Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH:20]([CH3:22])[CH3:21])=[CH:15][CH:14]=3)[O:10][N:9]=2)=[CH:4][N:3]=1.[CH3:23][N:24](C=O)C>[Zn].[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:19]([C:16]1[CH:17]=[CH:18][C:13]([C:11]2[O:10][N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([C:23]#[N:24])=[N:3][CH:4]=3)[N:12]=2)=[CH:14][CH:15]=1)[CH:20]([CH3:22])[CH3:21]
Reactant: CN(C)C=O
Reactant: CC(C)Cc1ccc(-c2nc(-c3ccc(Cl)nc3)no2)cc1
Agent: [Pd]
Agent: [Zn]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)Cc1ccc(-c2nc(-c3ccc(C#N)nc3)no2)cc1
Temperature: 25 °C
Yield: 59 %

Procedure:
A solution of 2-chloro-5-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]pyridine (5.0 g, 16.0 mmol), zinc cyamide (1.13 g, 9.58 mmol), tetrakis(triphenylphosphine) palladium (0) (0.74 g, 0.64 mmol) and DMF (16 mL) was stirred at 80° C. for 24 hours. The reaction mixture was cooled to room temperature, quenched with H2O (10 mL), and extracted with EtOAc (3×100 mL). The combined organic extracts were washed with H2O (2×100 mL) and brine (2×100 mL), dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography (silica, 2:8 EtOAc:hexanes) provided the title compound (2.87 g, 59% yield) as a solid.
Reaction SMILES: [CH3:1][C:2]1[C:3]([OH:10])=[CH:4][C:5]([OH:9])=[N:6][C:7]=1[CH3:8].[N+:11]([O-])([OH:13])=[O:12]>S(=O)(=O)(O)O>[CH3:1][C:2]1[C:3]([OH:10])=[C:4]([N+:11]([O-:13])=[O:12])[C:5]([OH:9])=[N:6][C:7]=1[CH3:8]
Reactant: Cc1nc(O)cc(O)c1C
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1nc(O)c([N+](=O)[O-])c(O)c1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 46 %

Procedure:
5,6-Dimethyl-pyridin-2,4-diol (6.5 g, 47 mmol) was stirred in 30 mL sulphuric acid and then cooled to 0° C. in an ice bath. Fuming nitric acid (10 mL) was added dropwise, and the mixture allowed to stir for 1 h after complete addition. The reaction mixture was poured onto crushed ice and the resulting yellow solid collected by filtration to give the title compound (3.9 g, 46%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9](Cl)=[O:10])=[CH:4][N:3]=1.[C:12]([NH2:16])([CH3:15])([CH3:14])[CH3:13].C(N(CC)CC)C>C1COCC1>[C:12]([NH:16][C:9]([C:5]1[C:6]([Cl:8])=[N:7][C:2]([Cl:1])=[N:3][CH:4]=1)=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)N
Reactant: O=C(Cl)c1cnc(Cl)nc1Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)c1cnc(Cl)nc1Cl
Temperature: -10 °C
Reaction time: 2 h

Procedure:
A solution of 24.85 g (117.5 mmol) of 2,4-dichloro-pyrimidine-5-carbonyl chloride in 125 ml of THF is cooled to −15° C. It is slowly mixed with a solution of 13.2 ml (124.5 mmol) of tert-buylamine and 17.4 ml (125.7 mmol) of triethylamine in 50 ml of THF, so that the temperature of the reaction mixture remains less than −10° C. It is stirred for another 2 hours at −10° C., then the cooling bath is removed, and the reaction mixture is heated to room temperature while being stirred. After 1 hour, the precipitate that is formed is filtered off, and the filtrate is completely concentrated by evaporation. The residue that is obtained is purified by chromatography (hexane/ethyl acetate 4:1). 14.01 g (56.6 mmol, corresponding to 50% of theory) of the product is obtained.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][CH:15]=[CH:16][C:9]=23)[C:5]([C:17]2[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=2)=[N:4]1)[CH3:2].[CH2:24]([N:26]=[C:27]=[O:28])[CH3:25]>>[CH2:24]([NH:26][C:27]([NH:21][C:20]1[CH:22]=[CH:23][C:17]([C:5]2[C:6]([C:8]3[CH:13]=[CH:12][N:11]=[C:10]4[NH:14][CH:15]=[CH:16][C:9]=34)=[CH:7][N:3]([CH2:1][CH3:2])[N:4]=2)=[CH:18][CH:19]=1)=[O:28])[CH3:25]
Reactant: CCN=C=O
Reactant: CCn1cc(-c2ccnc3[nH]ccc23)c(-c2ccc(N)cc2)n1
Product: CCNC(=O)Nc1ccc(-c2nn(CC)cc2-c2ccnc3[nH]ccc23)cc1

Procedure:
Following the procedure described in Example 1 with 4-[1-ethyl-4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl]aniline and ethyl isocyanate provided the title compound. ESMS [M+H]+: 375.2
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([O:10]C)=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18].[OH-].[Na+]>C1COCC1>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18]
Reactant: COC(=O)c1ccc(-c2ccccc2C)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccccc1-c1ccc(C(=O)O)cc1C
Temperature: 100 °C
Yield: 95.9 %

Procedure:
To a solution of methyl 2,2′-dimethyl-1,1′-biphenyl-4-carboxylate (15 g, 62.2 mmol) in THF (100 mL) was added 10% sodium hydroxide (100 mL) and the mixture was heated to 100° C. overnight. THF was removed under reduced pressure and the aqueous residue was washed with EtOAc. The aqueous layer was then acidified with 3N HCl to pH 2-3 and extracted with DCM. The organic phase was washed with water and dried over sodium sulfate and concentrated under reduced pressure to obtain get the title compound as a white solid (13.5 g, 95%). 1H NMR (DMSO-d6, 400 MHz) δ 12.89 (brs, 1H), 7.89 (s, 1H), 7.82-7.80 (d, 1H), 7.32-7.23 (m, 3H), 7.19-7.11 (d, 1H), 7.07-7.05 (d, 1H), 2.04 (s, 3H), 1.98 (s, 3H). LC/MS, M+(ESI): 227.0.
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1[C:12]2[CH:11]=[CH:10][S:9][C:8]=2[CH:7]=[CH:6][CH:5]=1.C([O-])(=O)C.[Na+]>ClCCl>[Br:1][C:11]1[C:12]2[C:4]([CH3:3])=[CH:5][CH:6]=[CH:7][C:8]=2[S:9][CH:10]=1
Reactant: BrBr
Reactant: Cc1cccc2sccc12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cccc2scc(Br)c12
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of bromine (2.94 ml) in dichloromethane (30 ml) was added dropwise under nitrogen at −5° C. to a stirred mixture of 4-methylbenzo[b]thiophene (7.68 g), sodium acetate (6.38 g) and dichloromethane (100 ml). The mixture was stirred at ambient temperature for 6 hours, then it was filtered and the solvent was removed in vacuo. The residue was was distilled in vacuo to give 3-bromo-4-methylbenzo[b]thiophene (6.04 g) as a yellow oil, b.p. 100-120° C. @ 0.4 mmHg, which was used without further purification.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C:9]([CH3:14])([C:11]([OH:13])=O)[CH3:10])=[O:7])([CH3:4])[CH3:3].C(N(C(C)C)C(C)C)C.F[P-](F)(F)(F)(F)F.CN(C(ON1C2=NC=CC=C2N=N1)=[N+](C)C)C.[CH3:48][C:49]1[CH:54]=[CH:53][CH:52]=[C:51]([CH3:55])[C:50]=1[O:56][C:57]1[N:62]=[CH:61][C:60]([NH2:63])=[CH:59][CH:58]=1>CN(C)C=O>[CH3:48][C:49]1[CH:54]=[CH:53][CH:52]=[C:51]([CH3:55])[C:50]=1[O:56][C:57]1[N:62]=[CH:61][C:60]([NH:63][C:11](=[O:13])[C:9]([NH:8][C:6](=[O:7])[O:5][C:2]([CH3:1])([CH3:3])[CH3:4])([CH3:10])[CH3:14])=[CH:59][CH:58]=1
Reactant: Cc1cccc(C)c1Oc1ccc(N)cn1
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(C)c1Oc1ccc(NC(=O)C(C)(C)NC(=O)OC(C)(C)C)cn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 50.4 %

Procedure:
In a 8 mL vial N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-methylalanine (204 mg, 1.003 mmol) and N-ethyl-N-(1-methylethyl)-2-propanamine (0.219 mL, 1.253 mmol) were dissolved in N,N-Dimethylformamide (4 mL) to give a pale yellow solution. N-[(dimethylamino)(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylidene]-N-methylmethanaminium hexafluorophosphate (381 mg, 1.003 mmol) was added. The reaction mixture became bright yellow and was stirred at room temperature for 15 minutes. 6-[(2,6-dimethylphenyl)oxy]-3-pyridinamine (Intermediate 42, 223.8 mg) was added and the reaction mixture was warmed at 60° C. After 4 hours, the reaction was complete. The solvent was evaporated under vacuum using the Genevac affording a dark brown oil which was purified by silica gel chromatography (Biotage system, 25 g SNAP column) using as eluents a gradient Cyclohexane/EtOAc from 3:1 to 1:1 in 10 CV; then 1:1 for 5 CV. The collected fractions afforded the title compound as a pale yellow solid (202.1 mg).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3([C:13]([NH:15][C:16]4[N:21]=[C:20]([C:22]5[CH:23]=[N:24][C:25]([O:29]C)=[C:26]([CH3:28])[CH:27]=5)[C:19]([CH3:31])=[CH:18][CH:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:7][CH:8]=2)[CH2:3][O:2]1.[Si](I)(C)(C)C>C(#N)C.C(Cl)Cl>[CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[CH:18][C:19]([CH3:31])=[C:20]([C:22]5[CH:27]=[C:26]([CH3:28])[C:25](=[O:29])[NH:24][CH:23]=5)[N:21]=4)=[O:14])[CH2:11][CH2:12]3)=[CH:7][CH:8]=2)[CH2:3][O:2]1
Reactant: COc1ncc(-c2nc(NC(=O)C3(c4ccc5c(c4)COC5)CC3)ccc2C)cc1C
Agent: C[Si](C)(C)I
Solvent: ClCCl
Solvent: CC#N
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)COC4)CC2)nc1-c1c[nH]c(=O)c(C)c1
Temperature: 50 °C
Reaction time: 0.33 h

Procedure:
To a solution of 1-(1,3-dihydroisobenzofuran-5-yl)-N-(6′-methoxy-3,5′-dimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide (40 mg, 0.1 mmol) in acetonitrile (2 mL) was added TMS-Iodide (54.8 μL, 0.39 mmol). The reaction was stirred at 50° C. for 20 min. The reaction solution was diluted with CH2Cl2 and washed with saturated NaHSO3 (2×), brine, dried over MgSO4 and concentrated. The crude product was dissolved in DMSO (1 mL) and purified by reverse phase HPLC (10-99% CH3CN/water). ESI-MS m/z calc. 401.1. found 402.5 (M+1)+. Retention time 1.29 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](=[O:18])[C:7]3[C:14]([C:15]([OH:17])=[O:16])=[N:13][NH:12][C:8]=3[C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:33]1(O)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.O>CN(C)C=O>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](=[O:18])[C:7]3[C:14]([C:15]([O:17][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[O:16])=[N:13][NH:12][C:8]=3[C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1
Reactant: Oc1ccccc1
Reactant: O=C(O)c1n[nH]c2c(=O)[nH]c3cc(Cl)ccc3c(=O)c12
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Oc1ccccc1)c1n[nH]c2c(=O)[nH]c3cc(Cl)ccc3c(=O)c12
Temperature: 70 °C
Reaction time: 24 h
Yield: 52.2 %

Procedure:
A solution of 7-chloro-3-(carboxy)pyrazolo[3,4-c][1]benzazepine-4,10(1H,9H)-dione (500 mg, 1.72 mmol) (compound of Example 9) and 1,1′-carbonyldiimidazole (418 mg, 2.58 mmol) in N,N-dimethylformamide (7 mL) was stirred for 16.75 hours. In one portion, phenol (486 mg, 5.16 mmol) was added and the solution was stirred for 24 hours at 70° C. To the resulting solution was added water (30 mL), giving a precipitate which was separated by filtration. This crude product was purified by chromatography eluting with chloroform: 2-propanol (98:2-90:10) to give the title compound (330 mg, 53% yield, m.p. 265° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=[O:20])[C@@H:15]([NH2:19])[CH:16]([CH3:18])[CH3:17])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(N(CC)CC)C.[CH3:28][N:29]([CH3:34])[S:30](Cl)(=[O:32])=[O:31].Cl>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=[O:20])[C@@:15]([NH2:19])([S:30](=[O:32])(=[O:31])[N:29]([CH3:34])[CH3:28])[CH:16]([CH3:17])[CH3:18])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: COc1ccc(CCNC(=O)[C@@H](N)C(C)C)cc1OC
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COc1ccc(CCNC(=O)[C@](N)(C(C)C)S(=O)(=O)N(C)C)cc1OC

Procedure:
7.2 g of (S)-2-amino-3-methyl-butyric acid N-[2-(3,4-dimethoxyphenyl)-ethyl]-amide and 4 ml of triethylamine are initially introduced in 120 ml of 1,4-dioxane at room temperature, while stirring. 2.8 ml of N,N-dimethylsulfamoyl chloride are added dropwise in the course of 5 minutes. The reaction mixture is then stirred at room temperature for 20 hours and subsequently introduced into 80 ml of 2N hydrochloric acid. The mixture is extracted twice with 200 ml of ethyl acetate each time. The organic phases are washed once with 80 ml of 2N hydrochloric acid, once with 80 ml of saturated sodium chloride solution, once with 80 ml of 5% sodium bicarbonate solution and once with 80 ml of saturated sodium chloride solution, combined, dried over sodium sulfate and concentrated. (S)-2-(N,N-dimethylsulfamoyl)-amino-3-methyl-butyric acid N-[2-(3,4-dimethoxyphenyl)-ethyl]-amide, which can be purified by recrystallization from ethyl acetate/hexane, is obtained, melting point 97°-99° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](Cl)=[O:5].[CH3:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]=1[NH:18][CH:19]1[CH2:24][O:23][C:21](=[O:22])[CH2:20]1.N1C=CC=CC=1>ClCCl>[CH3:1][O:2][CH2:3][C:4]([N:18]([CH:19]1[CH2:24][O:23][C:21](=[O:22])[CH2:20]1)[C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:16]=[CH:17][C:8]=1[CH3:7])=[O:5]
Reactant: COCC(=O)Cl
Reactant: Cc1ccc2ccccc2c1NC1COC(=O)C1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COCC(=O)N(c1c(C)ccc2ccccc12)C1COC(=O)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 2.4 g (0.022 mol) sample of methoxyacetyl chloride was added dropwise to a solution of 5.5 g (0.022 mol) 3-(N-2-methylnaphth-1-ylamino)-gamma-butyrolactone and 1.7 g (0.022 mol) pyridine in 100 ml dichloromethane. The reaction mixture was stirred one hour at about 25° C. and then heated under reflux for 6 hours. After cooling overnight, the reaction mixture was washed successively with water, saturated sodium bicarbonate solution, water, dried over magnesium sulfate and evaporated under reduced pressure. The residue was chromatographed through a silica gel column. Elution with 25% acetone/75% petroleum ether gave 4.3 g of the product, m.p. 42°-46° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[CH:16]=[C:15](B3OC(C)(C)C(C)(C)O3)[CH:14]=[C:13]([CH3:26])[N:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1.Br[C:28]1[CH:33]=[CH:32][N:31]=[C:30]([CH3:34])[CH:29]=1>>[CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[CH:16]=[C:15]([C:28]3[CH:33]=[CH:32][N:31]=[C:30]([CH3:34])[CH:29]=3)[CH:14]=[C:13]([CH3:26])[N:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc(NC(=O)c2cc(B3OC(C)(C)C(C)(C)O3)cc(C)n2)ccn1
Reactant: Cc1cc(Br)ccn1
Product: Cc1cc(NC(=O)c2cc(-c3ccnc(C)c3)cc(C)n2)ccn1

Procedure:
The title compound, was prepared from 6-Methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine-2-carboxylic acid (2-methyl-pyridin-4-yl)-amide in accordance with the general method of example 131, step 2 using 4-Bromo-2-methylpyridine instead of 3-Trifluoromethyl-5-bromopyridine to yield the final compound as a colorless amorphous, MS (ISP): m/e=319.2 (M+H)+.
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:21]3[N:20]4[C:16](=[CH:17][CH:18]=[CH:19]4)[C:15](=[O:22])[C:14]=3[S:13][CH:12]=2)=[CH:7][CH:6]=1>C(Cl)(Cl)Cl>[Br:1][C:18]1[CH:17]=[C:16]2[N:20]([C:21]3[C:11]([C:8]4[CH:7]=[CH:6][C:5]([O:4][CH3:3])=[CH:10][CH:9]=4)=[CH:12][S:13][C:14]=3[C:15]2=[O:22])[CH:19]=1
Reactant: BrBr
Reactant: COc1ccc(-c2csc3c2-n2cccc2C3=O)cc1
Solvent: ClC(Cl)Cl
Product: COc1ccc(-c2csc3c2-n2cc(Br)cc2C3=O)cc1
Reaction time: 2 h

Procedure:
2.1 mmol of bromine are added to a solution of 1.8 mmol of 3-(4-methoxyphenyl)-8H-thieno[2.3-b]pyrrolizin-8-one in 50 ml of chloroform. After two hours' stirring the solvent is evaporated off under reduced pressure. Chromatography on silica gel (dichloromethane) allows the expected product to be isolated.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([O:16][CH3:17])[C:13]=1[O:14][CH3:15])[CH:6]=[CH:7][C:8]([OH:10])=O.S(Cl)(Cl)=O.[NH2:22][CH:23]([C:31]1[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][CH:32]=1)CC1C=CC=CC=1.[OH-].[Na+]>ClCCl>[CH3:17][O:16][C:12]1[CH:11]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:13]=1[O:14][CH3:15])[CH:6]=[CH:7][C:8]([NH:22][CH2:23][C:31]1[CH:32]=[CH:33][C:34]([C:35]([OH:37])=[O:36])=[CH:38][CH:39]=1)=[O:10]
Reactant: NC(Cc1ccccc1)c1ccc(C(=O)O)cc1
Reactant: COc1cc(C=CC(=O)O)cc(OC)c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: COc1cc(C=CC(=O)NCc2ccc(C(=O)O)cc2)cc(OC)c1OC
Yield: 113.1 %

Procedure:
3,4,5-trimethoxycinnamic acid (2.38 g, 10 mmol), thionylchloride (4.72 g, 40 mmol), dichloromethane (10 ml), 4-(1-amino-2-phenylethyl)benzoic acid (2.41 g, 10 mmol), and 10 ml of 1 mol/L sodium hydroxide are used according to the method for the production of compound III in Method one to obtain 4.20 g of 4-[(3,4,5-trimethoxycinnamoyl)aminomethyl]benzoic acid (intermediate M-42) as a white solid, with a yield of 91.2%.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:15](=[O:16])[O:14][C:12](=[O:13])[C:8]2=[N:9][C:10]=1[CH3:11])(=[O:3])[CH3:2].[CH3:17][C@@:18]([C:23]([NH2:25])=[O:24])([CH:20]([CH3:22])[CH3:21])[NH2:19]>>[C:1]([O:4][C:5]1[C:10]([CH3:11])=[N:9][C:8]([C:12](=[O:13])[NH:19][C:18]([C:23](=[O:24])[NH2:25])([CH3:17])[CH:20]([CH3:22])[CH3:21])=[C:7]([CH:6]=1)[C:15]([OH:14])=[O:16])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cc2c(nc1C)C(=O)OC2=O
Reactant: CC(C)[C@](C)(N)C(N)=O
Product: CC(=O)Oc1cc(C(=O)O)c(C(=O)NC(C)(C(N)=O)C(C)C)nc1C

Procedure:
6.3 g (28.48 mmol) 5-acetoxy-6-methyl-pyridine-2,3-dicarboxylic acid anhydride and 4.1 g (31.33 mmol) 2-methyl-valinamide are stirred under nitrogen for 2 days at room temperature, and then the precipitated crystalline product is filtered off.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH2:8][CH:9]([NH:11][C:12]2[CH:17]=[CH:16][NH:15][C:14](=[O:18])[C:13]=2[C:19]2[NH:37][C:22]3=[CH:23][C:24]4[C:25](=O)[N:26]([CH2:31][CH2:32][N:33]([CH3:35])[CH3:34])[C:27](=[O:30])[C:28]=4[CH:29]=[C:21]3[N:20]=2)[CH3:10])[CH:7]=1.[C:38](O)(=O)C>[Zn]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:38])=[C:6]([CH2:8][CH:9]([NH:11][C:12]2[CH:17]=[CH:16][NH:15][C:14](=[O:18])[C:13]=2[C:19]2[NH:37][C:22]3=[CH:23][C:24]4[CH2:25][N:26]([CH2:31][CH2:32][N:33]([CH3:35])[CH3:34])[C:27](=[O:30])[C:28]=4[CH:29]=[C:21]3[N:20]=2)[CH3:10])[CH:7]=1
Reactant: CC(Cc1cccc(F)c1)Nc1cc[nH]c(=O)c1-c1nc2cc3c(cc2[nH]1)C(=O)N(CCN(C)C)C3=O
Reactant: CC(=O)O
Agent: [Zn]
Product: Cc1ccc(F)cc1CC(C)Nc1cc[nH]c(=O)c1-c1nc2cc3c(cc2[nH]1)CN(CCN(C)C)C3=O
Yield: 74 %

Procedure:
Compound 2-(4-(1-(5-fluorophenyl)propan-2-ylamino)-2-oxo-1,2-dihydropyridin-3-yl)-6-(2-(dimethylamino)ethyl)imidazo[4,5-f]isoindole-5,7(1H,6H)-dione (1.32 g, 2.56 mmol) and zinc powder (4.01 g, 61.32 mmol) were suspended in acetic acid (60 mL). The reaction mixture was stirred and heated to reflux overnight under argon. Then, the solvent was removed under reduced pressure. The residue solid was stirred in 100 mL of saturated K2CO3 solution. The white solid was filtered out, dried under vacuum and extracted with CH2Cl2/MeOH (7/3 v/v) three times (300 mL). The extracts were concentrated to dryness. The residue was purified by column chromatography (silica-gel, CH2Cl2/MeOH=9/1 v/v) to give a white solid product, 0.85 g, 74% yield. MS: 503.1 [M+H]+. 1H NMR (DMSO-d6, 300 MHz): δ 13.07 (s, 1H), 11.17 (s, 1H), 11.09-11.05 (m, 1H), 7.97 (s, 0.5H), 7.86 (s, 0.5H), 7.80 (s, 0.5H), 7.70 (s, 0.5H), 7.30-7.10 (m, 3H), 6.92-6.84 (m, 1H), 6.15-6.11 (m, 1H), 4.54 (s, 2H), 4.18-4.14 (m, 1H), 3.64 (t, 2H, J=6.0 Hz), 3.02-2.97 (m, 2H), 2.53-2.49 (m, 2H), 2.36 (d, 3H, J=3.9 Hz), 2.20 (s, 6H), 1.35-1.33 (m, 3H).
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:8]=[C:9]([NH:13][C:14](=[O:32])[NH:15][CH2:16][C:17]([N:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:18])[CH:10]=[CH:11][CH:12]=1>ClCCl>[OH:6][C:7]1[CH:8]=[C:9]([NH:13][C:14](=[O:32])[NH:15][CH2:16][C:17]([N:19]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:18])[CH:10]=[CH:11][CH:12]=1
Reactant: COc1cccc(NC(=O)NCC(=O)N(c2ccccc2)c2ccccc2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(NCC(=O)N(c1ccccc1)c1ccccc1)Nc1cccc(O)c1
Temperature: -50 °C
Reaction time: 2 h
Yield: 32.5 %

Procedure:
A 1M methylene chloride solution (25 cc) of boron tribromide is added in the course of 15 minutes at a temperature in the region of -50° C. to a solution, maintained under a nitrogen atmosphere, of 2-[3-(3-methoxyphenyl)ureido]-N,N-diphenylacetamide (1.6 g) in dichloromethane (25 cc). The mixture obtained is stirred for 2 hours at a temperature in the region of -50° C. and then for 20 hours at a temperature in the region of 20° C. The precipitate formed is separated by filtration, washed with distilled water (6×10 cc) and dried in the air. After recrystallization in acetonitrile, 2-[3-(3-hydroxyphenyl)ureido]-N,N-diphenylacetamide (0.5 g), m.p. 244° C., is obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=1.[CH2:10]([C:14]1[N:15]=[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][N:17]2[CH:23]=1)[CH2:11][C:12]#[CH:13]>>[F:22][C:19]1[CH:20]=[CH:21][C:16]2[N:17]([CH:23]=[C:14]([CH2:10][CH2:11][C:12]#[C:13][C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=3)[N:15]=2)[CH:18]=1
Reactant: FCc1cccc(Br)n1
Reactant: C#CCCc1cn2cc(F)ccc2n1
Product: FCc1cccc(C#CCCc2cn3cc(F)ccc3n2)n1

Procedure:
The title compound was prepared in accordance with the general method of Example 190(F), from 2-bromo-6-(fluoromethyl)pyridine (220 mg, 1.10 mol) and 2-(but-3-ynyl)-6-fluoro-imidazo[1,2-a]pyridine (220 mg, 1.14 mmol). The crude residue was purified over C18 chromatography (prepacked 35 g silicagel column, H2O/CH3CN: from 95/5 to 55/45 as eluent) to afford 155 mg of 6-fluoro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)H-imidazo[1,2-a]pyridine (Yield: 46%) as a white powder (Mp=140-141.8° C.).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]2[C:19]([N+:20]([O-:22])=[O:21])=[C:18](Cl)[N:17]=[C:16]([O:24][CH:25]=[O:26])[CH:15]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:28][NH2:29]>C(O)C>[C:1]([O:5][C:6](=[O:27])[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]2[C:19]([N+:20]([O-:22])=[O:21])=[C:18]([NH:29][CH3:28])[N:17]=[C:16]([O:24][CH:25]=[O:26])[CH:15]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2cc(OC=O)nc(Cl)c2[N+](=O)[O-])C1
Reactant: CN
Solvent: CCO
Product: CNc1nc(OC=O)cc(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)c1[N+](=O)[O-]
Reaction time: 48 h
Yield: 75.9 %

Procedure:
In a dry reaction bottle, 16 g (R)-1-[2-formyloxy-5-nitro-6-chloropyridin-4-yl]piperidine-3-carbamic acid tert-butyl ester (40 mmol) was added and dissolved in 50 mL ethanol. 31 g 40% methylamine aqueous solution (400 mmol) was added. The stirring was continued for 2 days at 60° C. The reaction solution was extracted with dichloromethane, dried, and evaporated to dryness to afford a crude product as yellow solid, which was purified through a column chromatography (ethyl acetate:petroleum ether=1:1) to afford 12 g titled product with a yield of 75.9%.
Reaction SMILES: Cl.[C:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[N+:18]([O-])=O)=[CH:7][CH:6]=1)(=[O:4])[CH3:3].[OH-].[Na+].ClCCl>C(O)C>[C:2]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[NH2:18])=[CH:9][CH:10]=1)(=[O:4])[CH3:3]
Reactant: CC(=O)c1ccc(Nc2ccncc2[N+](=O)[O-])cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Product: CC(=O)c1ccc(Nc2ccncc2N)cc1

Procedure:
4-(4-Acetylphenyl)amino-3-nitropyridine hydrochloride (2.0 g, 71.8 mmol) was partitioned between aqueous sodium hydroxide and dichloromethane (3×20 ml). The combined organic phases were (kPa) for 3.5 hours. The catalyst was filtered off, and the solvent removed under reduced pressure to give a brown solid, (1.8 g) which was used directly for the next reaction without purification, m.p. 165°-166° C. (after recrystallisation from ethanol).
Reaction SMILES: C(O[C@H]1C[C@H]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])CN(C(OCC2C=CC=CC=2)=O)C1)(=O)C1C=CC=CC=1.[Si:34]([O:41][C@@H:42]1[CH2:47][C@@H:46](O)[CH2:45][N:44]([C:49]([O:51][CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)=[O:50])[CH2:43]1)([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35]>>[C:20]([O:19][C:17]([NH:16][C@H:46]1[CH2:47][C@@H:42]([O:41][Si:34]([C:37]([CH3:39])([CH3:38])[CH3:40])([CH3:36])[CH3:35])[CH2:43][N:44]([C:49]([O:51][CH2:52][C:53]2[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=2)=[O:50])[CH2:45]1)=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](O)CN(C(=O)OCc2ccccc2)C1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](OC(=O)c2ccccc2)CN(C(=O)OCc2ccccc2)C1
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN(C(=O)OCc2ccccc2)C1

Procedure:
Followed method to synthesis of (3S,5S)-benzyl 3-(benzoyloxy)-5-(tert-butoxycarbonylamino)-piperidine-1-carboxylate starting from (3R,5R)-benzyl 3-(tert-butyldimethylsilyloxy)-5-hydroxypiperidine-1-carboxylate. LC/MS (m/z): 365.2 (MH+-Boc), Rt: 1.37.