc(C(F)(F)F)cnc1NCC(F)(F)F
Temperature: 25 °C
Reaction time: 10 h
Yield: 79.4 %

Procedure:
A mixture of 2-chloro-3-nitro-5-trifluoromethylpyridine (2.60 g), 2,2,2-trifluoroethylamine (0.79 g), N,N-diisopropylethylamine (1.04 g) and N-methyl-2-pyrrolidone (5 ml) was stirred at room temperature for 10 hours. To the reaction mixture was poured aqueous 10% citric acid solution, and then the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, and concentrated under reduced pressure to give (3-nitro-5-trifluoromethylpyridin-2-yl)-(2,2,2-trifluoroethyl)amine (1.83 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]3[CH2:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([F:35])=[C:21]([NH:23][S:24]([C:27]3[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:22]=2)[CH:5]=[CH:4][N:3]=1.[CH3:36][S:37]([N:40]1[CH2:45][CH2:44][CH:43]([NH2:46])[CH2:42][CH2:41]1)(=[O:39])=[O:38]>C1COCC1>[CH:13]1([C:11]2[S:12][C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:46][CH:43]4[CH2:44][CH2:45][N:40]([S:37]([CH3:36])(=[O:39])=[O:38])[CH2:41][CH2:42]4)[N:7]=3)=[C:9]([C:17]3[CH:18]=[CH:19][C:20]([F:35])=[C:21]([NH:23][S:24]([C:27]4[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=4[F:34])(=[O:26])=[O:25])[CH:22]=3)[N:10]=2)[CH2:16][CH2:15][CH2:14]1
Reactant: CS(=O)(=O)N1CCC(N)CC1
Reactant: O=S(=O)(Nc1cc(-c2nc(C3CCC3)sc2-c2ccnc(Cl)n2)ccc1F)c1cc(F)ccc1F
Solvent: C1CCOC1
Product: CS(=O)(=O)N1CCC(Nc2nccc(-c3sc(C4CCC4)nc3-c3ccc(F)c(NS(=O)(=O)c4cc(F)ccc4F)c3)n2)CC1
Yield: 98 %

Procedure:
Following a procedure analogous to the procedure described in Example 1 using N-{5-[5-(2-chloro-4-pyrimidinyl)-2-cyclobutyl-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide (0.10 g, 0.19 mmol) was added 1-(methylsulfonyl)-4-piperidinamine (0.33 g, 1.9 mmol) and THF (2 mL) the title compound was obtained (0.12 g, 0.18 mmol, 98% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.77 (s, 1H), 8.08 (d, J=5.1 Hz, 1H), 7.64-7.19 (m, 7H), 6.34-6.01 (m, 1H), 3.83 (quin, J=8.5 Hz, 1H), 3.72-3.40 (m, 2H), 2.91-2.64 (m, 5H), 2.43-2.15 (m, 6H), 2.08-1.77 (m, 3H), 1.63-1.33 (m, 2H). MS (ESI): 679 [M+H]+.
Reaction SMILES: [OH-:1].[K+].C(N[C:7]1[C:8]([N+:18]([O-:20])=[O:19])=[C:9]([C:13]([Cl:17])=[CH:14][C:15]=1[Cl:16])[C:10]([OH:12])=[O:11])(=O)C>O>[Cl:16][C:15]1[CH:14]=[C:13]([Cl:17])[C:9]([C:10]([OH:12])=[O:11])=[C:8]([N+:18]([O-:20])=[O:19])[C:7]=1[OH:1]
Reactant: [OH-]
Reactant: CC(=O)Nc1c(Cl)cc(Cl)c(C(=O)O)c1[N+](=O)[O-]
Agent: [K+]
Solvent: O
Product: O=C(O)c1c(Cl)cc(Cl)c(O)c1[N+](=O)[O-]
Temperature: 130 °C
Yield: 94.6 %

Procedure:
A solution of KOH (73.4 g,) in H2O (330 mL) was added to 3-acetamido-4,6-dichloro-2-nitrobenzoic acid 1-5 (38.1 g, 0.130 mol). The resulting brown solution was heated to reflux for 18 h (bath temp 130° C.). The reaction was cooled and extracted with ether. The aqueous layer was then acidified to pH 2 with concentrated HCl and extracted into EtOAc (×4). The combined organic layers were washed with brine (×3), dried over Na2SO4, filtered and concentrated to provide 4,6-dichloro-3-hydroxy-2-nitrobenzoic acid 1-6 as a brown solid (31.0 g, 95%). 1H NMR (400 MHz, d6-DMS) 57.88 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10](=[O:19])[C:11](=[N:17]O)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=[CH:6][CH:7]=1.O.[C:21](O)(=[O:23])[CH3:22]>C(OC(=O)C)(=O)C.[Zn]>[C:21]([NH:17][CH:11]([C:10](=[O:19])[CH2:9][CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13])(=[O:23])[CH3:22]
Reactant: CC(=O)O
Reactant: CCOC(=O)C(=NO)C(=O)CCc1cccc(Cl)c1
Agent: [Zn]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)C(NC(C)=O)C(=O)CCc1cccc(Cl)c1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of the product from step (ii) in acetic acid (125 ml) and acetic anhydride (40 ml) was added zinc dust (45 g) portionwise at a rate to maintain the internal temperature <40° C. The mixture was stirred for 30 min and water (125 ml) was added at such a rate as to maintain the temperature at around 40° C. The mixture was stirred at room temperature for 2 hours and filtered. The mother liquor was extracted with dichloromethane and further washed with water. The organic layer was collected, dried (MgSO4) and solvent evaporated under reduced pressure to give the subtitle product.
Reaction SMILES: [Cl:1][S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].N#N.[F:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH2:22])=[CH:19][CH:18]=1.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.C1COCC1>[F:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH:22][C:9]([C:8]2[CH:12]=[CH:13][C:5]([S:2]([Cl:1])(=[O:4])=[O:3])=[CH:6][CH:7]=2)=[O:10])=[CH:19][CH:18]=1
Reactant: NCc1ccc(F)cc1
Reactant: O=C(Cl)c1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NCc1ccc(F)cc1)c1ccc(S(=O)(=O)Cl)cc1
Reaction time: 8 h
Yield: 80 %

Procedure:
Add 4-chlorosulfonyl-benzoyl chloride (103 g (0.433 mol) and anhydrous THF (1.2 L) to a 5-L 3-neck round bottom equipped with overhead stirrer, dropping funnel, N2 line, and temperature probe and cool to −78° C. Add to the stirring solution dropwise over 4 h a solution of 4-fluorobenzylamine (52 g, 0.416 mol), triethylamine (42 g, 0.415 mol), and 4-DMAP (5.3 g, 0.043 mol) in dry THF (1.2 L). Slowly bring to room temperature the resulting mixture and stir overnight. Filter the solids, back-wash with THF, and concentrate the filtrate to a solid. Partition the solid between 1N HCl (1 L) and ethyl acetate (2×1 L). Combine the organics, dry over magnesium sulfate, filter, and concentrate to a solid. Suspend the solid in methyl t-butyl ether (1 L), stir at room temperature for 2 h, filter, and back-wash with ethyl ether (500 mL). Dry the resulting white powder (20 mm Hg, 40° C.) to give 4-(4-fluoro-benzylcarbamoyl)-benzenesulfonyl chloride as a white solid (108.5 g, 80%): 1HNMR(DMSO-d6) δ 9.07 (t, J=5.9 Hz, 1H), 7.82 (d, J=8.3 Hz, 2H), 7.65 (d, J=7.8 Hz, 2H), 7.35 (m, 2H), 7.14 (t, J=8.8 Hz, 2H), 4.44 (d, J=5.9 Hz, 2H); MS(ESI) m/z 326 (m−H); HPLC, 93.6%.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([O:10][C:11]2[C:16]([F:17])=[CH:15][C:14]([NH:18][C:19](=[O:24])[CH2:20][C:21]([OH:23])=O)=[C:13]([F:25])[CH:12]=2)[CH:7]=[CH:6][N:5]=1)(=[O:3])[NH2:2].[C:26]1([CH:32]([NH2:34])[CH3:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:17][C:16]1[CH:15]=[C:14]([NH:18][C:19](=[O:24])[CH2:20][C:21](=[O:23])[NH:34][CH:32]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH3:33])[C:13]([F:25])=[CH:12][C:11]=1[O:10][C:8]1[CH:7]=[CH:6][N:5]=[C:4]([C:1]([NH2:2])=[O:3])[CH:9]=1
Reactant: CC(N)c1ccccc1
Reactant: NC(=O)c1cc(Oc2cc(F)c(NC(=O)CC(=O)O)cc2F)ccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(NC(=O)CC(=O)Nc1cc(F)c(Oc2ccnc(C(N)=O)c2)cc1F)c1ccccc1
Reaction time: 15 h
Yield: 37 %

Procedure:
To a homogeneous mixture of 3-(4-(2-carbamoylpyridin-4-yloxy)-2,5-difluorophenylamino)-3-oxopropanoic acid (89 mg, 0.25 mmol) and (±)-1-phenyl-ethanamine (Aldrich, 0.05 mL, 0.38 mmol) in DMF (3 mL) was added DIPEA (0.07 mL, 0.38 mmol) and O-benzotriazol-1-yl-N,N,N′,N′-bis(tetramethylene)uranium hexafluorophosphate (TBTU) (121 mg, 0.38 mmol). The resulting solution was stirred for 15 hours before being quenched with 10% LiCl (aq). The mixture was partitioned between EtOAc and 10% LiCl (aq), the layers separated, and the aqueous layer extracted with EtOAc. The combined organic layers were washed twice with 10% LiCl (aq), then concentrated in vacuo. The residue was purified by silica gel chromatography (eluting with 1:3 hexane/EtOAc) and the appropriate fractions were concentrated in vacuo to afford the title compound (42 mg, 37%). HRMS(ESI+), 455.1532 (M+H)+ calcd., 455.1528 (M+H)+ found.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[C:4]=2[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:7]=1.CC1(C)C(C)(C)OB([C:31]2[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][CH:32]=2)O1.B(O)O>>[N:8]1([C:6]2[N:7]=[C:2]([C:31]3[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][CH:32]=3)[C:3]3[CH2:16][CH2:15][N:14]([C:17]4[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=4)[C:4]=3[N:5]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: Clc1nc(N2CCOCC2)nc2c1CCN2c1ccncc1
Reactant: CC1(C)OB(c2ccc(C#N)cc2)OC1(C)C
Agent: OBO
Product: N#Cc1ccc(-c2nc(N3CCOCC3)nc3c2CCN3c2ccncc2)cc1

Procedure:
In the same manner as Example 1-B-10, using 4-chloro-2-morpholin-4-yl-7-pyridin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine, and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile as a boronic acid, 4-(2-morpholin-4-yl-7-pyridin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-benzonitrile was obtained, and subsequently 1 equivalent of 1M hydrochloric acid was added, followed by stirring at room temperature, which was concentrated under reduced pressure, to obtain the desired compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[N:6][CH:7]=1.C([Li])CCC.C([Li])(C)(C)C.CN(C)[CH:29]=[O:30]>O1CCCC1.O>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][NH:8][C:5]2[N:6]=[CH:7][C:2]([CH:29]=[O:30])=[CH:3][CH:4]=2)=[CH:11][CH:12]=1
Reactant: CN(C)C=O
Reactant: Clc1ccc(CNc2ccc(Br)cn2)cc1
Agent: [Li]C(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1ccc(NCc2ccc(Cl)cc2)nc1
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
To (5-Bromo-pyridin-2-yl)-(4-chloro-benzyl)-amine (56, 10.00 g, 0.03360 mol) in tetrahydrofuran (400.0 mL) under an atmosphere of nitrogen at −78° C. was added n-butyllithium (17.5 mL, 2.00 M in cyclohexane). After 90 minutes, tert-butyllithium (42.00 mL, 1.70 M in hexane) was added to the reaction. After 80 minutes, N,N-dimethylformamide (6.9 mL, 0.089 mol) was added to the reaction. The reaction mixture was stirred at −78° C. for 2 hours, then allowed to warm to room temperature for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate mid concentrated to give the crude compound, which was crystallized from tert-butoxyl methyl ether to provide compound (57, 7.66 g, 92.2%).